Split (1)

train · 7.32k rows

page_title stringlengths 1 91	page_text stringlengths 0 34.2k
Cefaclor	Cefaclor, sold under the trade name Ceclor among others, is a second-generation cephalosporin antibiotic used to treat certain bacterial infections such as pneumonia and infections of the ear, lung, skin, throat, and urinary tract. It is also available from other manufacturers as a generic.It was patented in 1973 and approved for medical use in 1979. Medical uses Cefaclor belongs to the family of antibiotics known as the cephalosporins (cefalosporins). The cephalosporins are broad-spectrum antibiotics that are used for the treatment of septicaemia, pneumonia, meningitis, biliary tract infections, peritonitis, and urinary tract infections. The pharmacology of the cephalosporins is similar to that of the penicillins, excretion being principally renal. Cephalosporins penetrate the cerebrospinal fluid poorly unless the meninges are inflamed; cefotaxime is a more suitable cephalosporin than cefaclor for infections of the central nervous system, e.g. meningitis. Cefaclor is active against many bacteria, including both Gram-negative and Gram-positive organisms. Spectrum of activity Cefaclor is frequently used against bacteria responsible for causing skin infections, otitis media, urinary tract infections, and others. Cefaclor has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections: Gram positive aerobes - Staphylococci (including coagulase-positive, coagulase-negative, and penicillinase-producing strains), Streptococcus pneumoniae, and Streptococcus pyogenes (group A β-hemolytic streptococci). The following represents MIC susceptibility data for a few medically significant microorganisms. Haemophilus influenzae: 0.03 μg/mL - 128 μg/mL Staphylcoccus aureus: 0.6 μg/mL - 128 μg/mL Streptococcus pyogenes: 0.06 μg/mL - 4 μg/mL Cautions and contraindications Cautions include known sensitivity to beta-lactam antibacterials, such as penicillins (Cefaclor should be avoided if there is a history of immediate hypersensitivity reaction); renal impairment (no dose adjustment required, although manufacturer advises caution); pregnancy and breast-feeding (but appropriate to use); false positive urinary glucose (if tested for reducing substances) and false positive Coombs test. Cefaclor has also been reported to cause a serum sickness-like reaction in children.Cefaclor is contraindicated in case of hypersensitivity (i.e. allergy) to cephalosporins. Side effects The principal side effect of the cephalosporins is hypersensitivity. Penicillin-sensitive patients will also be allergic to the cephalosporins, depending on the cephalosporin generation. The previous percentage of 10% cross reactivity rates are often overestimated. Allergic reactions may present as, for example, rashes, pruritus (itching), urticaria, serum sickness-like reactions with rashes, fever and arthralgia, and anaphylaxis. The frequency and severity of serum sickness-like reactions in children has led researchers to question its role in pediatric illness. Other side effects include gastrointestinal disturbances (e.g. diarrhea, nausea and vomiting, abdominal discomfort, disturbances in liver enzymes, transient hepatitis and cholestatic jaundice), headache, and Stevens–Johnson syndrome. Rare side effects include eosinophilia and blood disorders (including thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia); reversible interstitial nephritis; hyperactivity, nervousness, sleep disturbances, hallucinations, confusion, hypertonia, and dizziness. Toxic epidermal necrolysis has been reported. In the UK, The Committee on the Safety of Medicines (CSM) has warned that the risk of diarrhea and rarely antibiotic-associated colitis are more likely with higher doses. Pregnancy and breastfeeding Cefaclor is passed into the breast milk in small quantities, but is generally accepted to be safe to take during breastfeeding. Cefaclor is not known to be harmful in pregnancy. Interactions Coumarins Cephalosporins possibly enhance the anticoagulant effect of coumarins (e.g. Warfarin) - change in patients clinical condition, particularly associated with liver disease, intercurrent illness, or drug administration, necessitates more frequent testing of INR, and dose adjustment as necessary. Probenecid Excretion of cephalosporins is reduced by probenecid (resulting in increased concentrations of drug in the blood plasma). Antacids Absorption of cefaclor is reduced by antacids. Therefore antacids should not be taken right before or at the same time as cefaclor. == References ==
Norethisterone	Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.Side effects of norethisterone include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth. Norethisterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak androgenic and estrogenic activity, mostly at high dosages, and no other important hormonal activity.Norethisterone was discovered in 1951 and was one of the first progestins to be developed. It was first introduced for medical use on its own in 1957 and was introduced in combination with an estrogen for use as a birth control pill in 1963. It is sometimes referred to as a "first-generation" progestin. Along with desogestrel, it is one of the only progestins that is widely available as a progestogen-only "mini pill" for birth control. Norethisterone is marketed widely throughout the world. It is available as a generic medication. In 2019, it was the 143rd most commonly prescribed medication in the United States, with more than 4 million prescriptions. It is on the World Health Organizations List of Essential Medicines. Medical uses Norethisterone is used as a hormonal contraceptive in combination with an estrogen – usually ethinylestradiol (EE) – in combined oral contraceptive pills and alone in progestogen-only pills. Another medical use of norethisterone is to alleviate endometriosis related pain. In fact, 50% of patients who received medical or surgical treatment for endometriosis-related pelvic pain have benefited from progestin therapy. This could be due to the fact that norethisterone induces endometrial proliferation during secretory phase, which has been shown to alleviate endometrial pain complaints. Another way in which norethisterone may be acting to reduce endometrial pain is via inhibition of ovulation. Endometriosis pain and discomfort is worse during ovulation. Contraindications High-dose (10 mg/day) norethisterone has been associated with hepatic veno-occlusive disease, and because of this adverse effect, norethisterone should not be given to patients undergoing allogeneic bone marrow transplantation, as it has been associated with substantially lower one-year survival post-transplantation.: 217 Side effects At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), norethisterone has essentially progestogenic side effects only. In most clinical studies of norethisterone for contraception or menopausal hormone therapy, the drug has been combined with an estrogen, and for this reason, it is difficult to determine which of the side effects were caused by norethisterone and which of them were caused by estrogen in such research. However, NETE, an intramuscularly administered prodrug of norethisterone which is used as a long-acting contraceptive, is used without an estrogen, and hence can be employed as a surrogate for norethisterone in terms of understanding its effects and tolerability. In clinical studies, the most common side effect with NETE has been menstrual disturbances, including prolonged bleeding or spotting and amenorrhea.: 253 Other side effects have included periodic abdominal bloating and breast tenderness, both of which are thought to be due to water retention and can be relieved with diuretics.: 253 There has been no association with weight gain, and blood pressure, blood clotting, and glucose tolerance have all remained normal.: 253 However, a decrease in HDL cholesterol has been observed.: 253 At high doses (5 to 60 mg/day), for instance those used in the treatment of gynecological disorders, norethisterone can cause hypogonadism due to its antigonadotropic effects and can have estrogenic and weak androgenic side effects. High doses of NETA (10 mg/day) have been associated with abnormal liver function tests, including significant elevations in liver enzymes. These liver enzymes included lactate dehydrogenase and glutamate pyruvate transaminase. Although they were described as having no clinical relevance, the elevated liver enzymes associated with NETA may have precluded its further development for male hormonal contraception. Androgenic Due to its weak androgenic activity, norethisterone can produce androgenic side effects such as acne, hirsutism, and voice changes of slight severity in some women at high dosages (e.g., 10 to 40 mg/day). This is notably not the case with combined oral contraceptives that contain norethisterone and EE, however. Such formulations contain low dosages of norethisterone (0.35 to 1 mg/day) in combination with estrogen and are actually associated with improvement in acne symptoms. In accordance, they are in fact approved by the FDA for the treatment of acne in women in the United States. The improvement in acne symptoms is believed to be due to a 2- to 3-fold increase in sex hormone-binding globulin (SHBG) levels and a consequent decrease in free testosterone levels caused by EE, which results in an overall decrease in androgenic signaling in the body.The sebaceous glands are highly androgen-sensitive and their size and activity are potential markers of androgenic effect. A high dosage of 20 mg/day norethisterone or NETA has been found to significantly stimulate the sebaceous glands, whereas lower dosages of 5 mg/day and 2.5 mg/day norethisterone and NETA, respectively, did not significantly stimulate sebum production and were consequently regarded as devoid of significant androgenicity. Conversely, dosages of norethisterone of 0.5 to 3 mg/day have been found to dose-dependently decrease SHBG levels (and hence to suppress hepatic SHBG production), which is another highly sensitive marker of androgenicity.A large clinical study of high to very high oral dosages of norethisterone (10 to 40 mg/day) administered for prolonged periods of time (4 to 35 weeks) to prevent miscarriage in pregnant women found that 5.5% of the women experienced mild androgenic side effects such as mild voice changes (hoarseness), acne, and hirsutism and that 18.3% of female infants born to the mothers showed, in most cases only slight, virilization of the genitals. Maternal androgenic symptoms occurred most often in women who received a dosage of norethisterone of 30 mg/day or more for a period of 15 weeks or longer. In the female infants who experienced virilization of the genitals, the sole manifestation in 86.7% of the cases was varied but almost always slight enlargement of the clitoris. In the remaining 13.3% of the affected cases, marked clitoral enlargement and partial fusion of the labioscrotal folds occurred. The dosages used in these cases were 20 to 40 mg/day.In a letter to the editor on the topic of virilization caused by high dosages of NETA in women, a physician expressed that they had not observed the "slightest evidence of virilization" and that there had "certainly been no hirsutism nor any voice changes" in 55 women with advanced breast cancer that they had treated with 30 to 60 mg/day norethisterone for up to six months.High-dosage norethisterone has been used to suppress menstruation in women with severe intellectual disability who were incapable of handling their own menses. A study of 118 nulliparous women treated with 5 mg/day norethisterone for a period of 2 to 30 months found that the drug was effective in producing amenorrhea in 86% of the women, with breakthrough bleeding occurring in the remaining 14%. Side effects including weight gain, hirsutism, acne, headache, nausea, and vomiting all did not appear to increase in incidence and no "disturbing side effects" were noted in any of the women. Another study of 5 mg/day norethisterone in 132 women also made no mention of androgenic side effects. These findings suggest little to no risk of androgenic side effects with norethisterone at a dosage of 5 mg/day. A study of 194 women treated with 5 to 15 mg/day NETA for a median duration of 13 months of therapy to suppress symptoms of endometriosis observed no side effects in 55.2% of patients, weight gain in 16.1%, acne in 9.9%, mood lability in 8.9%, hot flashes in 8.3%, and voice deepening in two women (1.0%). Estrogenic Norethisterone is weakly estrogenic (via conversion into its metabolite EE), and for this reason, it has been found at high dosages to be associated with high rates of estrogenic side effects such as breast enlargement in women and gynecomastia in men, but also with improvement of menopausal symptoms in postmenopausal women. It has been suggested that very high dosages (e.g., 40 mg/day, which are sometimes used in clinical practice for various indications) of NETA (and by extension norethisterone) may result in an increased risk of venous thromboembolism (VTE) analogously to high dosages (above 50 μg/day) of EE, and that even doses of NETA of 10 to 20 mg, which correspond to EE doses of approximately 20 to 30 μg/day, may in certain women be associated with increased risk. A study also found that ethinylestradiol and norethisterone had a greater influence on coagulation factors when the dose of norethisterone was 3 or 4 mg than when it was 1 mg. This might have been due to additional ethinylestradiol generated by higher doses of norethisterone. Overdose There have been no reports of serious side effects with overdose of norethisterone, even in small children. As such, overdose usually does not require treatment. High dosages of as much as 60 mg/day norethisterone have been studied for extended treatment durations without serious adverse effects described. Interactions 5α-Reductase plays an important role in the metabolism of norethisterone, and 5α-reductase inhibitors such as finasteride and dutasteride can inhibit its metabolism. Norethisterone is partially metabolized via hydroxylation by CYP3A4, and inhibitors and inducers of CYP3A4 can significantly alter circulating levels of norethisterone. For instance, the CYP3A4 inducers rifampicin and bosentan have been found to decrease norethisterone exposure by 42% and 23%, respectively, and the CYP3A4 inducers carbamazepine and St. Johns wort have also been found to accelerate norethisterone clearance. Pharmacology Pharmacodynamics Norethisterone is a potent progestogen and a weak androgen and estrogen. That is, it is a potent agonist of the progesterone receptor (PR) and a weak agonist of the androgen receptor (AR) and the estrogen receptor (ER). Norethisterone itself has insignificant affinity for the ER; its estrogenic activity is from an active metabolite that is formed in very small amounts, ethinylestradiol (EE), which is a very potent estrogen. Norethisterone and its metabolites have negligible affinity for the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) and hence have no glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity. Progestogenic activity Norethisterone is a potent progestogen and binds to the PR with approximately 150% of the affinity of progesterone. In contrast, its parent compounds, testosterone, nandrolone (19-nortestosterone), and ethisterone (17α-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR. Unlike norethisterone, its major active metabolite 5α-dihydronorethisterone (5α-DHNET), which is formed by transformation via 5α-reductase, has been found to possess both progestogenic and marked antiprogestogenic activity, although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone. Norethisterone produces similar changes in the endometrium and vagina, such as endometrial transformation, and is similarly antigonadotropic, ovulation-inhibiting, and thermogenic in women compared to progesterone, which is in accordance with its progestogenic activity. Androgenic activity Norethisterone has approximately 15% of the affinity of the anabolic–androgenic steroid (AAS) metribolone (R-1881) for the AR, and in accordance, is weakly androgenic. In contrast to norethisterone, 5α-DHNET, the major metabolite of norethisterone, shows higher affinity for the AR, with approximately 27% of the affinity of metribolone. However, although 5α-DHNET has higher affinity for the AR than norethisterone, it has significantly diminished and in fact almost abolished androgenic potency in comparison to norethisterone in rodent bioassays. Similar findings were observed for ethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone (19-nortestosterone) in rodent bioassays. As such, it appears that the ethynyl group of norethisterone at the C17α position is responsible for its loss of androgenicity upon 5α-reduction.Norethisterone (0.5 to 3 mg/day) has been found to dose-dependently decrease circulating SHBG levels, which is a common property of androgens and is due to AR-mediated suppression of hepatic SHBG production. The drug also has estrogenic activity, and estrogens are known to increase SHBG hepatic production and circulating levels, so it would appear that the androgenic activity of norethisterone overpowers its estrogenic activity in this regard.Norethisterone is bound to a considerable extent (36%) to SHBG in circulation. Although it has lower affinity for SHBG than endogenous androgens and estrogens, Norethisterone may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects. Estrogenic activity Norethisterone binds to the ERs, the ERα and the ERβ, with 0.07% and 0.01% of the relative binding affinity of estradiol. Due to these very low relative affinities, it is essentially inactive itself as a ligand of the ERs at clinical concentrations. However, norethisterone has been found to be a substrate for aromatase and is converted in the liver to a small extent (0.35%) to the highly potent estrogen ethinylestradiol (EE), and for this reason, unlike most other progestins, norethisterone has some estrogenic activity. However, with typical dosages of norethisterone used in oral contraceptives (0.5 to 1 mg), the levels of EE produced are low, and it has been said that they are probably without clinical relevance. Conversely, doses of 5 and 10 mg of norethisterone, which are used in the treatment of gynecological disorders, are converted at rates of 0.7% and 1.0% and produce levels of EE that correspond to those produced by 30 and 60 μg dosages of EE, respectively. The levels of EE formed by 0.5 and 1 mg of norethisterone have been estimated based on higher dosages as corresponding to 2 and 10 μg dosages of EE, respectively. At high doses, norethisterone may increase the risk of venous thromboembolism due to metabolism into EE. Neurosteroid activity Like progesterone and testosterone, norethisterone is metabolized into 3,5-tetrahydro metabolites. Whether these metabolites of norethisterone interact with the GABAA receptor similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone like allopregnanolone and 3α-androstanediol, respectively, is a topic that does not appear to have been studied and hence requires clarification. Steroidogenesis inhibition Norethisterone is a substrate for and is known to be an inhibitor of 5α-reductase, with 4.4% and 20.1% inhibition at 0.1 and 1 μM, respectively. However, therapeutic concentrations of norethisterone are in the low nanomolar range, so this action may not be clinically relevant at typical dosages.Norethisterone and its major active metabolite 5α-DHNET have been found to act as irreversible aromatase inhibitors (Ki = 1.7 μM and 9.0 μM, respectively). However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages. 5α-DHNET specifically has been assessed and found to be selective in its inhibition of aromatase, and does not affect cholesterol side-chain cleavage enzyme (P450scc), 17α-hydroxylase/17,20-lyase, 21-hydroxylase, or 11β-hydroxylase. Since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike norethisterone, 5α-DHNET has been proposed as a potential therapeutic agent in the treatment of ER-positive breast cancer. Other activities Norethisterone is a very weak inhibitor of CYP2C9 and CYP3A4 (IC50 = 46 μM and 51 μM, respectively), but these actions require very high concentrations of norethisterone that are far above therapeutic circulating levels (which are in the nanomolar range) and hence are probably not clinically relevant.Norethisterone and some of its 5α-reduced metabolites have been found to produce vasodilating effects in animals that are independent of sex steroid receptors and hence appear to be non-genomic in mechanism.Norethisterone stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies. Antigonadotropic effects Due to its progestogenic activity, norethisterone suppresses the hypothalamic–pituitary–gonadal axis (HPG axis) and hence has antigonadotropic effects. The estrogenic activity of norethisterone at high doses would also be expected to contribute to its antigonadotropic effects. Due to its antigonadotropic effects, norethisterone suppresses gonadal sex hormone production, inhibits ovulation in women, and suppresses spermatogenesis in men.The ovulation-inhibiting dosage of both oral norethisterone and oral NETA is about 0.5 mg/day in women. However, some conflicting data exist, suggesting that higher doses might be necessary for full inhibition of ovulation. An intramuscular injection of 200 mg NETE has been found to prevent ovulation and suppress levels of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in women.Early studies of oral norethisterone in men employing doses of 20 to 50 mg/day observed suppression of 17-ketosteroid excretion, increased estrogen excretion (due to conversion into ethinylestradiol), suppression of spermatogenesis, libido, and erectile function, and incidence of gynecomastia. A dosage of oral norethisterone of 25 mg/day for 3 weeks in men has been reported to suppress testosterone levels by about 70%, to 100 to 200 ng/dL, within 4 or 5 days, as well as to suppress sperm count and to have no effect on libido or erectile function over this short time period. In healthy young men, NETA alone at a dose of 5 to 10 mg/day orally for 2 weeks suppressed testosterone levels from ~527 ng/dL to ~231 ng/dL (–56%). A single 200 mg intramuscular injection of NETE alone or in combination with 2 mg estradiol valerate has been found to produce a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men. Intramuscular injections of 200 mg NETE once every 3 weeks have also been found to suppress spermatogenesis in men. Similarly, a single intramuscular injection of 50 mg NETE in combination with 5 mg estradiol valerate has been found to strongly suppress testosterone levels in men. Levels of testosterone decreased from ~503 ng/dL at baseline to ~30 ng/dL at the lowest point (–94%) which occurred at day 7 post-injection. Pharmacokinetics The pharmacokinetics of norethisterone have been reviewed. Absorption The oral bioavailability of norethisterone is between 47 and 73%, with a mean oral bioavailability of 64%. Micronization has been found to significantly improve the oral bioavailability of norethisterone by increasing intestinal absorption and reducing intestinal metabolism. A single 2 mg oral dose of norethisterone has been found to result in peak circulating levels of the drug of 12 ng/mL (40 nmol/L), whereas a single 1 mg oral dose of norethisterone in combination with 2 mg estradiol resulted in peak levels of norethisterone of 8.5 ng/mL (29 nmol/L) one-hour post-administration. Distribution The plasma protein binding of norethisterone is 97%. It is bound 61% bound to albumin and 36% bound to SHBG. Metabolism Norethisterone has an elimination half-life of 5.2 to 12.8 hours, with a mean elimination half-life of 8.0 hours. The metabolism of norethisterone is very similar to that of testosterone (and nandrolone) and is mainly via reduction of the Δ4 double bond to 5α- and 5β-dihydronorethisterone, which is followed by the reduction of the C3 keto group to the four isomers of 3,5-tetrahydronorethisterone. These transformations are catalyzed by 5α- and 5β-reductase and 3α- and 3β-hydroxysteroid dehydrogenase both in the liver and in extrahepatic tissues such as the pituitary gland, uterus, prostate gland, vagina, and breast. With the exception of 3α,5α- and 3β,5α-tetrahydronorethisterone, which have significant affinity for the ER and are estrogenic to some degree, the 3,5-tetrahydro metabolites of norethisterone are inactive in terms of affinity for sex steroid receptors (specifically, the PR, AR, and ER). A small amount of norethisterone is also converted by aromatase into EE. Norethisterone is metabolized in the liver via hydroxylation as well, mainly by CYP3A4. Some conjugation (including glucuronidation and sulfation) of norethisterone and its metabolites occurs in spite of steric hindrance by the ethynyl group at C17α. The ethynyl group of norethisterone is preserved in approximately 90% of all of its metabolites.Norethisterone is used in birth control pills, opposed to progesterone itself, because it is not metabolized as rapidly as progesterone when consumed orally. When progesterone is consumed orally it is rapidly metabolized in the gastrointestinal tract and the liver, and broken down into many different metabolites. Whereas, norethisterone is not as rapidly metabolized allowing norethisterone to be present in higher quantities allowing it to more effectively compete for progesterone receptor binding sites. Elimination Norethisterone is eliminated 33 to 81% in urine and 35 to 43% in feces. Chemistry Norethisterone, also known as 17α-ethynyl-19-nortestosterone or as 17α-ethynylestra-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is specifically a derivative of testosterone in which an ethynyl group has been added at the C17α position and the methyl group at the C19 position has been removed; hence, it is a combined derivative of ethisterone (17α-ethynyltestosterone) and nandrolone (19-nortestosterone). These modifications result in increased progestogenic activity and oral bioavailability as well as decreased androgenic/anabolic activity. Derivatives Norethisterone (NET) is the parent compound of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives. This group is divided by chemical structure into the estranes (derivatives of norethisterone) and the gonanes (18-methylgonanes or 13β-ethylestranes; derivatives of levonorgestrel) and includes the following marketed medications: Several of these act as prodrugs of norethisterone, including NETA, NETE, etynodiol diacetate, lynestrenol, and quingestanol acetate. Noretynodrel may also be a prodrug of norethisterone. NETA is taken by mouth similarly to norethisterone, while NETE is given by injection into muscle. Non-17α-ethynylated 19-Nortestosterone (19-NT) progestins which are technically not derivatives of norethisterone (as they do not have a C17α ethynyl group) but are still closely related (with other substitutions at the C17α and/or C16β positions) include the following marketed medications: The C17α vinyl (ethenyl) derivatives norgesterone (17α-vinyl-δ5(10)-19-NT) and norvinisterone (17α-vinyl-19-NT) The C17α allyl derivatives allylestrenol (3-deketo-17α-allyl-19-NT) and altrenogest (17α-allyl
Norethisterone	-δ9,11-19-NT) The C17α alkyl derivative normethandrone (17α-methyl-19-NT) The C17α cyanomethyl derivative dienogest (17α-cyanomethyl-δ9-19-NT) The C16β ethyl derivative oxendolone (16β-ethyl-19-NT)Many anabolic steroids of the 19-nortestosterone family, like norethandrolone and ethylestrenol, are also potent progestogens, but were never marketed as such. Synthesis Chemical syntheses of norethisterone have been published. Synthesis 1 Estradiol 3-methyl ether (1, EME) is partially reduced to the 1,5-diene (2) as also occurs for the first step in the synthesis of nandrolone. Oppenauer oxidation then transforms the C17β hydroxyl group into a ketone functionality (3). This is then reacted with metal acetylide into the corresponding C17α ethynyl compound (4). Hydrolysis of the enol ether under mild conditions leads directly to (5), which appears to be noretynodrel (although Lednicer states that it is "etynodrel" in his book (which may be a synonym etynodiol); etynodrel is with a chlorine atom attached), an orally active progestin. This is the progestogen component of the first oral contraceptive to be offered for sale (i.e., Enovid). Treatment of the ethynyl enol ether with strong acid leads to norethisterone (6).In practice, these and all other combined oral contraceptives are mixtures of 1 to 2% EE or mestranol and an oral progestin. It has been speculated that the discovery of the necessity of estrogen in addition to progestin for contraceptive efficacy is due to the presence of a small amount of unreduced EME (1) in early batches of 2. This when subjected to oxidation and ethynylation, would of course lead to mestranol (3). In any event, the need for the presence of estrogen in the mixture is now well established experimentally. Synthesis 2 Norethisterone is made from estr-4-ene-3,17-dione (bolandione), which in turn is synthesized by partial reduction of the aromatic region of the 3-O-methyl ether of estrone with lithium in liquid ammonia, and simultaneously of the keto group at C17α to a hydroxyl group, which is then oxidized back to a keto group by chromium trioxide in acetic acid. The conjugated C4-C5 olefin and the carbonyl group at C3 is then transformed to dienol ethyl ether using ethyl orthoformate. The obtained product is ethynylated by acetylene in the presence of potassium tert-butoxide. After hydrochloride hydrolysis of the formed O-potassium derivative, during which the enol ether is also hydrolyzed, and the remaining double bond is shifted, the desired norethisterone is obtained. History Norethisterone was synthesized for the first time by chemists Luis Miramontes, Carl Djerassi, and George Rosenkranz at Syntex in Mexico City in 1951. It was derived from ethisterone, and was found to possess about 20-fold greater potency as a progestogen in comparison. Norethisterone was the first highly active oral progestogen to be synthesized, and was preceded (as a progestogen) by progesterone (1934), ethisterone (1938), 19-norprogesterone (1944), and 17α-methylprogesterone (1949) as well as by nandrolone (1950), whereas noretynodrel (1952) and norethandrolone (1953) followed the synthesis of norethisterone. The drug was introduced as Norlutin in the United States in 1957. Norethisterone was subsequently combined with mestranol and marketed as Ortho-Novum in the United States in 1963. It was the second progestin, after noretynodrel in 1960, to be used in an oral contraceptive. In 1964, additional contraceptive preparations containing norethisterone in combination with mestranol or EE, such as Norlestrin and Norinyl, were marketed in the United States. Society and culture Generic names Norethisterone is the INN and BAN of the drug while norethindrone is its USAN. Brand names Norethisterone (NET), including as NETA and NETE, has been marketed under many brand names throughout the world. Availability United States Norethisterone was previously available alone in 5 mg tablets under the brand names Norlutin in the United States, but this formulation has since been discontinued in this country. However, NETA remains available alone in 5 mg tablets under the brand name Aygestin in the United States. It is one of the only non-contraceptive progestogen-only drug formulations that remains available in the United States. The others include progesterone, medroxyprogesterone acetate, megestrol acetate, and hydroxyprogesterone caproate, as well as the atypical agent danazol.Both norethisterone and NETA are also available in the United States as contraceptives. Norethisterone is available both alone (brand names Camila, Errin, Heather, Micronor, Nor-QD, others) and in combination with EE (Norinyl, Ortho-Novum, others) or mestranol (Norinyl, Ortho-Novum, others), while NETA is available only in combination with EE (Norlestrin, others). NETE is not available in the United States in any form. Research Norethisterone, as NETA and NETE, has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.Long-acting norethisterone microspheres for intramuscular injection have been studied for potential use in birth control. References Further reading External links "Norethindrone". Drug Information Portal. U.S. National Library of Medicine.
Velaglucerase alfa	Velaglucerase alfa, sold under the brand name Vpriv and manufactured by Shire plc, is a hydrolytic lysosomal glucocerebroside-specific enzyme, which is a recombinant form of glucocerebrosidase indicated as a long-term enzyme replacement therapy for those with Gaucher disease Type 1. It has an identical amino acid sequence to the naturally occurring enzyme. It was approved for use by the U.S. Food and Drug Administration (FDA) on February 26, 2010.The most common side effects include abdominal (belly) pain, headache, dizziness, bone pain, arthralgia (joint pain), back pain, infusion-related reactions, asthenia (weakness) or fatigue (tiredness), and pyrexia (fever) or increased body temperature.Velaglucerase alfa was approved for medical use in the European Union in August 2010. Medical uses Velaglucerase alfa is indicated for long-term enzyme-replacement therapy (ERT) in people with type-1 Gaucher disease. Competitive products Imiglucerase is Genzymes version of recombinant glucocerebrosidase. It is marketed globally under the trade name of Cerezyme. In addition, Protalix and Pfizer have received approval for marketing taliglucerase alpha in Israel, Brazil, Canada and the U.S. The companies are expected also to file for marketing authorization in Europe and elsewhere around the world. References External links "Velaglucerase alfa". Drug Information Portal. U.S. National Library of Medicine.
Prucalopride	Prucalopride, brand names Resolor and Motegrity among others, is a drug acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride was approved for medical use in the European Union in 2009, in Canada in 2011, in Israel in 2014, and in the United States in December 2018. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction. Medical uses The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week. Further measures are improvements in PAC-QOL (a quality of life measure) and PAC-SYM (a range of stool, abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo. There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants). The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.Small clinical trials suggested that prucalopride administration results in the 5-HT4 receptor agonism-associated memory enhancing in healthy participants improving their ability to recall and increasing neural activation in the hippocampus and functionally related areas. Contraindications Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohns disease, and ulcerative colitis and toxic megacolon/megarectum. Side effects Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment. Mechanism of action Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation. The observed effects are exerted via highly selective action on 5-HT4 receptors: prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors. Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channel respectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs. Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo. Pharmacokinetics Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in feces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours, and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products. Approval In the European Economic Area, prucalopride was originally approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Subsequently, it has been approved by the European Commission for use in adults – that is, including male patients – for the same indication. References External links "Prucalopride". Drug Information Portal. U.S. National Library of Medicine. "Prucalopride succinate". Drug Information Portal. U.S. National Library of Medicine.
C1-inhibitor	C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation but also as the major regulator of the contact system. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and MBL. Although named after its complement inhibitory activity, C1-inhibitor also inhibits proteases of the fibrinolytic, clotting, and kinin pathways. Note that C1-inhibitor is the most important physiological inhibitor of plasma kallikrein, fXIa, and fXIIa. Proteomics C1-inhibitor is the largest member among the serpin superfamily of proteins. It can be noted that, unlike most family members, C1-inhibitor has a 2-domain structure. The C-terminal serpin domain is similar to other serpins, which is the part of C1-inhibitor that provides the inhibitory activity. The N-terminal domain (also some times referred to as the N-terminal tail) is not essential for C1-inhibitor to inhibit proteases. This domain has no similarity to other proteins. C1-inhibitor is highly glycosylated, bearing both N- and O-glycans. N-terminal domain is especially heavily glycosylated. Genetics The human C1-inhibitor gene (SERPING1) is located on the eleventh chromosome (11q11-q13.1). Role in disease Deficiency of this protein is associated with hereditary angioedema ("hereditary angioneurotic edema"), or swelling due to leakage of fluid from blood vessels into connective tissue. Deficiency of C1-inhibitor permits plasma kallikrein activation, which leads to the production of the vasoactive peptide bradykinin. Also, C4 and C2 cleavage goes unchecked, resulting in auto-activation of the complement system. In its most common form, it presents as marked swelling of the face, mouth and/or airway that occurs spontaneously or to minimal triggers (such as mild trauma), but such swelling can occur in any part of the body. In 85% of the cases, the levels of C1-inhibitor are low, while in 15% the protein circulates in normal amounts but it is dysfunctional. In addition to the episodes of facial swelling and/or abdominal pain, it also predisposes to autoimmune diseases, most markedly lupus erythematosus, due to its consumptive effect on complement factors 3 and 4. Mutations in the gene that codes for C1-inhibitor, SERPING1, may also play a role in the development of age-related macular degeneration. At least 97 disease-causing mutations in this gene have been discovered.Despite uncontrolled auto-activation, it is important to note that levels of key complement components are low during an acute attack because they are being consumed - indeed, low levels of C4 are a key diagnostic test for hereditary angioedema. This situation is analogous to the low levels of clotting factors found in disseminated intravascular coagulation (DIC). Medical use Hereditary angioedema Blood-derived C1-inhibitor is effective but does carry the risk associated with the use of any human blood product. Cinryze, a pharmaceutical-grade C1-inhibitor, was approved for the use of HAE in 2008 in the US after having been available in Europe for decades. It is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product; it has been approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE.A recombinant C1-inhibitor obtained from the milk of transgenic rabbits, conestat alfa (trade name Ruconest), is approved for the treatment of acute HAE attacks in adults.While C1-inhibitor therapy has been used acutely for more than 35 years in Europe in patients with C1-inhibitor deficiency, new methods of treating acute attacks have emerged: a plasma kallikrein inhibitor and the bradykinin receptor antagonist icatibant. Other products also have been introduced including plasma-derived products such as Berinert and Haegarda. For other conditions The activation of the complement cascade can cause damage to cells, therefore the inhibition of the complement cascade can work as a medicine in certain conditions. When someone has a heart attack, for instance, the lack of oxygen in heart cells causes necrosis in heart cells: Dying heart cells spill their contents in the extracellular environment, which triggers the complement cascade. Activation of the complement cascade attracts phagocytes that leak peroxide and other reagents, which may increase the damage for the surviving heart cells. Inhibition of the complement cascade can decrease this damage. Synthesis C1-inhibitor is contained in the human blood; it can, therefore, be isolated from donated blood. Risks of infectious disease transmission (viruses, prions, etc.) and relative expense of isolation prevented widespread use. It is also possible to produce it by recombinant technology, but Escherichia coli (the most commonly used organism for this purpose) lacks the eukaryotic ability to glycosylate proteins; as C1-inhibitor is particularly heavily glycosylated, this sialylated recombinant form would have a short circulatory life (the carbohydrates are not relevant to the inhibitor function). Therefore, C1-inhibitor has also been produced in glycosylated form using transgenic rabbits. This form of recombinant C1-inhibitor also has been given orphan drug status for delayed graft function following organ transplantation and for capillary leakage syndrome. References Further reading External links Human SERPING1 genome location and SERPING1 gene details page in the UCSC Genome Browser. "SERPING1". Drug Information Portal. U.S. National Library of Medicine. The MEROPS online database for peptidases and their inhibitors: I04.024 B02AB03 (WHO) Overview of all the structural information available in the PDB for UniProt: P05155 (Plasma protease C1 inhibitor) at the PDBe-KB.
Azathioprine	Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohns disease, ulcerative colitis, and systemic lupus erythematosus, and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans). It is taken by mouth or injected into a vein.Common side effects include bone-marrow suppression and vomiting. Bone-marrow suppression is especially common in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. Other serious risk factors include an increased risk of certain cancers. Use during pregnancy may result in harm to the baby. Azathioprine is in the purine analogue and antimetabolite family of medications. It works via 6-thioguanine to disrupt the making of RNA and DNA by cells.Azathioprine was first made in 1957. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 335th-most commonly prescribed medication in the United States, with more than 800,000 prescriptions. Medical uses Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of autoimmune diseases, including rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Behçets disease, and other forms of vasculitis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica (Devics disease), restrictive lung disease, and others. It is also an important therapy and steroid-sparing agent for inflammatory bowel disease (such as Crohns disease and ulcerative colitis) and for multiple sclerosis.In the United States, it is approved by the Food and Drug Administration for use in kidney transplantation from human donors, and for rheumatoid arthritis. Transplantation Azathioprine is used to prevent rejections of kidney or liver allografts, usually in conjunction with other therapies including corticosteroids, other immunosuppressants, and local radiation therapy. The administration protocol starts either at the time of transplantation or within the following two days. Rheumatoid arthritis Being a disease-modifying antirheumatic drug (DMARD), azathioprine has been used for the management of the signs and symptoms of adult rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended. Inflammatory bowel disease Azathioprine has been used in the management of moderate to severe chronically active Crohns disease, to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients, and to provide benefit in people with fistulizing Crohns disease. The onset of action is slow, and it may require several months to achieve clinical response.Azathioprine treatment is associated with an increased risk of lymphoma, but if this is due to the drug or a predisposition related to Crohns disease is unclear. Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohns disease, without causing many side effects. It may also be used to prevent flares in those with ulcerative colitis. Others Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher of prednisone in those who experience recurrent flares.It is used as an add-on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent. Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.It can be very effective in eczema and atopic dermatitis, though it is not commonly used. The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of malignancy has led to a decreased use, yet it is still used in maintenance treatment for people who frequently relapse. A 2007 Cochrane review found that azathioprine reduced the number of relapses in the first year of treatment and disease progression in the first two to three years and did not find an increase in cancer, and noted the need for direct comparison of azathioprine and interferon beta, conflicting conclusions regarding cancer, and the potential for long-term risks.A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and N-acetylcysteine. A 2012 study showed that outcomes were worse with this combination than with placebo. Adverse effects Nausea and vomiting are common adverse effects, especially at the beginning of a treatment. Such cases are met with taking azathioprine after meals or transient intravenous administration. Side effects that are probably hypersensitivity reactions include dizziness, diarrhea, fatigue, and rashes. Hair loss is often seen in transplant patients receiving the drug, but rarely occurs under other indications. Because azathioprine suppresses the bone marrow, patients can develop anaemia and be more susceptible to infection; regular monitoring of the blood count is recommended during treatment. Acute pancreatitis can also occur, especially in patients with Crohns disease. Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to on-exchange LC-MS (liquid chromotography - mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.Under FDA rules, like many other immunosuppressants, the use of this drug excludes eligibility for blood donation.It is listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans). Pharmacogenetics The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprines mechanism of action. The first metabolic step that azathioprine undergoes in the body is the conversion to 6-mercaptopurine (6-MP; see Pharmacokinetics), which is itself an immunosuppressant prodrug. The TPMT enzyme is responsible, in part, for the methylation of 6-MP into the inactive metabolite 6-methylmercaptopurine - this methylation prevents 6-MP from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving azathioprine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify patients with reduced TPMT activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely. The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity. Indeed, testing for TPMT activity is one of the few examples of pharmacogenetics being translated into routine clinical care. Missense SNP in NUDT15 (e.g., rs116855232, inducing R139C)) has been identified to be a causal factor for AZA-induced leukopenia through a genome wide association study (GWAS) in East Asians. Cancers Azathioprine is listed as a human carcinogen in the 12th Report on Carcinogens by the National Toxicology Program of U.S. Department of Health and Human Services, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans." Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies by International Agency for Research on Cancer have provided "sufficient" evidence of azathioprine carcinogenicity in humans (group 1), although the methodology of past studies and the possible underlying mechanisms are questioned.The various diseases requiring transplantation may in themselves increase the risks of non-Hodgkin lymphoma, squamous cell carcinomas of the skin, hepatobiliary carcinomas, and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lower risk than those undergoing transplantation.Cases of hepatosplenic T-cell lymphoma – a rare type of lymphoma – have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease. Adolescents and young adult males were the majority of cases. They presented with a very aggressive disease course, and with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue. Skin cancers In transplant patients, skin cancer is 50 to 250 times more common than in the general population, and between 60 and 90% of patients are affected 20 years after transplantation. The use of immunosuppressive medication including azathioprine in organ transplantation has been linked to increased rates of developing skin cancer. Azathioprine causes the accumulation of 6-thioguanine (6-TG) in patients DNA, which might trigger cancer when the patient is later exposed to ultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light. Overdose Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count, and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression. Interactions Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine. Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders. This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.Azathioprine decreases the effects of the anticoagulant warfarin and of nondepolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants. It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia. Pregnancy and breastfeeding Azathioprine can cause birth defects. A 2003 population-based study in Denmark showed that the use of azathioprine and related mercaptopurine resulted in a seven-fold incidence of fetal abnormalities, as well as a 20-fold increase in miscarriage. Birth defects in a child whose father was taking azathioprine have also been reported. Although no adequate and well-controlled studies have taken place in humans, when given to animals in doses equivalent to human dosages, teratogenesis was observed. Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts with the later-developed drugs tacrolimus and mycophenolate, which are contraindicated during pregnancy.Traditionally, as for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine, but the "lactation risk category" reported by Thomas Hale in his book Medications and Mothers Milk lists azathioprine as "L3", termed "moderately safe". Pharmacology Pharmacokinetics Azathioprine is absorbed from the gut to about 88%. Bioavailability varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver. Highest blood plasma concentrations, counting not only the drug itself, but also its metabolites, are reached after 1–2 hours, and the average plasma half-life is 26 to 80 minutes for azathioprine and 3–5 hours for drug plus metabolites. 20 to 30% are bound to plasma proteins while circulating in the bloodstream.Azathioprine is a prodrug, a substance that is not an active drug itself, but is activated in the body. This happens in several steps; at first, it is slowly and almost completely converted to 6-mercaptopurine (6-MP) by reductive cleavage of the thioether (–S–). This is mediated by glutathione and similar compounds in the intestinal wall, the liver, and on red blood cells, without the aid of enzymes. 6-MP is metabolized analogously to natural purines, giving thioguanosine triphosphate (TGTP) and thiodeoxyguanosine triphosphate (TdGTP) via thioinosine monophosphate (TIMP) and several further intermediates. On a second path, the sulfur atom of 6-MP and TIMP is methylated. The end products of azathioprine metabolism are thiouric acid (38%) and various methylated and hydroxylated purines, which are excreted via the urine. Mechanism of action Azathioprine inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cells, thus causing immunosuppression. Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to 6-thioguanine by the addition of an amino group. Both 6-MP and 6-thioguanine are conjugated with ribose, and then phosphorylated to form the nucleotides thioinosinic acid and thioguanylic acid, respectively. These nucleotides masquerade, respectively, as inosinic acid and guanylic acid; the former is the starting point for purine nucleotide biosynthesis, while the latter is one of the building blocks of DNA and RNA. The nucleotides are incorporated into newly synthesized (but nonfunctional) DNA, halting replication. The nucleotides act to inhibit glutamine-phosphoribosyl pyrophosphate amidotransferase (GPAT), one of the enzymes involved in purine biosynthesis, one of the earlier steps in the synthesis of DNA and RNA. They achieve GPAT inhibition through a form of negative feedback called product inhibition. Because actively replicating cells (such as cancer cells and the T cells and B cells of the immune system) are most active in synthesizing purine, making new DNA, these cells are most strongly affected. A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These bind to GTP-binding protein Rac1, blocking synthesis of the protein Bcl-xL, thus sending activated T cells and mononuclear cells into apoptosis (programmed cell death). Increased apoptosis of mononuclear cells is seen in inflammatory bowel disease patients treated with azathioprine. Chemistry Azathioprine is a thiopurine linked to a second heterocycle (an imidazole derivative) via a thioether. It is a pale yellow solid with a slightly bitter taste and a melting point of 238–245 °C. It is practically insoluble in water and only slightly soluble in lipophilic solvents such as chloroform, ethanol, and diethylether. It dissolves in alkaline aqueous solutions, where it hydrolyzes to 6-mercaptopurine.Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1H-imidazole and 6-mercaptopurine in dimethyl sulfoxide. The synthesis of the former starts with an amide from methylamine and diethyl oxalate, which is then cyclized and chlorinated with phosphorus pentachloride; the nitro group is introduced with nitric and sulfuric acid. History Azathioprine was synthesized by George Herbert Hitchings and Gertrude Elion in 1957 (named BW 57-322) to produce 6-MP in a metabolically active, but masked form, and at first used as a chemotherapy drug.Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibodies when given to rabbits together with antigens. Following the work done by Sir Peter Medawar and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, and Schwartzs researches on 6-MP, Sir Roy Calne, the British pioneer in transplantation, introduced 6-MP as an experimental immunosuppressant for kidney and heart transplants. When Calne asked Elion for related compounds to investigate, she suggested azathioprine, which was subsequently found out to be superior (as effective and less toxic to the bone marrow) by Calne.On 5 April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time. For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978. Ciclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart-related transplantations. Moreover, despite being considerably more expensive, mycophenolate mofetil is also increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infections, and a lower incidence of acute rejection. References Further reading Dean L (2012). "Azathioprine Therapy and TPMT Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520349. Bookshelf ID: NBK100661. External links "Azathioprine". Drug Information Portal. U.S. National Library of Medicine.
Bivalirudin	Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI).Chemically, it is a synthetic congener of the naturally occurring drug hirudin, found in the saliva of the medicinal leech Hirudo medicinalis. Bivalirudin lacks many of the limitations seen with indirect thrombin inhibitors, such as heparin. A short, synthetic peptide, it is a potent and highly specific inhibitor of thrombin that inhibits both circulating and clot-bound thrombin, while also inhibiting thrombin-mediated platelet activation and aggregation. Bivalirudin has a quick onset of action and a short half-life. It does not bind to plasma proteins (other than thrombin) or to red blood cells. Therefore, it has a predictable antithrombotic response. There is no risk for heparin-induced thrombocytopenia or heparin-induced thrombosis-thrombocytopenia syndrome. It does not require a binding cofactor such as antithrombin and does not activate platelets. These characteristics make bivalirudin an ideal alternative to heparin. Bivalirudin clinical studies demonstrated consistent positive outcomes in patients with stable angina, unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI) undergoing PCI in seven major randomized trials. Patients receiving bivalirudin had fewer adverse events compared to patients that received heparin. Indications US (United States) Bivalirudin is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). Bivalirudin with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). Bivalirudin is indicated for patients with, or at risk of HIT/HITTS undergoing PCI. Bivalirudin is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin EU (European) Percutaneous Coronary Intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. Bivalirudin is also indicated for the treatment of adult patients with unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention. Bivalirudin should be administered with aspirin and clopidogrel. Basic chemical and pharmacological properties Chemistry Bivalirudin is a 20 amino acid long peptide with the sequence D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu (FPRPGGGGNGDFEEIPEEYL), where the first residue is D-phenylalanine instead of the natural L-phenylalanine. Mechanism of action Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process. It cleaves fibrinogen into fibrin monomers, activates Factor V, VIII, and XIII, allowing fibrin to develop a covalently cross-linked framework that stabilizes the thrombus. Thrombin also promotes further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions. Pharmacokinetics Following an IV bolus of bivalirudin of 1 mg/kg and a 4-hour 2.5 mg/kg/h IV infusion a mean steady state concentration of 12.3 ± 1.7 µg/mL is achieved Bivalirudin is cleared from plasma by a combination of renal mechanisms and proteolytic cleavage Half-life:-Normal renal function (≥ 90 mL/min) = 25 minutes -Mild renal dysfunction (60–89 mL/min) = 22 minutes -Moderate renal dysfunction (30-59 mL/min) = 34 minutes -Severe renal dysfunction (≤ 29 mL/min) = 57 minutes -Dialysis-dependent = 3.5 hours Clearance is reduced approximately 20% in patients with moderate and severe renal impairment and by 80% in dialysis-dependent patients Bivalirudin is hemodialyzable and approximately 25% is cleared by hemodialysis.PharmacodynamicsCoagulation times return to baseline approximately 1 hour following cessation of bivalirudin administration. Dosing and administration Bivalirudin is intended for IV use only and is supplied as a sterile, lyophilized product in single-use, glass vials. After reconstitution, each vial delivers 250 mg of bivalirudin. US dosing: PCI Bolus: 0.75 mg/kg PCI Infusion: 1.75 mg/kg/hEU dosing: UA/NSTEMI-Bolus: 0.1 mg/kg -Infusion: 0.25 mg/kg/h for up to 72 hours for medical management -If patient proceeds to PCI, an additional bolus of 0.5 mg/kg of bivalirudin should be administered before the procedure and the infusion increased to 1.75 mg/kg/h for the duration of the procedure. PCI-Bolus: 0.75 mg/kg -Infusion: 1.75 mg/kg/h Coronary Artery Bypass Graft (CABG)-Patients proceeding to CABG surgery off-pump: The IV infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, a 0.5 mg/kg bolus dose should be administered followed by a 1.75 mg/kg/h infusion for the duration of the surgery. -Patients proceeding to CABG surgery on-pump: The IV infusion of bivalirudin should be continued until 1 hour prior to surgery after which the infusion should be discontinued Five minutes after the bolus dose has been administered, an activating clotting time (ACT) should be performed and an additional bolus of 0.3 mg/kg should be given if needed.Continuation of the bivalirudin infusion following PCI for up to 4 hours post-procedure is optional, at the discretion of the treating physician. After 4 hours, an additional IV infusion of bivalirudin may be initiated at a rate of 0.2 or 0.25 mg/kg/h for up to 20 hours, if needed.Bivalirudin should be administered with optimal antiplatelet therapy (aspirin plus clopidogrel).Renal impairment A reduction in the infusion dose of bivalirudin should be considered in patients with moderate or severe renal impairment. If a patient is on hemodialysis, the infusion should be reduced to 0.25 mg/kg/h. No reduction in the bolus dose is needed. Safety information Bivalirudin is contraindicated in patients with active major bleeding and hypersensitivity to bivalirudin or its components. (In the EU bivalirudin is also contraindicated in patients with an increased risk of bleeding due to hemostasis disorders and/or irreversible coagulation disorders, severe uncontrolled hypertension, subacute bacterial endocarditis, and severe renal impairment [GFR<30 ml/min] and in dialysis-dependent patients).Bivalirudin is an anticoagulant. Therefore, bleeding is an expected adverse event. In clinical trials, bivalirudin treated patients exhibited statistically significantly lower rates of bleeding than patients treated with heparin plus a GP IIb/IIIa inhibitor. The most common (≥10%) adverse events of bivalirudin are back pain, pain, nausea, headache, and hypotension.Bivalirudin is classified as Pregnancy Category B. Pediatric experience The U.S. Food and Drug Administration (FDA) granted pediatric exclusivity for bivalirudin, based on studies submitted in response to a written request by the FDA to investigate the use of bivalirudin in pediatric patients aged birth to 16-years old. The submission was based on a prospective, open-label, multi-center, single arm study evaluating bivalirudin as a procedural anticoagulant in the pediatric population undergoing intravascular procedures for congenital heart disease. Study outcomes suggest that the pharmacokinetic (PK) and pharmacodynamic (PD) response of bivalirudin in the pediatric population is predictable and behaves in a manner similar to that in adults. Comparative results Bivalirudin is supported by 7 major randomized trials. These trials include REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events-2), BAT (Bivalirudin Angioplasty Trial), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy Trial), and HORIZONS AMI (Harmonizing Outcomes With Revascularization and Stents in AMI). A total of 25,000 patients with a low to high risk for ischemic complications undergoing PCI were evaluated. Bivalirudin with or without provisional GPIIb/IIIa demonstrated similar angiographic and procedural outcomes and improved clinical outcomes when compared with heparin plus GPIIb/IIIa.HORIZONS-AMIHORIZONS AMI was a prospective, randomized, open-label, double-arm multicenter trial in STEMI patients undergoing primary PCI. 30 Day Results The incidence of net adverse clinical events (9.2% vs. 12.1%) and major bleeding (4.9% vs. 8.3%) was significantly reduced by bivalirudin monotherapy versus unfractionated heparin (UFH) plus a GP IIb/IIIa inhibitor with similar rates of major adverse cardiovascular events (5.4 vs. 5.5%) at 30 days. A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was observed (1.8% vs. 2.9%) at 30 days. Patients receiving Angiomax monotherapy had similar rates of overall stent thrombosis (Academic Research Consortium (ARC) definition) at 30 days versus UFH plus a GP IIb/IIIa inhibitor (2.5% vs. 1.9%), with the exception of acute stent thrombosis (<24 hours), which was higher for the bivalirudin-treated patients at 1.3% vs 0.3% for the UFH-GP IIb/IIIa-inhibitor-treated patients.1-Year Results At 1-year follow-up, a reduction in the incidence of net adverse clinical events (15.7% vs. 18.3%) and major bleeding (5.8% vs. 4.9%) was maintained in the bivalirudin monotherapy group versus UFH plus a GP IIb/IIIa inhibitor group, with no difference in the rate of major adverse cardiovascular events (11.9% vs. 11.9%) A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was maintained at 1 year in the HORIZONS AMI trial (2.1% vs. 3.8%)The incidence of stent thrombosis at 1 year was also similar between the 2 treatment groups (3.5% in the Angiomax group vs. 3.2% in the UFH plus GP IIb/IIIa inhibitor group).2-Year Results At 2-year follow-up, a reduction in the incidence of net adverse clinical events (22.3% vs. 24.8%) and major bleeding (6.4% vs. 9.6%) was maintained in the bivalirudin monotherapy group versus UFH plus a GP IIb/IIIa inhibitor group, with no difference in the rate of major adverse cardiovascular events (18.7% vs. 18.8%) A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was maintained at 2 year in the HORIZONS AMI trial (2.5% vs. 4.2%) At 2-year follow-up, treatment with bivalirudin monotherapy resulted in a 25% reduction in all-cause mortality, representing 15 lives saved per 1000 patients treated (number needed to treat [NNT] = 67 to save 1 life). The incidence of stent thrombosis (ARC definite/probable) at 2 years was also similar between the 2 treatment groups (4.6% in the Angiomax group vs. 4.3% in the UFH plus GP IIb/IIIa inhibitor group).ACUITYACUITY was a large multicenter, prospective, open-label, 3-arm trial designed to establish the optimal antithrombotic treatment regimens in patients with UA/NSTEMI undergoing early invasive management. 30-Day Results Bivalirudin monotherapy provided superior net clinical outcomes compared to any heparin regimen with GP IIb/IIIa inhibitor (10.1% vs 11.7%) at 30 days. The incidence of ACUITY scale major bleeding (non-CABG) was decreased significantly by 47% in the bivalirudin monotherapy group vs the heparin with GP IIb/IIIa inhibitor group (3.0% vs 5.7%) at 30 days.1-Year Results Bivalirudin alone demonstrated no difference in the rates of composite ischemic complications (death, MI, unplanned revascularization for ischemia) versus heparin with GP IIb/IIIa inhibition (16.4% vs 16.3%) at 12 months.REPLACE-2REPLACE-2 was a multicenter, double-blind, triple-dummy randomized clinical trial in patients with low to moderate risk for ischemic complications undergoing PCI. 30 Days The incidence of net adverse clinical events (9.2% vs. 10.0%) and major adverse cardiovascular events (7.6% vs. 7.1%) was reduced by bivalirudin monotherapy versus unfractionated heparin (UFH) plus a GP IIb/IIIa inhibitor with significant reduction in rates of major bleeding (2.4 vs. 4.1%) at 30 days.1-Year Results Differences in mortality favoring bivalirudin at 30 days and 6 months was maintained at 12 months and demonstrated a 24% risk reduction in death compared to heparin plus GP IIb/IIIa inhibition.BATThe Phase III Bivalirudin Angioplasty Trial (BAT) was a randomized, prospective, double blind, multicenter study in patients with unstable angina undergoing PTCA. The composite endpoint of death, MI or revascularization occurred in 6.2% of patients treated with bivalirudin and in 7.9% of patients treated with heparin. Significant reductions in clinical events were maintained at 90 days with absolute benefits being sustained through 180 days. The incidence of major hemorrhage for the entire hospitalization period in patients assigned bivalirudin was 3.7% compared to 9.3% in patients randomized to heparin. Guidelines Bivalirudin has Class I recommendations in multiple national guidelines. US guidelines EU guidelines References External links Heparin More Effective Than Bivalirudin in Treating Patients During PCI - Diagnostic and interventional cardiology magazine
Desonide	Desonide (INN) is a low-potency topical corticosteroid anti-inflammatory that has been available since the 1970s. It is primarily used to treat atopic dermatitis (eczema), seborrheic dermatitis, contact dermatitis and psoriasis in both adults and children. It has a fairly good safety profile and is available as a cream, ointment, lotion, and as a foam under the tradename Verdeso Foam. Other trade names for creams, lotions, and ointments include Tridesilon, DesOwen, Desonate. It is a group VI corticosteroid under US classification, the second least potent group. Medical uses Desonide is a prescription topical treatment for redness, swelling, itching, and discomfort of various skin conditions. Regardless of the vehicle used, desonide is applied 2 to 3 times a day, at the same times each day. Skin conditions typically improve in the first two weeks of treatment. Patients are instructed to use desonide for the minimum amount of time necessary for conditions to improve. Adverse effects The safety of desonide has not been determined beyond 4 weeks of use. Patients with allergies to corticosteroids (like hydrocortisone or prednisone) should use caution when taking desonide. Pharmacists and prescribing physicians should be aware that this medication may contain inactive ingredients than can cause allergic reactions. Desonide should not be used if there is an infection or open wound in the treatment area. Systemic absorption of topical corticosteroids can produce adverse effects. Indication of Cushings syndrome, hyperglycemia, and glycosuria have been observed in some patients receiving treatment. After stopping treatment, reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency is possible. The cosyntropin (ACTH1-24) laboratory test can evaluate patients for HPA axis suppression. HPA function can be reversed after the cessation of treatment or replacement with another less potent corticosteroid. If glucocorticosteroid insufficiency occurs, supplemental systemic corticosteroids may be required. Side effects of desonide requiring immediate contact with the prescribing physician: Blistering, burning, crusting, dryness, or flaking of the skin burning, itching, redness, skin rash, swelling, or soreness at the application site flushing or redness of the skin irritation itching, scaling, severe redness, soreness, or swelling of the skin peeling of the skin raised, dark red, wart-like spots on the skin, especially when used on the face stinging and burning unusually warm skinSide effects that may go away as the body adjusts to the medication: Body aches or pain chills cough difficulty with breathing ear congestion fever headache loss of voice nasal congestion runny nose sneezing sore throat unusual tiredness or weakness Pregnancy The FDA has labeled desonide as pregnancy category C. Desonide should only be used during pregnancy when absolutely necessary. Breastfeeding It is currently unknown whether topical application of Desonide can pass into breast milk. Similar drugs taken orally have been seen to pass into breast milk. The prescribing doctor should be consulted prior to breast-feeding. Mechanism of action Desonide is a synthetic nonfluorinated corticosteroid; topical corticosteroids have anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of these properties, however, is unclear for the dermal route of administration. Following absorption through the skin, corticosteroids follow pharmacokinetic pathways similarly to intravenously administered corticosteroids. The mechanism of corticosteroids is thought to induce phospholipase A2 inhibitory proteins (lipocortins). Lipocortins control the biosynthesis of inflammation mediators, like prostaglandins and leukotrienes. Lipocortins can inhibit the common precursor of inflammation mediators, arachidonic acid. Interactions Common medications causing a minor negative drug interaction include: Insulin and Metformin. Common medications checked in combination, but that are not known to create a negative drug interaction, include: Aspirin, Cymbalta (duloxetine), Fish Oil, Acetaminophen, Vitamin B12, Vitamin C, Vitamin D3, and Zyrtec. History Desonide was first introduced in the United States under the trade name Tridesilon by Dome Laboratories in 1972. Since the discovery in the United States, several other countries have introduced different brand names of desonide, including Italy, Spain, United Kingdom, and Germany. The FDA first approved Connetics Corporation’s Verdeso Foam® on September 16, 2006. Just shortly after, the FDA approved SkinMedica Inc.’s Desonate® hydrogel delivery vehicle on October 20, 2006.Desonate® gel is currently manufactured by Bayer HealthCare Pharmaceuticals Inc. in Whippany, NJ. DesOwen® creams, ointments, and lotions are currently manufactured by DPT Laboratories, Ltd. in San Antonio Texas and is marketed by Galderma Laboratories. Other suppliers for the generic desonide include Rebel Distributors Corp and Perrigo New York Inc. Research and clinical trials Desonate was approved by the FDA following two major clinical trials in 2006. Each randomized, double-blind, placebo-controlled study enrolled 582 pediatric patients (between the ages of 3 months and 18 years). The patient was topically administered the drug or placebo two times a day for four weeks. Using the Investigator’s Global Severity Score (IGSS), the treatment was considered successful if at Week 4 there was at least a two (2) point decrease from the patient’s baseline IGSS. In clinical trial 1, 44% of patients succeeded successful treatment of Desonate versus 14% treated with the placebo. In clinical trial 2, 28% of patients succeeded successful treatment of Desonate versus 6% treated with the placebo. The FDA approved Tridesilon for the following treatments: Contact Dermatitis, Rhus Dermatitis, Eczema, Dermatitis, Discoid Lupus Erythematosus, Granuloma Annulare, Seborrheic Dermatitis, Polymorphous Light Eruption, Pruritus, Psoriasis, Lichen Simplex, Atopic Dermatitis, Lichen Planus, Xerosis, Exfoliative Dermatitis.Recently, in late 2014, phase 3 clinical trials were completed to evaluate treatments using Desonide cream versus amino acid moisturizing cream. Patients with eczema or atopic dermatitis could be enrolled in this study, both male and female, over the age of 18. The randomized, double-blind, active control, 5-week study compared the effects of treatment of both creams through twice-a-day application. The clinical trial is sponsored by NeoStrata Company, Inc.No research has been completed to evaluate the carcinogenic or photoco-carcinogenic potential of desonide. Additionally, no research has been completed to determine the effect on fertility. These are current opportunities for improvement to learn more about the risks and benefits associated with desonide. Regulatory The first US. patent for desonide was US4185100A was granted on January 22, 1980. The patent was for topical anti-inflammatory treatment using desonide. The patent defends the suitability of the anti-inflammatory for the treatment of cutaneous disorders or disruptions characterized by skin inflammation and/or hyperproliferative activity in the epidermis. Side effects and the mechanism of action are both disclosed. This patent is currently expired. == References ==
Levoketoconazole	Levoketoconazole, sold under the brand name Recorlev, is a steroidogenesis inhibitor that is used for the treatment of Cushings syndrome. Levoketoconazole was approved for medical use in the United States in December 2021.Levoketoconazole is the levorotatory or (2S,4R) enantiomer of ketoconazole, and it is an inhibitor of the enzymes CYP11B1 (11β-hydroxylase), CYP17A1 (17α-hydroxylase/17,20-lyase), and CYP21A2 (21-hydroxylase). It inhibits glucocorticoid biosynthesis and hence circulating levels of glucocorticoids, thereby treating Cushings syndrome. In addition to its increased potency, the drug is 12-fold less potent than racemic ketoconazole in inhibiting CYP7A1 (cholesterol 7α-hydroxylase), theoretically resulting in further reduced interference with bile acid production and metabolite elimination and therefore less risk of hepatotoxicity. Levoketoconazole has also been found to inhibit CYP11A1 (cholesterol side-chain cleavage enzyme) and CYP51A1 (lanosterol-14α-demethylase), similarly but more potently relative to ketoconazole. References External links "Levoketoconazole". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03277690 for "A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushings Syndrome" at ClinicalTrials.gov Clinical trial number NCT01838551 for "Treatment for Endogenous Cushings Syndrome (SONICS)" at ClinicalTrials.gov
Selegiline	Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinsons disease and major depressive disorder. It is provided in the form of a capsule or tablet taken by mouth for Parkinsons disease and as a patch applied to skin for depression. Selegiline acts as a monoamine oxidase inhibitor, and increases levels of monoamine neurotransmitters in the brain. At typical clinical doses used for Parkinsons disease, selegiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B), increasing levels of dopamine in the brain. In larger doses (more than 20 mg/day), it loses its specificity for MAO-B and also inhibits MAO-A, which increases serotonin and norepinephrine levels in the brain. Medical uses Parkinsons disease In its pill form, selegiline is used to treat symptoms of Parkinsons disease. It is most often used as an adjunct to drugs such as levodopa (L-DOPA), although it has been used off-label as a monotherapy. The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the motor complications of levodopa therapy. Selegiline delays the point when levodopa treatment becomes necessary from about 11 months to about 18 months after diagnosis. There is some evidence that selegiline acts as a neuroprotectant and reduces the rate of disease progression, though this is disputed.Selegiline has also been used off-label as a palliative treatment for dementia in Alzheimers disease. Depression Selegiline is also delivered via a transdermal patch used as a treatment for major depressive disorder. Administration of transdermal selegiline bypasses hepatic first pass metabolism. This avoids inhibition of gastrointestinal and hepatic MAO-A activity, which would result in an increase of food-borne tyramine in the blood and possible related adverse effects, while allowing for a sufficient amount of selegiline to reach the brain for an antidepressant effect.A quantitative review published in 2015 found that for the pooled results of the pivotal trials, the number needed to treat (a sign of effect size, so a low number is better) for the patch for symptom reduction was 11, and for remission, was 9. The number needed to harm (inverse of the NNT, a high number here is better) ranged from 387 for sexual side effects to 7 for application site reaction. With regard to the likelihood to be helped or harmed (LHH), the analysis showed that the selegiline patch was 3.6 times as likely to lead to a remission vs. a discontinuation due to side effects; the LHH for remission vs. incidence of insomnia was 2.1; the LHH for remission vs. discontinuation due to insomnia was 32.7. The LHH for remission vs. insomnia and sexual dysfunction were both very low. Special populations For all human uses and all forms, selegiline is pregnancy category C: studies in pregnant lab animals have shown adverse effects on the fetus but there are no adequate studies in humans. Side effects Side effects of the tablet form in conjunction with levodopa include, in decreasing order of frequency, nausea, hallucinations, confusion, depression, loss of balance, insomnia, increased involuntary movements, agitation, slow or irregular heart rate, delusions, hypertension, new or increased angina pectoris, and syncope. Most of the side effects are due to a high dopamine signaling, and can be alleviated by reducing the dose of levodopa.The main side effects of the patch form for depression include application-site reactions, insomnia, diarrhea, and sore throat. The selegiline patch carries a black box warning about a possible increased risk of suicide, especially for young people, as do all antidepressants since 2007. Interactions Both the oral and patch forms come with strong warnings against combining selegiline with drugs that could produce serotonin syndrome, such as SSRIs and the cough medicine dextromethorphan. Selegiline in combination with the opioid analgesic pethidine is not recommended, as it can lead to severe adverse effects. Several other synthetic opioids such as tramadol and methadone, as well as various triptans, are contraindicated due to potential for serotonin syndrome.Birth control pills containing ethinylestradiol and a progestin increase the bioavailability of selegiline by 10- to 20-fold. High levels can lead to loss of MAO-B selectivity, and selegiline may begin inhibiting MAO-A as well. This increases susceptibility to side effects of non-selective MAOIs, such as tyramine-induced hypertensive crisis and serotonin toxicity when combined with serotonergic medications.Both forms of the drug carry warnings about food restrictions to avoid hypertensive crisis that are associated with MAO inhibitors. The patch form was created in part to overcome food restrictions; clinical trials showed that it was successful. Additionally, in post-marketing surveillance from April 2006 to October 2010, only 13 self-reports of possible hypertensive events or hypertension were made out of 29,141 exposures to the drug, and none were accompanied by objective clinical data. The lowest dose of the patch method of delivery, 6 mg/24 hours, does not require any dietary restrictions. Higher doses of the patch and oral formulations, whether in combination with the older non-selective MAOIs or in combination with the reversible MAO-A inhibitor moclobemide, require a low-tyramine diet. Pharmacology Pharmacodynamics Selegiline is a selective inhibitor of MAO-B, irreversibly inhibiting it by binding to it covalently. It is generally believed to exert its effects by blocking the breakdown of dopamine, thus increasing its activity; however, recent evidence suggests that MAO-A is solely or almost entirely responsible for the metabolism of dopamine. Its possible neuroprotective properties may be due to protecting nearby neurons from the free oxygen radicals that are released by MAO-B activity. At higher doses, selegiline loses its selectivity for MAO-B and inhibits MAO-A as well.Selegiline also inhibits CYP2A6 and can increase the effects of nicotine as a result. Selegiline also appears to activate σ1 receptors, having a relatively high affinity for these receptors of approximately 400 nM. Pharmacokinetics Selegiline has an oral bioavailability of about 10%, which increases when ingested together with a fatty meal, as the molecule is fat soluble. Selegiline and its metabolites bind extensively to plasma proteins (at a rate of 94%). They cross the blood–brain barrier and enter the brain, where they most concentrated at the thalamus, basal ganglia, midbrain, and cingulate gyrus.Selegiline is mostly metabolized in the intestines and liver; it and its metabolites are excreted in the urine.Buccal administration of selegiline results in 5-fold higher bioavailability, more reproducible blood concentration, and produces less amphetamine metabolites than the oral tablet form. Metabolism Selegiline is metabolized by cytochrome P450 to L-desmethylselegiline and levomethamphetamine. Desmethylselegiline has some activity against MAO-B, but much less than that of selegiline. It is thought to be further metabolized by CYP2C19. Levomethamphetamine (the less potent of the two enantiomers of methamphetamine) is converted to levoamphetamine (the less potent of the two enantiomers of amphetamine, with regards to psychological effects). Due to the presence of these metabolites, people taking selegiline may test positive for "amphetamine" or "methamphetamine" on drug screening tests. While the amphetamine metabolites may contribute to selegilines ability to inhibit reuptake of the neurotransmitters dopamine and norepinephrine, they have also been associated with orthostatic hypotension and hallucinations. The amphetamine metabolites are hydroxylated and, in phase II, conjugated by glucuronyltransferase. A newer anti-Parkinson MAO-B inhibitor, rasagiline, metabolizes into 1(R)-aminoindan, which has no amphetamine-like characteristics. Patch Following application of the patch to humans, an average of 25% to 30% of the selegiline content is delivered systemically over 24 hours. Transdermal dosing results in significantly higher exposure to selegiline and lower exposure to all metabolites when compared to oral dosing; this is due to the extensive first-pass metabolism of the pill form and low first-pass metabolism of the patch form. The site of application is not a significant factor in how the drug is distributed. In humans, selegiline does not accumulate in the skin, nor is it metabolized there. Chemistry Selegiline belongs to the phenethylamine and amphetamine chemical families. It is also known as L-deprenyl, as well as (R)-(–)-N,α-dimethyl-N-(2-propynyl)phenethylamine or (R)-(–)-N-methyl-N-2-propynylamphetamine. The compound is a derivative of levomethamphetamine (L-methamphetamine) with a propargyl group attached to the nitrogen atom. This detail is borrowed from pargyline, an older MAO-B inhibitor of the phenylalkylamine group. Selegiline is the levorotatory enantiomer of the racemic mixture deprenyl. Selegiline is synthesized by the alkylation of (–)-methamphetamine using propargyl bromide.Another clinically used MAOI of the amphetamine class is tranylcypromine. History Following the discovery that the tuberculosis drug iproniazid elevated the mood of people taking it, and the subsequent discovery that the effect was likely due to inhibition of MAO, many people and companies started trying to discover MAO inhibitors to use as antidepressants. Selegiline was discovered by Zoltan Ecseri at the Hungarian drug company, Chinoin (part of Sanofi since 1993), which they called E-250.: 66–67 Chinoin received a patent on the drug in 1962 and the compound was first published in the scientific literature in English in 1965.: 67 Work on the biology and effects of E-250 in animals and humans was conducted by a group led by József Knoll at Semmelweis University which was also in Budapest.: 67 Deprenyl is a racemic compound a mixture of two isomers called enantiomers. Further work determined that the levorotatory enantiomer was a more potent MAO-inhibitor, which was published in 1967, and subsequent work was done with the single enantiomer L-deprenyl.: 67 In 1971, Knoll showed that selegiline selectively inhibits the B-isoform of monoamine oxidase (MAO-B) and proposed that it is unlikely to cause the infamous "cheese effect" (hypertensive crisis resulting from consuming foods containing tyramine) that occurs with non-selective MAO inhibitors. A few years later, two Parkinsons disease researchers based in Vienna, Peter Riederer and Walther Birkmayer, realized that selegiline could be useful in Parkinsons disease. One of their colleagues, Prof. Moussa B.H. Youdim, visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, Birkmayers group published the first paper on the effect of selegiline in Parkinsons disease.In the 1970s there was speculation that it could be useful as an anti-aging drug or aphrodisiac.In 1987 Somerset Pharmaceuticals in New Jersey, which had acquired the US rights to develop selegiline, filed a new drug application (NDA) with the FDA to market the drug for Parkinsons disease in the US. While the NDA was under review, Somerset was acquired in a joint venture by two generic drug companies, Mylan and Bolan Pharmaceuticals. Selegiline was approved for Parkinsons disease by the FDA in 1989.In the 1990s, J. Alexander Bodkin at McLean Hospital, an affiliate of Harvard Medical School, began a collaboration with Somerset to develop delivery of selegiline via a transdermal patch in order to avoid the well known dietary restrictions of MAO inhibitors. Somerset obtained FDA approval to market the patch in 2006. Society and culture In E for Ecstasy (a book examining the uses of the street drug ecstasy in the UK) the writer, activist and ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline. Consignments of ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, ephedrine and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.David Pearce wrote The Hedonistic Imperative six weeks after starting taking selegiline.In Gregg Hurwitzs novel Out of the Dark, selegiline (Emsam) and tyramine-containing food were used to assassinate the president of the United States. Veterinary use In veterinary medicine, selegiline is sold under the brand name Anipryl (manufactured by Zoetis). It is used in dogs to treat canine cognitive dysfunction and, at higher doses, pituitary-dependent hyperadrenocorticism (PDH). Canine cognitive dysfunction is a form of dementia that mimics Alzheimers disease in humans. Geriatric dogs treated with selegiline show improvements in sleeping pattern, reduced incontinence, and increased activity level; most show improvements by one month. Though it is labeled for dog use only, selegiline has been used off-label for geriatric cats with cognitive dysfunction.Selegilines efficacy in treating pituitary-dependent hyperadrenocorticism has been disputed. Theoretically, it works by increasing dopamine levels, which downregulates the release of ACTH, eventually leading to reduced levels of cortisol. Some claim that selegiline is only effective at treating PDH caused by lesions in the anterior pituitary (which comprise most canine cases). The greatest sign of improvement is lessening of abdominal distention.Side effects in dogs are uncommon, but they include vomiting, diarrhea, diminished hearing, salivation, decreased weight and behavioral changes such as hyperactivity, listlessness, disorientation, and repetitive motions.Selegiline does not appear to have a clinical effect on horses. Research Selegiline has been limitedly studied in the treatment of attention deficit hyperactivity disorder (ADHD) in both children/adolescents and adults. In a small randomized trial of selegiline for treatment of ADHD in children, there were improvements in attention, hyperactivity, and learning/memory performance but not in impulsivity. In another small randomized controlled trial of selegiline for the treatment of adult ADHD, a high dose of the medication for 6 weeks was not significantly more effective than placebo in improving symptoms. == References ==
Lomitapide	Lomitapide , sold under the brand name Juxtapid in the US and Lojuxta in the EU, is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate.The US Food and Drug Administration (FDA) approved lomitapide in December 2012, as an orphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density lipoprotein (non-HDL) cholesterol in people with homozygous familial hypercholesterolemia (HoFH).In July 2013, the European Commission approved lomitapide as an adjunct to a low-fat diet and other lipid-lowering medicinal products with or without low density lipoprotein (LDL) apheresis in adults with HoFH. Mechanism of action Lomitapide inhibits the microsomal triglyceride transfer protein (MTP or MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver.In December 2012, drug manufacturer Aegerion announced they had been approved by the FDA to as "an adjunct to a low-fat diet and other lipid-lowering treatments...in patients with homozygous familial hypercholesterolemia (HoFH)." Side effects In a Phase III study, lomitapide led to elevated aminotransferase levels and fat accumulation in the liver. References External links "Lomitapide". Drug Information Portal. U.S. National Library of Medicine.
Pafolacianine	Pafolacianine, sold under the brand name Cytalux, is an optical imaging agent used in fluorescence-guided surgery.The most common side effects of pafolacianine include infusion-related reactions, including nausea, vomiting, abdominal pain, flushing, dyspepsia, chest discomfort, itching and hypersensitivity.It was approved for medical use in the United States in November 2021.Pafolacianine is a fluorescent drug that targets the folate receptor alpha (FRa). Medical uses Pafolacianine is indicated as an adjunct for intraoperative identification of malignant lesions in people with ovarian cancer. History The safety and effectiveness of pafolacianine was evaluated in a randomized, multi-center, open-label study of women diagnosed with ovarian cancer or with high clinical suspicion of ovarian cancer who were scheduled to undergo surgery. Of the 134 women (ages 33 to 81 years) who received a dose of pafolacianine and were evaluated under both normal and fluorescent light during surgery, 26.9% had at least one cancerous lesion detected that was not observed by standard visual or tactile inspection.The U.S. Food and Drug Administration (FDA) granted the application for pafolacianine orphan drug, priority review, and fast track designations. The FDA granted the approval of Cytalux to On Target Laboratories, LLC. Figures References External links "Pafolacianine". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03180307 for "OTL38 for Intra-operative Imaging of Folate Receptor Positive Ovarian Cancer" at ClinicalTrials.gov
Triclabendazole	Triclabendazole, sold under the brand name Egaten among others, is a medication used to treat fascioliasis and paragonimiasis. It is very effective for both conditions. Treatment in hospital may be required. It is taken by mouth with typically one or two doses being required.Side effects are generally few, but can include abdominal pain and headaches. Biliary colic may occur due to dying worms. While no harm has been found with use during pregnancy, triclabendazole has not been studied well in this population. It is a member of the benzimidazole family of medications for worms.Triclabendazole was approved for medical use in the United States in 2019. It is on the World Health Organizations List of Essential Medicines. For human use, it can be obtained from the World Health Organization. It is also used in animals. Chemistry It is a member of the benzimidazole family of anthelmintics. The benzimidazole drugs share a common molecular structure, triclabendazole being the exception in having a chlorinated benzene ring but no carbamate group. Benzimidazoles such as triclabendazole are generally accepted to bind to beta-tubulin therefore preventing the polymerization of microtubules. History Since late 1990s, triclabendazole became available as a generic drug, as patents expired in many countries. Many products were developed then. Among them, Trivantel 15, a 15% triclabendazole suspension, was launched by Agrovet Market Animal Health in the early 2000s. In 2009, the first triclabendazole injectable solution (combined with ivermectin) was developed and launched, also by Agrovet Market Animal Health. The product, Fasiject Plus, a triclabendazole 36% and ivermectin 0.6% solution, is designed to treat infections by Fasciola hepatica (both immature and adult liver flukes), roundworms and ectoparasites, as well. Fasinex is a brandname for veterinary use while Egaten is a brandname for human use. References Further reading "Report of the WHO Informal Meeting on use of triclabendazole in fascioliasis control" (PDF). World Health Organization (WHO). 2006. External links "Triclabendazole". Drug Information Portal. U.S. National Library of Medicine. "Drug Trials Snapshots: Egaten". U.S. Food and Drug Administration (FDA). 13 February 2019.
Meprobamate	Meprobamate—marketed as Miltown by Wallace Laboratories and Equanil by Wyeth, among others—is a carbamate derivative used as an anxiolytic drug. It was the best-selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines due to their wider therapeutic index (lower risk of toxicity at therapeutically prescribed doses) and lower incidence of serious side effects. History Frank Berger was working in a laboratory of a British drug company, looking for a preservative for penicillin, when he noticed that a compound called mephenesin calmed laboratory rodents without actually sedating them. Berger subsequently referred to this “tranquilizing” effect in a now-historic article, published by the British Journal of Pharmacology in 1946. However, three major drawbacks existed to the use of mephenesin as a tranquilizer: a very short duration of action, greater effect on the spinal cord than on the brain (resulting in a very low therapeutic index), and a weak activity.In May 1950, after moving to Carter Products in New Jersey, Berger and a chemist, Bernard John Ludwig, synthesized a chemically related tranquilizing compound, meprobamate, that overcame these three drawbacks. Wallace Laboratories, a subsidiary of Carter Products, bought the license and named their new product "Miltown" after the borough of Milltown, New Jersey. Launched in 1955, it rapidly became the first blockbuster psychotropic drug in American history, becoming popular in Hollywood and gaining fame for its seemingly miraculous effects. It has since been marketed under more than 100 trade names, from Amepromat through Quivet to Zirpon.A December 1955 study of 101 patients at the Mississippi State Hospital in Whitfield, Rankin County, Mississippi, found meprobamate useful in the alleviation of "mental symptoms": 3% of patients made a complete recovery, 29% were greatly improved, 50% were somewhat better, while 18% realized little change. Self-destructive patients became cooperative and calmer, and experienced a resumption of logical thinking. In 50% of the cases, relaxation brought about more favorable sleep habits. Following the trial, hydrotherapy and all types of shock treatment were subsequently halted. Meprobamate was found to help in the treatment of alcoholics by 1956. By 1957, over 36 million prescriptions had been filled for meprobamate in the US alone, a billion pills had been manufactured, and it accounted for fully a third of all prescriptions written. Berger, clinical director of Wallace Laboratories, described it as a relaxant of the central nervous system, whereas other tranquilizers suppressed it. A University of Michigan study found that meprobamate affected driving skills. Though patients reported being able to relax more easily, meprobamate did not completely alleviate their tense feelings. The disclosures came at a special scientific meeting at the Barbizon Plaza Hotel in New York City, at which Aldous Huxley addressed an evening session. He predicted the development of many chemicals "capable of changing the quality of human consciousness", in the next few years.Meprobamate was one of the first drugs to be widely advertised to the general public, with user Milton Berle promoting the drug heavily on his television show, calling himself Uncle Miltown. Miltown soon became ubiquitous in 1950s American life, with 1 in 20 Americans having used it by late 1956, and popular comedians making as many jokes about the drug as they did about Elvis Presley.In January 1960, Carter Products, Inc. and American Home Products Corporation (which marketed meprobamate as Equanil) were charged with having conspired to monopolize the market in mild tranquilizers. It was revealed that the sale of meprobamate earned $40,000,000 for the defendants. Of this amount, American Home Products accounted for about two-thirds and Carter about one-third. The U.S. government sought an order mandating that Carter make its meprobamate patent available at no charge to any company desiring to use it.In April 1965, meprobamate was removed from the list of tranquilizers when experts ruled that the drug was a sedative, instead. The U.S. Pharmacopoeia published the ruling. At the same time, the Medical Letter disclosed that meprobamate could be addictive at doses not much above recommended. In December 1967, meprobamate was placed under abuse control amendments to the Food, Drug and Cosmetic Act. Records on production and distribution were required to be kept. Limits were placed on prescription duration and refills.Production continued throughout the 1960s, but by 1970, meprobamate was listed as a controlled substance after it was discovered to cause physical and psychological dependence. On January 19, 2012, the European Medicines Agency withdrew marketing authorization in the European Union for all medicines containing meprobamate, "due to serious side effects seen with the medicine." The Agency’s Committee for Medicinal Products for Human Use "concluded that the benefits of meprobamate do not outweigh its risks." In October 2013, Canada also withdrew marketing authorization. Pharmacology Although it was marketed as being safer, meprobamate has most of the pharmacological effects and dangers of barbiturates and acts at the barbiturate binding site (though it is less sedating at effective doses). It is reported to have some anticonvulsant properties against absence seizures, but can exacerbate generalized tonic-clonic seizures. Meprobamates mechanism of action is not completely known. It has been shown in animal studies to have effects at multiple sites in the central nervous system, including the thalamus and limbic system. Meprobamate binds to GABAA receptors which interrupts neuronal communication in the reticular formation and spinal cord, causing sedation and altered perception of pain. Meprobamate has the ability to activate currents even in the absence of GABA. This relatively unique property makes meprobamate exceptionally dangerous when used in combination with other GABA-mediated drugs (including alcohol). It is also a potent adenosine reuptake inhibitor. Related drugs include carisoprodol and tybamate (prodrugs of meprobamate), phenprobamate, felbamate, mebutamate, and methocarbamol. Indications Meprobamate is licensed for the short-term relief of anxiety, although whether the purported antianxiety effects of meprobamate are separable from its sedative effects is not known. Its effectiveness as a selective agent for the treatment of anxiety has not been proven in humans, and is not used as often as the benzodiazepines for this purpose. Meprobamate is available in 200- and 400-mg tablets for oral administration. It is also a component of the combination drug Equagesic (discontinued in the UK in 2002), acting as a muscle relaxant. Meprobamate, like barbiturates, possesses an analgesic/anesthetic potential. It is also found as a component of the combination analgesic Stopayne capsules (along with paracetamol (acetaminophen), caffeine, and codeine phosphate). Side effects and overdose Symptoms of meprobamate overdose include drowsiness, headache, sluggishness, unresponsiveness, or coma; loss of muscle control; severe impairment or cessation of breathing; or shock. Death has been reported with ingestion of as little as 12 g of meprobamate and survival with as much as 40 g. In an overdose, meprobamate tablets may form a gastric bezoar, requiring physical removal of the undissolved mass of tablets through an endoscope; therefore, administration of activated charcoal should be considered even after 4 or more hours or if levels are rising. Health issues Meprobamate is a Schedule IV drug (US) (S5 in South Africa) under the Convention on Psychotropic Substances. With protracted use, it can cause physical dependence and a potentially life-threatening abstinence syndrome similar to that of barbiturates and alcohol (delirium tremens). For this reason, discontinuation is often achieved through an extended regimen of slowly decreasing doses over a period of weeks or even months. Alternatively, the patient may be switched to a longer-acting gabaergic agent such as diazepam (in a manner similar to the use of methadone therapy for opiate addiction) before attempting tapering. While an acute cerebral edema is widely believed to be the initial cause of actor and martial artist Bruce Lees death in 1973, another factor which may have compounded and thereby contributed to Lee’s death, was his decision to take Equagesic (a brand which combined meprobamate and aspirin)."In the January 2008 issue of Drug Safety Update, a stop press article announced the recent European review of carisoprodol for which the Committee for Medicinal Products for Human Use concluded that the risks of treatment outweigh the benefits. This review was triggered by concerns from the Norwegian Medical Agency that carisoprodol (converted to meprobamate after administration) was associated with increased risk of abuse, addiction, intoxication, and psychomotor impairment." February 2008.The European Medicines Agency recommended suspension of marketing authorisations for meprobamate-containing medicines in the European Union in January 2012. Synthesis Meprobamate, 2-methyl-2-propyl-1,3-propanediol dicarbamate is synthesized by the reaction of 2-methylvaleraldehyde with two molecules of formaldehyde and the subsequent transformation of the resulting 2-methyl-2-propylpropan-1,3-diol into the dicarbamate via successive reactions with phosgene and ammonia. See also 2-Methyl-2-propyl-1,3-propanediol Carisoprodol Lorbamate Pentabamate Phenprobamate Mothers Little Helper (song) References External links List of psychotropic substances under international control. The Comparative Toxicogenomics Database: Meprobamate. RxList.com - Meprobamate
Zolpidem	Zolpidem, sold under the brand name Ambien, among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.Common side effects include daytime sleepiness, headache, nausea, and diarrhea. More severe side effects include memory problems and hallucinations. The previously recommended dose was decreased in 2013, by the US Food and Drug Administration (FDA), to the immediate-release 10 mg for men, and 5 mg for women, in an attempt to reduce next-day somnolence. Newer extended-release formulations include the 6.25 mg for women, and 12.5 mg or 6.25 mg for men, which also cause next-day somnolence when used in higher doses. Additionally, driving the next morning is not recommended with either higher doses or the long-acting formulation. While flumazenil, a GABAA–receptor antagonist, can reverse zolpidems effects, usually supportive care is all that is recommended in overdose.Zolpidem is a nonbenzodiazepine which acts as a sedative and hypnotic. Zolpidem is a GABAA receptor agonist of the imidazopyridine class. It works by increasing GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines. It generally has a half-life of two to three hours. This, however, is increased in those with liver problems.Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a Schedule IV controlled substance under the Controlled Substances Act of 1970 (CSA). More than ten million prescriptions are filled each year in the United States, making it one of the most commonly used treatments for sleeping problems. In 2020, it was the 47th most commonly prescribed medication in the United States, with more than 14 million prescriptions. Medical uses Zolpidem is labelled for short-term (usually about two to six weeks) treatment of insomnia at the lowest possible dose. It may be used for both improving sleep onset, sleep onset latency, and staying asleep.Guidelines from NICE, the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia (including possibly zolpidem) only as a second line treatment after non-pharmacological treatment options have been tried (e.g. cognitive behavioral therapy for insomnia). This is based in part on a 2012 review which found that zolpidems effectiveness is nearly as much due to psychological effects as to the medication itself.A lower-dose version (3.5 mg for men and 1.75 mg for women) is given as a tablet under the tongue and used for middle-of-the-night awakenings. It can be taken if there are at least 4 hours between the time of administration and when the person must be awake. Contraindications Zolpidem should not be taken by people with obstructive sleep apnea, myasthenia gravis, severe liver disease, respiratory depression; or by children, or people with psychotic illnesses. It should not be taken by people who are or have been addicted to other substances.Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem, but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers. In 2013, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men due to impaired function the day after taking the drug.Zolpidem should not be prescribed to older people, who are more sensitive to the effects of hypnotics including zolpidem and are at an increased risk of falls and adverse cognitive effects, such as delirium and neurocognitive disorder.Zolpidem has not been assigned to a pregnancy category by the FDA. Animal studies have revealed evidence of incomplete ossification and increased intrauterine fetal death at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks. Adverse effects The most common adverse effects of short-term use include headache (reported by 7% of people in clinical trials), drowsiness (2%), dizziness (1%), and diarrhea (1%); the most common side effects of long-term use included drowsiness (8%), dizziness (5%), allergy (4%), sinusitis (4%), back pain (3%), diarrhea (3%), drugged feeling (3%), dry mouth (3%), lethargy (3%), sore throat (3%), abdominal pain (2%), constipation (2%), heart palpitations (2%), lightheadedness (2%), rash (2%), abnormal dreams (1%), amnesia (1%), chest pain (1%), depression (1%), flu-like symptoms (1%), and sleep disorder (1%).Zolpidem increases risk of depression, falls and bone fracture, poor driving, suppressed respiration, and has been associated with an increased risk of death. Upper and lower respiratory infections are also common (experienced by between 1 and 10% of people).Residual hangover effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following nighttime administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures. Around 3% of people taking zolpidem are likely to break a bone as a result of a fall due to impaired coordination caused by the drug.Some users have reported unexplained sleepwalking while using zolpidem, as well as sleep driving, night eating syndrome while asleep, and performing other daily tasks while sleeping. Research by Australias National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy. In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning concerning this adverse effect. Tolerance, dependence and withdrawal As zolpidem is associated with drug tolerance and substance dependence, its prescription guidelines are only for severe insomnia and short periods of use at the lowest effective dose. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other adverse effects, especially if used for prolonged periods and at high doses. When drug tolerance and physical dependence to zolpidem develop, treatment usually entails a gradual dose reduction over a period of months to minimize withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some people, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABAA–receptor as an antagonist, thus stopping (and effectively detoxifying) zolpidem from being able to bind as an agonist on GABAA–receptor; slowly drug dependence or addiction to zolpidem will wane.Alcohol has cross tolerance with GABAA receptor positive allosteric modulators, such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem. It is not typically prescribed in people with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs. A 2014 review found evidence of drug-seeking behavior, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.Rodent studies of the tolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but in primates, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines. Overdose Overdose can lead to coma or death. When overdose occurs, there are often other drugs in the persons system.Zolpidem overdose can be treated with the GABAA receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABAA receptor to rapidly reverse the effects of the zolpidem. It is unknown if dialysis is helpful. Detection in body fluids Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300 μg/L in persons receiving the drug therapeutically, 100–700 μg/L in those arrested for impaired driving, and 1000–7000 μg/L in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography. Pharmacology Mechanism of action Zolpidem is a ligand of high-affinity positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α1 subunits of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. Opposed to diazepam, zolpidem is able to bind to binary αβ GABA receptors, where it was shown to bind to the α1–α1 subunit interface. Zolpidem has about 10-fold lower affinity for the α2- and α3- subunits than for α1, and no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and are found primarily in the brain, the ω2 receptors are those that contain the α2-, α3-, α4-, α5-, or α6 subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather than the spine. Zolpidem has no affinity for γ1 and γ3 subunit-containing receptors and, like the vast majority of benzodiazepine-like drugs, it lacks affinity for receptors containing α4 and α6. Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of the orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.Like zaleplon, zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep. A meta-analysis that compared benzodiazepines against nonbenzodiazepines has shown few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness. Pharmokinetics Microsome studies indicate zolpidem is metabolized by CYP3A4 (61%) CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%). It is principally metabolized into three metabolites, none of which are believed to be pharmocologically active. The absolute bioavailability of zolpidem is about 70%. The drug reaches peak concentration in about 2 hours and has a half life in healthly adults of about 2-3 hours. Zolpidems half life is decreased in children and increased in the elderly and people with liver issues. While some studies show men metabolize zolipdem faster than women (possibly due to testosterone), others do not. A review found only a 33% lower clearance in women compared to men, suggesting the FDAs dosage reduction of 50% for women may have been too large. Interactions People should not consume alcohol while taking zolpidem, and should not be prescribed opioid drugs nor take such illicit drugs recreationally. Opioids can also increase the risk of becoming psychologically dependent on zolpidem. Use of opioids with zolpidem increases the risk of respiratory depression and death. The US Food and Drug Administration (FDA) is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS).Next day sedation can be worsened if people take zolpidem while they are also taking antipsychotics, other sedatives, anxiolytics, antidepressant agents, antiepileptic drugs, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, and clarithromycin will increase the effects of a given dose of zolpidem. Cytochrome P450 activators like St. Johns Wort may decrease the activity of zolpidem. One study found that caffeine increases the concentration over time curve of zolpidem by about 20% and furthermore found that caffeine cannot adequately compensate for the impaired cognition caused by zolpidem. Chemistry Three syntheses of zolpidem are common. 4-methylacetophenone is used as a common precursor. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involving thionyl chloride or sodium cyanide. These reagents are challenging to handle and require thorough safety assessments. Though such safety procedures are common in industry, they make clandestine manufacture difficult. A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products. History Zolpidem was used in Europe starting in 1988, and was brought to market there by Synthelabo. Synthelabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name "Ambien". It became available as a generic medication in 2007.In 2015, the American Geriatrics Society said that zolpidem, eszopiclone and zaleplon met the Beers criteria and should be avoided in individuals 65 and over "because of their association with harms balanced with their minimal efficacy in treating insomnia." The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate." Society and culture Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly in relation to concern about prescribing addictive drugs in the midst of the opioid crisis. Military use The United States Air Force uses zolpidem as one of the hypnotics approved as a "no-go pill" (with a six-hour restriction on subsequent flight operation) to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and zaleplon.) "Ground tests" are required prior to authorization issued to use the medication in an operational situation. Recreational use Zolpidem has potential for either medical misuse when the drug is continued long term without or against medical advice, or for recreational use when the drug is taken to achieve a "high". The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur with use, but some believe it may be more likely when used without a doctors recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs.Other drugs, including benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone. US Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when caught driving erratically at 3 a.m. "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said. Nonmedical use of zolpidem is increasingly common in the US, Canada, and the UK. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations. Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy. Regulation For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like Z-drugs) is a Schedule IV substance under the Controlled Substances Act in the US. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. Use in crime The Z-drugs including zolpidem have been used as date rape drugs. Zolpidem is available legally by prescription, and broadly prescribed unlike other date rape drugs: gamma-hydroxybutyrate (GHB), which is used to treat narcolepsy, or flunitrazepam (Rohypnol), which is only prescribed as a second-line choice for insomnia. Zolpidem can typically be detected in bodily fluids for 36 hours, though it may be possible to detect it by hair testing much later, which is due to the short elimination half-life of 2.5–3 hours. This use of the drug was highlighted during proceedings against Darren Sharper, who was accused of using the tablets he was prescribed to facilitate a series of rapes. Sleepwalking Zolpidem received widespread media coverage in Australia after the death of a student who fell 20 metres (66 ft) from the Sydney Harbour Bridge while under the influence of zolpidem. Brands As of September 2018, zolpidem was marketed under many brands: Adorma, Albapax, Ambien, Atrimon, Belbien, Bikalm, Cymerion, Dactive, Dalparan, Damixan, Dormeben, Dormilam, Dormilan, Dormizol, Eanox, Edluar, Flazinil, Fulsadem, Hypnogen, Hypnonorm, Intermezzo, Inzofresh, Ivadal, Ivedal, Le Tan, Lioram, Lunata, Medploz, Mondeal, Myslee, Nasen, Niterest, Nocte, Nottem, Noxidem, Noxizol, Nuo Bin, Nytamel, Nyxe, Olpitric, Onirex, Opsycon, Patz, Polsen, Sanval, Semi-Nax, Sleepman, Somex, Somidem, Somit, Somnil, Somnipax, Somnipron, Somno, Somnogen, Somnor, Sonirem, Sove, Soza, Stilnoct, Stilnox, Stilpidem, Stimin, Sublinox, Sucedal, Sumenan, Vicknox, Viradex, Xentic, Zasan, Zaviana, Ziohex, Zipsoon, Zodem, Zodenox, Zodium, Zodorm, Zolcent, Zoldem, Zoldorm, Zoldox, Zolep, Zolfresh, Zolip, Zolman, Zolmia, Zolnox, Zolnoxs, Zolodorm, Zolnyt, Zolpeduar, Zolpel, Zolpi, Zolpi-Q, Zolpic, Zolpidem, Zolpidem tartrate, Zolpidemi tartras, Zolpidemtartraat, Zolpidemtartrat, Zolpidemum, Zolpigen, Zolpihexal, Zolpimist, Zolpineo, Zolpinox, Zolpirest, Zolpistar, Zolpitop, Zolpitrac, Zolpium, Zolprem, Zolsana, Zolta, Zoltar, Zolway, Zomnia, Zonadin, Zonoct, Zopid, Zopidem, Zopim, and Zorimin. Research While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefit. Zolpidem has also been studied in persistent vegetative states with unclear effect. A 2017 systematic review concluded that while there is preliminary evidence of benefit for treating disorders of movement and consciousness other than insomnia (including Parkinsons disease), more research is needed. More recent research has found zolpidem treatment to be effective in the short term, but only in a small proportion of cases (estimated at around 5%) and only when the brain injury is of a specific type. Tolerance to the beneficial effects also develops rapidly, and so for these reasons while zolpidem may sometimes be used as a "last resort" treatment, it has numerous disadvantages and research continues into novel treatments that might provide the same kind of benefits in a larger proportion of patients, and with a more sustained benefit.Animal studies in FDA files for zolpidem showed a dose dependent increase in some types of tumors, although the studies were too small to reach statistical significance. Some observational epidemiological studies have found a correlation between use of benzodiazepines and certain hypnotics including zolpidem and an increased risk of getting cancer, but others have found no correlation; a 2017 meta-analysis of such studies found a correlation, stating that use of hypnotics was associated with a 29% increased risk of cancer, and that "zolpidem use showed the strongest risk of cancer" with an estimated 34% increased risk, but noted that the results were tentative because some of the studies failed to control for confounders like cigarette smoking and alcohol use, and some of the studies analyzed were case–controls, which are more prone to some forms of bias. Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer. References External links "Zolpidem". Drug Information Portal. U.S. National Library of Medicine.
Lumasiran	Lumasiran, sold under the brand name Oxlumo, is a medication for the treatment of primary hyperoxaluria type 1 (PH1).The most common side effects include injection site reactions and abdominal pain.Lumasiran is a double-stranded small interfering ribonucleic acid (siRNA) that reduces levels of glycolate oxidase (GO) enzyme by targeting the HAO1 messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. This results in reduction of urinary and plasma oxalate levels, the underlying cause of disease manifestations in people with PH1. As the GO enzyme is upstream of the deficient alanine:glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation.Lumasiran was approved for medical use in the European Union and in the United States in November 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Lumasiran is indicated for the treatment of primary hyperoxaluria type 1 (PH1) in adults and children of all ages.PH1 is a rare illness that causes the liver to produce an excessive amount of oxalate. Oxalate is removed by the kidneys and through the urine. In people with PH1, the extra oxalate can cause kidney stones and kidney failure. The extra oxalate can also build up, and damage other parts of the body, including eyes, heart, skin, and bone. This is called oxalosis. History Lumasiran was evaluated by the U.S. Food and Drug Administration (FDA) in two studies of participants with PH1: a randomized, placebo-controlled trial in participants six years and older and an open-label study in participants younger than six years (NCT03681184 and NCT03905694). Participants ranged in age from four months to 61 years at the first dose. In the first study, 26 participants received a monthly injection of lumasiran followed by a maintenance dose every three months; 13 participants received placebo injections. Neither the patients nor the healthcare providers knew which treatment was being given until after the trial was completed. The primary endpoint was the amount of oxalate measured in the urine over 24 hours. In the lumasiran group, participants had, on average, a 65% reduction of oxalate in the urine, compared to an average 12% reduction in the placebo group. By the sixth month of the study, 52% of participants treated with lumasiran reached a normal 24-hour urinary oxalate level; no participants treated with the placebo did. In the second study, 16 participants younger than six years all received lumasiran. Using another measure of oxalate in the urine, the study showed, on average, a 71% decrease in urinary oxalate by the sixth month of the study. The trials were conducted at 25 centers in the United States, Europe, and the Middle East.The FDA granted the application for lumasiran orphan drug and breakthrough therapy designations. In addition, the manufacturer received a rare pediatric disease priority review voucher. The FDA granted the approval of Oxlumo to Alnylam Pharmaceuticals, Inc. Society and culture Legal status Lumasiran is available under the UK Early Access to Medicines Scheme (EAMS) as of July 2020.On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Oxlumo, intended for the treatment of primary hyperoxaluria type 1 (PH1). The applicant for this medicinal product is Alnylam Netherlands B.V.Lumasiran was approved for medical use in the European Union and in the United States in November 2020. References External links "Lumasiran". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03681184 for "A Study to Evaluate Lumasiran in Children and Adults With Primary Hyperoxaluria Type 1 (ILLUMINATE-A)" at ClinicalTrials.gov Clinical trial number NCT03681184 for "A Study of Lumasiran in Infants and Young Children With Primary Hyperoxaluria Type 1 (ILLUMINATE-B)" at ClinicalTrials.gov
Insys Therapeutics	Insys Therapeutics was an American specialty pharmaceutical company based in Chandler, Arizona. Its main product was Subsys, a sublingual liquid form of the drug fentanyl. Fentanyl is an extremely fast-acting and powerful opioid used to relieve peaks of pain in cancer patients.Founded in 1990, the company and its executives are facing legal issues related to the opioid crisis and marketing activities by the company, including accusations of bribes and misleading advertising. Several company executives were convicted of racketeering in a jury trial rendered in May 2019.Insys filed for bankruptcy in 2019. The filing came just 10 days after the company agreed to pay $225 million to settle separate criminal and civil cases brought by the U.S. Justice Department. Products In addition to Subsys, Insys Therapeutics marketed Syndros, a synthetic THC product, and was working toward approval of other cannabis derivatives. Despite delta-9 THC being classified as a Schedule I substance by the U.S. Drug Enforcement Administration, Syndros was classified as a Schedule II substance used in adults to treat loss of appetite (anorexia) in people with AIDS who have lost weight, as well as nausea and vomiting caused by anti-cancer medicines (chemotherapy) in people whose nausea and vomiting have not improved with usual anti-nausea medicines. Syndros was the first and only FDA-approved liquid THC formulation, which allows for fast absorption, flexible dosing, and a potential solution for patients who may prefer a liquid medication. The disparity between the US DEA scheduling of THC and of Syndros is pre- and post-formulation, respectively, according to Title 21 United States Code of Controlled Substances Act. History The company was founded in 1990 by American multi-millionaire John Kapoor, who served as CEO and president after former CEO Michael Babich was arrested. Kapoor retired from Insys in 2017 due to racketeering conspiracy charges and was ultimately replaced by Saeed Motahari.Insys had a practice of paying doctors speaking fees to promote their products. They had set up the Insys Reimbursement Center, in which Insys workers would call insurers on behalf of doctors’ offices to get them to authorize payment for Subsys. Even tough Subsys was only supposed to be for cancer related patients, the reps would mislead the insurers into paying for it. In 2012, a sales rep for Insys filed a whistleblower lawsuit against the company. He gathered documents, emails and even audio recordings to bolster his case, yet the government declined to intervene.In March 2013, the company had its IPO. The public paid no attention to the lawsuit and accusations, and the company was the best performing IPO that year.In 2016, the company was ranked No. 52 on the Deloitte Fast 500 North America list.In 2017, U.S. Senator Claire McCaskill released a report and audio recording of an Insys representative allegedly falsely claiming to represent a doctors office and lying about a patients diagnosis in order to circumvent prescribing rules for Subsys. The patient later died due to an adverse reaction to her medications.A study done by physician and scientist Scott Hadland, examined the marketing of Insys Therapeutics and found that it was responsible for half of all marketing dollars to doctors. Hadland’s study was cited in a 2017 federal case against the company CEO John Kapoor and several executives, which resulted in their conviction by a federal jury of racketeering conspiracy. Political advocacy In 2016, Insys donated $500,000 to Arizonans for Responsible Drug Policy, a group opposing a marijuana legalization ballot initiative in the state of Arizona. Investor filings confirm the company was concerned about the impact of legalization on sales for a cannabis-based drug it was developing. The reason publicly given for opposing the measure was to "protect children". However, medical marijuana advocates have criticized Insys position as hypocritical, profit-driven, and an appeal to emotion, as the company actively developed its own cannabis-derived products. In a September 2016 statement, J.P. Holyoak, a representative from the pro-legalization campaign, commented, "It appears they are trying to kill a non-pharmaceutical market for marijuana in order to line their own pockets." That same month, the opposition campaign defended Insys involvement, stating: "We are grateful that Insys Therapeutics – an Arizona-based company – has chosen to join Governor Ducey, the Arizona Association of County School Superintendents, the Arizona Small Business Association, the Arizona Hospital and Healthcare Association, the Arizona Catholic Conference of Bishops, the Arizona Chamber of Commerce and several other community organizations in defeating Prop. 205 in November." The ballot measure eventually failed to pass, losing 51.32% to 48.68%. Litigation and bankruptcy In December 2016, seven former executives and managers employed by Insys were taken into custody, including CEO John Kapoor and charged with conspiracy to bribe medical staff in several states to prescribe a specific pain medication to their patients. The accusations were the topic of an NBC special feature report on Megyn Kellys Sunday Night on June 4, 2017.In August 2017, Insys Therapeutics was sued by Arizona Attorney General Mark Brnovich for misleading patients and doctors about the dangers of the drug Subsys, and for lying to insurers about the condition of the patients in a bid to get payment for the drug. He said the firm deceived insurers and pharmaceutical benefit companies into agreeing to pay for the expensive drug by misleading them to believe that the payment request was coming from a doctors office and not the company making the drug. Brnovich also said those Insys employees misrepresented the medical conditions of the patients, lying that they had breakthrough pain, lying that the patients had tried other medications, and lying that the patients needed the sublingual spray rather than less expensive pills marketed by other firms because they had difficulty swallowing. Insys Therapeutics issued a response to the Arizona filing on their website, stating, in part, that "[t]he allegations contained in the Arizona Attorney Generals complaint relate to former employees and physicians that are no longer associated with our Company or our speaker bureau."In October 2017, Insys founder John Kapoor was arrested in Arizona and charged with RICO conspiracy, conspiracy to commit wire fraud, and conspiracy to violate the anti-kickback law related to Insys effort to secure prescriptions of Subsys. Kapoor is also alleged to have conspired to defraud health insurance providers.In December 2018, former Insys CEO Michael Babich agreed to plead guilty to one count of conspiracy and one count of mail fraud, in connection to bribes paid to doctors and their assistants. In April 2019, Alec Burlakoff, the former vice president of sales for Insys, agreed to pay the State of Arizona $9.5 million in a civil settlement with Attorney General Mark Brnovich for his role in the alleged bribery campaign of doctors to prescribe Insys products to patients. Brnovich had accused Burlakoff of operating a program that paid doctors lucrative "speaking fees" in order to encourage them to prescribe more Subsys, Insys fentanyl-based pain medication. Burlakoff is required to pay the state $5.2 million from the proceeds he made from the operation, as well as $4.3 million in civil penalties. As part of the settlement, Burlakoff agreed to testify against Insys in ongoing litigation and will be permanently banned from advertising or selling any pharmaceutical drugs in Arizona.On May 2, 2019, a federal jury found top executives of Insys Therapeutics guilty of racketeering charges. The jury, after deliberating for 15 days, issued guilty verdicts against the companys founder, the one-time billionaire John Kapoor, and four former executives, finding they had conspired to fuel sales of its highly potent drug, Subsys, by not only bribing doctors to prescribe its product but also by misleading insurers about patients need for the drug. Other Insys employees also found guilty included Richard M. Simon, former national director of sales; Sunrise Lee, regional sales director; Joseph A. Rowan, regional sales director; and Michael J. Gurry, former vice president of managed markets. A sentencing hearing has not been scheduled but is expected to take place in early August 2019. In June 2019, Insys Therapeutics agreed to pay $225 million to settle the federal governments criminal and civil investigations into the companys marketing practices. In January 2020, Kapoor was sentenced by a federal court to five and a half years in prison.Insys filed for bankruptcy in Delaware Bankruptcy Court on June 10, 2019. Andrew Long, the companys CEO, claims the company is struggling due to: 1) extensive litigation, and 2) declining revenues relating to its Subsys product. The bankruptcy filing came just 10 days after the company reached a settlement with the U.S. Justice Department. The U.S. government has agreed to accept an unsecured claim of $190 million in the case. See also The Crime of the Century References == External links ==
Bexarotene	Bexarotene, sold under the brand Targretin, is an antineoplastic (anti-cancer) agent used for the treatment of cutaneous T cell lymphoma (CTCL). It is a third-generation retinoid.It was approved by the U.S. Food and Drug Administration (FDA) in December 1999, and the European Medicines Agency (EMA) in March 2001. It is available as a generic medication. Medical uses Bexarotene is indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in people who are refractory to at least one prior systemic therapy (oral) and for the topical treatment of cutaneous lesions in patients with CTCL who have refractory or persistent disease after other therapies or who have not tolerated other therapies (topical).It has been used off-label for non-small cell lung cancer and breast cancer. Contraindications Known contraindications include: Adverse effects Overall the most common adverse effects are skin reactions (mostly itchiness and rashes), leucopenia, headache, weakness, thyroid anomalies (which seem to be mediated by RXR-mediated downregulation of thyroid stimulating hormone) and blood lipid anomalies such as hypercholesterolaemia (high blood cholesterol) and hyperlipidaemia, hypothyroidism. Interactions Its plasma concentration may be increased by concomitant treatment with CYP3A4 inhibitors such as ketoconazole. It may also induce CYP3A4, and hence CYP3A4 substrates like cyclophosphamide may have their plasma concentrations reduced. Likewise consumption of grapefruit juice might increase bexarotenes plasma concentrations, hence potentially altering its therapeutic effects. Mechanism Bexarotene is a retinoid that selectively activates retinoid X receptors (RXRs), as opposed to the retinoic acid receptors, the other major target of retinoic acid (the acid form of vitamin A). By so doing it induces cell differentiation and apoptosis and prevents the development of drug resistance. It also has anti-angiogenic effects and inhibits cancer metastasis. The retinoic acid receptors (RARs) regulate cell differentiation and proliferation whereas RXRs regulate apoptosis. Physical properties Bexarotene is a solid, white powder. It is poorly soluble in water; the solubility is estimated to be about 10-50 μM. It is soluble in DMSO at 65 mg/mL and in ethanol at 10 mg/mL with warming. History SRI International and the La Jolla Cancer Research Foundation (now the Sanford-Burnham Medical Research Institute) collaborated on work that resulted in patent filings for the drug.The developer of bexarotene (brand name Targretin) was Ligand Pharmaceuticals, a San Diego biotech company which received FDA approval for the drug in 1999. The FDA approved bexarotene on 29 December 1999.Japanese pharmaceutical Eisai bought the rights to Targretin and three other anti-cancer products from Ligand in 2006. In the United States, patents on the drug expired in 2016.It received EMA approval on 29 March 2001.Early-stage preclinical studies suggested that bexarotene reduced amyloid plaques and improved mental functioning in a small sample of mice engineered to exhibit Alzheimers-like symptoms although subsequent studies have yielded mixed results.The results of CCMR-One, a clinical trial of the effects of bexarotene on patients with multiple sclerosis operated by the University of Cambridge, have shown that the drug can cause remyelination, but will not lead to the drug being used as a therapy, due to its risk profile. References External links "Bexarotene". Drug Information Portal. U.S. National Library of Medicine.
Sular	Sular may refer to: Nisoldipine, a pharmaceutical Sular, Iran, a village
Clomifene	Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. Use results in a greater chance of twins. It is taken by mouth once a day, with a course of treatment that usually lasts for 5 days.Common side effects include pelvic pain and hot flashes. Other side effects can include changes in vision, vomiting, trouble sleeping, ovarian cancer, and seizures. It is not recommended in people with liver disease or abnormal vaginal bleeding of unknown cause or who are pregnant. Clomifene is in the selective estrogen receptor modulator (SERM) family of medication and is a nonsteroidal medication. It works by causing the release of GnRH by the hypothalamus, and subsequently gonadotropin from the anterior pituitary.Clomifene was approved for medical use in the United States in 1967. It is on the World Health Organizations List of Essential Medicines, under the category "Ovulation inducers" (Complementary List). Its introduction began the era of assisted reproductive technology.Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men. Medical uses Ovulation induction Clomifene is one of several alternatives for ovulation induction in those who are infertile due to anovulation or oligoovulation. Evidence is lacking for the use of clomifene in those who are infertile without a known reason. In such cases, studies have observed a clinical pregnancy rate 5.6% per cycle with clomifene treatment vs. 1.3%–4.2% per cycle without treatment.Proper timing of the drug is important; it should be taken starting on about the fifth day of the cycle, and there should be frequent intercourse.The following procedures may be used to monitor induced cycles: Follicular monitoring with vaginal ultrasound, starting 4–6 days after the last pill. Serial transvaginal ultrasound can reveal the size and number of developing follicles. It can also provide presumptive evidence of ovulation such as the sudden collapse of the preovulatory follicle, and an increase in fluid volume in the rectouterine pouch. After ovulation, it may reveal signs of luteinization such as loss of clearly defined follicular margins and appearance of internal echoes. Serum estradiol levels, starting 4–6 days after the last pill Adequacy of LH surge by urine LH surge tests 3 to 4 days after last clomifene pill Post-coital test 1–3 days before ovulation to check whether there are at least 5 progressive sperm per HPF Mid-luteal progesterone, with at least 10 ng/ml 7–9 days after ovulation being regarded as adequate.Repeat dosing: This 5-day treatment course can be repeated every 30 days. The dosage may be increased by 50-mg increments in subsequent cycles until ovulation is achieved. It is not recommended by the manufacturer to use clomifene for more than 6 cycles.It is no longer recommended to perform an ultrasound examination to exclude any significant residual ovarian enlargement before each new treatment cycle. Other uses Clomifene has also been used with other assisted reproductive technology to increase success rates of these other modalities.Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy. The medication has been used at a dosage of 20 to 50 mg three times per week to once day for this indication. It has been found to increase testosterone levels by 2- to 2.5-times in hypogonadal men at such dosages. Despite the use of questionnaires in testosterone replacement comparator trials being called into question, clomifenes lower cost, therapeutic benefits, and greater value towards hypogonadism improvement have been noted.Clomifene consists of two stereoisomers in equal proportion: enclomifene and zuclomifene. Zuclomifene has pro-estrogenic properties, whereas enclomifene is pro-androgenic, i.e. it promotes testosterone production through stimulation of the HPG axis. For this reason, purified enclomifene isomer has been found to be twice as effective in boosting testosterone compared to the standard mix of both isomers. Additionally, enclomifene has a half-life of just 10 hours, but zuclomifene has a half-life of 30 days—therefore if the goal is to boost testosterone, taking regular clomifene may produce far longer-lasting pro-estrogenic effects than pro-androgenic effects. Clomifene has been used in the treatment of gynecomastia. It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifen or raloxifene for this indication. It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition. Pure enclomifene isomer is likely to be more effective than clomifene at treating gynecomastia, because of the lack of the zuclomifene isomer (as noted above). Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation (261 days after discontinuation with a half-life of 30 days, there is still 0.24% of the peak level of zuclomifene being excreted, whereas with a half-life of 10 hours, enclomifene reaches the same 0.24% level in less than 4 days). Because of its potential for boosting testosterone, clomifene is listed as banned for use by competitive sportsmen, both in and out of competition, by the World Anti-Doping Agency, absent an organic etiology of primary hypogonadism. Contraindications Contraindications include an allergy to the medication, pregnancy, prior liver problems, abnormal vaginal bleeding of unclear cause, ovarian cysts other than those due to polycystic ovarian syndrome, unmanaged adrenal or thyroid problems, and pituitary tumors. Side effects The most common adverse drug reaction associated with the use of clomifene (>10% of people) is reversible ovarian enlargement.Less common effects (1–10% of people) include visual symptoms (blurred vision, double vision, floaters, eye sensitivity to light, scotomata), headaches, vasomotor flushes (or hot flashes), light sensitivity and pupil constriction, abnormal uterine bleeding and/or abdominal discomfort.Rare adverse events (<1% of people) include: high blood level of triglycerides, liver inflammation, reversible baldness and/or ovarian hyperstimulation syndrome.Clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of ~1% in the general population) and triplets. Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility. Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity. Cancer risk Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer. This may only be the case in those who have never been and do not become pregnant. Subsequent studies have failed to support those findings.Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer. Thyroid cancer risk was not associated with the number of pregnancies carried to viability. Pharmacology Pharmacodynamics Selective estrogen receptor modulator activity Clomifene is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM). It consists of a racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties. It is a mixed agonist and antagonist of the estrogen receptor (ER). Clomifene activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels. Conversely, it is an antagonist of the ERβ. Clomifene has antiestrogenic effects in the uterus. There is little clinical research on the influence of clomifene in many target tissues, such as lipids, the cardiovascular system, and the breasts. Positive effects of clomifene on bone have been observed. Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours. Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene. The affinity of clomifene for the ER relative to estradiol ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%). 4-Hydroxyclomifene, a major active metabolite of clomifene, and afimoxifene (4-hydroxytamoxifen), a major active metabolite of tamoxifen, show 89–251% and 41–246% of the affinity of estradiol for the ER in human MCF-7 breast cancer cells, respectively. The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol. 4-Hydroxy-N-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the ER. In one study, the affinities of clomifene and its metabolites for the ERα were ~100 nM for clomifene, ~2.4 nM for 4-hydroxyclomifene, ~125 nM for N-desmethylclomifene, and ~1.4 nM for 4-hydroxy-N-desmethylclomifene.Even though clomifene has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation. Clomifene appears to act mostly in the hypothalamus where it depletes hypothalamic ERs and blocks the negative feedback effect of circulating endogenous estradiol, which in turn results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In normal physiologic female hormonal cycling, at 7 days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH, and LH at the hypothalamus and anterior pituitary. If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG). This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy. Therapeutically, clomifene is given early in the menstrual cycle. It is typically prescribed beginning on day 3 and continuing for 5 days. By that time, FSH levels are rising steadily, causing the development of a few follicles. Follicles, in turn, produce the estrogen, which circulates in serum. In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle. Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin release. (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene. In normal men, 50 mg/day clomifene for 8 months has been found to increase testosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men. Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men. These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men. In men with hypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL. In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day clomifene increased testosterone levels from 309 ng/dL to 642 ng/dL after 3 months of therapy. No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly. Other activities Clomifene is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase. Concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer. Continuous use of clomifene has been found to increase desmosterol levels by 10% and continuous high doses of clomifene (200 mg/day) have been reported to produce visual disturbances. Pharmacokinetics Clomifene produces N-desmethylclomifene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desmethylclomifene as metabolites. Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene, which are the most active of its metabolites. In one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/L for clomifene, 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desmethylclomifene.Clomifene has an onset of action of 5 to 10 days following course of treatment and an elimination half-life about 5 days. In one study, after a single 50 mg dose of clomifene, the half-life of clomifene was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-N-desmethylclomifene was 15 hours. Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene.Most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. Clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation. Chemistry Clomifene is a triphenylethylene derivative. It is a mixture of two geometric isomers, enclomifene ((E)-clomifene) and zuclomifene ((Z)-clomifene). These two isomers have been found to contribute to the mixed estrogenic and antiestrogenic properties of clomifene. History A team at William S. Merrell Chemical Company led by Frank Palopoli synthesized clomifene in 1956; after its biological activity was confirmed a patent was filed and issued in November 1959. Scientists at Merrell had previously synthesized chlorotrianisene and ethamoxytriphetol. Clomifene was studied in the treatment of advanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns about desmosterolosis with extended use. Short-term use (e.g. days to months) did not raise the same concerns however and clomifene continued to be studied for other indications. Clinical studies were conducted under an Investigational New Drug Application; clomifene was third drug for which an IND had been filed under the 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act that had been passed in response to the thalidomide tragedy. It was approved for marketing in 1967 under the brand name Clomid. It was first used to treat cases of oligomenorrhea but was expanded to include treatment of anovulation when women undergoing treatment had higher than expected rates of pregnancy.The drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era of assisted reproductive technology, and the beginning of what in the words of Eli Y. Adashi, was "the onset of the US multiple births epidemic".The company was acquired by Dow Chemical in 1980, and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow. In 1995 Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow. Hoechst in turn became part of Aventis in 1999,: 9–11 and subsequently a part of Sanofi. It became the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation. Society and culture Brand names Clomifene is marketed under many brand names worldwide, including Beclom, Bemot, Biogen, Blesifen, Chloramiphene, Clofert, Clomene, ClomHEXAL, Clomi, Clomid, Clomidac, Clomifen, Clomifencitrat, Clomifene, Clomifène, Clomifene citrate, Clomifeni citras, Clomifeno, Clomifert, Clomihexal, Clomiphen, Clomiphene, Clomiphene Citrate, Cloninn, Clostil, Clostilbegyt, Clovertil, Clovul, Dipthen, Dufine, Duinum, Fensipros, Fertab, Fertec, Fertex, Ferticlo, Fertil, Fertilan, Fertilphen, Fertin, Fertomid, Ferton, Fertotab, Fertyl, Fetrop, Folistim, Genoclom, Genozym, Hete, I-Clom, Ikaclomin, Klofit, Klomen, Klomifen, Lomifen, MER 41, Milophene, Ofertil, Omifin, Ova-mit, Ovamit, Ovinum, Ovipreg, Ovofar, Ovuclon, Ovulet, Pergotime, Pinfetil, Profertil, Prolifen, Provula, Reomen, Serofene, Serophene, Serpafar, Serpafar, Surole, Tocofeno, and Zimaquin. Regulation Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport. It is listed because it is an "anti-estrogenic substance". Research Clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women.Clomifene was studied for treatment and prevention of breast cancer, but issues with toxicity led to abandonment of this indication, as did the discovery of tamoxifen. Like the structurally related drug triparanol, clomifene is known to inhibit the enzyme 24-dehydrocholesterol reductase and increase circulating desmosterol levels, making it unfavorable for extended use in breast cancer due to risk of side effects like irreversible cataracts. References External links "Clomifene". Drug Information Portal. U.S. National Library of Medicine.
Nicardipine	Nicardipine (Cardene) is a medication used to treat high blood pressure and angina. It belongs to the dihydropyridine class of calcium channel blockers. It is also used for Raynauds phenomenon. It is available in by mouth and intravenous formulations. It has been used in percutaneous coronary intervention. Nicardipine has been used as an alternative to sodium nitroprusside, especially because sodium nitroprusside is light sensitive and a fresh solution must be prepared. Its mechanism of action and clinical effects closely resemble those of nifedipine and the other dihydropyridines (amlodipine, felodipine), except that nicardipine is more selective for cerebral and coronary blood vessels. Nicardipine also has a longer half-life than nifedipine. Nicardipine was approved by the FDA in December 1988. The patent for both Cardene and Cardene SR expired in October 1995.It was patented in 1973 and approved for medical use in 1981. See also Calcium channel blocker toxicity == References ==
Perphenazine	Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades. Perphenazine is roughly ten times as potent as chlorpromazine at the dopamine-2 (D2) receptor; thus perphenazine is considered a medium-potency antipsychotic. Medical uses In low doses it is used to treat agitated depression (together with an antidepressant). Fixed combinations of perphenazine and the tricyclic antidepressant amitriptyline in different proportions of weight exist (see Etrafon below). When treating depression, perphenazine is discontinued as fast as the clinical situation allows. Perphenazine has no intrinsic antidepressive activity. Several studies show that the use of perphenazine with fluoxetine (Prozac) in patients with psychotic depression is most promising, although fluoxetine interferes with the metabolism of perphenazine, causing higher plasma levels of perphenazine and a longer half-life. In this combination the strong antiemetic action of perphenazine attenuates fluoxetine-induced nausea and vomiting (emesis), as well as the initial agitation caused by fluoxetine. Both actions can be helpful for many patients. Perphenazine has been used in low doses as a normal or minor tranquilizer in patients with a known history of addiction to drugs or alcohol, a practice which is now strongly discouraged.Perphenazine has sedating and anxiolytic properties, making the drug useful for the treatment of agitated psychotic patients. A valuable off-label indication is the short-time treatment of hyperemesis gravidarum, in which pregnant women experience violent nausea and vomiting. This problem can become severe enough to endanger the pregnancy. As perphenazine has not been shown to be teratogenic and works very well, it is sometimes given orally in the smallest possible dose. Effectiveness Perphenazine is used to treat psychosis (e.g. in people with schizophrenia and the manic phases of bipolar disorder). Perphenazine effectively treats the positive symptoms of schizophrenia, such as hallucinations and delusions, but its effectiveness in treating the negative symptoms of schizophrenia, such as flattened affect and poverty of speech, is unclear. Earlier studies found the typical antipsychotics to be ineffective or poorly effective in the treatment of negative symptoms, but two recent, large-scale studies found no difference between perphenazine and the atypical antipsychotics. A 2015 systematic review compared perphenazine with other antipsychotic drugs: Side effects As a member of the phenothiazine type of antipsychotics, perphenazine shares in general all allergic and toxic side-effects of chlorpromazine. A 2015 systematic review of the data on perphenazine conducted by the Cochrane Collaboration concluded that "there were no convincing differences between perphenazine and other antipsychotics" in the incidence of adverse effects. Perphenazine causes early and late extrapyramidal side effects more often than placebo, and at a similar rate to other medium-potency antipsychotics and the atypical antipsychotic risperidone.When used for its strong antiemetic or antivertignosic effects in cases with associated brain injuries, it may obscure the clinical course and interferes with the diagnosis. High doses of perphenazine can cause temporary dyskinesia. As with other typical antipsychotics, permanent or lasting tardive dyskinesia is a risk. Discontinuation The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped. Pharmacology Pharmacodynamics Perphenazine has the following binding profile towards cloned human receptors unless otherwise specified: Acronyms: RS — Rat striatum receptor. RB — Rat brain receptor. Pharmacokinetics Perphenazine has an oral bioavailability of approximately 40% and a half-life of 8 to 12 hours (up to 20 hours), and is usually given in 2 or 3 divided doses each day. It is possible to give two-thirds of the daily dose at bedtime and one-third during breakfast to maximize hypnotic activity during the night and to minimize daytime sedation and hypotension without loss of therapeutic activity. Formulations It is sold under the brand names Trilafon (single drug) and Etrafon/Triavil/Triptafen (contains fixed dosages of amitriptyline). A brand name in Europe is Decentan pointing to the fact that perphenazine is approximately 10-times more potent than chlorpromazine. Usual oral forms are tablets (2, 4, 8, 16 mg) and liquid concentrate (4 mg/ml). The Perphenazine injectable USP solution is intended for deep intramuscular (i.m.) injection, for patients who are not willing to take oral medication or if the patient is unable to swallow. Due to a better bioavailability of the injection, two-thirds of the original oral dose is sufficient. The incidence of hypotension, sedation and extrapyramidal side-effects may be higher compared to oral treatment. The i.m.-injections are appropriate for a few days, but oral treatment should start as soon as possible. In many countries, depot forms of perphenazine exist (as perphenazine enanthate and perphenazine decanoate). One injection works for 1 to 4 weeks depending on the dose of the depot-injection. Depot-forms of perphenazine should not be used during the initial phase of treatment as the rare neuroleptic malignant syndrome may become more severe and uncontrollable with this form. Extrapyramidal side-effects may be somewhat reduced due to constant plasma-levels during depot-therapy. Also, patient compliance is sure, as many patients do not take their oral medication, particularly if feeling better once improvement in psychosis is achieved. Interactions Fluoxetine causes higher plasma levels and a longer elimination half-life of perphenazine, therefore a dose reduction of perphenazine might be necessary. Perphenazine intensifies the central depressive action of drugs with such activity (tranquilizers, hypnotics, narcotics, antihistaminics, OTC-antiemetics etc.). A dose reduction of perphenazine or the other drug may be necessary. In general, all neuroleptics may lead to seizures in combination with the opioid tramadol (Ultram). Perphenazine may increase the insulin needs of diabetic patients. Monitor blood glucose levels of insulin-dependent patients regularly during long-term treatment. == References ==
Metreleptin	Metreleptin, sold under the brand name Myalept among others, is a synthetic analog of the hormone leptin used to treat various forms of dyslipidemia. It has been approved in Japan for metabolic disorders including lipodystrophy and in the United States as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.The most common side effects include hypoglycaemia (low blood glucose) and weight loss. Medical uses In the European Union, metreleptin is indicated in addition to diet to treat lipodystrophy, where people have a loss of fatty tissue under the skin and a build-up of fat elsewhere in the body such as in the liver and muscles. It is used in adults and children above the age of two years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome); and in adults and children above the age of twelve years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.In the United States, it is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in people with congenital or acquired generalized lipodystrophy. Research Metreleptin is currently being investigated for the treatment of diabetes and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy, syndromes characterized by abnormalities in adipose tissue distribution, and severe metabolic abnormalities. The FDA approved Metreleptin injection for treating complications of leptin deficiency in February 2014.In a three-year study of metreleptin in patients with lipodystrophy organized by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health, metreleptin treatment was associated with a significant decrease in blood glucose (A1c decreased from 9.4% at baseline to 7.0% at study end) and triglyceride concentration (from 500 mg/dl at baseline to 200 mg/dl at study end). Metreleptin is effective in most patients with generalized lipodystrophy where circulating leptin levels are extremely low. Analogous to insulin replacement for patients with type 1 Diabetes, metreleptin restores the function of a deficient hormone. However, in patients with partial lipodystrophy where there is only a relative leptin deficiency, the response to metreleptin is not universal. This may or may not be due to anti-leptin antibodies. NHS England will commission metreleptin treatment for patients (all ages) with congenital leptin deficiency from April 1, 2019. References External links "Metreleptin". Drug Information Portal. U.S. National Library of Medicine.
Ursodeoxycholic acid	Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of bears of genus Ursus, from which its name derived. In purified form, it has been used to treat or prevent several diseases of the liver or bile ducts. It is available as a generic medication. Medical uses UDCA has been used as medical therapy in gallstone disease (cholelithiasis) and for biliary sludge. UDCA helps reduce the cholesterol saturation of bile and leads to gradual dissolution of cholesterol-rich gallstones.UDCA may be given after bariatric surgery to prevent cholelithiasis, which commonly occurs due to the rapid weight loss producing biliary cholesterol oversaturation and also biliary dyskinesia secondary hormonal changes. Primary biliary cholangitis UDCA is used as therapy in primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis) where it can produce an improvement in biomarkers. Meta-analyses have borne out conflicting results on the mortality benefit. However analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant. A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation, pruritus or fatigue. Ursodiol and obeticholic acid are FDA-approved for the treatment of primary biliary cholangitis. Primary sclerosing cholangitis UDCA use is associated with improved serum liver tests that do not always correlate with improved liver disease status. WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day.UDCA in a dose of 28-30mg/kg/day increases risk of death and need for liver transplant by 2.3 folds among those with primary sclerosing cholangitis, despite decrease in liver enzymes. Intrahepatic cholestasis of pregnancy UDCA has been used for intrahepatic cholestasis of pregnancy. UDCA lessens itching in the mother and may reduce the number of preterm births. Effects on fetal distress and other adverse outcomes are unlikely to be great. Cholestasis UDCA use is not licensed in children, as its safety and effectiveness have not been established. Evidence is accumulating that ursodeoxycholic acid is ineffective, unsafe and its use is associated with significant risk of morbidity and mortality in neonatal hepatitis and neonatal cholestasis. Other conditions UDCA has been suggested to be an adequate treatment of bile reflux gastritis.In cystic fibrosis there is insufficient evidence to justify routine use of UDCA, especially as there is a lack of available data for long-term outcomes such as death or need for liver transplantation.UDCA has also been in effective in non-alcoholic fatty liver disease, in liver bile duct-paucity syndromes. It is contraindicated in obstruction of biliary tracts such as biliary atresia. Its not effective in liver allograft rejection, and in Graft-versus-host disease involving the liver. Adverse effects Diarrhea was the most frequent adverse event seen in trial of UDCA in gallstone dissolution, occurring in 2 to 9%, which is less frequent than with chenodeoxycholic acid therapy. Bacterial conversion of UDCA to chenodeoxycholic acid may be the mechanism for this side effect. Right upper quadrant abdominal pain and exacerbation of pruritus was occasionally reported in trials in patients with PBC. Additional symptoms may include bloating, weight gain, and occasionally, thinning of hair. Mechanisms of action Choleretic effects Primary bile acids are produced by the liver and stored in the gall bladder. When secreted into the intestine, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. Ursodeoxycholic acid helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol. The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery. There are multiple mechanisms involved in cholestatic liver diseases. Immunomodulating effects Ursodeoxycholic acid has also been shown experimentally to suppress immune response such as immune cell phagocytosis. Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic. Anti-inflammatory effects Ursodeoxycholic acid has been shown to exert anti-inflammatory and protective effects in human epithelial cells of the gastrointestinal tract. It has been linked to regulation of immunoregulatory responses by regulation of cytokines, antimicrobial peptides defensins, and take an active part in increased restitution of wound in the colon. Moreover, UDCAs effects has been shown to have exert actions outside the epithelial cells.While some bile acids are known to be colon tumor promoters (e.g. deoxycholic acid), others such as ursodeoxycholic acid are thought to be chemopreventive, perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells. Chemistry Ursodeoxycholic acid is an epimer of chenodeoxycholic acid, which has similar choleretic effects and a wider species distribution. However, CDCA is not as well-tolerated in humans and it does not show immunomodulating or chemoprotective effects. Both are 7-hydroxyl derivatives of deoxycholic acid, but UDCA has the group in the beta instead of the alpha orientation. Biosynthesis Among mammals, only bears (Ursidae; excluding giant pandas) produce UDCA at useful amounts (>30%). It is produced in the bear liver, but the pathway remains unknown.Other vertebrates produce UDCA in much smaller amounts by gut bacteria. CDCA is oxidized into 7-oxo-CDCA then reduced into UDCA. Industrial production UDCA is most commonly produced from cholic acid (CA) derived from bovine bile, a by-product of the beef industry. The current yield of this semisynthesis is about 30%. Society and culture Names The term is from the Latin noun ursus meaning bear, as bear bile contains the substance.Ursodeoxycholic acid can be chemically synthesized and is marketed under multiple trade names, including Ursetor, Udikast, Actibile, Actigall, Biliver, Deursil, Egyurso, Udcasid, Udiliv, Udinorm, Udoxyl, Urso, Urso Forte, Ursocol, Ursoliv, Ursofalk, Ursosan, Ursoserinox, Udimarin, Ursonova, and Stener. History Bear bile, a natural source of UDCA, is used in traditional Chinese medicine since the seventh century. Japanese scientists successfully synthesized UDCA chemically in 1955. The earliest reference to UDCA in PubMed dates to 1957 under an alternative spelling "ursodesoxycholic acid", in a small-scale clinical trial.Ursodeoxycholic acid (application filed by Allergan) was approved for use in the United States in December 1987, and was designated an orphan drug. References External links "Ursodiol". Drug Information Portal. U.S. National Library of Medicine. Ursodeoxycholic acid in the British National Formulary (BNF is only available in the UK)
Magnesium citrate	Magnesium citrate is a magnesium preparation in salt form with citric acid in a 1:1 ratio (1 magnesium atom per citrate molecule). The name "magnesium citrate" is ambiguous and sometimes may refer to other salts such as trimagnesium citrate which has a magnesium:citrate ratio of 3:2. Magnesium citrate is used medicinally as a saline laxative and to completely empty the bowel prior to a major surgery or colonoscopy. It is available without a prescription, both as a generic and under various brand names. It is also used in the pill form as a magnesium dietary supplement. It contains 11.23% magnesium by weight. Compared to trimagnesium citrate, it is much more water-soluble, less alkaline, and contains less magnesium. As a food additive, magnesium citrate is used to regulate acidity and is known as E number E345. Mechanism of action Magnesium citrate works by attracting water through the tissues by a process known as osmosis. Once in the intestine, it can attract enough water into the intestine to induce defecation. The additional water stimulates bowel motility. This means it can also be used to treat rectal and colon problems. Magnesium citrate functions best on an empty stomach, and should always be followed with a full (eight ounce or 250 ml) glass of water or juice to help the magnesium citrate absorb properly and help prevent any complications. Magnesium citrate solutions generally produce bowel movement in one half to three hours. Use and dosage The maximum upper tolerance limit (UTL) for magnesium in supplement form for adults is 350 mg of elemental magnesium per day, according to the National Institutes of Health (NIH). In addition, according to the NIH, total dietary requirements for magnesium from all sources (in other words, food and supplements) is 320–420 mg of elemental magnesium per day, though there is no UT for dietary magnesium. Laxative Magnesium citrate is used as a laxative agent.As a laxative syrup with a concentration of 1.745 g of magnesium citrate per fluid ounce, a typical dose for adults and children twelve years or older is between 7 and 10 US fluid ounces (210 and 300 ml; 7.3 and 10.4 imp fl oz), followed immediately with a full 8 US fluid ounces (240 ml; 8.3 imp fl oz) glass of water. Consuming an adult dose of 10 oz of laxative syrup (@ 1.745 g/oz) implies a consumption of 17.45 g of magnesium citrate in a single 10 US fl oz (300 ml; 10 imp fl oz) dose resulting in a consumption of approximately 2.0 g of elemental magnesium per single dose. This laxative dose contains five times the recommended nutritional dose for children. Magnesium citrate is not recommended for use in children and infants two years of age or less. Magnesium deficiency treatment Although less common, as a magnesium supplement the citrate form is sometimes used because it is believed to be more bioavailable than other common pill forms, such as magnesium oxide. But, according to one study, magnesium gluconate was found to be marginally more bioavailable than even magnesium citrate.Potassium-Magnesium Citrate, as a supplement in pill form, is useful for the prevention of kidney stones. Side effects Magnesium citrate is generally not a harmful substance, but care should be taken by consulting a healthcare professional if any adverse health problems are suspected or experienced. Extreme magnesium overdose can result in serious complications such as slow heart beat, low blood pressure, nausea, drowsiness, etc. If severe enough, an overdose can even result in coma or death. However, a moderate overdose will be excreted through the kidneys, unless one has serious kidney problems. Rectal bleeding or failure to have a bowel movement after use could be signs of a serious condition. See also ATC code A12 Magnesium aspartate Magnesium oxide References External links Saline laxatives. MedicineNet. Magnesium citrate Patient Advice. Drugs.com.
Imiglucerase	Imiglucerase is a medication used in the treatment of Gauchers disease.It is a recombinant DNA-produced analogue of the human enzyme β-glucocerebrosidase. Cerezyme is a freeze-dried medicine containing imiglucerase, manufactured by Genzyme Corporation. It is given intravenously after reconstitution as a treatment for Type 1 and Type 3 Gauchers disease. It is available in formulations containing 200 or 400 units per vial. The specific activity of highly purified human enzyme is 890,000 units/mg, meanwhile the enzyme activity produced by recombinant DNA technology is approximately 40 units/mg. A typical dose is 2.5U/kg every two weeks, up to a maximum of 60 U/kg once every two weeks, and safety has been established from ages 2 and up. It is one of more expensive medications, with an annual cost of $200,000 per person in the United States. Imiglucerase has been granted orphan drug status in the United States, Australia, and Japan.Cerezyme was one of the drugs manufactured at Genzymes Allston, Massachusetts plant, for which production was disrupted in 2009 after contamination with Vesivirus 2017. Side effects The most common side effect is hypersensitivity, which occurs in about 3% of patients. It is associated with symptoms such as cough, shortness of breath, rashes, itching, and angiooedema. Less common side effects include dizziness, headache, nausea, diarrhoea, and reactions at the injection site; they are found in less than 1% of patients. Interactions No clinical interaction studies have been conducted. Miglustat appears to increase the clearance of imiglucerase by 70%, resulting in decreased enzyme activity. See also Other drugs for the treatment of Gauchers disease Afegostat (development terminated) Eliglustat Miglustat Velaglucerase alfa taliglucerase alfa == References ==
Moexipril	Moexipril an angiotensin converting enzyme inhibitor (ACE inhibitor) used for the treatment of hypertension and congestive heart failure. Moexipril can be administered alone or with other antihypertensives or diuretics.It works by inhibiting the conversion of angiotensin I to angiotensin II.It was patented in 1980 and approved for medical use in 1995. Moexipril is available from Schwarz Pharma under the trade name Univasc. Side effects Moexipril is generally well tolerated in elderly patients with hypertension. Hypotension, dizziness, increased cough, diarrhea, flu syndrome, fatigue, and flushing have been found to affect less than 6% of patients who were prescribed moexipril. Mechanism of action As an ACE inhibitor, moexipril causes a decrease in ACE. This blocks the conversion of angiotensin I to angiotensin II. Blockage of angiotensin II limits hypertension within the vasculature. Additionally, moexipril has been found to possess cardioprotective properties. Rats given moexipril one week prior to induction of myocardial infarction, displayed decreased infarct size. The cardioprotective effects of ACE inhibitors are mediated through a combination of angiotensin II inhibition and bradykinin proliferation. Increased levels of bradykinin stimulate in the production of prostaglandin E2 and nitric oxide, which cause vasodilation and continue to exert antiproliferative effects. Inhibition of angiotensin II by moexipril decreases remodeling effects on the cardiovascular system. Indirectly, angiotensin II stimulates of the production of endothelin 1 and 3 (ET1, ET3) and the transforming growth factor beta-1 (TGF-β1), all of which have tissue proliferative effects that are blocked by the actions of moexipril. The antiproliferative effects of moexipril have also been demonstrated by in vitro studies where moexipril inhibits the estrogen-stimulated growth of neonatal cardiac fibroblasts in rats. Other ACE inhibitors have also been found to produce these actions, as well. Pharmacology Moexipril is available as a prodrug moexipril hydrochloride, and is metabolized in the liver to form the pharmacologically active compound moexiprilat. Formation of moexiprilat is caused by hydrolysis of an ethyl ester group. Moexipril is incompletely absorbed after oral administration, and its bioavailability is low. The long pharmacokinetic half-life and persistent ACE inhibition of moexipril allows once-daily administration.Moexipril is highly lipophilic, and is in the same hydrophobic range as quinapril, benazepril, and ramipril. Lipophilic ACE inhibitors are able to penetrate membranes more readily, thus tissue ACE may be a target in addition to plasma ACE. A significant reduction in tissue ACE (lung, myocardium, aorta, and kidney) activity has been shown after moexipril use.It has additional PDE4-inhibiting effects. Synthesis The synthesis of the all-important dipeptide-like side chain involves alkylation of the tert-butyl ester of L-alanine (2) with ethyl 2-bromo-4-phenylbutanoate (1); the presominane of the desired isomer is attributable to asymmetric induction from the adjacent chiral center. Reaction of the product with hydrogen chloride then cleaves the tert-butyl group to give the half acid (3). Coupling of that acid to the secondary amine on tetrahydroisoquinoline (4) gives the corresponding amine. The tert-butyl ester in this product is again cleaved with hydrogen chloride to afford moexipril (5). == References ==
Brolucizumab	Brolucizumab (sold, depending on part of the world, under trade names Beovu or Vsiqq), is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD).The most common side effects are reduced visual acuity, cataract (clouding of the lens in the eye), conjunctival haemorrhage (bleeding at the front of the eye) and vitreous floaters (spots in the vision). The most serious side effects are blindness, endophthalmitis (an infection inside the eye), retinal artery occlusion (blockage of the artery in the retina) and retinal detachment (separation of the retina from the back of the eye).Brolucizumab was designed to attach to and block a substance called vascular endothelial growth factor A (VEGF-A). VEGF-A is a protein that makes blood vessels grow and leak fluid and blood, damaging the macula. By blocking VEGF-A, brolucizumab reduces the growth of the blood vessels and controls the leakage and swelling. History This drug was developed by ESBATech (discovery to phase 2a), Alcon Laboratories (phase 2b), and Novartis (phase 3).Brolucizumab is U.S. Food and Drug Administration (FDA) approved in ophthalmology as Beovu.Brolucizumab successfully completed phase III development in wet age-related macular degeneration (AMD) meeting the primary efficacy endpoint of non-inferiority to aflibercept in mean change in best corrected visual acuity (BCVA) from baseline to week 48. Furthermore, brolucizumab demonstrated superiority to aflibercept in key secondary endpoint measures of disease activity in wet AMD, a leading cause of blindness in two head-to-head pivotal Phase III studies.On 8 October 2019, Novartis announced that the U.S. Food and Drug Administration (FDA) approved brolucizumab injection for the treatment of wet AMD. Beovu is the first FDA approved anti-VEGF to offer both greater fluid resolution versus aflibercept and the ability to maintain eligible wet AMD patients on a three-month dosing interval immediately after a three-month loading phase with uncompromised efficacy.The FDA approved Beovu based on evidence from two clinical trials (Trial 1/ NCT02307682 and Trial 2/NCT02434328) of 1459 patients, 50–97 years old, with wet AMD. The trials were conducted at 336 sites in the United States, Canada, Central and South America, European countries, Israel, Turkey, Australia, New Zealand, Japan, South Korea, Singapore, Taiwan, and Vietnam.While brolucizumab was initially developed for ophthalmology, non-ophthalmology indications (to which Cell Medica hold development rights) are also under investigation, under the name DLX1008. DLX1008 is under preclinical development for Kaposi sarcoma and glioblastoma.Brolucizumab was approved for use in the European Union in February 2020. Safety concerns On 23 February 2020, the American Society of Retina Specialists reported side effects of the drug, specifically in 14 cases of retinal vasculitis reported in Beovu patients, 11 of the cases were occlusive retinal vasculitis that can lead to vision loss.Novartis responded with a statement standing behind the efficacy of Beovu.On 11 June 2020, the FDA approved an updated Beovu label, that included additional safety information specifically including the characterization of adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of intraocular inflammation observed in HAWK (NCT02307682) and HARRIER (NCT02434328) clinical trials and noted in the original prescribing information. Names Laboratory development names were RTH258 (Novartis Compound Code) and ESBA1008 (ESBATech AG).Brolucizumab is the International Nonproprietary Name (INN) and the United States Adopted Name (USAN) References External links "Brolucizumab". Drug Information Portal. U.S. National Library of Medicine.
Makena	Makena may refer to: Makena Onjerika, Kenyan writer and 2018 Caine Prize winner A brand name of hydroxyprogesterone caproate Makena, Hawaii, a census-designated place in Maui County, Hawaii Makena State Park Makena Beach & Golf Resort, a resort in Maui See also McKenna (disambiguation) MacKenna (disambiguation)
Enfuvirtide	Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche). Structural formula Enfuvirtide is a 36-amino acid peptide with the following sequence:CH3CO-Tyr-Thr-Ser-Leu-Ile-His-Ser-Leu-Ile-Glu-Glu-Ser-Gln-Asn-Gln-Gln-Glu-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe-NH2 (Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2) History Enfuvirtide originated at Duke University, where researchers formed a pharmaceutical company known as Trimeris. Trimeris began development on enfuvirtide in 1996 and initially designated it T-20. In 1999, Trimeris entered into partnership with Hoffmann-La Roche to complete the development of the drug. It was approved by the U.S. Food and Drug Administration (FDA) on March 13, 2003 as the first HIV fusion inhibitor, a new class of antiretroviral drugs. It was approved on the basis of two studies which compared the effect of optimized regimens of antiretroviral medication with and without the addition of enfuvirtide on serum viral load. Pharmacology Mechanism of action Enfuvirtide works by disrupting the HIV-1 molecular machinery at the final stage of fusion with the target cell, preventing uninfected cells from becoming infected. A biomimetic peptide, enfuvirtide was designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Drugs that disrupt fusion of virus and target cell are termed entry inhibitors or fusion inhibitors.HIV binds to the host CD4+ cell receptor via the viral protein gp120; gp41, a viral transmembrane protein, then undergoes a conformational change that assists in the fusion of the viral membrane to the host cell membrane. Enfuvirtide binds to gp41 preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell.Enfuvirtide is also an activator of the chemotactic factor receptor, formyl peptide receptor 1, and thereby activates phagocytes and presumably other cells bearing this receptor (see formyl peptide receptors). The physiological significance of this activation is unknown. Microbiology Enfuvirtide is considered to be active against HIV-1 only. Low activity against HIV-2 isolates has been demonstrated in vitro.Variable susceptibility to enfuvirtide has been observed in clinical isolates, with acquired resistance the result of a mutated 10 amino acid motif in viral gp41. Primary resistance, however, has yet to be observed. Clinical use Indications Enfuvirtide is indicated for the treatment of HIV-1 infection, in combination therapy with other antiretrovirals, in patients where all other treatments have failed. Dosage forms By virtue of its peptide nature, enfuvirtide is marketed in injectable form. The lyophilised enfuvirtide powder must be reconstituted by the patient and administered twice daily by subcutaneous injection. Due to the chronic nature of this kind of therapy, this dosage form may be a major problem for the patients adherence to this drug regimen. Adverse effects Common adverse drug reactions (≥1% of patients) associated with enfuvirtide therapy include: injection site reactions (pain, hardening of skin, erythema, nodules, cysts, itch; experienced by nearly all patients, particularly in the first week), peripheral neuropathy, insomnia, depression, cough, dyspnoea, anorexia, arthralgia, infections (including bacterial pneumonia) and/or eosinophilia. Various hypersensitivity reactions occur infrequently (0.1–1% of patients), symptoms of which include rash, fever, nausea, vomiting, chills, rigors, hypotension, elevated hepatic transaminases; and possibly more severe reactions including respiratory distress, glomerulonephritis and/or anaphylaxis – rechallenge is not recommended. References External links "Enfuvirtide". Drug Information Portal. U.S. National Library of Medicine.
Maribavir	Maribavir, sold under the brand name Livtencity, is an antiviral medication that is used to treat post-transplant cytomegalovirus (CMV).The most common side effects include taste disturbance, nausea, diarrhea, vomiting and fatigue.Maribavir is a cytomegalovirus pUL97 kinase inhibitor that works by preventing the activity of human cytomegalovirus enzyme pUL97, thus blocking virus replication.Maribavir was approved for medical use in the United States in November 2021. Medical uses Maribavir is indicated to treat people twelve years of age and older and weighing at least 35 kilograms (77 lb) with post-transplant cytomegalovirus infection/disease that does not respond (with or without genetic mutations that cause resistance) to available antiviral treatment for cytomegalovirus. Adverse effects Adverse effects of maribavir include taste disturbances, nausea, and vomiting. Contraindications Maribavir may reduce the antiviral activity of ganciclovir and valganciclovir, so coadministration with these medications is not recommended. History Maribavir is licensed by ViroPharma from GlaxoSmithKline in 2003, for the prevention and treatment of human cytomegalovirus (HCMV) disease in hematopoietic stem cell/bone marrow transplant patients. The mechanism by which maribavir inhibits HCMV replication is by inhibition of an HCMV encoded protein kinase enzyme called UL97 or pUL97. Maribavir showed promise in Phase II clinical trials and was granted fast track status, but failed to meet study goals in a Phase III trial. However, the dosage used in the Phase III trial may have been too low to be efficacious.A Phase II study with maribavir demonstrated that prophylaxis with maribavir displayed strong antiviral activity, as measured by statistically significant reduction in the rate of reactivation of CMV in recipients of hematopoietic stem cell/bone marrow transplants. In an intent-to-treat analysis of the first 100 days after the transplant, the number of subjects who required pre-emptive anti-CMV therapy was statistically significantly reduced with maribavir compared to placebo.ViroPharma conducted a Phase III clinical study to evaluate the prophylactic use for the prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplant patients. In February 2009, ViroPharma announced that the Phase III study failed to achieve its goal, showing no significant difference between maribavir and a placebo at reducing the rate at which CMV DNA levels were detected in patients.The safety and efficacy of maribavir were evaluated in a Phase III, multicenter, open-label, active-controlled trial that compared maribavir with a treatment assigned by a researcher running the study, which could include one or two of the following antivirals used to treat cytomegalovirus: ganciclovir, valganciclovir, foscarnet, or cidofovir. In the study, 352 transplant recipients with cytomegalovirus infections who did not respond (with or without resistance) to treatment randomly received maribavir or treatment assigned by a researcher for up to eight weeks. The study compared the two groups plasma cytomegalovirus DNA concentration levels at the end of the studys eighth week, with efficacy defined as having a level below what is measurable. Of the 235 participants who received maribavir, 56% had levels of cytomegalovirus DNA below what was measurable versus 24% of the 117 participants who received an investigator-assigned treatment.The U.S. Food and Drug Administration (FDA) granted the application for maribavir orphan drug, breakthrough therapy and priority review designations. The FDA granted the approval of Livtencity to Takeda Pharmaceuticals Company Limited. Society and culture Legal status On 15 September 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Livtencity, intended for the treatment of cytomegalovirus (CMV) infection and/or disease that is refractory to one or more prior therapies. The applicant for this medicinal product is Takeda Pharmaceuticals International AG Ireland Branch. References External links "Maribavir". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02931539 for "Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir" at ClinicalTrials.gov
Retapamulin	Retapamulin is a topical antibiotic developed by GlaxoSmithKline. It is the first drug in the new class of pleuromutilin antibiotics to be approved for human use. It is marketed as an ointment under the brand names Altabax and Altargo. Retapamulin was approved by the United States Food and Drug Administration in April 2007 for the treatment of bacterial skin infections such as impetigo. In May 2007, retapamulin received approval in the EU from the European Medicines Agency for the same indication. Clinical trials have demonstrated its efficacy against certain Gram-positive bacteria including MRSA. Indications Retapamulin is indicated for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible only) or Streptococcus pyogenes. Pharmacology Mechanism of action Retapamulin is an antibacterial agent, specifically a protein synthesis inhibitor. The medication selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of the bacterial ribosome through an interaction that differs from other antibiotics. Pharmacokinetics Systemic exposure following topical application through intact skin is low. Contraindications None yet reported. Adverse reactions The most common reported adverse reaction was irritation at the application site. == References ==
Vibegron	Vibegron, sold under the brand name Gemtesa, is a medication for the treatment of overactive bladder.Vibegron (other names: RVT-901; MK4618; KRP114V; URO-901) is a selective beta 3 adrenergic receptor agonist. The most common side effects include headache, urinary tract infection, common cold, diarrhea, nausea, and upper respiratory tract infection.It was approved for medical use in the United States in December 2020. Medical uses Vibegron is indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults. History and Discovery The beta 3 adrenergic receptor was discovered in the late 1980s and initially beta3AR agonists were investigated as treatment for obesity and diabetes. A number of compounds were tested in clinical trials but didnt show sufficient benefits in these areas.Since the 2000s there is evidence that there are beta3AR on the detrusor muscle of the bladder. The detrusor muscle contracts during urination and remains relaxed to allow the bladder to store urine. Mirabegron was the first FDA approved selective agonist approved to treat overactive bladder (OAB).Vibegron is a selective beta3AR agonist that is developed in Japan by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co.,Ltd and Urovant Sciences to treat overactive bladders and pain caused by irritable bowel syndrome. It was globally approved on September 21, 2018, in Japan for OAB.Vibegron has been proven effective in 5 key clinical trials.A phase IIb global trial completed in 2013 of 1395 patients, of which 89.7% were women and 63.3% had not been treated previously, demonstrated a significant decrease in daily micturitions and urgent urinary incontinence episodes upon administration of vibegron.An international phase III trial of 506 participants completed in 2019 found statistically significant efficacy of vibegron after 2 weeks of daily administration. The adverse effect rates in patients treated with vibegron were comparable to those in patients who received a placebo.GEMTESA, a drug using vibegron as an active ingredient was approved by the FDA on December 23, 2020, after an additional phase III international trial of 1085 patients. Society and culture Legal status Vibegron was approved for medical use in the United States in December 2020. Names Vibegron is the international nonproprietary name (INN). Mechanism of action Vibegron is a selective agonist for the beta-3 adrenergic receptor (β3-AR). The receptors are located in the kidneys, urinary tract and bladder tissue. Upon binding, the β3 receptor undergoes a conformational change. This induces the activation of adenylate cyclases via G proteins and thereby promotes the formation of cyclic adenosine monophosphate (cAMP). The consequence of this cascade is an increased intracellular cAMP concentration which triggers activation of cAMP-dependent protein kinase A and causes a reduction of Ca2+ concentration in the cytoplasm. The kinase then phosphorylates myosin chains and thereby inhibits muscle contraction.The final effect of vibegron is muscle relaxation in the bladder. Due to this muscle relaxation, bladder capacity increases and symptoms of overactive bladder are relieved. Metabolism The two main metabolic pathways are the oxidation and glucuronidation of vibegron. Two oxidative metabolites and three glucuronide metabolites can be formed. The exact structure of these metabolites have not been studied yet. In vitro, CYP3A4 is the enzyme responsible for the metabolism of vibegron, facilitating oxidative metabolism. Eventually, still a large part of the unmodified drug is excreted through feces and urine. Indications Vibegron is indicated for people with OAB. Urgency urinary incontinence (UUI), urgency and urinary frequency in adults are the most common symptoms for this condition.The drug is contraindicated in patients with known hypersensitivity to Vibegron itself or single components of the drug. The inactive components of the drug for which allergic reactions can occur are sodium croscarmellose, hydroxypropyl cellulose, magnesium stearate, mannitol and microcrystalline cellulose. The thin coating of the drug with green color contains FD&C Blue No.2.Vibegron treatment should be discontinued if urinary retention occurs. Use with nonselective muscarinic antagonists may increase the risk of urinary retention. The manufacturer suggests discontinuing vibegron if an elevated digoxin concentration occurs. Efficacy and side effects Efficacy Vibegron was evaluated in patients with overactive bladder (OAB) in several clinical studies. A large active-controlled study, called Empower, showed the beneficial effects of the drug to treat the condition and UUI. Primary outcomes of different clinical trials showed there was an overall increase in efficacy. These outcomes concluded that there was a reduction in urgency to urinate, a decrease in micturitions and a decrease in average volume voided per micturition. There is also an improvement observed of the symptoms when Vibegron is administered over a longer period (52 weeks) concluding that it is effective and safe for longer use. In severe patients, increasing the dose was accompanied by similar beneficial effects when there was first a lack of these. Quality of life of the patients is improved, including a reduction of nocturia. Adverse effects The most common side effects of Vibegron are a dry mouth, constipation, headache, nasopharyngitis, diarrhea, nausea, bronchitis, urinary tract infection and upper respiratory tract infection. An indication is made that upon urinary retention development, the patient should stop using the drug. Risk assessment for the drug in pregnant women has yet to be evaluated. Interactions Vibegron is in contrast to other OAB drugs very selective and leads to a lesser degree in unwanted side effects. Vibegron is found to be a substrate for CYP3A4 in vivo, but does not actually induce or inhibit any of the cytochrome P450 enzymes and is thus less likely to take part in drug–drug interactions (DDI). Here vibegron differs from the previous overactive bladder drug mirabegron, which was known to be associated in various drug–drug interactions by inhibiting CYP2D6 or inducing CYP3A4, CYP2D6 and CYP2C9 in the liver.Using Vibegron only (monotherapy) has positive effects on OAB and UUI, but a combination with other drugs can have additional effects. In a study with antimuscarinic drugs, more DDIs were investigated using a model of Rhesus monkeys. Dose combinations of vibegron and tolterodine showed increased bladder capacity, the effects of both drugs at low dosis strengthened each other, known as synergism. The addition of darifenacin to vibegron created greater bladder relaxation only when used at high doses. Additionally, co-administration with Imidafenacin shows an increase in bladder capacity and voided volume in comparison to monotherapy. Possibly, a widely adapted treatment will be the combination of beta-3-adrenergic agonist with a nonselective M2/M3 antagonist as the most prevalent option.Clinical studies show no significant drug–drug interaction (DDI), aside from a serum concentration increase of digoxin when taken with vibegron. Maximal concentrations and systemic exposure (Cmax and area under the curve (AUC)) of digoxin are both increased as a result of DDI. Apart from the no to little DDIs, Vibegron has an additional safety quality in that it does not cross the blood-brain barrier and therefore does not induce cognitive impairment. Furthermore, Vibegron can be taken with or without food, this does not have an effect on vibegron plasma concentrations. Toxicity Effects on animals Pregnant rats were given very high daily oral doses of Vibegron during the period of organogenesis and showed no embryo-fetal developmental toxicity up to 300 mg/kg/day. Similar data was found in rabbits. Maternal toxicity was observed when doses exceeded 100 mg/kg/day in lactating rats. Clinical studies show that Vibegron is not toxic, safe and well-tolerated in patients. References External links "Vibegron". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03492281 for "A Study to Examine the Safety and Efficacy of a New Drug in Patients With Symptoms of Overactive Bladder (OAB) (Empowur)" at ClinicalTrials.gov
Estradiol/drospirenone	Estradiol/drospirenone (E2/DRSP), sold under the brand name Angeliq, is a combination of estradiol (E2), an estrogen, and drospirenone (DRSP), a progestin, antimineralocorticoid, and antiandrogen, which is used in menopausal hormone therapy, specifically the treatment of menopausal syndrome and osteoporosis, in postmenopausal women. It is taken by mouth and contains 0.5 to 1 mg E2 and 0.25 to 0.5 mg DRSP per tablet. The medication was approved in the United States in 2005. It is marketed widely throughout the world. See also Estetrol/drospirenone Ethinylestradiol/drospirenone Ethinylestradiol/drospirenone/levomefolic acid Ethinylestradiol/drospirenone/prasterone List of combined sex-hormonal preparations § Estrogens and progestogens References External links Angeliq (estradiol/drospirenone) FDA Label Estradiol/drospirenone (Angeliq) - AdisInsight
Alfentanil	Alfentanil (R-39209, trade name Alfenta, Rapifen in Australia) is a potent but short-acting synthetic opioid analgesic drug, used for anaesthesia in surgery. It is an analogue of fentanyl with around one-fourth to one-tenth the potency, one-third the duration of action, and an onset of action four times faster than that of fentanyl. Alfentanil has a pKa of approximately 6.5, which leads to a very high proportion of the drug being uncharged at physiologic pH, a characteristic responsible for its rapid onset. It is an agonist at mu opioid receptors. While alfentanil tends to cause fewer cardiovascular complications than other similar drugs such as fentanyl and remifentanil, it tends to give stronger respiratory depression and so requires careful monitoring of breathing and vital signs. Almost exclusively used by anesthesia providers during portions of a case where quick, fast-acting (though not long-lasting) pain control is needed (as, for example, during nerve blocks), alfentanil is administered by the parenteral (injected) route for fast onset and precise control of dosage. Discovered at Janssen Pharmaceutica in 1976, alfentanil is classified as a Schedule II drug in the United States.Side effects of fentanyl analogs are similar to those of fentanyl itself and include itching, nausea and potentially life-threatening respiratory depression. Fentanyl analogs have killed hundreds of people throughout Europe and the former Soviet republics since the most recent resurgence in use began in Estonia in the early 2000s, and novel derivatives continue to appear. References External links Medline Plus Patient Information - 09/01/2010 https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm February 2017 Genf interaction table- https://www.hug.ch/sites/interhug/files/structures/pharmacologie_et_toxicologie_cliniques/carte_cytochromes_2016_final.pdf February 2017
Maralixibat chloride	Maralixibat chloride, sold under the brand name Livmarli, is a medication used to treat cholestatic pruritus in people with Alagille syndrome. Maralixibat chloride is an ileal bile acid transporter (IBAT) inhibitor.Maralixibat was approved for medical use in the United States in September 2021. History Maralixibat was granted orphan drug designations in 2013, and in 2020. Society and culture Legal status On 13 October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Livmarli, intended for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS). The applicant for this medicinal product is Mirum Pharmaceuticals International B.V. Names Maralixibat chloride is the international nonproprietary name (INN). References External links "Maralixibat". Drug Information Portal. U.S. National Library of Medicine. "Maralixibat chloride". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02160782 for "Safety and Efficacy Study of LUM001 (Maralixibat) With a Drug Withdrawal Period in Participants With Alagille Syndrome (ALGS) (ICONIC)" at ClinicalTrials.gov
Pentamidine	Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypanosomiasis it is used for early disease before central nervous system involvement, as a second line option to suramin. It is an option for both visceral leishmaniasis and cutaneous leishmaniasis. Pentamidine can be given by injection into a vein or muscle or by inhalation.Common side effects of the injectable form include low blood sugar, pain at the site of injection, nausea, vomiting, low blood pressure, and kidney problems. Common side effects of the inhaled form include wheezing, cough, and nausea. It is unclear if doses should be changed in those with kidney or liver problems. Pentamidine is not recommended in early pregnancy but may be used in later pregnancy. Its safety during breastfeeding is unclear. Pentamidine is in the aromatic diamidine family of medications. While the way the medication works is not entirely clear, it is believed to involve decreasing the production of DNA, RNA, and protein.Pentamidine came into medical use in 1937. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In regions of the world where the disease is common pentamidine is provided for free by the World Health Organization (WHO). Medical uses Treatment of PCP caused by Pneumocystis jirovecii Prevention of PCP in adults with HIV who have one or both of the following: History of PCP CD4+ count ≤ 200mm³ Treatment of leishmaniasis Treatment of African trypanosomiasis caused by Trypanosoma brucei gambiense Balamuthia infections Pentamidine is classified as an orphan drug by the U.S. Food and Drug Administration Other uses Use as an antitumor drug has also been proposed. Pentamidine is also identified as a potential small molecule antagonist that disrupts this interaction between S100P and RAGE receptor. Special Populations Pregnancy It has not been shown to cause birth defects in animal studies when given intravenously. There are no controlled studies to show if pentamidine can harm the fetus in pregnant women. It is only recommended if the drug of choice trimethoprim-sulfamethoxazole is contraindicated. Breastfeeding There is no information regarding the excretion of pentamidine in breast milk, but since the adverse effects on breastfed infants are unknown currently, it is recommended by the manufacturer for the infant to not be breastfed or for the mother to stop the drug. Risks versus benefits for the mother should be considered when making this decision. Children Pentamidine can be used in the prevention of PCP in children with HIV who cannot tolerate Trimethoprim/Sulfamethoxazole and can use a nebulizer. Intranvenous solutions of pentamidine should only be used in children with HIV older than 2 years old when other treatments are unavailable Elderly There is no data for the use of pentamidine in this specific population. Contraindications Patients with a history of anaphylaxis or hypersensitivity to pentamidine isethionate Side effects Common Burning pain, dryness, or sensation of lump in throat Chest pain Coughing difficulty in breathing difficulty in swallowing skin rash wheezing Rare Nausea and vomiting Pain in upper abdomen, possibly radiating to the back Severe pain in side of chest Shortness of breath Others Blood: Pentamidine frequently causes leukopenia and less often thrombopenia, which may cause symptomatic bleeding. Some cases of anemia, possibly related to folic acid deficiency, have been described. Cardiovascular: Hypotension, which may be severe. Severe or fatal arrhythmias and heart failure are quite frequent. Kidney: 25 percent develop signs of nephrotoxicity ranging from mild, asymptomatic azotemia (increased serum creatinine and urea) to irreversible renal failure. Ample fluids or intravenous hydration may prevent some nephrotoxicity. Liver: Elevated liver enzymes are associated with intravenous use of pentamidine. Hepatomegaly and hepatitis have been encountered with long term prophylactic use of pentamidine inhalation. Neurological: Dizziness, drowsiness, neuralgia, confusion, hallucinations, seizures and other central side effects are reported. Pancreas: Hypoglycemia that requires symptomatic treatment is frequently seen. On the other hand, pentamidine may cause or worsen diabetes mellitus. Respiratory: Cough and bronchospasm, most frequently seen with inhalation. Skin: Severe local reactions after extravasculation of intravenous solutions or following intramuscular injection treatment have been seen. Pentamidine itself may cause rash, or rarely Stevens–Johnson syndrome or Lyell syndrome. Eye discomfort, conjunctivitis, throat irritation, splenomegaly, Herxheimer reaction, electrolyte imbalances (e.g. hypocalcemia). Drug interactions The additional or sequential use of other nephrotoxic drugs like aminoglycosides, amphotericin B, capreomycin, colistin, polymyxin B, vancomycin, foscarnet, or cisplatin should be closely monitored, or whenever possible completely avoided. Mechanism of action The mechanism seems to vary with different organisms and is not well understood. However, pentamidine is suspected to work through various methods of interference of critical functions in DNA, RNA, phospholipid and protein synthesis. Pentamidine binds to adenine-thymine-rich regions of the Trypanosoma parasite DNA, forming a cross-link between two adenines four to five base pairs apart. The drug also inhibits topoisomerase enzymes in the mitochondria of Pneumocystis jirovecii. Similarly, pentamidine inhibits type II topoisomerase in the mitochondria of the Trypanosoma parasite, resulting in a broken and unreadable mitochondrial genome. Resistance Strains of the Trypanosoma brucei parasite that are resistant to pentamidine have been discovered. Pentamidine is brought into the mitochondria through carrier proteins, and the absence of these carriers prevents the drug from reaching its site of action. Pharmacokinetics Absorption: Pentamidine is completely absorbed when given intravenously or intramuscularly. When inhaled through a nebulizer, pentamidine accumulates in the bronchoalveolar fluid of the lungs at a higher concentration compared to injections. The inhaled form is minimally absorbed in the blood. Absorption is unreliable when given orally.Distribution: When injected, pentamidine binds to tissues and proteins in the plasma. It accumulates in the kidney, liver, lungs, pancreas, spleen, and adrenal glands. Additionally, pentamidine does not reach curative levels in the cerebrospinal fluid. It has a volume of distribution of 286-1356 liters when given intravenously and 1658-3790 liters when given intramuscularly. Inhaled pentamidine is mainly deposited into the bronchoalveolar lavage fluid of the lungs.Metabolism: Pentamidine is primarily metabolized by Cytochrome P450 enzymes in the liver. Up to 12% of pentamidine is eliminated in the urine unchanged.Elimination: Pentamidine has an average half-life of 5–8 hours when given intravenously and 7–11 hours when given intramuscularly. However, these may increase with severe kidney problems. Pentamidine can remain in the system for as long as 8 months after the first injection. Chemistry Pentamidine isethionate for injection is commercially available as a lyophilized, white crystalline powder for reconstitution with sterile water or 5% Dextrose. After reconstitution, the mixture should be free from discoloration and precipitation. Reconstitution with sodium chloride should be avoided due to formation of precipitates. Intravenous solutions of pentamidine can be mixed with intravenous HIV medications like zidovidine and intravenous heart medications like diltiazem. However, intravenous solutions of antiviral foscarnet and antifungal fluconazole are incompatible with pentamidine. To avoid side-effects associated with intravenous administration, the solution should be slowly infused to minimize the release of histamine. History Pentamidine was first used to treat African trypanosomiasis in 1937 and leishmaniasis in 1940 before it was registered as pentamidine mesylate in 1950. Its efficacy against Pneumocystis jirovecii was demonstrated in 1987, following its re-emergence on the drug market in 1984 in the current isethionate form. Trade names and dose form For oral inhalation and for nebulizer use: NebuPent Nebulizer (APP Pharmaceuticals LLC - US)For intravenous and intramuscular use: US and Canada: Pentacarinat 300 injection powder 300 mg vial (Avantis Pharma Inc - Canada) Pentam 300 (APP Pharmaceuticals LLC - US) Pentamidine isethionate 300 mg for injection (David Bull Laboratories LTD - Canada, Hospira Healthcare Corporation - Canada) International Brands:Pentamidine isethionate (Abbott) Pentacarinat (Sanofi-Aventis) Pentacrinat (Abbott) Pentam (Abbott) Pneumopent See also Netropsin Lexitropsin References External links "Pentamidine". Drug Information Portal. U.S. National Library of Medicine.
Omadacycline	Omadacycline, sold under the brand name Nuzyra, is a broad spectrum antibiotic medication belonging to the aminomethylcycline subclass of tetracycline antibiotics. In the United States, it was approved in October 2018, for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections. In vitro studies In vitro studies have shown that omadacycline has activity against a broad range of Gram-positive and select Gram-negative pathogens. Omadacycline has potent in vitro activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant and multi-drug resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus. Omadacycline also has antimicrobial activity against common Gram-negative aerobes, some anaerobes, and atypical bacteria such as Legionella and Chlamydia. This activity translated to potent efficacy for omadacycline in an in vivo systemic infection model in mice.Additional in vitro and in vivo studies of omadacycline metabolism, disposition, and drug interactions show that omadacycline is metabolically stable (i.e., it does not undergo significant biotransformation) and neither inhibits nor interacts with metabolizing enzymes or transporters. Mechanism of action The mechanism of action of omadacycline is similar to that of other tetracyclines – inhibition of bacterial protein synthesis. Omadacycline has activity against bacterial strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection). Clinical trials A phase II study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections. Patients were randomized at 11 sites in the US to receive either omadacycline 100 mg intravenously once daily with an option to transition to 200 mg orally once daily or linezolid 600 mg intravenously twice daily with an option to transition to 600 mg orally twice daily. The results indicated that omadacycline is well tolerated and has the potential to be an effective treatment in patients with complicated skin and skin structure infections.In June 2013, the US Food and Drug Administration (FDA) designated the intravenous and oral formulations of omadacycline as a qualified infectious disease product in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.A 650-patient phase III registration study comparing omadacycline to linezolid for the treatment of acute bacterial skin and skin structure infections began in June 2015. Omadacycline met the primary efficacy endpoint of early clinical response with statistical non-inferiority (10% margin) compared to linezolid, and was generally safe and well tolerated. The most common treatment-emergent adverse events were gastrointestinal side effects (18.0% for omadacycline vs. 15.8% for linezolid).A 750-patient phase III study comparing omadacycline to moxifloxacin for the treatment of community-acquired bacterial pneumonia began in November 2015. Omadacycline was statistically non-inferior to moxifloxacin at the early clinical response, 72 to 120 hours after therapy was initiated.In May 2016, a phase Ib study of omadacycline in urinary tract infection was initiated.In August 2016, a second phase III study of omadacycline was initiated in patients with acute bacterial skin and skin structure infections, comparing the efficacy and safety of once-daily, oral omadacycline to that of twice-daily, oral linezolid. In July 2017, analysis of the data showed that all of the primary and secondary endpoints required for submission to the FDA and EMA were met. This was the third phase 3 registration study of omadacycline with favorable results. Discovery Omadacycline was invented at Tufts University School of Medicine by a research team led by Mark L. Nelson with Mohamed Ismail while at Tufts and Kwasi Ohemeng and Laura Honeyman at Paratek Pharmaceuticals, Boston. The team applying their chemistry methods to the tetracycline scaffolds created over 3000 new derivatives, leading to the novel third-generation compounds omadacycline and sarecycline. References External links "Omadacycline". Drug Information Portal. U.S. National Library of Medicine. "Omadacycline tosylate". Drug Information Portal. U.S. National Library of Medicine. "Omadacycline Injection". MedlinePlus.
DPT vaccine	The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus. The vaccine components include diphtheria and tetanus toxoids and either killed whole cells of the bacterium that causes pertussis or pertussis antigens. The term toxoid refers to vaccines which use an inactivated toxin produced by the pathogen which they are targeted against in order to generate an immune response. In this way, the toxoid vaccine generates an immune response which is targeted against the toxin which is produced by the pathogen and causes disease, rather than a vaccine which is targeted against the pathogen itself. The whole cells or antigens will be depicted as either "DTwP" or "DTaP", where the lower-case "w" indicates whole-cell inactivated pertussis and the lower-case "a" stands for “acellular”. In comparison to alternative vaccine types, such as live attenuated vaccines, the DTP vaccine does not contain the pathogen itself, but rather uses inactivated toxoid to generate an immune response; therefore, there is not a risk of use in populations that are immune compromised since there is not any known risk of causing the disease itself. As a result, the DTP vaccine is considered a safe vaccine to use in anyone and it generates a much more targeted immune response specific for the pathogen of interest. However, booster doses are recommended every ten years to maintain immune protection against these pathogens. In the United States, the DPT vaccine was administered as part of the childhood vaccines recommended by the Centers for Disease Control and Prevention (CDC) until 1996 when the acellular DTaP vaccine was licensed for use. History In the 20th century, the advancements in vaccinations helped to reduce the incidence of childhood pertussis and had a dramatically positive effect on the health of populations in the United States. However, in the early 21st century, reported instances of the disease increased 20-fold due to a downturn in the number of immunizations received and resulted in numerous fatalities. During the 21st century, many parents declined to vaccinate their children against pertussis for fear of perceived side effects despite scientific evidence showing vaccines to be highly effective and safe. In 2009, the journal Pediatrics concluded the largest risk among unvaccinated children was not the contraction of side effects, but rather the disease that the vaccination aims to protect against.Diphtheria and tetanus toxoids and pertussis (DTP) vaccination was licensed in 1949. Since the introduction of the combination vaccine, there has been an extensive decline in the incidence of pertussis, or whooping cough, the disease which the vaccine protects against. Additionally, the rates of disease have continued to decline as more extensive immunization strategies have been implemented, including booster doses and increased emphasis on increasing health literacy. Vaccination Rates In 2016, the CDC reported that 80.4% of children in the US have received 4 or more DTaP vaccinations by 2 years of life. Vaccination rates for children aged 13–17 with one or more TDaP shots was 90.2% in 2019. Only 43.6% of adults (older than 18) have received a TDaP shot in the last 10 years. The CDC aims to increase vaccination rate among 2 year olds from 80.4% to 90.0% Combination vaccines with acellular pertussis DTaP and Tdap are both combination vaccines against diphtheria, tetanus, and pertussis. The lower-case "d" and "p" indicate smaller concentrations of diphtheria toxoids and pertussis antigens, and "a" in "ap/aP" indicates that the pertussis toxoids are acellular. DTaP DTaP (also DTPa and TDaP) is a combination vaccine against diphtheria, tetanus, and pertussis, in which the pertussis component is acellular. This is in contrast to whole-cell, inactivated DTP (DTwP). The acellular vaccine uses selected antigens of the pertussis pathogen to induce immunity. Because it uses fewer antigens than the whole-cell vaccines, it is considered to cause fewer side effects, but it is also more expensive. Research suggests that the DTP vaccine is more effective than DTaP in conferring immunity, because DTaPs narrower antigen base is less effective against current pathogen strains. Tdap Tdap, (also dTpa), is a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine. It was licensed in the United States for use in adults and adolescents on 10 June 2005. Two Tdap vaccines are available in the US. In January 2011, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended the use of Tdap in adults of all ages, including those age 65 and above. In October 2011, in an effort to reduce the burden of pertussis in infants, the ACIP recommended that unvaccinated pregnant women receive a dose of Tdap. On 24 October 2012, the ACIP voted to recommend the use of Tdap during every pregnancy.The ACIP and Canadas National Advisory Committee on Immunization (NACI) recommended that both adolescents and adults receive Tdap in place of their next Td booster (recommended to be given every ten years). Tdap and Td can be used as prophylaxis for tetanus in wound management. People who will be in contact with young infants are encouraged to get Tdap even if it has been less than five years since Td or TT to reduce the risk of infants being exposed to pertussis. NACI suggests intervals shorter than five years can be used for catch-up programs and other instances where programmatic concerns make five-year intervals difficult.The World Health Organization (WHO) recommends a pentavalent vaccine, combining the DTP vaccine with vaccines against Haemophilus influenzae type B and hepatitis B. Evidence on how effective this pentavalent vaccine is compared to the individual vaccines has not yet been determined.A 2019 study in the American Economic Journal found that state requirements mandating the use of the Tdap vaccine "increased Tdap vaccine take-up and reduced pertussis (whooping cough) incidence by about 32 percent." Related combination vaccines Excluding Pertussis DT and Td vaccines, lack the pertussis component. The Td vaccine is administered to children over the age of seven as well as to adults. It is most commonly administered as a booster shot every 10 years. The Td booster shot may also be administered as protection from a severe burn or dirty wound. The DT vaccine is given to children under the age of seven, who are unable to receive the pertussis antigen in the DTaP vaccine due to a contraindication. Including Polio In the United States, a combined vaccine inactivated polio vaccine (IPV), DTaP, and hepatitis B vaccine is available for children. In the UK, all babies born on or after 1 August 2017 are offered a hexavalent vaccine: DTaP, IPV, Haemophilus influenzae, and hepatitis B. Contraindications The DPT vaccine should be avoided in persons who experienced a severe allergic reaction, such as anaphylaxis, to a past vaccine containing tetanus, diphtheria, or pertussis. It should also be avoided in persons with a known severe allergy to an ingredient in the vaccine. If the reaction was caused by tetanus toxoids, the CDC recommends considering a passive immunization with tetanus immune globulin (TIG) if a person has a large or unclean wound. The DPT vaccine should also be avoided if a person developed encephalopathy (seizures, coma, declined consciousness) within seven days of receiving any pertussis-containing vaccine and the encephalopathy cannot be traced to another cause. A DT vaccine is available for children under the ages of seven who have contraindications or precautions to pertussis-containing vaccines. Side effects DTaP Common side effects include soreness where the shot was given, fever, irritability, tenderness, loss of appetite, and vomiting. Most side effects are mild to moderate and may last from one to three days. More serious but rare reactions after a DTaP vaccination may include seizures, lowered consciousness, or a high fever over 105 °F (41 °C). Allergic reactions are uncommon, but are medical emergencies. Signs of an allergic reaction include hives, dyspnea, wheezing, swelling of face and throat, syncope, and tachycardia and the child should be rushed to the nearest hospital. Tdap Common side effects include pain or swelling where the shot was given, mild fever, headache, tiredness, nausea, vomiting, diarrhea, and stomach ache. Allergic reactions are possible and have the same presentation and indications as described above for allergic reactions in DTaP. Any individual who has experienced a life-threatening allergic reaction after receiving a previous dose of diphtheria, tetanus, or pertussis containing vaccine should not receive the Tdap vaccination.In pregnant women, research suggests that Tdap administration may be associated with an increased risk of chorioamnionitis, a placental infection. Increased incidence of fever is also noted in pregnant women. Despite the observed increase in incidence of chorioamnionitis in pregnant women following Tdap administration, there has been no observed increase in the incidence of preterm birth, for which chorioamnionitis is a risk factor. Research has not discerned an association between Tdap administration during pregnancy and other serious pregnancy complications such as neonatal death and stillbirth. An association between Tdap administration during pregnancy and pregnancy-related hypertensive disorders (such as pre-eclampsia) has not been identified. Immunization schedules and requirements France In France, DTP is mandatory and given at 2 months (1st dose) and 4 months (2nd dose) with a booster at 11 months. Subsequent boosters are recommended at ages 6, 11–13, 25, 45, 65, then every ten years. Netherlands In the Netherlands, pertussis is known as kinkhoest and DKTP refers to the DTaP-IPV combination vaccine against diphtheria, kinkhoest, tetanus, and polio. DTP is given as part of the National Immunisation Programme. United Kingdom In the United Kingdom, DTP is called the "3-in-1 teenage booster" and protects against tetanus, diphtheria and polio. It is given by the NHS to all teenagers aged 14 (the hexavalent vaccine is given to infants and provides the first stage of protection against diphtheria, tetanus, and polio, as well as pertussis, Haemophilus influenzae type B and Hepatitis B). Subsequent boosters are recommended for foreign travellers where more than 10 years has passed since their last booster. This is provided on the NHS free of charge due to the significant risk that an imported case of polio could pose to public health in Britain. United States The standard immunization regimen for children within the United States is five doses of DTaP between the ages of two months and fifteen years. To be considered fully vaccinated, the Center for Disease Control and Prevention (CDC) typically requires five doses of Tdap. The CDC recommends that children receive their first dose at two months, the second dose at four months, the third dose at six months, the fourth dose between 15 and 18 months, and the fifth dose between 4–6 years. If the fourth dose of the DTaP immunization regimen falls on or subsequent to the recipients fourth birthday, the CDC states that only four doses are required to be fully vaccinated. In the instance that an individual under 18 has not received the DTaP vaccine, individuals should be vaccinated on the schedule in accordance with the vaccination "catch up schedule" provided by the CDC.Infants younger than 12 months of age, specifically less than three months of age, are at highest risk of acquiring pertussis. In U.S, there is no current tetanus-diphtheria-pertussis vaccination (whooping cough) recommended or licensed for new born infants. As a result, in their first few months of life, unprotected infants are at highest risk of life-threatening complications and infections from pertussis. Infants should not receive pertussis vaccination younger than six weeks of age. Ideally, Infants should receive DTaP (name of whooping cough vaccine for children from age 2 months through 6 years) at 2, 4, 6 months of age and they are not protected until the full series is completed. To protect infants younger than twelve months of age not vaccinated with Tdap against pertussis, ACIP also recommends adults (e.g., parents, siblings, grandparents, childcare providers, and healthcare personnel) and children to receive Tdap at least two weeks before being in contact with the infant.The CDC recommends that adults who have received their childhood DTP series receive a Td or Tdap booster every ten years. For adults that have not received the DTP series, the CDC recommends a three-part vaccine series followed by a Td or Tdap booster every ten years. In pregnancy According to the CDCs Advisory Committee on Immunization Practices (ACIP) guidelines, one dose of Tdap is recommended during each pregnancy to ensure protection against pertussis in newborn infants. Optimal timing to administer a dose of Tdap during each pregnancy is between 27 through 36 weeks gestation. If Tdap is administered early in pregnancy, it is not recommended to administer again during the 27 through 36 weeks gestation period as only one dose is recommended during pregnancy. In October 2022, Boostrix (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed [Tdap]) was approved for immunization during the third trimester of pregnancy to prevent pertussis, commonly known as whooping cough, in infants younger than two months of age.Pregnant women who have not previously vaccinated with Tdap (i.e., have never received DTP, DTaP, or DT as child or Td or TT as an adult) are recommended to receive a series of three Td vaccinations starting during pregnancy to ensure protection against maternal and neonatal tetanus. In such cases, administration of Tdap is recommended after 20 weeks gestation, and in earlier pregnancy a single dose of Tdap can be substituted for one dose of Td, and then the series completed with Td. For pregnant women not previously vaccinated with Tdap, if Tdap is not administered during pregnancy, it should be administered immediately postpartum. Postpartum administration of TDaP is not equivalent to administration of the vaccination during pregnancy. Because the vaccine is administered postpartum, the mother is unable to develop antibodies that can be transferred to the infant in utero, consequently, leaving the infant vulnerable to the diseases preventable by the Tdap Vaccine. Postpartum administration of the TdaP vaccine to the mother seeks to reduce the likelihood that the mother will contract disease that can be subsequently passed on the infant, albeit there will still be a two week period prior to the protective effects of the vaccine setting in. Postpartum administration is an extension of the concept of "cocooning," a term that refers to the full vaccination of all individuals that may come into direct contact with the infant. Cocooning, like postpartum Tdap aministration, is not recommended by the CDC. Cocooning depends on ensuring full vaccination of all individuals that the infant may come into contact with, and there may be financial, administrative or personal barriers that preclude full and timely vaccination of all individuals within the "cocoon." Brand names Australia United Kingdom Brand names in the United Kingdom include Revaxis (Sanofi Pasteur). United States As of January 2020, there are six DTaP vaccines and two Tdap vaccines licensed and available for use in the United States. All of them are indicated as childhood vaccinations with the schedules as follows: References Diphtheria World Health Organization (2009). The immunological basis for immunization : module 2: diphtheria - update 2009. World Health Organization (WHO). hdl:10665/44094. ISBN 9789241597869. Ramsay M, ed. (2013). "Chapter 15: Diphtheria". Immunisation against infectious disease. Public Health England. Roush SW, Baldy LM, Hall MA, eds. (March 2019). Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC). Pertussis World Health Organization (2017). The immunological basis for immunization series: module 4: pertussis, update 2017. World Health Organization (WHO). hdl:10665/259388. ISBN 9789241513173. Ramsay M, ed. (2013). "Chapter 24: Pertussis". Immunisation against infectious disease. Public Health England. Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 16: Pertussis". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119. Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 10: Pertussis". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC). Tetanus World Health Organization (2018). The immunological basis for immunization series: module 3: tetanus: update 2018. World Health Organization (WHO). hdl:10665/275340. ISBN 9789241513616. Ramsay M, ed. (2013). "Chapter 30: Tetanus". Immunisation against infectious disease. Public Health England. Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 21: Tetanus". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119. Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 16: Tetanus". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC). External links "Tdap - Tetanus-Diphtheria-Pertussis Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 17 August 2021. "DTaP (Diphtheria, Tetanus, Pertussis) Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 17 August 2021. "DTaP/Tdap/Td ACIP Vaccine Recommendations". U.S. Centers for Disease Control and Prevention (CDC). 28 January 2020. Tetanus Toxoid at the US National Library of Medicine Medical Subject Headings (MeSH) Diphtheria-Tetanus Vaccine at the US National Library of Medicine Medical Subject Headings (MeSH) Diphtheria-Tetanus-Pertussis Vaccine at the US National Library of Medicine Medical Subject Headings (MeSH) Diphtheria-Tetanus-acellular Pertussis Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH)
Sulfacetamide	Sulfacetamide is a sulfonamide antibiotic. Uses Sulfacetamide 10% topical lotion, sold under the brand name Klaron or Ovace, is approved for the treatment of acne and seborrheic dermatitis. When combined with sulfur, it is sold under the brand names Plexion, Clenia, Prascion, and Avar, which contain 10% sulfacetamide and 5% sulfur.Sulfacetamide has been investigated for use in the treatment of pityriasis versicolor and rosacea. It also has anti-inflammatory properties when used to treat blepharitis or conjunctivitis (in eye-drop solution). It is believed to work by limiting the presence of folic acid which bacteria need to survive. It has been suggested that sulfacetamide may also serve as a treatment for mild forms of hidradenitis suppurativa. Sulfacetamide has antibacterial activity and is used to control acne. Products containing sulfacetamide and sulfur (a keratolytic) are commonly promoted for the treatment of acne rosacea (rosacea with papules, pustules, or both). There are several prescription topical products containing sulfacetamide, such as foams, shampoos, cream and washes. Some research indicates that sulfacetamide derivatives may act as antifungals by an CYP51A1-independent mechanism. Structure and chemical properties These are organic compounds containing an benzenesulfonamide moiety with an amine group attached to the benzene ring. The molecular formula is C8H10N2O3S. Its scientific name is N-(4-aminophenyl)sulfonylacetamide. At room temperature, it appears as a white powder. Degradation reactions and stability Sulfacetamide is stable under normal temperatures and pressures. No dangerous reactions occur under known conditions of normal use. It is an important bacteriostatic agent that is commonly used in human and veterinary medicine. Therefore it can accumulate in the environment (mostly surface water).It has a long lifetime in the environment so different degradation reactions are researched: The photocatalytic degradation of sulfacetamide in water solutions during illumination of UV radiation with TiO2 was examined. It was found that sulfacetamide is resistant to biodegradation and that it is toxic to the green alga Chlorella vulgaris. It undergoes photocatalytic degradation and the toxicity of the intermediate products is significantly lower than the initial toxicity. The intermediates can be mineralized in contrast to sulfacetamide.Sulfonamide → organic intermediate products (degradation) (in presence of OH−). At higher temperatures sulfacetamide solutions degrade to its hydrolysed product, sulphanilamide with a first-order rate constant.Also oxidation of sulfacetamide by diperiodatocuperate(III) in an aqueous alkaline medium can occur. Copper(III) is used, as it is involved in many biological electron transfer reactions.The sulphanilamide can oxidise to a blue product with a first order reaction and it can form azo dye with a second order reaction. Available forms Sulfacetamide as a medicine is available as solution, eye drops, lotion, and powder. It can also be found in the form of the sodium salt, sulfacetamide sodium.It is available in fixed-dose combinations with prednisolone. Mechanisms of action Sulfacetamide is a sulfonamide antibiotic. Sulfonamides are synthetic bacteriostatic antibiotics, that are active against gram-positive and gram-negative bacteria. It blocks the synthesis of dihydrofolic acid by inhibiting the enzyme dihydropteroate synthase. It is a competitive inhibitor of bacterial para-aminobenzoic acid (PABA). PABA is required for bacterial synthesis of folic acid and it is an essential component for bacterial growth. The multiplication of bacteria is therefore inhibited by the action of sulfacetamide. Biotransformation Sulfacetamide is absorbed orally. The oral absorption of sulfacetamide is found to be 100% and the plasma protein binding is 80–85%. In the liver it is metabolized to inactive metabolites. Plasma half-life is 7 – 12.8 hours.Sulfonamides are usually metabolized by several oxidative pathways, acetylation, and conjugation with sulfate or glucuronic acid. However, there are some differences in biotransformation between certain species. Acetylation, which reduces the solubility of sulfonamides, is for example poor developed in dogs. The acetylated, hydroxylated, and conjugated forms have little antibacterial activity. Furthermore, the hydroxylated and conjugated forms are less likely to precipitate in urine. The hydrolysis takes place by the action of amidases.It is excreted primarily in the urine. Secretory routes of less significance are bile, feces, milk and sweat. Glomerular filtration, active tubular secretion, and tubular reabsorption are the main processes involved. Efficacy Sulfacetamide is a sulfonamide antibiotic, that is used as a cream to treat skin infections and as eye drops to treat eye infections. On the skin it is used to treat acne and seborrheic dermatitis. In cream form it is used to treat bacterial infections on the skin. It can also be used orally to treat urinary tract infections. It kills the bacteria by restricting the production of folic acid, which is essential for bacterial growth. It mainly inhibits the multiplication of bacteria as it acts in a competitive inhibitor. Side effects The most common side effects are irritation, stinging or burning of the skin. Other side effects include nausea, vomiting, dizziness, tiredness and headache. There are however also severe side effects including severe allergic reactions, like (nettle) rash, itch, tightness in chest, difficult breathing and swelling in either the face, mouth, lips or tongue. Other severe side effects include bloody or severe diarrhea, fever, joint pain, red, blistered or swollen skin and stomach pain. In the eye, it can cause conjunctivitis. There are also life-threatening conditions which can be produced by the antibiotic, like Stevens Johnson syndrome and Erythema multiforme. Higher exposure can also cause unconsciousness. One case showed that sulfacetamide eyedrops can very rarely cause life-threatening skin condition toxic epidermal necrolysis (TEN). These are however not all side effects. For more information the health care provider can be contacted. Sulfacetamide should not be used by individuals who have a sensitivity to sulfur or sulfa. Toxicity The acute oral toxicity (LD50) in a mouse is 16.5 g/kg. As this falls within Toxicity Category IV of the toxicity category rating for oral administration, it is practically non-toxic and also not an irritant when taken in orally. However, it is very hazardous in case of skin contact (irritant), ingestion and inhalation. Research proved that it is more toxic in the presence of light than in the dark. Sulfacetamide is slightly irritant when UV-A light is present. In the presence of light sulfacetamide gets sensitized and degraded which might cause irritation which will lead to toxicity when it is used continuously. In the dark only slight irritation has been shown. Therefore it should be stored in the dark.There are no known carcinogenic and mutagenic effects. It has a moderate toxicity according to the Chemwatch hazard ratings. First aid measures First aid measures: Effects on organisms Sulfonamides are generally effective against most gram-positive and many gram-negative organisms. Specifically enteric bacteria and other eubacteria are affected by the antibiotic as it kills the bacteria by restricting the production of folic acid, which is essential for their growth. However strains of bacteria can be resistant to the antibiotic. If a bacterium is resistant to a sulfonamide, it is resistant to all the forms. Furthermore, sulfacetamide is toxic to soil organisms. Synthesis Sulfacetamide is synthesized either by direct alkylation of acetamide with 4-aminobenzenesulfonyl chloride, or by reacting 4-aminobenzenesulfonamide with acetic anhydride and subsequent selective, reductive deacylation of the resultant acetamide using a system of zinc-sodium hydroxide. == References ==
Ceftazidime	Ceftazidime, sold under the brand name Fortaz among others, is a third-generation cephalosporin antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for joint infections, meningitis, pneumonia, sepsis, urinary tract infections, malignant otitis externa, Pseudomonas aeruginosa infection, and vibrio infection. It is given by injection into a vein, muscle, or eye.Common side effects include nausea, allergic reactions, and pain at the site of injection. Other side effects may include Clostridium difficile diarrhea. It is not recommended in people who have had previous anaphylaxis to a penicillin. Its use is relatively safe during pregnancy and breastfeeding. It is in the third-generation cephalosporin family of medications and works by interfering with the bacterias cell wall.Ceftazidime was patented in 1978 and came into commercial use in 1984. It is on the World Health Organizations List of Essential Medicines. Ceftazidime is available as a generic medication. Medical uses Ceftazidime is used to treat lower respiratory tract, skin, urinary tract, blood-stream, joint, and abdominal infections, and meningitis.Ceftazidime is the first-line treatment for the tropical infection, melioidosis, an important cause of sepsis in Asia and Australia.Labeled indications include the treatment of patients with: Pseudomonas aeruginosa infections other Gram-negative, aerobic infections neutropenic feverAs a class, cephalosporins have activity against Gram-positive and Gram-negative bacteria. The balance of activity tips toward Gram-positive organisms for earlier generations; later generations of cephalosporins have more Gram-negative coverage. Ceftazidime is one of the few in this class with activity against Pseudomonas aeruginosa. It is not active against methicillin-resistant Staphylococcus aureus. Spectrum of activity Clinically relevant organisms against which ceftazidime has activity include: Gram-negative aerobes such as Enterobacter, Escherichia coli, Haemophilus influenzae, Klebsiella spp., Proteus spp., Pseudomonas aeruginosa, and Neisseria meningitidis Gram-positive aerobes, such as group B streptococci, Streptococcus pneumoniae, and Streptococcus pyogenesCeftazidime generally has poor efficacy against anaerobes, such as Bacteroides spp.The following represents MIC susceptibility data for a few clinically significant pathogens: Escherichia coli – 0.015 μg/mL – 512 μg/mL Pseudomonas aeruginosa – ≤0.03 μg/mL – 1024 μg/mL Side effects Ceftazidime is generally well tolerated. When side effects occur, they are most commonly local effects from the intravenous line site, allergic reactions, and gastrointestinal symptoms. According to one manufacturer, in clinical trials, allergic reactions including itching, rash, and fever, happened in fewer than 2% of patients. Rare but more serious allergic reactions, such as toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme, have been reported with this class of antibiotics, including ceftazidime. Gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal pain, were reported in fewer than 2% of patients.Another source reported, in addition, blood tests of patients may show increased eosinophils (8%), increased lactate dehydrogenase (6%), increased gamma-glutamyl transferase (5%), positive direct Coombs test (4%), increased platelets (thrombocythemia) (2%), increased ALT (7%), increased AST (6%), or increased alkaline phosphatase (4%). Contraindications Ceftazidime is contraindicated in people with a known allergy to ceftazidime or to any other cephalosporin antibiotic. Precautions Ceftazidime is mainly eliminated by the kidneys into the urine. As such, drug levels in the blood may build up in persons with kidney injury or kidney disease. This includes those on dialysis. In these cases of renal impairment, the drug is dosed less frequently. No dose adjustment is needed for those with liver disease. Pregnancy According to the manufacturer, research studies in mice and rats showed no evidence of harm to the fetus, even at up to 40 times the human dose of ceftazidime. Importantly, though, no high-quality research studies of the effects of the drug in pregnant women were conducted. Mechanism of action Third-generation cephalosporins differ from earlier generations in the presence of a C=N-OCH3 group in their chemical structure (cefuroxime & cefuzonam also bear this functional group but are only listed as class II). This group provides improved stability against certain beta-lactamase enzymes produced by Gram-negative bacteria. These bacterial enzymes rapidly destroy earlier-generation cephalosporins by breaking open the drugs beta-lactam chemical ring, leading to antibiotic resistance. Though initially active against these bacteria, with widespread use of third-generation cephalosporins, some Gram-negative bacteria that produce extended-spectrum beta-lactamases (ESBLs) are even able to inactivate the third-generation cephalosporins. Infections caused by ESBL-producing Gram-negative bacteria are of particular concern in hospitals and other healthcare facilities. Chemistry In addition to the syn-configuration of the imino side chain, compared to other third-generation cephalosporins, the more complex moiety (containing two methyl and a carboxylic acid group) confers extra stability to β-lactamase enzymes produced by many Gram-negative bacteria. The extra stability to β-lactamases increases the activity of ceftazidime against otherwise resistant Gram-negative organisms including Pseudomonas aeruginosa. The charged pyridinium moiety increases water-solubility. Ceftazidime shares the same variable R-group side chain with aztreonam, a monobactam antibiotic; the two drugs share a similar spectrum of activity, including activity against Pseudomonas aeruginosa. See also Ceftazidime/avibactam References External links "Ceftazidime". Drug Information Portal. U.S. National Library of Medicine.
Vestura	Vestura is a monotypic moth genus of the family Erebidae erected by Charles Swinhoe in 1904. Its only species, Vestura minereusalis, was first described by Francis Walker in 1859. It is found in Borneo, Sumatra and Singapore. == References ==
Dornase alfa	Dornase alfa (proprietary name Pulmozyme from Genentech) is a highly purified solution of recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. Dornase alfa hydrolyzes the DNA present in sputum/mucus of cystic fibrosis patients and reduces viscosity in the lungs, promoting improved clearance of secretions. This protein therapeutic agent is produced in Chinese hamster ovary cells. Cystic fibrosis Dornase alfa is the most recent therapeutic agent developed with this basic mechanism of action. Prior to the cloning of the human enzyme, bovine DNase I was on the market for many years, though its utility was limited by the inherent antigenic response to a cow protein in the lungs of patients. Other DNases, such as DNase II, have therapeutic potential as well, but no further DNases have been brought to market yet for cystic fibrosis. Dornase alfa is an orphan drug. Contraindications Hypersensitivity to dornase alfa Hypersensitivity to Chinese hamster ovary cell products Economy Dornase alpha 1000 units (1 mg/ml)2.5ml (2500units) = £18.52 (GBP) Off label use Dornase alfa has recently been shown to improve lung function in non-cystic fibrosis pre-term infants atelectasis where other therapies have failed.In studies conducted, Dornase alfa has been thought to help resolve mucus secretion in COVID-19 patients as well as in the treatment of cystic fibrosis, but since it is taken with nebulizer in general use and there is a possibility of aerosolization of the virus, it is not preferred in most medical centers to avoid secondary infections. == References ==
Hydromorphone	Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours.Common side effects include dizziness, sleepiness, nausea, itchiness, and constipation. Serious side effects may include abuse, low blood pressure, seizures, respiratory depression, and serotonin syndrome. Rapidly decreasing the dose may result in opioid withdrawal. Generally, use during pregnancy or breastfeeding is not recommended. Hydromorphone is believed to work by activating opioid receptors, mainly in the brain and spinal cord. Hydromorphone 2 mg IV is equivalent to approximately 10 mg morphine IV.Hydromorphone was patented in 1923. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2017, it was the 205th most commonly prescribed medication in the United States, with more than two million prescriptions. Hydromorphone is made from morphine. Medical use Hydromorphone is used to treat moderate to severe pain. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours. Typically, long-term use is only recommended for pain due to cancer. A 2016 Cochrane review found little difference in benefit between hydromorphone and other opioids for cancer pain. Side effects Adverse effects of hydromorphone are similar to those of other potent opioid analgesics, such as morphine and heroin. The major hazards of hydromorphone include dose-related respiratory depression, urinary retention, bronchospasm, and sometimes, circulatory depression. More common side effects include lightheadedness, dizziness, sedation, itching, constipation, nausea, vomiting, headache, perspiration, and hallucinations. These symptoms are common in ambulatory patients and in those not experiencing severe pain. Simultaneous use of hydromorphone with other opioids, muscle relaxants, tranquilizers, sedatives, and general anesthetics may cause a significant increase in respiratory depression, progressing to coma or death. Taking benzodiazepines (such as diazepam) in conjunction with hydromorphone may increase side effects such as dizziness and difficulty concentrating. If simultaneous use of these drugs is required, dose adjustment may be made.A particular problem that may occur with hydromorphone is accidental administration in place of morphine due to a mix-up between the similar names, either at the time the prescription is written or when the drug is dispensed. This has led to several deaths and calls for hydromorphone to be distributed in distinctly different packaging from morphine to avoid confusion.Massive overdoses are rarely observed in opioid-tolerant individuals, but when they occur, they may lead to circulatory system collapse. Symptoms of overdose include respiratory depression, drowsiness leading to coma and sometimes to death, drooping of skeletal muscles, low heart rate, and decreasing blood pressure. At the hospital, individuals with hydromorphone overdose are provided supportive care, such as assisted ventilation to provide oxygen and gut decontamination using activated charcoal through a nasogastric tube. Opioid antagonists, such as naloxone, also may be administered concurrently with oxygen supplementation. Naloxone works by reversing the effects of hydromorphone, and only is administered in the presence of significant respiratory depression and circulatory depression.Sugar cravings associated with hydromorphone use are the result of a glucose crash after transient hyperglycemia following injection, or a less profound lowering of blood sugar over a period of hours, in common with morphine, heroin, codeine, and other opiates. Hormone imbalance As with other opioids, hydromorphone (particularly during heavy chronic use) often causes temporary hypogonadism or hormone imbalance. Neurotoxicity In the setting of prolonged use, high dosage, and/or kidney dysfunction, hydromorphone has been associated with neuroexcitatory symptoms such as tremor, myoclonus, agitation, and cognitive dysfunction. This toxicity is less than that associated with other classes of opioids such as the pethidine class of synthetics in particular. Withdrawal Users of hydromorphone may experience painful symptoms if the drug is suspended. Some people cannot tolerate the symptoms, which results in continuous drug use. Symptoms of opioid withdrawal are not easy to decipher, as there are differences between drug-seeking behaviors and true withdrawal effects. Symptoms associated with hydromorphone withdrawal include: Abdominal pain Anxiety or panic attacks Depression Goose bump skin Inability to enjoy daily activities Muscle and joint pain Nausea Runny nose and excessive secretion of tears Sweating VomitingIn the clinical setting, excessive secretion of tears, yawning, and dilation of pupils are helpful presentations in diagnosing opioid withdrawal. Hydromorphone is a rapid acting pain killer; however, some formulations may last up to several hours. Patients who stop taking this drug abruptly may experience withdrawal symptoms, which may start within hours of taking the last dose of hydromorphone, and last up to several weeks. Withdrawal symptoms in people who stopped taking the opioid may be managed by using opioids or non-opioid adjuncts. Methadone is an opioid commonly used for this kind of therapy. However, the selection of therapy should be tailored to each specific person. Methadone also is used for detoxification in people who have opiate addiction, such as heroin or drugs similar to morphine. It may be given orally or intramuscularly. There is controversy regarding the use of opioids for people experiencing withdrawal symptoms, since these agents also may cause relapse on patients when they suspend therapy. Clonidine is a non-opioid adjunct, which may be used in situations where opioid use is not desired, such as in patients with high blood pressure. Interactions CNS depressants may enhance the depressant effects of hydromorphone, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, benzodiazepines, phenothiazines, chloral hydrate, dimenhydrinate, and glutethimide. The depressant effect of hydromorphone also may be enhanced by monoamine oxidase inhibitors (MAO inhibitors), first-generation antihistamines (brompheniramine, promethazine, diphenhydramine, chlorphenamine), beta blockers, and alcohol. When combined therapy is contemplated, the dose of one or both agents should be reduced. Pharmacology Hydromorphone is a semi-synthetic μ-opioid agonist. As a hydrogenated ketone of morphine, it shares the pharmacologic properties typical of opioid analgesics. Hydromorphone and related opioids produce their major effects on the central nervous system and gastrointestinal tract. These include analgesia, drowsiness, mental clouding, changes in mood, euphoria or dysphoria, respiratory depression, cough suppression, decreased gastrointestinal motility, nausea, vomiting, increased cerebrospinal fluid pressure, increased biliary pressure, and increased pinpoint constriction of the pupils. Formulations Hydromorphone is available in parenteral, rectal, subcutaneous, and oral formulations, and also can be administered via epidural or intrathecal injection. Hydromorphone also has been administered via nebulization to treat shortness of breath, but it is not used as a route for pain control due to low bioavailability. Transdermal delivery systems are also under consideration to induce local skin analgesia.Concentrated aqueous solutions of hydromorphone hydrochloride have a visibly different refractive index from pure water, isotonic 9‰ (0·9 per cent) saline and the like, especially when stored in clear ampoules and phials may acquire a slight clear amber discolouration upon exposure to light; this reportedly has no effect on the potency of the solution, but 14-dihydromorphinones such as hydromorphone, oxymorphone, and relatives come with instructions to protect from light. Ampoules of solution which have developed a precipitate should be discarded.Battery-powered intrathecal drug delivery systems are implanted for chronic pain when other options are ruled out, such as surgery and traditional pharmacotherapy, provided that the patient is considered a suitable fit in terms of any contraindications, both physiological and psychological.An extended-release (once-daily) version of hydromorphone is available in the United States. Previously, an extended-release version of hydromorphone, Palladone, was available before being voluntarily withdrawn from the market after a July 2005 FDA advisory warned of a high overdose potential when taken with alcohol. As of March 2010, it is still available in the United Kingdom under the brand name Palladone SR, Nepal under the brand name Opidol, and in most other European countries. Pharmacokinetics The chemical modification of the morphine molecule to hydromorphone results in higher lipid solubility and greater ability to cross the blood–brain barrier to produce more rapid and complete central nervous system penetration. On a per milligram basis, hydromorphone is considered to be five times as potent as morphine; although the conversion ratio may vary from 4–8 times, five times is in typical clinical usage. The development of tolerance also may vary among individuals. Patients with renal abnormalities must exercise caution when dosing hydromorphone. In those with renal impairment, the half-life of hydromorphone may increase to as much as 40 hours. The typical half-life of intravenous hydromorphone is 2.3 hours. Peak plasma levels usually occur between 30 and 60 minutes after oral dosing.The onset of action for hydromorphone administered intravenously is less than 5 minutes and within 30 minutes of oral administration (immediate release). Metabolism While other opioids in its class, such as codeine or oxycodone, are metabolized via CYP450 enzymes, hydromorphone is not. Hydromorphone is extensively metabolized in the liver to hydromorphone-3-glucoronide, which has no analgesic effects. As similarly seen with the morphine metabolite, morphine-3-glucoronide, a build-up in levels of hydromorphone-3-glucoronide may produce excitatory neurotoxic effects such as restlessness, myoclonus and hyperalgesia. Patients with compromised kidney function and older patients are at higher risk for metabolite accumulation. Chemistry With a formula of C17H19NO3 and a molecular weight of 285.343, both identical to morphine, hydromorphone can be considered a structural isomer of morphine and is a hydrogenated ketone thereof.Hydromorphone is made from morphine either by direct re-arrangement (made by reflux heating of alcoholic or acidic aqueous solution of morphine in the presence of platinum or palladium catalyst) or reduction to dihydromorphine (usually via catalytic hydrogenation), followed by oxidation with benzophenone in presence of potassium tert butoxide or aluminium tert butoxide (Oppenauer oxidation). The 6 ketone group may be replaced with a methylene group via the Wittig reaction to produce 6-Methylenedihydrodesoxymorphine, which is 80× stronger than morphine.Changing morphine into hydromorphone increases its activity and, therefore, makes hydromorphone approximately eight times stronger than morphine on a weight basis, all other things being equal. Changed also is lipid solubility, contributing to hydromorphones having a more rapid onset of action and alterations to the overall absorption, distribution, metabolism, and elimination profile as well as the side effect profile (in general, less nausea and itching) versus that of morphine. The semi-synthetic opiates, of which hydromorphone and its codeine analogue hydrocodone are among the best-known and oldest, include a huge number of drugs of varying strengths and with differences among themselves both subtle and stark, allowing for many different options for treatment. Hydromorphone is more soluble in water than morphine; therefore, hydromorphone solutions may be produced to deliver the drug in a smaller volume of water. The hydrochloride salt is soluble in three parts of water, whereas a gram of morphine hydrochloride dissolves in 16 ml of water; for all common purposes, the pure powder for hospital use can be used to produce solutions of virtually arbitrary concentration. When the powder appeared on the street, this very small volume of powder needed for a dose means that overdoses are likely for those who mistake it for heroin or other powdered narcotics, especially those that have been diluted prior to consumption. Endogenous production Hydromorphone is made from morphine via catalytic hydrogenation and also is produced in trace amounts by human and other mammalian metabolisms of morphine. It occasionally appears in assays of opium latex in very small quantities, apparently forming in the plant in an unknown percentage of cases under poorly understood conditions. Bacteria Some bacteria have been shown to be able to turn morphine into closely related drugs, including hydromorphone and dihydromorphine among others. The bacterium Pseudomonas putida serotype M10 produces a naturally-occurring NADH-dependent morphinone reductase that can work on unsaturated 7,8 bonds, with result that, when these bacteria are living in an aqueous solution containing morphine, significant amounts of hydromorphone form, as it is an intermediary metabolite in this process; the same goes for codeine being turned into hydrocodone.The process gave rise to various concentrations of hydromorphone, dihydromorphine, hydromorphinol, and oxymorphone during the experiments. Three paths were found: from morphine to hydromorphone with dihydromorphine as the penultimate step, from morphine to hydromorphone with morphinone as the penultimate step, and from morphine to hydromorphinol to hydromorphone. History Hydromorphone was patented in 1923. It was introduced to the mass market in 1926 under the brand name Dilaudid, indicating its derivation and degree of similarity to morphine (by way of laudanum). Society and culture Names Hydromorphone is known in various countries around the world by the brand names Hydal, Dimorphone, Exalgo, Sophidone LP, Dilaudid, Hydrostat, Hydromorfan, Hydromorphan, Hymorphan, Laudicon, Opidol, Palladone, Hydromorph Contin, and others. An extended-release version of hydromorphone, called Palladone, was available for a short time in the United States before being voluntarily withdrawn from the market after a July 2005 FDA advisory warned of a high overdose potential when taken with alcohol. As of March 2010, it is still available in Nepal under the brand name Opidol, in the United Kingdom under the brand name Palladone SR, and in most other European countries. There has also been a once-daily prolonged release version of hydromorphone available in Australia under the brand name Jurnista as of May 2009. Legal status In the United States, the main drug control agency, the Drug Enforcement Administration, reports an increase in annual aggregate production quotas of hydromorphone from 766 kilograms (1,689 pounds) in 1998 to 3,300 kilograms (7,300 lb) in 2006, and an increase in prescriptions in this time of 289%, from about 470,000 to 1,830,000. The 2013 production quota was 5,968 kilograms (13,157 lb).Like all opioids used for analgesia, hydromorphone is potentially habit-forming and is listed in Schedule II of the United States Controlled Substances Act of 1970 as well as in similar levels under the drugs laws of practically all other countries and it is listed in the Single Convention On Narcotic Drugs. The DEA ACSCN for hydromorphone is 9150. Hydromorphone is listed under the German Betäubungsmittelgesetz as a Betäubungsmittel in the most restricted schedule for medicinal drugs; it is controlled similarly in Austria (Suchtgift) under the SMG and the Swiss BetmG. The Misuse of Drugs Act 1971 (United Kingdom) and comparable French, Canadian, Australian, Italian, Czech, Croatian, Slovenian, Swedish, Polish, Spanish, Greek, Russian, and other laws similarly control it, as do regulations in virtually all other countries. Use in executions In 2009, Ohio approved the use of an intramuscular injection of 500 mg of hydromorphone and a supratherapeutic dose of midazolam as a backup means of carrying out executions when a suitable vein cannot be found for intravenous injection.Hydromorphone and midazolam was injected intravenously to execute double-murderer Joseph Wood in Arizona on 24 July 2014. Wood was heavily sedated (surgical anesthesia) within four minutes from start, but took almost two hours to transition to stage 4 (cessation of respiration) and death. References External links "Hydromorphone". Drug Information Portal. U.S. National Library of Medicine. Article discussing withdrawal of extended-release hydromorphone from the U.S. market Dihydromorphinones from morphine & analogues United States DEAs perspective, including statistics on manufacture and prescription levels from 1998 to 2006 "When is a pain doctor a drug pusher?", The New York Times, 17 Jun 2007
Hydroxocobalamin	Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment for cyanide poisoning, Lebers optic atrophy, and toxic amblyopia. It is given by injection into a muscle or vein.Side effects are generally few. They may include diarrhea, low blood potassium, allergic reactions, and high blood pressure. Normal doses are considered safe in pregnancy. Hydroxocobalamin is the natural form of vitamin B12 and a member of the cobalamin family of compounds. Hydroxocobalamin, or another form of vitamin B12, are required for the body to make DNA.Hydroxocobalamin was first isolated in 1949. It is on the World Health Organizations List of Essential Medicines. Hydroxocobalamin is available as a generic medication. Commercially it is made using one of a number of types of bacteria. Medical uses Vitamin B12 deficiency Standard therapy for treatment of vitamin B12 deficiency has been intramuscular (IM) or intravenous (IV) injections of hydroxocobalamin (OHCbl), since the majority of cases are due to malabsorption by the enteral route (gut). It is used pediatric patients with intrinsic cobalamin metabolic diseases, vitamin B12-deficient patients with tobacco amblyopia due to cyanide poisoning, and patients with pernicious anemia who have optic neuropathy.In a newly diagnosed vitamin B12-deficient patient, normally defined as when serum levels are less than 200 pg/ml, daily IM injections of hydroxocobalamin up to 1,000 μg (1 mg) per day are given to replenish the bodys depleted cobalamin stores. In the presence of neurological symptoms, following daily treatment, injections up to weekly or biweekly are indicated for six months before initiating monthly IM injections. Once clinical improvement is confirmed, maintenance supplementation of B12 will generally be needed for life. Cyanide poisoning Hydroxocobalamin is first line therapy for people with cyanide poisoning. Hydroxocobalamin converts cyanide to the much less toxic cyanocobalamin. Cyanocobalamin is renally cleared. The use of hydroxocobalamin became first line due to its low adverse risk profile, rapid onset of action, and ease of use in the prehospital setting. Injectable hydroxocobalamin Injection of hydroxocobalamin is used to rectify the following causes of vitamin B12 deficiency (list taken from the drug prescription label published by the U.S. Food and Drug Administration) Dietary deficiency of vitamin B12 occurring in strict vegetarians and in their breastfed infants (isolated vitamin B12 deficiency is very rare) Malabsorption of vitamin B12 resulting from damage to the stomach, where intrinsic factor is secreted, or damage to the ileum, where intrinsic factor facilitates vitamin B12 absorption. These conditions include tropical sprue and nontropical sprue (celiac disease). Inadequate secretion of intrinsic factor, resulting from lesions that destroy the gastric mucosa (which can be caused by ingestion of corrosives, extensive tumors, and conditions associated with gastric atrophy, such as multiple sclerosis, certain endocrine disorders, iron deficiency, and subtotal gastrectomy) Structural lesions leading to vitamin B12 deficiency, including regional ileitis, ileal reactions, and malignancies Competition for vitamin B12 by intestinal parasites or bacteria. The tapeworm from undercooked fish (Diphyllobothrium latum) absorbs huge quantities of vitamin B12, and infested patients often have associated gastric atrophy. The blind loop syndrome may produce deficiency of vitamin B12 or folate. Inadequate use of vitamin B12, which may occur if antimetabolites for the vitamin are employed in the treatment of neoplasiaPernicious anemia is the most common cause of vitamin B12 deficiency. While it technically refers to anemia caused specifically by autoimmune deficiency of intrinsic factor, it is commonly used to refer to B12-deficient anemia as a whole, regardless of cause. Side effects The literature data on the acute toxicity profile of hydroxocobalamin show it is generally regarded as safe with local and systemic exposure. The ability of hydroxocobalamin to rapidly scavenge and detoxify cyanide by chelation has resulted in several acute animal and human studies using systemic hydroxocobalamin doses at suprapharmacological doses as high as 140 mg/kg to support its use as an intravenous (IV) treatment for cyanide exposure. The US FDA at the end of 2006 approved the use hydroxocobalamin as an injection for the treatment of cyanide poisoning. The drug causes a reddish discoloration of the urine (chromaturia), which can look like blood in the urine. Properties Hydroxocobalamin acetate occurs as odorless, dark-red orthorhombic crystals. The injection formulations appear as clear, dark-red solutions. It has a distribution coefficient of 1.133 × 10-5 and a pKa of 7.65. Mechanism of action Vitamin B12 refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folate, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions: the mitochondrial methylmalonyl-CoA mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and the activation of methionine synthase, which is the rate-limiting step in the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate.Cobalamins are characterized by a porphyrin-like corrin nucleus that contains a single cobalt atom bound to a benzimidazolyl nucleotide and a variable residue (R) group. The variable R group gives rise to the four most commonly known cobalamins: CNCbl, methylcobalamin, 5-deoxyadenosylcobalamin, and OHCbl. In the serum, hydroxocobalamin and cyanocobalamin are believed to function as storage or transport forms of the molecule, whereas methylcobalamin and 5-deoxyadenosylcobalamin are the active forms of the coenzyme required for cell growth and replication. Cyanocobalamin is usually converted to hydroxocobalamin in the serum, whereas hydroxocobalamin is converted to either methylcobalamin or 5-deoxyadenosyl cobalamin. Cobalamins circulate bound to serum proteins called transcobalamins (TC) and haptocorrins. Hydroxocobalamin has a higher affinity to the TC II transport protein than cyanocobalamin, or 5-deoxyadenosylcobalamin. From a biochemical point of view, two essential enzymatic reactions require vitamin B12 (cobalamin).Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and 5-deoxyadenosylcobalamin. In the face of vitamin B12 deficiency, conversion of methylmalonyl-CoA to succinyl-CoA cannot take place, which results in accumulation of methylmalonyl-CoA and aberrant fatty acid synthesis. In the other enzymatic reaction, methylcobalamin supports the methionine synthase reaction, which is essential for normal metabolism of folate. The folate-cobalamin interaction is pivotal for normal synthesis of purines and pyrimidines and the transfer of the methyl group to cobalamin is essential for the adequate supply of tetrahydrofolate, the substrate for metabolic steps that require folate. In a state of vitamin B12 deficiency, the cell responds by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate. The resulting elevated concentrations of homocysteine and MMA are often found in patients with low serum vitamin B12 and can usually be lowered with successful vitamin B12 replacement therapy. However, elevated MMA and homocysteine concentrations may persist in patients with cobalamin concentrations between 200 and 350 pg/mL. Supplementation with vitamin B12 during conditions of deficiency restores the intracellular level of cobalamin and maintains a sufficient level of the two active coenzymes: methylcobalamin and deoxyadenosylcobalamin. See also Methylcobalamin Cyanocobalamin Adenosylcobalamin Vitamin B12 Cobalamin biosynthesis Nitric oxide References External links Hydroxocobalamin in the ChEBI database "Hydroxocobalamin". Drug Information Portal. U.S. National Library of Medicine.
Butalbital/acetaminophen	Butalbital/acetaminophen, sold under the brand name Butapap among others, is a combination medication used to treat tension headaches and migraine headaches. It contains butalbital, a barbiturate and paracetamol (acetaminophen), an analgesic. Versions also containing caffeine are sold under the brand name Fioricet among others. It is taken by mouth. The combination is also sold with codeine.The most common side effects include sleepiness, dizziness, trouble breathing, and abdominal pain. Other severe side effects may include liver problems, confusion, addiction, and allergic reactions. Frequent use may result in medication overuse headache. Barbiturate withdrawal may occur if rapidly stopped following long term use. Use is not generally recommended during pregnancy or breastfeeding.The combination was approved for medical use in the United States in 1984. It is available as a generic medication. In 2019, the combination butalbital/acetaminophen/caffeine was the 228th most commonly prescribed medication in the United States, with more than 2 million prescriptions. In the United States it is a schedule III controlled substance in some states but not federally. It is banned in a number of European countries. Medical uses Butalbital/acetaminophen is indicated for the treatment of tension headaches.Butalbital/acetaminophen/caffeine is indicated for the treatment of tension headaches. Side effects Commonly reported side effects include euphoria, dizziness or lightheadedness, drowsiness or sedation, intoxication, nausea, vomiting, dependence, shortness of breath, and abdominal pain.Prolonged use can cause rebound headaches.Rarely, use of barbiturates can lead to Stevens–Johnson syndrome. Overdose Butalbital exerts its toxicity through excessive sedation, resulting in respiratory depression and ultimately death via hypoxia. Nonlethal overdoses may also result in coma and death. There is no specific antidote to barbiturate overdose; treatment is supportive, generally including the administration of intravenous saline, naloxone, thiamine, glucose, sodium bicarbonate to alkalize the urine and increase rate of excretion, and activated charcoal via nasogastric tube.Acetaminophen exerts its toxicity through the production of a toxic metabolite that can cause liver damage at doses as low as four grams. Larger doses can precipitate acute liver failure, acute kidney injury, or gastrointestinal bleeding; death has been known to occur with ingestion of ten to fifteen grams. The specific antidote to acetaminophen overdose is N-acetylcysteine. Mechanism of action Butalbital exerts a generalized depressant effect on the central nervous system and, in very high doses, has peripheral effects. Acetaminophen has analgesic and antipyretic effects mediated by a metabolite that acts at cannabinoid receptors. Caffeine is thought to produce constriction of cerebral blood vessels and serves to counteract the sedative effect of butalbital.Butalbital has a half-life of about 35 hours. Acetaminophen has a half-life of about 1.25 to 3 hours, but may be increased by liver damage and after an overdose. Caffeine has a half-life of about 2.5 to 4.5 hours. References External links "Acetaminophen mixture with butalbital". Drug Information Portal. U.S. National Library of Medicine. "Acetaminophen mixture with butalbital and caffeine". Drug Information Portal. U.S. National Library of Medicine.
Permethrin	Permethrin is a medication and an insecticide. As a medication, it is used to treat scabies and lice. It is applied to the skin as a cream or lotion. As an insecticide, it can be sprayed onto clothing or mosquito nets to kill the insects that touch them.Side effects include rash and irritation at the area of use. Use during pregnancy appears to be safe. It is approved for use on and around people over the age of two months. Permethrin is in the pyrethroid family of medications. It works by disrupting the function of the neurons of lice and scabies mites.Permethrin was discovered in 1973. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 410th most commonly prescribed medication in the United States, with more than 150 thousand prescriptions. Uses Insecticide In agriculture, to protect crops (a drawback is that it is lethal to bees) In agriculture, to kill livestock parasites For industrial and domestic insect control In the textile industry, to prevent insect attack of woollen products In aviation, the WHO, IHR and ICAO require arriving aircraft be disinsected prior to embarkation, departure, descent, or deplaning in certain countries. Aircraft disinsection with permethrin-based products is recommended only prior to embarkation. Prior to departure (after boarding), at the top of descent or on arrival, d-phenothrin-based (1R-trans phenothrin) aircraft insecticides are recommended. Insect repellent As a personal protective measure, permethrin is applied to clothing. It is a cloth impregnant, notably in mosquito nets and field wear. While permethrin may be marketed as an insect repellent, it does not prevent insects from landing. Instead it works by incapacitating or killing insects before they can bite. In pet flea preventive collars or treatment (safe for use on dogs but not cats) In timber treatment Medical use Permethrin is available for topical use as a cream or lotion. It is indicated for the treatment and prevention in exposed individuals of head lice and treatment of scabies.For treatment of scabies: Adults and children older than 2 months are instructed to apply the cream to the entire body from head to the soles of the feet. Wash off the cream after 8–14 hours. In general, one treatment is curative.For treatment of head lice: Apply to hair, scalp, and neck after shampooing. Leave in for 10 minutes and rinse. Avoid contact with eyes. Pest control / effectiveness and persistence In agriculture, permethrin is mainly used on cotton, wheat, maize, and alfalfa crops. Its use is controversial because, as a broad-spectrum chemical, it kills indiscriminately; as well as the intended pests, it can harm beneficial insects, including honey bees, as well as cats and aquatic life.Permethrin kills ticks and mosquitoes on contact with treated clothing. A method of reducing deer tick populations by treating rodent vectors involves stuffing biodegradable cardboard tubes with permethrin-treated cotton. Mice collect the cotton for lining their nests. Permethrin on the cotton kills any immature ticks feeding on the mice. Permethrin is used in tropical areas to prevent mosquito-borne disease such as dengue fever and malaria. Mosquito nets used to cover beds may be treated with a solution of permethrin. This increases the effectiveness of the bed net by killing parasitic insects before they are able to find gaps or holes in the net. Personnel working in malaria-endemic areas may be instructed to treat their clothing with permethrin as well. Permethrin is the most commonly used insecticide worldwide for the protection of wool from keratinophagous insects such as Tineola bisselliella.To better protect soldiers from the risk and annoyance of biting insects, the British and US armies are treating all new uniforms with permethrin.Permethrin (as well as other long-term pyrethroids) is effective over several months, in particular when used indoors. International studies report that permethrin can be detected in house dust, in fine dust, and on indoor surfaces even years after the application. Its degradation rate under indoor conditions is approximately 10% after 3 months. Resistance Contrary to the most common mechanism of insecticide resistance evolution – selection for preexisting, low-frequency alleles – in Aedes aegypti permethrin resistance has arisen through the mechanism common to pyrethroids and DDT known as "knockdown resistance" (kdr) mutations. García et al 2009 found that a kdr allele has rapidly spread throughout Mexico and recently become dominant there. Side effects Permethrin application can cause mild skin irritation and burning. Permethrin has little systemic absorption, and is considered safe for topical use in adults and children over the age of two months. The FDA has assigned it as pregnancy category B. Animal studies have shown no effects on fertility or teratogenicity, but studies in humans have not been performed. The excretion of permethrin in breastmilk is unknown, and it is recommended that breastfeeding be temporarily discontinued during treatment. Skin reactions are uncommon. Excessive exposure to permethrin can cause nausea, headache, muscle weakness, excessive salivation, shortness of breath, and seizures. Worker exposure to the chemical can be monitored by measurement of the urinary metabolites, while severe overdose may be confirmed by measurement of permethrin in serum or blood plasma.Permethrin does not present any notable genotoxicity or immunotoxicity in humans and farm animals, but is classified by the EPA as a likely human carcinogen when ingested, based on reproducible studies in which mice fed permethrin developed liver and lung tumors. Pharmacokinetics Permethrin is a chemical categorized in the pyrethroid insecticide group. The chemicals in the pyrethroid family are created to emulate the chemicals found in the chrysanthemum flower. Absorption Absorption of topical permethrin is minimal. One in vivo study demonstrated 0.5% absorption in the first 48 hours based upon excretion of urinary metabolites. Distribution Distribution of permethrin has been studied in rat models, with highest amounts accumulating in fat and the brain. This can be explained by the lipophilic nature of the permethrin molecule. Metabolism Metabolism of permethrin occurs mainly in the liver, where the molecule undergoes oxidation by the cytochrome P450 system, as well as hydrolysis, into metabolites. Elimination of these metabolites occurs via urinary excretion. Stereochemistry Permethrin has four stereoisomers (two enantiomeric pairs), arising from the two stereocenters in the cyclopropane ring. The trans enantiomeric pair is known as transpermethrin. (1R,3S)-trans and (1R,3R)-cis enantiomers are responsible for the insecticidal properties of permethrin. History Permethrin was first made in 1973.Numerous synthetic routes exist for the production of the DV-acid ester precursor. The pathway known as the Kuraray Process uses four steps. In general, the final step in the total synthesis of any of the synthetic pyrethroids is a coupling of a DV-acid ester and an alcohol. In the case of permethrin synthesis, the DV-acid cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, ethyl ester, is coupled with the alcohol, m-phenoxybenzyl alcohol, through a transesterification reaction with base. Tetraisopropyl titanate or sodium ethylate may be used as the base.The alcohol precursor may be prepared in three steps. First, m-cresol, chlorobenzene, sodium hydroxide, potassium hydroxide, and copper chloride react to yield m-phenoxytoluene. Second, oxidation of m-phenoxytoluene over selenium dioxide provides m-phenoxybenzaldehyde. Third, a Cannizzaro reaction of the benzaldehyde in formaldehyde and potassium hydroxide affords the m-phenoxybenzyl alcohol. Brand names In Nordic countries and North America, a permethrin formulation for lice treatment is marketed under trade name Nix, available over the counter. Johnson & Johnsons UK brand Lyclear covers an assortment of different products, mostly non-insecticidal, but a few of which are based on permethrin.Stronger concentrations of permethrin are used to treat scabies (which embed inside the skin), compared to lice (which remain outside the skin). In the U.S. the more concentrated products such as Elimite are available by prescription only. Other animals It is known to be highly toxic to cats, fish and aquatic species with long-lasting effects. Cats Permethrin is toxic to cats; however, it has little effect on dogs. Pesticide-grade permethrin is toxic to cats. Many cats die after being given flea treatments intended for dogs, or by contact with dogs having recently been treated with permethrin. In cats it may induce hyperexcitability, tremors, seizures, and death.Toxic exposure of permethrin can cause several symptoms, including convulsion, hyperaesthesia, hyperthermia, hypersalivation, and loss of balance and coordination. Exposure to pyrethroid-derived drugs such as permethrin requires treatment by a veterinarian, otherwise the poisoning is often fatal. This intolerance is due to a defect in glucuronosyltransferase, a common detoxification enzyme in other mammals, that also makes the cat intolerant to paracetamol (acetaminophen). The use of any external parasiticides based on permethrin is contraindicated for cats. Aquatic organisms Permethrin is listed as a "restricted use" substance by the US Environmental Protection Agency (EPA) due to its high toxicity to aquatic organisms, so permethrin and permethrin-contaminated water should be properly disposed of. Permethrin is quite stable, having a half life of 51–71 days in an aqueous environment exposed to light. It is also highly persistent in soil. See also Benzyl benzoate DEET Methoprene Pyrethrin Pyrethrum References External links Permethrin in the Pesticide Properties DataBase (PPDB) Permethrin General Fact Sheet – National Pesticide Information Center Permethrin Technical Fact Sheet – National Pesticide Information Center Permethrin-treated Clothing Hot Topic – National Pesticide Information Center "Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms", National Research Council (1994, US) Permethrin Pesticide Information Profile – Extension Toxicology Network "Permethrin". Drug Information Portal. U.S. National Library of Medicine.
Etomidate	Etomidate (USAN, INN, BAN; marketed as Amidate) is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for short procedures such as reduction of dislocated joints, tracheal intubation, cardioversion and electroconvulsive therapy. It was developed at Janssen Pharmaceutica in 1964 and was introduced as an intravenous agent in 1972 in Europe and in 1983 in the United States.The most common side effects include venous pain on injection and skeletal muscle movements. Medical uses Sedation and anesthesia In emergency settings, etomidate can be used as a sedative hypnotic agent. It is used for conscious sedation and as a part of a rapid sequence induction to induce anaesthesia. It is used as an anaesthetic agent since it has a rapid onset of action and a safe cardiovascular risk profile, and therefore is less likely to cause a significant drop in blood pressure than other induction agents. In addition, etomidate is often used because of its easy dosing profile, limited suppression of ventilation, lack of histamine liberation and protection from myocardial and cerebral ischemia. Thus, etomidate is a good induction agent for people who are hemodynamically unstable. Etomidate also has interesting characteristics for people with traumatic brain injury because it is one of the only anesthetic agents able to decrease intracranial pressure and maintain a normal arterial pressure.In those with sepsis, one dose of the medication does not appear to affect the risk of death. Speech and memory test Another use for etomidate is to determine speech lateralization in people prior to performing lobectomies to remove epileptogenic centres in the brain. This is called the etomidate speech and memory test, or eSAM, and is used at the Montreal Neurological Institute. However, only retrospective cohort studies support the use and safety of etomidate for this test. Steroidogenesis inhibitor In addition to its action and use as an anesthetic, etomidate has also been found to directly inhibit the enzymatic biosynthesis of steroid hormones, including corticosteroids in the adrenal gland. As the only adrenal steroidogenesis inhibitor available for intravenous or parenteral administration, it is useful in situations in which rapid control of hypercortisolism is necessary or in which oral administration is unfeasible. Use in executions The U.S. state of Florida used the drug in a death penalty procedure when Mark James Asay, 53, was executed on August 24, 2017. He became the first person in the U.S. to be executed with etomidate as one of the drugs. Etomidate replaces midazolam as the sedative. Drug companies have made it harder to buy midazolam for executions. The etomidate was followed by rocuronium bromide, a paralytic, and finally, potassium acetate in place of the commonly used potassium chloride injection to stop the heart. Potassium acetate was first used for this purpose inadvertently in a 2015 execution in Oklahoma. Adverse effects Etomidate suppresses corticosteroid synthesis in the adrenal cortex by reversibly inhibiting 11β-hydroxylase, an enzyme important in adrenal steroid production; it leads to primary adrenal suppression. Using a continuous etomidate infusion for sedation of critically ill trauma patients in intensive care units has been associated with increased mortality due to adrenal suppression. Continuous intravenous administration of etomidate leads to adrenocortical dysfunction. The mortality of patients exposed to a continuous infusion of etomidate for more than 5 days increased from 25% to 44%, mainly due to infectious causes such as pneumonia.Because of etomidate-induced adrenal suppression, its use for patients with sepsis is controversial. Cortisol levels have been reported to be suppressed up to 72 hours after a single bolus of etomidate in this population at risk for adrenal insufficiency. For this reason, many authors have suggested that etomidate should never be used for critically ill patients with septic shock because it could increase mortality. However, other authors continue to defend etomidates use for septic patients because of etomidates safe hemodynamic profile and lack of clear evidence of harm. A study by Jabre et al. showed that a single dose of etomidate used for Rapid Sequence Induction prior to endrotracheal intubation has no effect on mortality compared to ketamine even though etomidate did cause transient adrenal suppression. In addition, a recent meta-analysis done by Hohl could not conclude that etomidate increased mortality. The authors of this meta-analysis concluded more studies were needed because of lack of statistical power to conclude definitively about the effect of etomidate on mortality. Thus, Hohl suggests a burden to prove etomidate is safe for use in septic patients, and more research is needed before it is used. Other authors advise giving a prophylactic dose of steroids (e.g. hydrocortisone) if etomidate is used, but only one small prospective controlled study in patients undergoing colorectal surgery has verified the safety of giving stress dose corticosteroids to all patients receiving etomidate. In a retrospective review of almost 32,000 people, etomidate, when used for the induction of anaesthesia, was associated 2.5-fold increase in the risk of dying compared with those given propofol. People given etomidate also had significantly greater odds of having cardiovascular morbidity and significantly longer hospital stay. These results, especially given the large size of study, strongly suggest that, at the very least, clinicians should use etomidate judiciously. However, given this is a retrospective study, it is clearly misinterpreting how etomidate is typically used: etomidate is a drug that is reserved for sicker patients whom may not tolerate the more severe hemodynamic liability (towards lower mean pressures) and, thus the bias of this retrospective study is inconclusive, at best.In people with traumatic brain injury, etomidate use is associated with a blunting of an ACTH stimulation test. The clinical impact of this effect has yet to be determined. In addition, concurrent use of etomidate with opioids and/or benzodiazepines, is hypothesized to exacerbate etomidate-related adrenal insufficiency. However, only retrospective evidence of this effect exists and prospective studies are needed to measure the clinical impact of this interaction. Etomidate is associated with a high incidence of burning on injection, postoperative nausea and vomiting, and superficial thrombophlebitis (with rates higher than propofol). Pharmacology Pharmacodynamics (R)-Etomidate is tenfold more potent than its (S)-enantiomer. At low concentrations (R)-etomidate is a modulator at GABAA receptors containing β2 and β3 subunits. At higher concentrations, it can elicit currents in the absence of GABA and behaves as an allosteric agonist. Its binding site is located in the transmembrane section of this receptor between the beta and alpha subunits (β+α−). β3-containing GABAA receptors are involved in the anesthetic actions of etomidate, while the β2-containing receptors are involved in some of the sedation and other actions that can be elicited by this drug. Pharmacokinetics At the typical dose, anesthesia is induced for the duration of about 5–10 minutes, though the half-life of drug metabolism is about 75 minutes, because etomidate is redistributed from the plasma to other tissues. Onset of action: 30–60 seconds Peak effect: 1 minute Duration: 3–5 minutes; terminated by redistribution Distribution: Vd: 2–4.5 L/kg Protein binding: 76% Metabolism: Hepatic and plasma esterases Half-life distribution: 2.7 minutes Half-life redistribution: 29 minutes Half-life elimination: 2.9 to 5.3 hours Metabolism Etomidate is highly protein-bound in blood plasma and is metabolised by hepatic and plasma esterases to inactive products. It exhibits a biexponential decline. Formulation Etomidate is usually presented as a clear colourless solution for injection containing 2 mg/ml of etomidate in an aqueous solution of 35% propylene glycol, although a lipid emulsion preparation (of equivalent strength) has also been introduced. Etomidate was originally formulated as a racemic mixture, but the R form is substantially more active than its enantiomer. It was later reformulated as a single-enantiomer drug, becoming the first general anesthetic in that class to be used clinically. References Citations Sources External links "Etomidate". Drug Information Portal. U.S. National Library of Medicine.
Zingo	Zingo is a Swedish soft drink, with a carbonated orange flavor. Zingo was introduced during the 1950s as Ingo-dricka ("Ingo drink"), named after the boxer Ingemar "Ingo" Johansson. After Ingo lost the world championship in heavy weight boxing, the drink was renamed Zingo in 1962. Originally Zingo was produced in Norrköping, Sweden by Pripps. Pripps was bought by Carlsberg in 2000 and they continue to manufacture Zingo. Sources Carlsberg Sweden Swedish Wikipedia on Zingo See also Zingo-nostalgi!
Propranolol	Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors, as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken by mouth or by injection into a vein. The formulation that is taken by mouth comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken by mouth.Common side effects include nausea, abdominal pain, and constipation. It should not be used in those with an already slow heart rate and most of those with heart failure. Quickly stopping the medication in those with coronary artery disease may worsen symptoms. It may worsen the symptoms of asthma. Caution is recommended in those with liver or kidney problems. Propranolol may cause harmful effects for the baby if taken during pregnancy. Its use during breastfeeding is probably safe, but the baby should be monitored for side effects. It is a non-selective beta blocker which works by blocking β-adrenergic receptors.Propranolol was patented in 1962 and approved for medical use in 1964. It is on the World Health Organizations List of Essential Medicines. Propranolol is available as a generic medication. In 2019, it was the 82nd most commonly prescribed medication in the United States, with more than 9 million prescriptions. Medical uses Propranolol is used for treating various conditions, including: Cardiovascular Hypertension Angina pectoris (with the exception of variant angina) Myocardial infarction Tachycardia (and other sympathetic nervous system symptoms, such as muscle tremor) associated with various conditions, including anxiety, panic, hyperthyroidism, and lithium therapy Portal hypertension, to lower portal vein pressure Prevention of esophageal variceal bleeding and ascites Anxiety Hypertrophic cardiomyopathyWhile once a first-line treatment for hypertension, the role for beta blockers was downgraded in June 2006 in the United Kingdom to fourth-line, as they do not perform as well as other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.Propranolol is not recommended for the treatment of high blood pressure by the Eighth Joint National Committee (JNC 8) because a higher rate of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke compared to an angiotensin receptor blocker was noted in one study. Psychiatric Propranolol is occasionally used to treat performance anxiety, although evidence to support its use in any anxiety disorders is poor. Its benefits appear similar to benzodiazepines in panic disorder with potentially fewer side effects such as addiction. Some experimentation has been conducted in other psychiatric areas: Post-traumatic stress disorder (PTSD) and specific phobias (see subsection below) Aggressive behavior of patients with brain injuries Treating the excessive drinking of fluids in psychogenic polydipsia PTSD and phobias Propranolol is being investigated as a potential treatment for PTSD. Propranolol works to inhibit the actions of norepinephrine, a neurotransmitter that enhances memory consolidation. In one small study individuals given propranolol immediately after trauma experienced fewer stress-related symptoms and lower rates of PTSD than respective control groups who did not receive the drug. Due to the fact that memories and their emotional content are reconsolidated in the hours after they are recalled/re-experienced, propranolol can also diminish the emotional impact of already formed memories; for this reason, it is also being studied in the treatment of specific phobias, such as arachnophobia, dental fear, and social phobia.Ethical and legal questions have been raised surrounding the use of propranolol-based medications for use as a "memory damper", including: altering memory-recalled evidence during an investigation, modifying behavioral response to past (albeit traumatic) experiences, the regulation of these drugs, and others. However, Hall and Carter have argued that many such objections are "based on wildly exaggerated and unrealistic scenarios that ignore the limited action of propranolol in affecting memory, underplay the debilitating impact that PTSD has on those who suffer from it, and fail to acknowledge the extent to which drugs like alcohol are already used for this purpose." Other uses Essential tremor. Evidence for use for akathisia however is insufficient Migraine and cluster headache prevention and in primary exertional headache Hyperhidrosis (excessive sweating) Proliferating infantile hemangioma Glaucoma Thyrotoxicosis by deiodinase inhibitionPropranolol may be used to treat severe infantile hemangiomas (IHs). This treatment shows promise as being superior to corticosteroids when treating IHs. Extensive clinical case evidence and a small controlled trial support its efficacy. Contraindications Propranolol may be contraindicated in people with: Reversible airway diseases, particularly asthma or chronic obstructive pulmonary disease (COPD) Slow heart rate (bradycardia) (<60 beats/minute) Sick sinus syndrome Atrioventricular block (second- or third-degree) Shock Severe low blood pressure Cocaine toxicity Adverse effects Propranolol should be used with caution in people with: Diabetes mellitus or hyperthyroidism, since signs and symptoms of hypoglycaemia may be masked Peripheral artery disease and Raynauds syndrome, which may be exacerbated Phaeochromocytoma, as hypertension may be aggravated without prior alpha blocker therapy Myasthenia gravis, which may be worsened Other drugs with bradycardic effects Pregnancy and lactation Propranolol, like other beta blockers, is classified as pregnancy category C in the United States and ADEC category C in Australia. β-blocking agents in general reduce perfusion of the placenta, which may lead to adverse outcomes for the neonate, including lung or heart complications, or premature birth. The newborn may experience additional adverse effects such as low blood sugar and a slower than normal heart rate.Most β-blocking agents appear in the milk of lactating women. However, propranolol is highly bound to proteins in the bloodstream and is distributed into breast milk at very low levels. These low levels are not expected to pose any risk to the breastfeeding infant, and the American Academy of Pediatrics considers propranolol therapy "generally compatible with breastfeeding". Overdose In overdose propranolol is associated with seizures. Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias, or cardiogenic shock which may ultimately culminate in bradycardic PEA. Interactions Since beta blockers are known to relax the cardiac muscle and to constrict the smooth muscle, beta-adrenergic antagonists, including propranolol, have an additive effect with other drugs which decrease blood pressure, or which decrease cardiac contractility or conductivity. Clinically significant interactions particularly occur with: Verapamil Epinephrine (adrenaline) β2-adrenergic receptor agonists Salbutamol, levosalbutamol, formoterol, salmeterol, clenbuterol etc. Clonidine Ergot alkaloids Isoprenaline (isoproterenol) Nonsteroidal anti-inflammatory drugs (NSAIDs) Quinidine Cimetidine Lidocaine Phenobarbital Rifampicin Fluvoxamine (slows down the metabolism of propranolol significantly, leading to increased blood levels of propranolol) Pharmacology Pharmacodynamics Propranolol is classified as a competitive non-cardioselective sympatholytic beta blocker that crosses the blood–brain barrier. It is lipid soluble and also has sodium channel blocking effects. Propranolol is a non-selective β-adrenergic receptor antagonist, or beta blocker; that is, it blocks the action of epinephrine (adrenaline) and norepinephrine (noradrenaline) at both β1- and β2-adrenergic receptors. It has little intrinsic sympathomimetic activity, but has strong membrane stabilizing activity (only at high blood concentrations, e.g. overdose). Propranolol is able to cross the blood–brain barrier and exert effects in the central nervous system in addition to its peripheral activity.In addition to blockade of adrenergic receptors, propranolol has very weak inhibitory effects on the norepinephrine transporter and/or weakly stimulates norepinephrine release (i.e., the concentration of norepinephrine is increased in the synapse). Since propranolol blocks β-adrenoceptors, the increase in synaptic norepinephrine only results in α-adrenoceptor activation, with the α1-adrenoceptor being particularly important for effects observed in animal models. Therefore, it can be looked upon as a weak indirect α1-adrenoceptor agonist in addition to potent β-adrenoceptor antagonist. In addition to its effects on the adrenergic system, there is evidence that indicates that propranolol may act as a weak antagonist of certain serotonin receptors, namely the 5-HT1A, 5-HT1B, and 5-HT2B receptors. The latter may be involved in the effectiveness of propranolol in the treatment of migraine at high doses.Both enantiomers of propranolol have a local anesthetic (topical) effect, which is normally mediated by blockade of voltage-gated sodium channels. Studies have demonstrated propranolols ability to block cardiac, neuronal, and skeletal voltage-gated sodium channels, accounting for its known membrane stabilizing effect and antiarrhythmic and other central nervous system effects. Mechanism of action Propranolol is a non-selective beta receptor antagonist. This means that it does not have preference to Beta-1 or Beta-2 receptors. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to beta 1 receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA(Protein Kinase A) activation. This results in less calcium influx to cardiac myocytes through voltage gated L-type calcium channels meaning there is a decreased sympathetic effect on cardiac cells, resulting in antihypertensive effects including reduced heart rate and lower arterial blood pressure. Blockage of neurotransmitter binding to B2 receptors on smooth muscle cells will increase contraction, which will increase hypertension. Pharmacokinetics Propranolol is rapidly and completely absorbed, with peak plasma levels achieved about 1–3 hours after ingestion. More than 90% of the drug is found bound to plasma protein in the blood. Coadministration with food appears to enhance bioavailability. Despite complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism. Hepatic impairment therefore increases its bioavailability. The main metabolite 4-hydroxypropranolol, with a longer half-life (5.2–7.5 hours) than the parent compound (3–4 hours), is also pharmacologically active. Most of the metabolites are excreted in the urine.Propranolol is a highly lipophilic drug achieving high concentrations in the brain. The duration of action of a single oral dose is longer than the half-life and may be up to 12 hours, if the single dose is high enough (e.g., 80 mg). Effective plasma concentrations are between 10 and 100 mg/L. Toxic levels are associated with plasma concentrations above 2000 mg/L. History Scottish scientist James W. Black developed propranolol in the 1960s. It was the first beta-blocker effectively used in the treatment of coronary artery disease and hypertension. In 1988, Black was awarded the Nobel Prize in Medicine for this discovery. Propranolol was inspired by the early β-adrenergic antagonists dichloroisoprenaline and pronethalol. The key difference, which was carried through to essentially all subsequent beta blockers, was the inclusion of an oxymethylene group (-O-CH2-) between the aryl and ethanolamine moieties of pronethalol, greatly increasing the potency of the compound. This also apparently eliminated the carcinogenicity found with pronethalol in animal models. Newer, more cardio-selective beta blockers (such as bisoprolol, nebivolol, carvedilol, or metoprolol) are now used preferentially in the treatment of hypertension. Society and culture In a 1987 study by the International Conference of Symphony and Opera Musicians, it was reported that 27% of interviewed members said they used beta blockers such as propranolol for musical performances. For about 10–16% of performers, their degree of stage fright is considered pathological. Propranolol is used by musicians, actors, and public speakers for its ability to treat anxiety symptoms activated by the sympathetic nervous system. It has also been used as a performance-enhancing drug in sports where high accuracy is required, including archery, shooting, golf, and snooker. In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals. Brand names Propranolol was first marketed under the brand name Inderal, manufactured by ICI Pharmaceuticals (now AstraZeneca), in 1965. Propranolol is also marketed under brand names Avlocardyl, Deralin, Dociton, Inderalici, InnoPran XL, Indoblok, Sumial, Anaprilin, and Bedranol SR (Sandoz). In India it is marketed under brand names such as Ciplar and Ciplar LA by Cipla. Hemangeol, a 4.28 mg/mL solution of propranolol, is indicated for the treatment of proliferating infantile hemangioma. References External links Stapleton MP (1997). "Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology". Texas Heart Institute Journal. 24 (4): 336–342. PMC 325477. PMID 9456487. "Propranolol". Drug Information Portal. U.S. National Library of Medicine.
Belinostat	Belinostat (trade name Beleodaq, previously known as PXD101) is a histone deacetylase inhibitor drug developed by TopoTarget for the treatment of hematological malignancies and solid tumors.It was approved in July 2014 by the US FDA to treat peripheral T-cell lymphoma.In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin and paclitaxel for relapsed ovarian cancer. Final results in late 2009 of a phase II trial for T-cell lymphoma were encouraging. Belinostat has been granted orphan drug and fast track designation by the FDA, and was approved in the US for the use against peripheral T-cell lymphoma on 3 July 2014. It is not approved in Europe as of August 2014.The approved pharmaceutical formulation is given intravenously.: 180 Belinostat is primarily metabolized by UGT1A1; the initial dose should be reduced if the recipient is known to be homozygous for the UGT1A1*28 allele.: 179 and 181 == References ==
Mercaptopurine	Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohns disease, and ulcerative colitis. For acute lymphocytic leukemia it is generally used with methotrexate. It is taken by mouth.Common side effects include bone marrow suppression, liver toxicity, vomiting, and loss of appetite. Other serious side effects include an increased risk of future cancer and pancreatitis. Those with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects. Use in pregnancy may harm the baby. Mercaptopurine is in the thiopurine and antimetabolite family of medications.Mercaptopurine was approved for medical use in the United States in 1953. It is on the World Health Organizations List of Essential Medicines. Medical uses It is used to treat acute lymphocytic leukemia, Crohns disease, and ulcerative colitis. Side effects Some of the adverse reactions of taking mercaptopurine may include diarrhea, nausea, vomiting, loss of appetite, fatigue, stomach/abdominal pain, weakness, skin rash, darkening of the skin, and hair loss. Serious adverse reactions include mouth sores, fever, sore throat, easy bruising or bleeding, pinpoint red spots on the skin, yellowing of eyes or skin, dark urine, and painful or difficult urination. Other more serious side effects include black or tarry stools (melena), bloody stools, and bloody urine. Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, i.e. thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to on-exchange LC-MS (liquid chromatography - mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.Symptoms of allergic reaction to mercaptopurine include rash, itching, swelling, dizziness, trouble breathing, and inflammation of the pancreas. In some cases, mercaptopurine may suppress the production of blood cells, both white blood cells and red blood cells. It may be toxic to bone marrow. Quarterly blood counts are necessary for people on mercaptopurine. People should stop taking the medication at least temporarily while considering alternate treatment if there is an unexplained, abnormally large drop in white blood cell count, or any other blood count. Toxicity of mercaptopurine can be linked to genetic polymorphisms in thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and inosine triphosphate pyrophosphatase (ITPA). People with specific allele variants will require dose adjustments, especially for those with homozygous variant genotypes. Large differences of TPMT and NUDT15 among ethnicities in terms of variant allele frequency should be taken into consideration in clinical practice. Caucasian people with a variant allele of the ITPA gene, experience higher rates of febrile neuropenia than people of other ethnic groups, due to differences in allelic frequencies among ethnicities. Precautions Mercaptopurine can lower the bodys ability to fight off infection. Those taking it should get permission from a doctor to receive immunizations and vaccinations. It is also recommended that, while on the drug, one should avoid those having recently received oral polio vaccine. This drug was formerly not recommended during pregnancy and early evidence indicated pregnant women on the drug (or the related azathioprine) showed a seven-fold incidence of fetal abnormalities as well as a 20-fold increase in miscarriage. There were also anecdotal reports linking mercaptopurine with spontaneous abortion, leading to the US FDA rating both AZA and mercaptopurine as category D drugs. However, Davis et al. 1999 found mercaptopurine, compared to methotrexate, was ineffective as a single-agent abortifacient; every woman in the mercaptopurine arm of the study had fetal cardiac activity at follow-up (two weeks later) and was given a suction abortion. A more recent, larger study, however, performed by the Cancers et Surrisque Associe aux Maladies inflamatoires intestinales En France (CESAME) indicated an overall rate of congenital malformations not significantly greater than the general population in France. The European Crohns and Colitis Organisation (ECCO) concluded in a consensus paper in 2010 that while AZA and mercaptopurine have an FDA rating of D, new research in both animals and humans indicates that "thiopurines are safe and well tolerated during pregnancy."Mercaptopurine causes changes to chromosomes in animals and humans, though a study in 1990 found, "while the carcinogenic potential of 6-MP cannot be precluded, it can be only very weak or marginal." Another study in 1999 noted an increased risk of developing leukemia when taking large doses of 6-MP with other cytotoxic drugs. Drug interactions Allopurinol inhibits xanthine oxidase, the enzyme that breaks down mercaptopurine. Those taking allopurinol (often used to prevent gout) are at risk for mercaptopurine toxicity. The dose should be reduced or allopurinol should be discontinued. Several published studies have demonstrated that the use of allopurinol in combination with low dose 6-MP helps reduce 6-MP levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6-MP for some inflammatory conditions. Mechanisms of action Official information from the package insert for purinethol: Mercaptopurine is an antimetabolite antineoplastic, as such it interferes with normal metabolic processes within cells, typically by combining with enzymes, to disrupt DNA and RNA synthesis (cell-cycle S phase-specific) leading to death of rapidly proliferating cells, especially malignant ones. Specifically, Mercaptopurine is a purine antimetabolite or purine antagonist as such inhibits DNA synthesis by inhibiting the production of the purine containing nucleotides, adenine and guanine thus halting DNA synthesis. Mercaptopurine also acts as an immunomodulator by inhibiting of several pathways in nucleic acid biosynthesis preventing proliferation of cells involved in the determination and amplification of the immune response. Mercaptopurine (6-MP) competes with the purine derivatives hypoxanthine and guanine for the enzyme HGPRT and is itself converted to thio inosine monophosphate (TIMP). TIMP inhibits several chemical reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP). Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate amidotransferase (PRPP amidotransferase). Since this enzyme is the rate limiting factor for purine synthesis, this alters the synthesis and function of RNA and DNA. Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis. Pharmacogenetics The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine – this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving mercaptopurine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of people are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify people with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely. The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify people at risk for myelotoxicity. Testing for TPMT activity is an example of pharmacogenetics being translated into routine clinical care. History 6-MP was discovered by Nobel Prize winning scientists Gertrude B. Elion and George H. Hitchings at Burroughs Wellcome in Tuckahoe, New York, and was clinically developed in collaboration with investigators at Memorial Hospital (now Memorial Sloan Kettering Cancer Center in New York City). The collaboration was initiated by Cornelius P. Rhoads who had run chemical weapons programs for the US army and had been involved in the work that led to the discovery that nitrogen mustards could potentially be used as cancer drugs, and had become the director of Memorial in 1948. See also Azathioprine Tioguanine References Further reading Dean L (2012). "Mercaptopurine Therapy and TPMT Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520348. Bookshelf ID: NBK100660. External links "Mercaptopurine". Drug Information Portal. U.S. National Library of Medicine.
Edrophonium	Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is sold under the trade names Tensilon and Enlon (according to FDA Orange Book). Clinical uses Edrophonium (by the so-called Tensilon test) is used to differentiate myasthenia gravis from cholinergic crisis and Lambert-Eaton. In myasthenia gravis, the body produces autoantibodies which block, inhibit or destroy nicotinic acetylcholine receptors in the neuromuscular junction. Edrophonium—an effective acetylcholinesterase inhibitor—will reduce the muscle weakness by blocking the enzymatic effect of acetylcholinesterase enzymes, prolonging the presence of acetylcholine in the synaptic cleft. It binds to a Serine-103 allosteric site, while pyridostigmine and neostigmine bind to the AchE active site for their inhibitory effects. In a cholinergic crisis, where a person has too much neuromuscular stimulation, edrophonium will make the muscle weakness worse by inducing a depolarizing block. However, the edrophonium and ice pack tests are no longer recommended as first-line tests due to false positive results. In practice, the edrophonium test has been replaced by testing for autoantibodies, including acetylcholine receptor (AchR) autoantibodies and muscle specific tyrosine kinase (MuSK) autoantibodies.Lambert-Eaton myasthenic syndrome (LEMS), is similar to myasthenia gravis in that it is an autoimmune disease. However, in LEMS the neuron is unable to release enough acetylcholine for normal muscle function due to autoantibodies attacking P/Q-type calcium channel that are necessary for acetylcholine release. This means there is insufficient calcium ion influx into presynaptic terminal resulting in reduced exocytosis of acetylcholine containing vesicles. Consequently, there will typically be not as much increase in muscle strength observed after edrophonium injection, if any with LEMS. The Tensilon test may also be used to predict if neurotoxic paralysis caused by snake envenomation is presynaptic or postsynaptic. If it is a postsynaptic then paralysis will be temporally reversed, indicating that can be reversed by adequate antivenom therapy. If the neurotoxic is presynaptic then the Tensilon test will show no response and antivenom will not reverse such paralysis. In this instance reversal of paralysis will not occur until the damaged terminal axons at the neuromuscular junction have recovered, this may take days or weeks.The drug may also be used for reversal of neuromuscular blockade at the end of a surgical procedure. Chemistry Edrophonium, ethyl-(3-hydroxyphenyl)dimethylammonium chloride, is made by reacting 3-dimethylaminophenol with ethyl bromide, which forms ethyl(3-hydroxyphenyl)dimethylammonium bromide, the bromine atom of which is replaced with a chlorine atom by reacting it with silver chloride, giving edrophonium. Pharmacokinetics The drug has a brief duration of action, about 10–30 mins. References == Further reading ==
Hepatitis A vaccine	Hepatitis A vaccine is a vaccine that prevents hepatitis A. It is effective in around 95% of cases and lasts for at least twenty years and possibly a persons entire life. If given, two doses are recommended beginning after the age of one. It is given by injection into a muscle. The first hepatitis A vaccine was approved in Europe in 1991, and the United States in 1995. It is on the World Health Organizations List of Essential Medicines.The World Health Organization (WHO) recommends universal vaccination in areas where the disease is moderately common. Where the disease is very common, widespread vaccination is not recommended as all people typically develop immunity through infection during childhood. The Centers for Disease Control and Prevention (CDC) recommends vaccinating: All children aged 12–23 months Unvaccinated children and adolescents aged 2–18 years International travelers Men who have sex with men People who use injection or non-injection drugs People who have occupational risk for infection People who anticipate close contact with an international adoptee People experiencing homelessness People with HIV People with chronic liver disease Any person wishing to obtain immunityIn addition, a person who has not previously received hepatitis A vaccine and who has direct contact with someone with hepatitis A should get hepatitis A vaccine within two weeks after exposure.Severe side effects are very rare. Pain at the site of injection occurs in about 15% of children and half of adults. Most hepatitis A vaccines contain inactivated virus while a few contain weakened virus. The ones with weakened virus are not recommended during pregnancy or in those with poor immune function. A few formulations combine hepatitis A with either hepatitis B or typhoid vaccine.Soreness or redness where the shot is given, fever, headache, tiredness, or loss of appetite can happen after hepatitis A vaccine. As with any medicine, there is a very remote chance of a vaccine causing a severe allergic reaction, other serious injury, or death. Medical uses Within the U.S., the vaccine "Vaqta" developed by Maurice Hilleman and his team at Merck & Co. was licensed in 1995. The vaccine was phased in, around 1996, for children living in high-risk areas. In 1999, its usage was spread to areas with elevating levels of infection. In the U.S. as of 2007, the vaccine is strongly recommended for all children 12 to 23 months of age in an attempt to eradicate the virus nationwide. Although the original Food and Drug Administration (FDA) license for Havrix by GlaxoSmithKline is dated in 1995, it had been approved in Europe in 1991.The U.S. Centers for Disease Control and Prevention (CDC), recommends vaccination of all children over one year of age, people whose sexual activity puts them at risk, people with chronic liver disease, people who are being treated with clotting factor concentrates, people working in close proximity to the virus, and people who are living in communities where an outbreak is present. Hepatitis A is the most common vaccine-preventable virus acquired during travel, so people traveling to places where the virus is common like the Indian subcontinent, Africa, Central America, South America, Asia, and Eastern Europe should be vaccinated.The vaccine is given in the muscle of the upper arm, in two doses for the best protection. The initial dose of the vaccine should be followed up by a booster six to twelve months later. Protection against hepatitis A begins approximately two to four weeks after the initial vaccination. Protection lasts at least 15 years and is estimated to last at least 25 years if the booster is administered.A Cochrane review found that both types of vaccines offer significant protection, for at least two years using the inactivated vaccine and at least five years with the attenuated vaccine. The review concluded that the inactivated vaccine is safe, but required more high quality evidence to assess the safety of the attenuated vaccine. Commercial vaccines Several commercial hepatitis A vaccines are available. The definition of (U)nits varies among manufacturers depending on how hepatitis A antigen is measured in their products. Avaxim: made by Sanofi Pasteur. Inactivated hepatitis A virus produced in MRC-5 cells. Each dose contains 160 U of antigen adsorbed on aluminium hydroxide (0.3 mg Al). Epaxal: made by Crucell. Also sold under the brand names HAVpur and VIROHEP-A. This vaccine consists of virosomes, artificial particles composed of synthetic lipids and influenza proteins in addition to the hepatitis A antigen. It does not contain aluminium. Havrix: made by GlaxoSmithKline. Inactivated hepatitis A virus produced in MRC-5 cells. Each adult dose contains 1440 ELISA units of viral antigen adsorbed on aluminium hydroxide (0.5 mg Al). The pediatric (child) doses contain half the amount of viral antigen and aluminium. Healive: made by Sinovac. Inactivated hepatitis A virus cultured in human diploid cell, followed by harvest, purification, inactivation, and aluminium adsorption. Each adult dose contains 500 U of viral antigen. The pediatric dose contains 250 U of viral antigen. Vaqta: made by Merck. Inactivated hepatitis A virus produced in MRC-5 cells. An adult dose contains 50 U of antigen adsorbed onto 0.45 mg of aluminium (as aluminium hydroxyphosphate sulfate); a child dose contains half the amounts of antigen and aluminium. Biovac-A: made by Pukang, sold under the brand name Biovac-A in India and under the brand names Mevac-A in Guatemala, Philippines, Bangladesh, Nepal, Uzbekistan and Chile etc. It is a freeze-dried live attenuated hepatitis A vaccine. Hepatitis A virus H2 strain is produced in human diploid cells. A pack of 0.5ml vial of Biovac-A and 0.5ml ampoule of SWFI (sterile water for injection), contains not be less than 6.5 Lg CCID50. Only a single dose is needed. It is recommended by the WHO. Long term persistence research data predicated that sero-conversion remained and antibody titre was not less than 128 IU/ml, 15 years after vaccination. Combination vaccines Hepatitis A and B vaccine is a vaccine against hepatitis A and hepatitis B. Hepatitis A and typhoid vaccine is a vaccine against hepatitis A and typhoid. References Further reading Ramsay M, ed. (2013). "Chapter 17: Hepatitis A". Immunisation against infectious disease. Public Health England. External links Hepatitis A Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH)
Methylphenidate	Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD. It may be taken by mouth or applied to the skin, and different formulations have varying durations of effect. Though there is little evidence, and in some cases contradictory evidence, to support its use as an athletic performance enhancer, cognitive enhancer, aphrodisiac or euphoriant, claims persist that it can be used for these purposes.Common adverse reactions of methylphenidate include: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. Withdrawal symptoms may include: chills, depression, drowsiness, dysphoria, exhaustion, headaches, irritability, lethargy, nightmares, restlessness, suicidal thoughts, and weakness.Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons. It is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes. Despite the claim made by some urban legends, it is not a cocaine derivative nor analog; cocaine is a local anesthetic and ligand channel blocker with SNDRI action, while methylphenidate is an NDRI with 2–3 fold selectivity for the dopamine transporter (DAT) over the norepinephrine transporter (NET). Cocaine is also more potent in serotonin transporters (SERTs) than NDRI sites.Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955. It was originally sold by Swiss company CIBA (now Novartis). It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012. In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15 million prescriptions. It is available as a generic medication.In the United Kingdom, through the National Health Service, the drug is first-line medication for the treatment of attention deficit hyperactivity disorder (ADHD). Uses Methylphenidate is most commonly used to treat ADHD and narcolepsy. Attention deficit hyperactivity disorder Methylphenidate is used for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy can have additional benefits on treatment outcome. The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose. Immediate release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms. Methylphenidate is not approved for children under six years of age.In children over the age of 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of substance use disorders as adults.The precise magnitude of improvement in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015. Methylphenidate is not included in the World Health Organization Essential Medicines List, as findings by the World Health Organization indicate that evidence of benefit versus harm to be unclear in the treatment of ADHD. A 2021 systematic review concluded that there is no clear evidence for using IR Methylphenidate (immediate-release) for adults.Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful. This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD. People in this category can then experience negative side-effects of the drug which worsen their condition. Narcolepsy Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance. Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to levels comparable to healthy people. Other medical uses Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. There is weak evidence in favor of methylphenidates effectiveness for depression, including providing additional benefit in combination with antidepressants. In individuals with terminal cancer, methylphenidate can be used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function. A 2021 systematic review and meta-analysis found that all studies on geriatric depression reported positive results of methylphenidate use; the review recommended short-term use in combination with citalopram. A 2018 review found low quality evidence supporting its use to treat apathy as seen in Alzheimers Disease in addition to slight benefits for cognition and cognitive performance. Enhancing performance A 2015 review found that therapeutic doses of amphetamine and methylphenidate result in modest improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults; the cognition-enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex. Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal. Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks, and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, performance-enhancing use rather than use as a recreational drug, is the primary reason that students use stimulants.Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control. Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system. Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia. While literature suggests it might improve cognition, most authors agree that using the drug as a study aid when ADHD diagnosis is not present does not actually improve GPA. Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues. Contraindications Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen". Adverse effects Overall, adverse events associated with long-acting MPH formulations are similar with the most common adverse effects including appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), oromandibular dystonia, lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), and tachycardia (rapid heart rate). Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day. Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms. It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link. Logorrhea is occasionally reported. Libido disorders, disorientation, and visual hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.US Food and Drug Administration-commissioned studies in 2011, indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.A 2018 review found tentative evidence that it may cause both serious and non-serious adverse effects in children. Overdose The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies. Addiction and dependence Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs; accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. When used above the medical dose range, stimulants are associated with the development of stimulant psychosis. As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate addiction. Biomolecular mechanisms Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brains reward system. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction. However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens. Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction. Interactions Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity. Pharmacology Pharmacodynamics Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative which also shares part of its basic structure with catecholamines. Methylphenidate is a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine. As models of ADHD suggest, it is associated with functional impairments in some of the brains neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor. By increasing the effects of norepinephrine and dopamine, methylphenidate increases the activity of the central nervous system and produces effects such as increased alertness, reduced fatigue, and improved attention.Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE). Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET). Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal dopamine activity, leading to nonresponse in those with low basal DA activity. On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex. Magnetic resonance imaging (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, amphetamine and methylphenidate) decreases abnormalities in brain structure and function found in subjects with ADHD.There exist some paradoxical findings that oppose the notion that methylphenidate acts primarily through DAT inhibition. 80% occupancy of the DAT is necessary for methphenidates euphoriant effect, but re-administration of methylphenidate beyond this level of DAT occupancy has been found to still produce euphoriant effects. More potent DAT inhibitors such as bupropion have not been observed to cause this effect. These observations help corroborate the hypothesis that methylphenidate may act as a "DAT inverse agonist" by reversing the direction of the dopamine efflux by the DAT.Both amphetamine and methylphenidate are predominantly dopaminergic drugs, yet their mechanisms of action are distinct. Methylphenidate acts as a norepinephrine–dopamine reuptake inhibitor, while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. Methylphenidates mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other phenethylamine derivatives, as methylphenidate is thought to increase neuronal firing rate, whereas amphetamine reduces firing rate, but causes monoamine release by reversing the flow of the monoamines through monoamine transporters via a diverse set of mechanisms, including TAAR1 activation and modulation of VMAT2 function, among other mechanisms. The difference in mechanism of action between methylphenidate and amphetamine results in methylphenidate inhibiting amphetamines effects on monoamine transporters when they are co-administered.Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.Methylphenidate may protect neurons from the neurotoxic effects of Parkinsons disease and methamphetamine use disorder. The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine-DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine-related reactive oxygen species.The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. The studied maximized daily dosage of OROS methyphenidate appears to be 144 mg/day. Pharmacokinetics Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for instant release (i.e. Ritalin), 3–8 hours for sustained release (i.e. Ritalin SR), and 8–12 hours for extended release (i.e. Concerta). The half-life of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours. Methylphenidate has a low plasma protein binding of 10-33% and a volume of distribution of 2.65 L/kg.Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal. The effects of a high fat meal on the observed Cmax differ between some extended release formulations, with combined IR/ER and OROS formulations showing reduced Cmax levels while liquid-based extended release formulations showed increased Cmax levels when administered with a high fat meal, according to some researchers. A 2003 study, however, showed no difference between a high fat meal administration and a fasting administration of oral methylphenidate.Methylphenidate is metabolized into ritalinic acid by CES1A1, enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate. 97% of the metabolised drug is excreted in the urine, and between 1 and 3% is excreted in the faeces. A small amount, less than 1%, of the drug is excreted in the urine in its unchanged form. Chemistry Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects. The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2R)-(+)-threo-methylphenidate hydrochloride has been published. Detection in biological fluids The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. History Methylphenidate was first synthesized in 1944. It was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure. Methylphenidate was not reported to be a stimulant until 1954. The drug was introduced for medical use in the United States in 1957. Originally, it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer. The erythro isomer was eliminated and now modern formulations of methyphenidate contain only the threo isomer at a 50:50 mixture of d- and l-isomers.Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression. It was later used to treat memory deficits in the elderly. Beginning in the 1960s, it was used to treat children with ADHD based on earlier work starting with the studies by American psychiatrist Charles Bradley on the use of psychostimulant drugs, such as Benzedrine, with then called "maladjusted children". Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.In 2000, Alza Corporation received US FDA approval to market Concerta, an extended-release form of methylphenidate. Society and culture Names Methylphenidate is produced in the United States, Switzerland, Canada, Mexico, Spain, Sweden, Pakistan, and India. It is also sold in the majority of countries worldwide.: 8–9 Brand names for methylphenidate include Ritalin (in honor to Rita, the wife of the molecule discoverer), Rilatin (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta, Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Equasym, Methylin, Penid, Phenida, Prohiper, and Tradea.: 8–9 Available forms The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade in both an immediate-release and an extended-release form. In some circumstances it may be prescribed instead of methylphenidate, however it has no significant advantages over methylphenidate at equipotent dosages and so it is sometimes considered to be an example of an evergreened drug. Immediate-release Methylphenidate was originally available as an immediate-release racemic mixture formulation under the Novartis brand name Ritalin, although a variety of generics are available, some under other brand names. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, Tranquilyn, and Rubifen. Extended-release Extended-release methylphenidate products include: Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the dose is immediate release, and the remaining 78% of the dose is released over 10–12 hours post-ingestion, with an initial increase over the first 6 to 7 hours, and subsequent decline in released drug.Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. Ritalin LA provides two standard doses – half the total dose being released immediately and the other half released four hours later. In total, each capsule is effective for about eight hours. Metadate CD capsules contain two types of beads; 30% are immediate release, and the other 70% are evenly sustained release.Medikinet Retard/CR/Adult/Modified Release tablets is an extended-release oral capsule form of Methylphenidate. It delivers 50% of dosage as IR MPH and the remaining 50% in 3-4 Hours. Theyre not equal in pharmacology but however Medikinet Retard usually referenced as German version of Ritalin LA. Skin patch A methylphenidate skin patch is sold under the brand name Daytrana in the United States. It was developed and marketed by Noven Pharmaceuticals and approved in the US in 2006. It is also referred to as methylphenidate transdermal system (MTS). It is approved as a once daily treatment in children — ages 6 to 17 — with ADHD. It is mainly prescribed as a second-line treatment when oral forms are not well tolerated or if people have difficulty with compliance. Novens original FDA submission indicated that it should be used for 12 hours. When the FDA rejected the submission they requested evidence that a shorter time period was safe and effective, Noven provided such evidence and it was approved for a 9-hour period.Orally administered methylphenidate is subject to first-pass metabolism,
Methylphenidate	by which the levo-isomer is extensively metabolized. By circumventing this first-pass metabolism, the relative concentrations of l-threo-methylphenidate are much higher with transdermal administration (50-60% of those of dexmethylphenidate instead of about 14-27%).A 39 nanograms/mL peak serum concentration of methylphenidate be has been found to occur between 7.5 and 10.5 hours after administration. However the onset to peak effect is 2 hours and the clinical effects remain up to 2 hours after patch has been removed. The absorption is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat and uninflamed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug. Cost Brand-name and generic formulations are available. Legal status Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances. In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for misuse. In the United Kingdom, methylphenidate is a controlled Class B substance. Possession without prescription carries a sentence up to 5 years or an unlimited fine, or both; supplying methylphenidate is 14 years or an unlimited fine, or both. In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act and is illegal to possess without a prescription, with unlawful possession punishable by up to three years imprisonment, or (via summary conviction) by up to one year imprisonment and/or fines of up to two thousand dollars. Unlawful possession for the purpose of trafficking is punishable by up to ten years imprisonment, or (via summary conviction) by up to eighteen months imprisonment. In New Zealand, methylphenidate is a class B2 controlled substance. Unlawful possession is punishable by six-month prison sentence and distribution by a 14-year sentence. In Australia, methylphenidate is a Schedule 8 controlled substance. Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment. In Russia, methylphenidate is a List I controlled psychotropic substance without recognized medical value. The Constant Committee for Drug Control of the Russian Ministry of Health has put methylphenidate and its derivatives on the National List of Narcotics, Psychotropic Substances and Their Precursors and the Government banned methylphenidate for any use on 25 October 2014. In Sweden, methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison. In France, methylphenidate is covered by the "narcotics" schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations. In India, methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physicians prescription. Legally, 2 grams of methylphenidate are classified as a small quantity, and 50 grams as a large or commercial quantity. In Hong Kong, methylphenidate is controlled under the schedule 1 of the Dangerous Drugs Ordinance (Cap. 134). Controversy Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major point of criticism. The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources, according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life". A study found that ADHD medication was not associated with increased risk of cigarette use, and in fact stimulant treatments such as Ritalin seemed to lower this risk. People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.Among countries with the highest rates of use of methylphenidate medication is Iceland, where research shows that the drug was the most commonly used substance among people who inject drugs. The study involved 108 people who inject drugs and 88% of them had injected methylphenidate within the last 30 days and for 63% of them, methylphenidate was the most preferred substance. Treatment of ADHD by way of methylphenidate has led to legal actions, including malpractice suits regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems. Research Methylphenidate may have benefit as a treatment of apathy in patients with Alzheimers disease. It may be useful in losing weight.Methylphenidate may provide possible protection from methamphetamine-induced dopamine neuron damage and possible protection from Parkinsons disease.Methylphenidate has been studied in the treatment of Parkinsons disease. Replacement therapy Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction in the same way that methadone is used as a replacement drug for physical dependence upon heroin. Its effectiveness in treatment of cocaine or psychostimulant addiction, or psychological dependence has not been proven and further research is needed. References External links "Methylphenidate". Drug Information Portal. U.S. National Library of Medicine.
Lamivudine/tenofovir	Lamivudine/tenofovir disoproxil, sold under the brand name Cimduo among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS in adults and children weighing more than 35 kilograms (77 lb). It contains lamivudine and tenofovir disoproxil. It is taken by mouth.Lamivudine/tenofovir was approved for medical use in the United States in February 2018. References Further reading "WHO Public Assessment Report: HA414 - Lamivudine/Tenofovir disoproxil fumarate - 300mg/300mg - Tablets - Mylan Laboratories Ltd - India". World Health Organization (WHO). Archived from the original on 26 March 2020. External links "Lamivudine". Drug Information Portal. U.S. National Library of Medicine. "Tenofovir disoproxil". Drug Information Portal. U.S. National Library of Medicine. "Tenofovir disoproxil fumarate". Drug Information Portal. U.S. National Library of Medicine.
Allopregnanolone	Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is used by injection into a vein over a 60-hour period under medical supervision.Side effects of brexanolone may include sedation, sleepiness, dry mouth, hot flashes, and loss of consciousness. It is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).Brexanolone was approved for medical use in the United States in 2019. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women. Medical uses Brexanolone is used to treat postpartum depression in adult women. Side effects Side effects of brexanolone include sedation (13–21%), dry mouth (3–11%), loss of consciousness (3–5%), and flushing (2–5%). It can also produce euphoria to a degree similar to that of alprazolam (3–13% at infusion doses of 90–270 μg over a one-hour period). Biological function Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, antiaggressive, prosexual, sedative, pro-sleep, cognitive, memory-impairment, analgesic, anesthetic, anticonvulsant, neuroprotective, and neurogenic effects. Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus. Mechanism of action Molecular interactions Allopregnanolone is an endogenous inhibitory pregnane neurosteroid. It is made from progesterone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity. Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation. Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors, and also appears to act as a negative allosteric modulator of the 5-HT3 receptor. Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.Unlike progesterone, allopregnanolone is inactive at the classical nuclear progesterone receptor (PR). However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, and for this reason, allopregnanolone can produce PR-mediated progestogenic effects. In addition, allopregnanolone was reported in 2012 to be an agonist of the membrane progesterone receptors (mPRs) discovered shortly before, including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor. The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties. Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs), including α1 subtypes Cav1.2 and Cav1.3. However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone. Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5). However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain. Biphasic actions at the GABAA receptor Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nmol/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABAA receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect. Antidepressant effects The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown. Other GABAA receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy, despite clinicians prescribing Alprazolam for depression in the past. Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub-populations differently than benzodiazepines. As examples, GABAA receptor-potentiating neurosteroids may preferentially target δ subunit-containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors. It is also possible that neurosteroids like allopregnanolone may act on other targets, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects. Pharmacology Pharmacokinetics Brexanolone has low oral bioavailability of less than 5%, necessitating non-oral administration. The volume of distribution of brexanolone is approximately 3 L/kg. Its plasma protein binding is more than 99%. Brexanolone is metabolized by keto-reduction mediated via aldo-keto reductases. The compound is also conjugated by glucuronidation via glucuronosyltransferases and sulfation via sulfotransferases. It is not metabolized importantly by the cytochrome P450 system. The three main metabolites of brexanolone are inactive. The elimination half-life of brexanolone is 9 hours. Its total plasma clearance is 1 L/h/kg. It is excreted 47% in feces and 42% in urine. Less than 1% is excreted as unchanged brexanolone. Chemistry Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 5α-Pregnane-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone (5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one). Biosynthesis The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone. Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala. Derivatives A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione). The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD). History In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women, the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for PPD.The efficacy of brexanolone was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks. The FDA approved allopregnanolone based on evidence from three clinical trials, conducted in the United States, (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression.The FDA granted the application for brexanolone priority review designation, breakthrough therapy designation, and granted approval of allopregnanolone to Sage Therapeutics, Inc. Society and culture Names Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid. Brexanolone is both the INN and the USAN in the context of its use as a medication.Zulresso is a brand name of the medication. Legal status In the United States, brexanolone is a Schedule IV controlled substance. Allopregnanolone is available only through a restricted program called the Zulresso REMS Program that requires the drug to be administered by a healthcare provider in a certified healthcare facility. The REMS requires that patients be enrolled in the program prior to administration of the drug. Dose It is given continuously by intravenous infusion over a period of 60 hours (2.5 days). The dosage of brexanolone is progressively adjusted over a range of 30 to 90 μg/kg/hour during this period.Several warnings and precautions are addressed in a boxed warning in the drugs prescribing information. Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood). While receiving the infusion, women must be accompanied during interactions with children. Women should be counseled on the risks of allopregnanolone treatment and instructed that they must be monitored for these effects at a healthcare facility for the entire 60 hours of infusion. Women who have received the treatment should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away. Available forms Brexanolone is an aqueous mixture of synthetic allopregnanolone and sulfobutyl ether β-cyclodextrin (betadex sulfobutyl ether sodium), a solubilizing agent. It is provided at an allopregnanolone concentration of 100 mg/20 mL (5 mg/mL) in single-dose vials for use by intravenous infusion. Each mL of brexanolone solution contains 5 mg allopregnanolone, 250 mg sulfobutyl ether β-cyclodextrin, 0.265 mg citric acid monohydrate, 2.57 mg sodium citrate dihydrate, and water for injection. The solution is hypertonic and must be diluted to a target concentration of 1 mg/mL with sterile water and sodium chloride prior to administration. Five infusion bags are generally required for the full infusion. More than five infusion bags are necessary for patients weighing more than 90 kg (200 lbs). Research Brexanolone was under development as an intravenously administered medication for the treatment of major depressive disorder, super-refractory status epilepticus, and essential tremor, but development for these indications was discontinued.Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations. Due to this, it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone. As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy, as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oral pregnenolone has also been found to act as a prodrug of allopregnanolone, though also of pregnenolone sulfate. References Further reading External links "Brexanolone". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02942004 for "A Study to Evaluate Efficacy and Safety of SAGE-547 in Participants With Severe Postpartum Depression (547-PPD-202B)" at ClinicalTrials.gov Clinical trial number NCT02614547 for "A Study to Evaluate SAGE-547 in Patients With Severe Postpartum Depression" at ClinicalTrials.gov Clinical trial number NCT02942017 for "A Study to Evaluate Safety and Efficacy of SAGE-547 in Participants With Moderate Postpartum Depression (547-PPD-202C)" at ClinicalTrials.gov
Orphenadrine	Orphenadrine (sold under many brand names) is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is a muscle relaxant that is used to treat muscle pain and to help with motor control in Parkinsons disease, but has largely been superseded by newer drugs. This substance is considered a dirty drug due to its multiple mechanism of action in different pathways. It was discovered and developed in the 1940s. Medical use Orphenadrine is a skeletal muscle relaxant. It is used to relieve pain caused by muscle injuries such as strains and sprains, in combination with rest and physical therapy. A 2004 review found fair evidence that orphenadrine is effective for acute back or neck pain, but found insufficient evidence to establish the relative efficacy of the drug in relation to other drugs in the study.Orphenadrine and other muscle relaxants are sometimes used to treat pain arising from rheumatoid arthritis but there is no evidence they are effective for that purpose.A 2003 Cochrane Review of the use of anticholinergic drugs to improve motor function in Parkinsons disease found that as a class, the drugs are useful for that purpose; it identified one single-site randomised, cross-over study of orphenadrine vs placebo. Although orphenadrine and other anticholinergics have largely been superseded by other drugs; they have a use in alleviating motor function symptoms, and appear to help about 20% of people with Parkinsons. Side effects Orphenadrine has the side effects of the other common antihistamines in large part. Stimulation is somewhat more common than with other related antihistamines, and is especially common in the elderly. Common side effects include dry mouth, dizziness, drowsiness, constipation, urine retention, blurred vision, and headache. Its use in Parkinsons is especially limited by these factors.People with glaucoma, digestive problems such as peptic ulcers or bowel obstruction, or sphincter relaxation disorders, or with enlarged prostate, bladder problems, or myasthenia gravis, should not take this drug. Pharmacology Orphenadrine is known to have this pharmacology: Nonselective mACh receptor antagonist (anticholinergic, 58% as potent as atropine) Various monographs and package inserts, nursing manuals, journal articles and so forth have proposed the theory that this anticholinergic (atropine-like) activity, NMDA antagonism and possible local anaesthetic and miscellaneous analgesic effects may be the reason for orphenadrines efficacy against muscle and other pain. These reasons are behind the use of orphenadrine and other drugs of a number of types which are used with paracetamol, aspirin, naproxen, and similar agents with or without opioid analgesics to more effectively manage pain of various types. H1 receptor antagonist (antihistamine) NMDA receptor antagonist (Ki value of 6.0 ± 0.7 μM, one hundred times less potent than phencyclidine, which binds with a Ki of 59 nM) NDRI (norepinephrine and dopamine reuptake inhibitor) Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker HERG potassium channel blocker History George Rieveschl was a professor of chemistry at the University of Cincinnati and led a research program working on antihistamines. In 1943, one of his students, Fred Huber, synthesized diphenhydramine. Rieveschl worked with Parke-Davis to test the compound, and the company licensed the patent from him. In 1947 Parke-Davis hired him as their Director of Research. While he was there, he led the development of orphenadrine, an analog of diphenhydramine.Prior to the development of amantadine in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinsons treatment. Formulation Orphenadrine has been available as a citrate salt and a hydrochloride salt; in the US as of February 2016 the citrate form was available in tablets, extended release tablets, compounding powder and by injection for acute use in a hospital setting.Orphenadrine is often available mixed with aspirin, paracetamol/acetaminophen, ibuprofen, caffeine, and/or codeine.The brand names Norflex and Norgesic are formulations of the citrate salt of orphenadrine and Disipal is the hydrochloride salt. Chemistry Orphenadrine is a derivative of diphenhydramine with a methyl group added to one of the phenyl rings. Stereochemistry Orphenadrine has a chiral center and two enantiomers. When employed as a therapeutic agent, it is typically supplied as the racemate. References External links MedlinePlus DrugInfo medmaster-a682162
Estropipate	Estropipate, also known as piperazine estrone sulfate and sold under the brand names Harmogen, Improvera, Ogen, Ortho-Est, and Sulestrex among others, is an estrogen medication which is used mainly in menopausal hormone therapy in the treatment of menopausal symptoms. It is a salt of estrone sulfate and piperazine, and is transformed into estrone and estradiol in the body. It is taken by mouth. Medical uses Estropipate is used to: Alleviate symptoms of menopause as menopausal hormone therapy Treat some types of infertility Treat some conditions leading to underdevelopment of female sexual characteristics Treat vaginal atrophy Treat some types of breast cancer (particularly in men and postmenopausal women) Treat prostate cancer Prevent osteoporosis Available forms Estropipate is available in the form of 0.75, 1.5, 3, and 6 mg oral tablets. Pharmacology Pharmacodynamics Estropipate is a prodrug of estrone and estradiol. Hence, it is an estrogen, or an agonist of the estrogen receptors. Pharmacokinetics Estropipate is hydrolyzed into estrone in the body. Estrone can then be transformed into estradiol by 17β-hydroxysteroid dehydrogenase. Chemistry History Estropipate was introduced for medical use by Abbott in 1968. It was approved by the FDA in the United States in 1991. Society and culture Generic names Estropipate is the generic name of the drug and its INN, USAN, and BAN. Brand names Estropipate is or has been marketed under the brand names Genoral, Harmogen, Improvera, Ogen, Ortho-Est, and Sulestrex among others. Availability Estropipate appears to remain available only in the United States. In the past, estropipate has also been marketed in Canada, the United Kingdom, Ireland, Switzerland, Australia, South Africa, Mexico, and Indonesia. == References ==
Rizatriptan	Rizatriptan, sold under the brand name Maxalt among others, is a medication used for the treatment of migraine headaches. It is taken by mouth.Common side effects include chest pain, dizziness, dry mouth, and tingling. Other side effects may include myocardial infarction, stroke, high blood pressure, serotonin syndrome, and anaphylaxis. Excessive use may result in medication overuse headaches. Use is not recommended during pregnancy and breastfeeding is not recommended within 24 hours after taking a dose. Rizatriptan is in the triptan class and is believed to work by activating the 5-HT1 receptor.Rizatriptan was patented in 1991 and came into medical use in 1998. It is available as a generic medication. In 2019, it was the 162nd most commonly prescribed medication in the United States, with more than 3 million prescriptions. Medical uses Rizatriptan is used to treat acute migraine attacks with or without aura. It does not prevent future migraine attacks. A 2010 review found rizatriptan to be more efficacious and tolerable than sumatriptan. Contraindications Rizatriptan and other triptans can cause vasoconstriction, they are contraindicated in people with cardiovascular conditions. Adverse effects Frequent adverse effects (incidence less than 10%) are dizziness, drowsiness, asthenia/fatigue, and nausea. Clinical adverse experiences were typically mild and short-lasting (2–3 hours). Interactions Propranolol Mechanism of action Rizatriptan acts as an agonist at serotonin 5-HT1B and 5-HT1D receptors. Like the other triptans sumatriptan and zolmitriptan, rizatriptan induces vasoconstriction—possibly by inhibiting the release of calcitonin gene-related peptide from sensory neurons in the trigeminal nerve. Names Brand names include Bizaliv, Rizalt, Rizact (India) and Maxalt. References External links "Rizatriptan benzoate". Drug Information Portal. U.S. National Library of Medicine.
Colestyramine	Colestyramine (INN) or cholestyramine (USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer. Colestyramine removes bile acids from the body by forming insoluble complexes with bile acids in the intestine, which are then excreted in the feces. As a result of this loss of bile acids, more plasma cholesterol is converted to bile acids in the liver to normalise levels. This conversion of cholesterol into bile acids lowers plasma cholesterol levels. Medical uses Bile acid sequestrants such as colestyramine were first used to treat hypercholesterolemia, but since the introduction of statins, now have only a minor role for this indication. They can also be used to treat the pruritus, or itching, that often occurs during liver failure and other types of cholestasis where the ability to eliminate bile acids is reduced.Colestyramine is commonly used to treat diarrhea resulting from bile acid malabsorption. It was first used for this in Crohns disease patients who had undergone ileal resection. The terminal portion of the small bowel (ileum) is where bile acids are reabsorbed. When this section is removed, the bile acids pass into the large bowel and cause diarrhea due to stimulation of chloride/fluid secretion by the colonocytes resulting in a secretory diarrhea. Colestyramine prevents this increase in water by making the bile acids insoluble and osmotically inactive. Colestyramine is also used in the control of other types of bile acid diarrhea. The primary, idiopathic form of bile acid diarrhea is a common cause of chronic functional diarrhea, often misdiagnosed as diarrhea-predominant irritable bowel syndrome (IBS-D), and most of these patients respond to colestyramine. It is beneficial in the treatment of postcholecystectomy syndrome chronic diarrhea. Colestyramine is also useful in treating post-vagotomy diarrhea.Colestyramine can be helpful in the treatment of Clostridium difficile infections, to absorb toxins A and B, and reduce the diarrhea and the other symptoms these toxins cause. However, because it is not an anti-infective, it is used in concert with vancomycin.It is also used in the "wash out" procedure in patients taking leflunomide or teriflunomide to aid drug elimination in the case of drug discontinuation due to severe side effects caused by leflunomide or teriflunomide.A case report suggests that colestyramine may be useful for cyanobacterial (microcystin) poisoning in dogs.Ointments containing colestyramine compounded with aquaphor have been used in topical treatment of diaper rash in infants and toddlers.Cholestyramine also binds with oxalate in the GI tract, ultimately reducing urine oxalate and calcium oxalate stone formation. Available forms Colestyramine is available as powder form, in 4-g packets, or in larger canisters. In the United States, it can be purchased either as a generic medicine, or as Questran or Questran Light (Bristol-Myers Squibb). Dosage A typical dose is 4 to 8 g once or twice daily, with a maximum dose of 24 g/d. Side effects These side effects have been noted: Most frequent: constipation Increased plasma triglyceridesIntestinal obstruction has been reported in patients with previous bowel surgery who should use colestyramine cautiously. Cholestyramine-induced hyperchloremic metabolic acidosis has also been reported rarely.Patients with hypothyroidism, diabetes, nephrotic syndrome, dysproteinemia, obstructive liver disease, kidney disease, or alcoholism should consult their doctor before taking this medication. Other drugs should be taken at least one hour before or four to six hours after colestyramine to reduce possible interference with absorption. Patients with phenylketonuria should consult with a physician before taking Questran Light because that product contains phenylalanine. Drug interactions Interactions with these drugs have been noted: Digitalis Estrogens and progestins Oral diabetes drugs Penicillin G Phenobarbital Spironolactone Tetracycline Thiazide-type diuretic pills Thyroid medication Warfarin LeflunomideMost interactions are due to the risk of decreased absorption of these drugs. The duration of treatment is not limited, but the prescribing physician should reassess at regular intervals if continued treatment is still necessary. The principal overdose risk is blockage of intestine or stomach. Colestyramine may interfere in the absorption of fat-soluble vitamins such as vitamins A, D, E, and K. No special considerations regarding alcohol consumption are made. Notes and references The Merck Index (12 ed.). p. 2257. External links U.S. National Library of Medicine: Drug Information Portal - Cholestyramine
Betaxolol	Betaxolol is a selective beta1 receptor blocker used in the treatment of hypertension and glaucoma. Being selective for beta1 receptors, it typically has fewer systemic side effects than non-selective beta-blockers, for example, not causing bronchospasm (mediated by beta2 receptors) as timolol may. Betaxolol also shows greater affinity for beta1 receptors than metoprolol. In addition to its effect on the heart, betaxolol reduces the pressure within the eye (intraocular pressure). This effect is thought to be caused by reducing the production of the liquid (which is called the aqueous humor) within the eye. The precise mechanism of this effect is not known. The reduction in intraocular pressure reduces the risk of damage to the optic nerve and loss of vision in patients with elevated intraocular pressure due to glaucoma. It was patented in 1975 and approved for medical use in 1983. Medical uses Oral: for the management of hypertension Ophthalmic: for the management of glaucoma the drug seems to have an effect of neuroprotection in glaucoma treatment Contraindications Hypersensitivity to the drug Patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure Side effects History Betaxolol was approved by the U.S. Food and Drug Administration (FDA) for ocular use as a 0.5% solution (Betoptic) in 1985 and as a 0.25% solution (Betoptic S) in 1989. Society and culture Brand names Brand names include Betoptic, Betoptic S, Lokren, Kerlone. See also Levobetaxolol Cicloprolol References External links Kerlone prescribing information
Etacrynic acid	Etacrynic acid (INN) or ethacrynic acid (USAN), trade name Edecrin, is a loop diuretic used to treat high blood pressure and the swelling caused by diseases like congestive heart failure, liver failure, and kidney failure. A con with etacyrnic acid compared to the other loop diuretic drugs such as furosemide is that it has a significantly steep dose-response curve, which means the drugs dosing is very important as small variance in dose can cause a significant difference in the biological response. Unlike the other loop diuretics, etacrynic acid is not a sulfonamide and thus use is not contraindicated in those with sulfa allergies. If a patient with sulfa allergies is in need of a loop diuretic, it is more likely for the physician to prescribe etacyrnic acid for this reason. Structural features Ethacrynic acid is a phenoxyacetic acid derivative, which means it contains a ketone group and a methylene group. Medical use Ethacrynic acid is a diuretic that is used to treat edema when a stronger agent is required. It is available as a pill or injected form. The pill is used to treat edema associated with congestive heart failure, cirrhosis and renal disease, accumulation of liquid in the belly associated with cancer or edema, and management of hospitalized children with congenital heart disease or nephrotic syndrome. The injected form is used to rapidly remove water from the body when needed – for example in acute pulmonary edema – or when a person cannot take the medicine in pill form. Adverse effects As a diuretic, ethacrynic acid can cause frequent urination, but this usually resolves after taking the drug for a few weeks. Ethacrynic acid can also cause low potassium levels, which may manifest as muscle cramps or weakness. It has also been known to cause reversible or permanent hearing loss (ototoxicity) and liver damage when administered in extremely high dosages. On oral administration, it produces diarrhea; intestinal bleeding may occur at higher doses. Mechanism of action Ethacrynic acid acts by inhibiting NKCC2 in the thick ascending loop of Henle and the macula densa. Loss of potassium ions is less marked but chances of hypochloremic alkalosis are greater. The dose response curve of ethacrynic acid is steeper than that of furosemide and, in general, it is less manageable; dose range is 50–150 mg. Ethacrynic acid and its glutathione-adduct are potent inhibitors of glutathione S-transferase family members, which are enzymes involved in xenobiotic metabolism. This family of enzymes has recently been shown to have a high rate of genetic variability. United States price history The ethacrynic acid tablet market had U.S. sales of approximately $17 million for the 12 months ending April 2020 according to IQVIA.National Average Drug Acquisition Cost data from the Centers for Medicare and Medicaid Services shows that the average price paid by retail pharmacies for an Edecrin 25 MG tablet was $5.24 as 11/28/13 by Bausch Health US, LLC, formerly Valeant Pharmaceuticals. The price from Bausch Health US, LLC increased to $21.72 per tablet as of 5/18/2016. In 2015, Valeant was involved in a number of controversies surrounding drug price hikes and the use of a specialty pharmacy for the distribution of its drugs.As of September 19, 2018, the price for the generic equivalent was $10.01 per tablet from West-ward Pharmaceuticals Corp., Edenbridge Pharmaceuticals, LLC and Oceanside Pharmaceuticals. As of July 22, 2020 the price decreased to $3.45 with availability from additional generic manufacturers. As of February 17, 2021 the average price paid by pharmacies was $5.69 per 25 MG tablet with 10 generic manufacturers. Up to date price information can be found at https://data.medicaid.gov/dataset/d5eaf378-dcef-5779-83de-acdd8347d68e/data?conditions[0] [property]=ndc_description&conditions[0] [value]=%25ethacrynic%20acid%25&conditions[0] [operator]=like Price fixing investigation It is known whether this apparent price fixing is actively being investigated, but the United States Department of Justice Antitrust Division Spring Update 2021 notes: "The Division remains committed to rooting out illegal conduct that corrupts critical healthcare markets. That work is more important now than ever before. In recent years, the Division has uncovered price-fixing, bid-rigging, and customer-allocation schemes in one of the most important markets for the health and wallets of American consumers: the generic drug industry. Indeed, nearly 90% of all prescriptions in the United States are filled with generic drugs." == References ==
Methylnaltrexone	Methylnaltrexone (MNTX, brand name Relistor), used in form of methylnaltrexone bromide (INN, USAN, BAN), is a medication that acts as a peripherally acting μ-opioid receptor antagonist that acts to reverse some of the side effects of opioid drugs such as constipation without significantly affecting pain relief or precipitating withdrawals. Because MNTX is a quaternary ammonium cation, it cannot cross the blood–brain barrier, and so has antagonist effects throughout the body, counteracting effects such as itching and constipation, but without affecting opioid effects in the brain such as pain relief. However, since a significant fraction (up to 60%) of opioid analgesia can be mediated by opioid receptors on peripheral sensory neurons, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain, MNTX may increase pain under such circumstances. Medical uses Methylnaltrexone is approved for the treatment of opioid-induced constipation in chronic non cancer pain or when ordinary laxatives have failed. Mechanism of action Methylnaltrexone is a peripheral acting mu-opioid receptor antagonist, and does not cross the blood brain barrier. Methylnaltrexone has restricted access through the blood brain barrier because it is a quaternary amine, which carries a positive charge when in a solution and more has polarity with lower lipid solubility than a lot of the opioid agonists used for pain treatment. The peripheral action of methylnaltrexone makes it effective for decreasing the constipating effects of opioids, without interfering with the analgesic effects (of opioids) on the central nervous system. This is the primary characteristic that makes methylnaltrexone behave differently than naltrexone.Furthermore, as methylnaltrexone cannot cross the blood–brain barrier, it does not reverse the pain-killing properties of opioid agonists or cause withdrawal symptoms, but since a small portion of analgesia comes from the peripheral opioid receptors, it can increase pain from inflammatory conditions such as arthritis. Side effects The most common side effects for methylnaltrexone include: Abdominal pain Dizziness Vomiting Nausea Diarrhea History In 1978, a dying friend and colleague presented the late University of Chicago pharmacologist Leon Goldberg with a clinical challenge. Struggling with the pain of prostatic cancer that had metastasized to his bones, the man was now declining the morphine he required for analgesia because of constipation. Research on opioids which would target only the sub-types of receptors associated with pain relief and not with side effects had seen little success outside of in-vitro models. Considering drugs such as loperamide, which acted on the opioid receptors in the gut without acting on the central nervous system, Goldberg proposed a targeted opioid receptor antagonist.Thousands of opioid-like molecules had been synthesized by pharmaceutical companies looking for the better analgesic - and many of those with no pain-relieving properties had been shelved. Screening these compounds led to the examination of putative antagonists which when modified had properties that suggested they might not readily cross the blood–brain barrier based on their size and charge. One of these compounds, N-methyl-naltrexone (MNTX), was amongst a group of compounds synthesized by Boehringer Ingelheim. The compound looked promising and passed initial screening in which rodents were given opioids along with charcoal meals to track GI transit, and were tested for analgesia. In a 1982 paper by Russell et al., it was first reported that the GI effects of the opioids could be prevented without affecting centrally mediated analgesia in this model. Subsequent preclinical studies also demonstrated this separation of central and peripherally mediated opioid effects for other smooth muscles of the GI tract and the cough reflex. Interest also developed in the potential for MNTX to act at the chemoreceptor trigger zone and block the emetic effect of opioids. This blockade of opioid-induced emesis was demonstrated in a canine model. Goldberg died before he could see the core of this idea come into clinical practice. Research on methylnaltrexone continued in the Department of Anesthesiology and Critical Care at the University of Chicago through the 1990s. More recent investigations, however, discovered opioid receptors on peripheral sensory neurons.In December 2005, Wyeth and Progenics entered into an exclusive, worldwide agreement for the joint development and commercialization of methylnaltrexone for the treatment of opioid-induced side effects, including constipation and post-operative ileus (POI), a prolonged dysfunction of the gastrointestinal tract following surgery. Under the terms of the agreement, the companies are collaborating on worldwide development. Wyeth received worldwide rights to commercialize methylnaltrexone, and Progenics retained an option to co-promote the product in the United States. Wyeth will pay Progenics royalties on worldwide sales and co-promotion fees within the United States. Methylnaltrexone is being developed in subcutaneous and oral forms to treat opioid induced constipation (OIC). The use of methylnaltrexone (Relistor) for more than 4 months has not been studied. Society and culture Approval On April 1, 2008, Progenics and Wyeth announced that Health Canada has approved methylnaltrexone for the treatment of opioid-induced constipation. It was later approved by the US FDA on April 24, 2008. Forms As of 2010, methylnaltrexone is supplied as an injection in trays containing seven one-dose vials containing 0.6 mL of solution. Each tray also contains seven 12 mm (0.47 in) 1 mL 27 gauge needles with retractable tips, and alcohol wipes for home use. A single vial can treat someone who weighs as much as 115 kilograms (254 lb). For hospital use, vials are available separately. See also Loperamide - an μ-opioid receptor agonist that doesnt cross the BBB in significant amounts, and treats diarrhea (in contrast to methynaltrexone, a Mu-opioid receptor antagonist that doesnt cross the BBB, avoiding opiate withdrawal effects in patients, while treating constipation) Naloxegol (trade names Movantik and Moventig) - another peripherally selective opioid antagonist used to treat opioid-induced constipation (+)-Naloxone - a non-opioid drug which also reduces some side effects of opioids without significantly affecting analgesia when used in small oral doses 6β-Naltrexol (6α-hydroxynaltrexone) - another naltrexone derivative that is also a peripherally selective opioid antagonist References == Further reading ==
Iduronidase	Iduronidase (EC 3.2.1.76, L-iduronidase, alpha-L-iduronidase, laronidase), sold as Aldurazyme, is an enzyme with the systematic name glycosaminoglycan alpha-L-iduronohydrolase. This enzyme catalyses the hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.It is a glycoprotein enzyme found in the lysosomes of cells. It is involved in the degeneration of glycosaminoglycans such as dermatan sulfate and heparan sulfate. The enzyme acts by hydrolyzing the terminal alpha-L-iduronic acid residues of these molecules, degrading them. The protein is reported as having a mass of approximately 83 kilodaltons. Pathology A deficiency in the IDUA protein is associated with mucopolysaccharidoses (MPS). MPS, a type of lysosomal storage disease, is typed I through VII. Type I is known as Hurler syndrome and type I,S is known as Scheie syndrome, which has a milder prognosis compared to Hurlers. In this syndrome, glycosaminoglycans accumulate in the lysosomes and cause substantial disease in many different tissues of the body. IDUA mutations result in the MPS 1 phenotype, which is inherited in an autosomal recessive fashion. The defective alpha-L-iduronidase results in an accumulation of heparan and dermatan sulfate within phagocytes, endothelium, smooth muscle cells, neurons, and fibroblasts. Under electron microscopy these structures present as laminated structures called Zebra bodies. Prenatal diagnosis of this enzyme deficiency is possible. Aldurazyme General Aldurazyme is the name of the commercialized variant of the enzyme iduronidase, which hydrolyzes the alpha-L-iduronic acid residues of dermatan sulfate and heparin sulfate. Produced in Chinese hamster ovaries by recombinant DNA technology, Aldurazyme is the manufactured by BioMarin Pharmaceutical Inc. and distributed by Genzyme Corporation (a subsidiary of Sanofi). Aldurazyme is administered as a slow intravenous infusion. The recombinant enzyme is 628 amino acids in length with 6 N-linked oligosaccharide modification sites and two oligosaccharide chains terminating in mannose sugars. Medical use Aldurazyme is indicated in the US for people with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for people with the Scheie form who have moderate to severe symptoms.Aldurazyme is indicated in the EU for long-term enzyme replacement therapy in patients with a confirmed diagnosis of mucopolysaccharidosis I (MPS I; alpha-L-iduronidase deficiency) to treat the nonneurological manifestations of the disease.Aldurazyme was approved for medical use in the United States and in the European Union in 2003. Pre-clinical work Dosing for human clinical studies was based on canine MPS I studies. Clinical trials Three clinical trials were performed to establish the pharmacology, efficacy, and safety of weekly intravenous administration of the drug. These studies included a Phase I open-label study, a Phase III randomized, double-blind, placebo-controlled study, and a Phase III open-label extension study. A Phase II Young Pediatric study was also conducted.Clinical trials and post-market safety data indicate that the most common adverse side effect of Aldurazyme is allergic reaction. In order to prevent allergic reaction and respiratory distress, the packet insert of Aldurazyme suggests that patients be administered antihistamines before infusion. Allergic reaction occurs in approximately 1% of patients. It is recommended that patients who are high-risk for respiratory distress be given their infusion in a facility equipped to deal with an anaphylactic response. (High-risk factors include sleep apnea, respiratory impairment, respiratory illness, or previous experience with allergic reaction to Aldurazyme. It is noted that risk-benefit must be weighed for patients with history of severe allergic response as to whether the drug should be administered again.) In a 2002 memorandum, Melanie Hartsough, Ph.D., DTP of the FDAs Department of Health and Human Services stated, "Aggregation of product could enhance immune responses, specifically neutralizing antibody, which may limit the response to therapy, whereas highly deaggregated product may induce immune tolerance." It appears that she then went on to ask for further justification of some relevant aspect of the production process, though the majority of this particular memorandum has not been publicly released and it is unclear as to whether this concern is relevant to the high rate of allergic response to this drug.Additionally, it is recommended that patients be administered antipyretics before use. According to Aldurazymes website, the most common adverse effects observed in a 26-week, placebo-controlled clinical trial of patients 6 years old or older are flushing, pyrexia, headache, and rash. Flushing was noted in 23% of patients, or five people, in this relatively small clinical study. This trial was extended. In the extension, it was noted that abdominal pain and infusion-site reaction occurred in some patients.The website also states that in a 52-week open-label uncontrolled clinical trial, the most common serious reactions in children younger than 6 were "otitis media (20%), and central venous catherization required for ALDURAZYME infusion (15%). The most commonly reported adverse reactions in patients 6 years and younger were infusion reactions reported in 35% (7 of 20) of patients and included pyrexia (30%), chills (20%), blood pressure increased (10%), tachycardia (10%), and oxygen saturation decreased (10%). Other commonly reported infusion reactions occurring in ≥5% of patients were pallor, tremor, respiratory distress, wheezing, crepitations (pulmonary), pruritus, and rash."A Phase IV clinical trial is currently recruiting participants to investigate whether Aldurazyme passes through breastmilk and whether it has any effect on nursing infants. Regulation Aldurazyme was the first drug approved by the United States Food and Drug Administration to be marketed as a treatment for MPS I. It was approved in April 2003. Marketing authorization in the European Union was granted in June 2003 by the European Commission. Aldurazyme enjoys orphan drug status in both the United States and the European Union, though in both its orphan drug exclusivity period has expired. (Orphan drug exclusivity, which prevents the FDA or similar European body from approving the same drug proposed by another company for the same listed use lasts only seven years in the United States and ten years in the European Union.) Aldurazyme was granted orphan designation for Treatment of patients with mucopolysaccharidosis-I on September 24, 1997.As of 2014, Aldurazyme was mandated to be produced using Good Manufacturing Practices (GMP) and, along with several other recombinant enzyme products produced by Biomarin, was manufactured at the production facility located in Novato, California. Both packaging and vialing were performed by contractors. All suppliers and contractors also are mandated to follow GMP, and they, as well as BioMarin, are subject to inspection and review. BioMarins facility has received both FDA and European Commission approval. Commercialization plan Aldurazyme is manufactured by BioMarin in California. It is commercialized and distributed by Genzyme in the United States, the European Union, and worldwide. The patent for Aldurazyme was filed by BioMarin on November 12, 1999, patent no. US 6426208 B1, "Recombinant α-L-iduronidase, methods for producing and purifying the same and methods for treating diseases caused by deficiencies thereof".Aldurazyme yielded a net $105.6 million net product revenue out of $738.4 million in net profit revenues in 2014, $83.6 million out of $538.4 million in 2013, and $82.2 million out of $496.5 million in 2012, making it BioMarins third-most profitable product behind Naglazyme and Kuvan. In 2011, Aldurazyme yielded a net product revenue of $82.8 million out of $437.6 million net revenue, and in 2010 it netted $71.2 million out of $369.7 million in net product revenues. Aldurazyme netted $70.2 million in profit revenues in 2009 out of a total $315.7 $72.5 million in revenue were netted in 2008 out of Biomarins $251.9 million in product revenues that year.BioMarin described its business strategy as the following in their 2014 United States Securities and Exchange Commission Form 10-K: BioMarin Pharmaceutical Inc. (BioMarin, we, us or our) develops and commercializes innovative pharmaceuticals for serious diseases and medical conditions. We select product candidates for diseases and conditions that represent a significant unmet medical need, have well-understood biology and provide an opportunity to be first-to-market or offer a significant benefit over existing products. Based on this business model, it is easy to understand why BioMarin would have targeted a disease like MPS I for treatment. It is, as described, an orphan condition with a well-defined mechanism. Furthermore, before the development of Aldurazyme, there were no drugs to treat MPS I, allowing BioMarin to be first-to-market with its new pharmaceutical. Since the release of Aldurazyme, one more drug has been released to treat MPS; Elaprase is a treatment for MPS II. In 2016, Aldurazyme had an average cost-per-patient of $355,816. Collaboration between BioMarin and Genzyme BioMarin/Genzyme is a 50/50 Limited Liability Company which co-owns the intellectual rights to Aldurazyme and works collaboratively on research and development. BioMarin is responsible for the production of Aldurazyme. It sells the finished product to Genzyme, which is a fully owned subsidiary of Sanofi. Genzyme pays a 39.5% - 50% royalty quarterly on worldwide net product sales to BioMarin. A portion of this royalty is considered to be product transfer royalties, meaning that if any Aldurazyme goes unsold, BioMarin merely retains the product transfer royalty, while not receiving any further royalties. Only in the case of defective product is Genzyme reimbursed for Aldurazyme product. References Further reading External links "Mucopolysaccharidosis type I". MedlinePlus. NBK1162. "Laronidase". Drug Information Portal. U.S. National Library of Medicine. Iduronidase at the US National Library of Medicine Medical Subject Headings (MeSH)
Cyproheptadine	Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties. It was patented in 1959 and came into medical use in 1961. Medical uses Cyproheptadine is used to treat allergic reactions (specifically hay fever). The evidence for its use for this purpose indicates its effectiveness but second generation antihistamines such as ketotifen and loratadine have shown equal results with fewer side effects.It is also used as a preventive treatment against migraine. In a 2013 study the frequency of migraine was dramatically reduced in patients within 7 to 10 days after starting treatment. The average frequency of migraine attacks in these patients before administration was 8.7 times per month, this was decreased to 3.1 times per month at 3 months after the start of treatment. This use is on the label in the UK and some other countries. It is also used off-label in the treatment of cyclical vomiting syndrome in infants; the only evidence for this use comes from retrospective studies.Cyproheptadine is sometimes used off-label to improve akathisia in people on antipsychotic medications.It is used off-label to treat various dermatological conditions, including psychogenic itch drug-induced hyperhidrosis (excessive sweating), and prevention of blister formation for some people with epidermolysis bullosa simplex.One of the effects of the drug is increased appetite and weight gain, which has led to its use (off-label in the USA) for this purpose in children who are wasting as well as people with cystic fibrosis.It is also used off-label in the management of moderate to severe cases of serotonin syndrome, a complex of symptoms associated with the use of serotonergic drugs, such as selective serotonin reuptake inhibitors (and monoamine oxidase inhibitors), and in cases of high levels of serotonin in the blood resulting from a serotonin-producing carcinoid tumor.Cyproheptadine has sedative effects and can be used to treat insomnia similarly to other centrally-acting antihistamines. The recommended dose for this use is 4 to 8 mg. Adverse effects Adverse effects include: Overdose Gastric decontamination measures such as activated charcoal are sometimes recommended in cases of overdose. The symptoms are usually indicative of CNS depression (or conversely CNS stimulation in some) and excess anticholinergic side effects. The LD50 in mice is 123 mg/kg and 295 mg/kg in rats. Pharmacology Pharmacodynamics Cyproheptadine is a very potent antihistamine or inverse agonist of the H1 receptor. At higher concentrations, it also has anticholinergic, antiserotonergic, and antidopaminergic activities. Of the serotonin receptors, it is an especially potent antagonist of the 5-HT2 receptors. This is thought to underlie its effectiveness in the treatment of serotonin syndrome. However, it is possible that blockade of 5-HT1 receptors may also contribute to its effectiveness in serotonin syndrome. Cyproheptadine has been reported to block 85% of 5-HT2 receptors in the human brain at a dose of 4 mg three times per day (12 mg/day total) and to block 95% of 5-HT2 receptors in the human brain at a dose of 6 mg three times per day (18 mg/day total) as measured with positron emission tomography (PET). The dose of cyproheptadine recommended to ensure blockade of the 5-HT2 receptors for serotonin syndrome is 20 to 30 mg. Besides its activity at neurotransmitter targets, cyproheptadine has been reported to possess weak antiandrogenic activity. Pharmacokinetics Cyproheptadine is well-absorbed following oral ingestion, with peak plasma levels occurring after 1 to 3 hours. Its terminal half-life when taken orally is approximately 8 hours. Chemistry Cyproheptadine is a tricyclic benzocycloheptene and is closely related to pizotifen and ketotifen as well as to tricyclic antidepressants. Research Cyproheptadine was studied in one small trial as an adjunct in people with schizophrenia whose condition was stable and were on other medication; while attention and verbal fluency appeared to be improved, the study was too small to draw generalizations from. It has also been studied as an adjuvant in two other trials in people with schizophrenia, around fifty people overall, and did not appear to have an effect.There have been some trials to see if cyproheptadine could reduce sexual dysfunction caused by SSRI and antipsychotic medications.Cyproheptadine has been studied for the treatment of posttraumatic stress disorder. Veterinary use Cyproheptadine is used in cats as an appetite stimulant: 1371 and as an adjunct in the treatment of asthma. Possible adverse effects include excitement and aggressive behavior. The elimination half-life of cyproheptadine in cats is 12 hours.Cyproheptadine is a second line treatment for pituitary pars intermedia dysfunction in horses. == References ==
Tobramycin	Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.It was patented in 1965, and approved for medical use in 1974. It is on the World Health Organizations List of Essential Medicines. Medical uses Like all aminoglycosides, tobramycin does not pass the gastro-intestinal tract, so for systemic use it can only be given intravenously or by injection into a muscle. Eye drops and ointments (tobramycin only, Tobrex, or combined with dexamethasone, sold as Tobradex) and nebulised formulations both have low systemic absorption. The formulation for injection is branded Nebcin. The nebulised formulation (brand name Tobi) is indicated in the treatment of exacerbations of chronic infection with Pseudomonas aeruginosa in people diagnosed with cystic fibrosis.Tobrex eye drops are a 0.3% tobramycin sterile ophthalmic solution produced by Alcon Pharmaceuticals. Benzalkonium chloride 0.01% is added as a preservative. It is available by prescription only in Bulgaria, Hungary, the United States, and Canada. In certain countries, it is available over the counter, It is also available in Egypt as Tobrin eye drops produced by EIPICo, Tobrex, Tobradex and Tobrin are indicated in the treatment of superficial infections of the eye, such as bacterial conjunctivitis.Tobramycin, in its injectable form, is also indicated for various severe or life-threatening infections caused by susceptible strains: sepsis, meningitis, lower respiratory tract infections, intra-abdominal infections, skin infections, bone infections, and skin structure infections, complicated and recurrent urinary tract infections. Spectrum of susceptibility Tobramycin has a narrow spectrum of activity and is active against Gram-positive Staphylococcus aureus and various Gram-negative bacteria. Clinically, tobramycin is frequently used to eliminate Pseudomonas aeruginosa in cystic fibrosis patients. The following represents the minimum inhibitory concentration (MIC) susceptibility data for a few strains of Pseudomonas aeruginosa: Pseudomonas aeruginosa - <0.25 µg/mL – 92 µg/mL [ref?] Pseudomonas aeruginosa (non-mucoid) – 0.5 µg/mL - >512 µg/mL [ref?] Pseudomonas aeruginosa (ATCC 27853) – 0.5 µg/mL – 2 µg/mLThe MIC for Klebsiella pneumoniae, KP-1, is 2.3±0.2 µg/mL at 25 °C [unpublished]. Contraindications Tobramycin is contraindicated in people with hypersensitivity against aminoglycoside antibiotics. The Infusion is also contraindicated in people with myasthenia gravis. Side effects Like other aminoglycosides, a major side effect for tobramycin is ototoxicity or a loss of equilibrioception, or both in genetically susceptible individuals. Other side effects include nephrotoxicity, neuromuscular toxicity, and hypersensitivity reactions. Nephrotoxicity can be particularly worrisome when multiple doses accumulate over the course of a treatment or when the kidney concentrates urine by increasing tubular reabsorption during sleep. Adequate hydration may help prevent excess nephrotoxicity and subsequent loss of renal function. For these reasons parenteral tobramycin needs to be carefully dosed by body weight, and its serum concentration monitored. Tobramycin is thus said to be a drug with a narrow therapeutic index. Interactions Muscle relaxants and diethylether can add to the neuromuscular blocking effects of tobramycin.Methoxyflurane, when used as an inhalational anesthetic, can aggravate the nephrotoxic effects of injected tobramycin. Likewise, combining injected tobramycin with other nephrotoxic or ototoxic drugs can lead to more adverse effects; examples include amphotericin B, ciclosporin, cisplatin, vancomycin, and the diuretic furosemide. Other diuretics can also increase the risk for side effects because they raise tobramycin concentrations in the body fluids.Combining tobramycin with betalactam antibiotics can be desirable because of their synergistic effects. However, when they are given through the same drip, as well as in people with reduced kidney function, they can react with each other to form antibiotically inactive amides. Pharmacology Mechanism of action Tobramycin works by binding to a site on the bacterial 30S and 50S ribosome, preventing formation of the 70S complex. As a result, mRNA cannot be translated into protein, and cell death ensues. Tobramycin also binds to RNA-aptamers, artificially created molecules to bind to certain targets. However, there seems to be no indication that Tobramycin binds to natural RNAs or other nucleic acids. The effect of tobramycin can be inhibited by metabolites of the Krebs (TCA) cycle, such as glyoxylate. These metabolites protect against tobramycin lethality by diverting carbon flux away from the TCA cycle, collapsing cellular respiration, and thereby inhibiting Tobramycin uptake and thus lethality. Pharmacokinetics Tobramycin is not absorbed in the gut. When given as infusion, it is distributed in the extracellular fluid. It can accumulate in the kidneys tubular cells and in the lymph of the inner ear. Only low concentrations reach the central nervous system and breast milk. Tobramycin passes the placenta: in the fetus, 20% of the mothers concentrations have been measured.The substance is neither bound to plasma proteins, nor is it metabolized. It is excreted in unchanged form via the kidneys with a biological half-life of about 2 to 3 hours. Elimination from deep compartments such as the renal cortex follows after 8 to 12 hours. In newborns the half-life is 4.6 hours on average; in those with a low birth weight it is as long as 8.7 hours on average. People with reduced kidney function also have a longer half-life for tobramycin, while in those with severe burns it can be shorter. References Further reading Davis BD (September 1987). "Mechanism of bactericidal action of aminoglycosides". Microbiological Reviews. 51 (3): 341–50. doi:10.1128/MMBR.51.3.341-350.1987. PMC 373115. PMID 3312985. External links "Tobramycin". Drug Information Portal. U.S. National Library of Medicine.
Prednisolone	Prednisolone is a steroid medication used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthritis, dermatitis, eye inflammation, asthma, and multiple sclerosis. It can be taken by mouth, injected into a vein, used topically as a skin cream, or as eye drops.Side effects with short-term use include nausea and feeling tired. More severe side effects include psychiatric problems, which may occur in about 5% of people. Common side effects with long term use include bone loss, weakness, yeast infections, and easy bruising. While short-term use in the later part of pregnancy is safe, long-term use or use in early pregnancy is occasionally associated with harm to the baby. It is a glucocorticoid made from hydrocortisone (cortisol).Prednisolone was discovered and approved for medical use in 1955. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 139th most commonly prescribed medication in the United States, with more than 4 million prescriptions. Medical uses Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and autoimmune conditions such as asthma, uveitis, pyoderma gangrenosum, rheumatoid arthritis, urticaria, angioedema, ulcerative colitis, pericarditis, temporal arteritis and Crohns disease, Bells palsy, multiple sclerosis, cluster headaches, vasculitis, acute lymphoblastic leukemia and autoimmune hepatitis, systemic lupus erythematosus, Kawasaki disease, dermatomyositis, and sarcoidosis.Prednisolone acetate ophthalmic suspension (eye drops) is an adrenocortical steroid product, prepared as a sterile ophthalmic suspension and used to reduce swelling, redness, itching, and allergic reactions affecting the eye. It has been explored as a treatment option for bacterial keratitis.Prednisolone can also be used for allergic reactions ranging from seasonal allergies to drug allergic reactions.Prednisolone can also be used as an immunosuppressive drug for organ transplants.Prednisolone in lower doses can be used in cases of primary adrenal insufficiency (Addisons disease).Corticosteroids inhibit the inflammatory response to a variety of inciting agents and, it is presumed, delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation with inflammation. Adverse effects Adverse reactions from the use of prednisolone include: Increased appetite, weight gain, nausea, and malaise Increased risk of infection Cardiovascular events Dermatological effects including reddening of face, bruising/skin discoloration, impaired wound healing, thinning of skin, skin rash, fluid build up and abnormal hair growth Hyperglycemia; patients with diabetes may need increased insulin or diabetic therapies Menstrual abnormalities Lower response to hormones, especially during stressful instances such as surgery or illness Change in electrolytes: rise in blood pressure, increased sodium and low potassium, leading to alkalosis GI system effects: swelling of stomach lining, reversible increase in liver enzymes, and risk of stomach ulcers Muscular and skeletal abnormalities, such as muscle weakness/muscle loss, osteoporosis (see steroid-induced osteoporosis), long bone fractures, tendon rupture, and back fractures Neurological effects, including involuntary movements (convulsions), headaches, and vertigo Behavioral disturbances Nasal septum perforation and bowel perforation (in some pathologic conditions).Withdrawal from prednisolone after long-term or high-dose use can lead to adrenal insufficiency. Pregnancy and breastfeeding Although there are no major human studies of prednisolone use in pregnant women, studies in several animals show that it may cause birth defects including increase cleft palate. Prednisolone should be used in pregnant women when benefits outweigh the risks and children born from mothers using prednisolone during pregnancy should be monitored for impaired adrenal function. Prednisolone is found in breast milk of mothers taking prednisolone. Pharmacology As a glucocorticoid, the lipophilic structure of prednisolone allows for easy passage through the cell membrane where it then binds to its respective glucocorticoid receptor (GCR) located in the cytoplasm. Upon binding, formation of the GC/GCR complex causes dissociation of chaperone proteins from the glucocorticoid receptor enabling the GC/GCR complex to translocate inside the nucleus. This process occurs within 20 minutes of binding. Once inside the nucleus, the homodimer GC/GCR complex binds to specific DNA binding-sites known as glucocorticoid response elements (GREs) resulting in gene expression or inhibition. Complex binding to positive GREs leads to synthesis of anti-inflammatory proteins while binding to negative GREs blocks the transcription of inflammatory genes. Chemistry Prednisolone is a synthetic pregnane corticosteroid closely related to its cognate prednisone, having identical structure save for two fewer hydrogens near C11. It is also known as δ1-cortisol, δ1-hydrocortisone, 1,2-dehydrocortisol, or 1,2-dehydrohydrocortisone, as well as 11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione. Society and culture Dosage forms In the United States: Prednisolone sodium phosphate oral solution (Pediapred) Prednisolone acetate oral suspension (Flo-Pred) Prednisolone oral tablets (Millipred) Prednisolone sodium phosphate oral dissolving tablets (Orapred ODT) Prednisolone acetate ophthalmic suspension (Omnipred, Pred Forte) Athletics As a glucocorticosteroid, unauthorized or ad hoc use of prednisolone during competition via oral, intravenous, intramuscular or rectal routes is banned under World Anti-Doping Agency (WADA) anti-doping rules. Veterinary uses Prednisolone is used in the treatment of inflammatory and allergic conditions in cats, dogs, horses, small mammals such as ferrets, birds, and reptiles. Its usage in treating inflammation, immune-mediated disease, Addison’s disease, and neoplasia is often ‘off label’ or ‘extra label’. Many drugs are commonly prescribed for off label use in veterinary medicine." Studies in ruminating species, such as alpacas, have shown that oral administration of the drug is associated with a reduced bioavailability compared to intravenous administration, however, levels that are therapeutic in other species can be achieved with oral administration in alpacas. See also Loteprednol Methylprednisolone References External links "Prednisolone". Drug Information Portal. U.S. National Library of Medicine. "Prednisolone Ophthalmic". MedlinePlus. US patent 2837464, Arthur Nobile, "Process for production of dienes by corynebacteria", published 1958-06-03, issued 1958-06-03, assigned to SCHERING CORP
Estradiol valerate/dienogest	Estradiol valerate/dienogest (EV/DNG), sold under the brand names Lafamme, Natazia and Qlaira among others, is a combination product of estradiol valerate, an estrogen, and dienogest, a progestogen, which is used in menopausal hormone therapy in and as a birth control pill to prevent pregnancy in women. It is taken by mouth. Birth control pills containing EV/DNG are associated with a significantly increased risk of venous thromboembolism. However, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin. See also Estradiol valerate/cyproterone acetate Estradiol/nomegestrol acetate List of combined sex-hormonal preparations References External links "Dienogest mixture with Estradiol valerate". Drug Information Portal. U.S. National Library of Medicine.
Mepivacaine	Mepivacaine is a local anesthetic of the amide type. Mepivacaine has a reasonably rapid onset (more rapid than that of procaine) and medium duration of action (shorter than that of procaine) and is marketed under various trade names including Carbocaine and Polocaine. Mepivacaine became available in the United States in the 1960s. Mepivacaine is used in any infiltration and local anesthesia. It is supplied as the hydrochloride salt of the racemate, which consists of R(-)-mepivacaine and S(+)-mepivacaine in equal proportions. These two enantiomers have markedly different pharmacokinetic properties.Mepivacaine was originally synthesized in Sweden at the laboratory of Bofors Nobelkrut in 1956. References External links Mepivacaine at RxList
Hydroxyzine	Hydroxyzine, sold under the brand names Atarax, Vistaril and others, is an antihistamine medication. It is used in the treatment of itchiness, anxiety, and nausea, including that due to motion sickness. It is used either by mouth or injection into a muscle.Common side effects include sleepiness, headache, and a dry mouth. Serious side effects may include QT prolongation. It is unclear if use during pregnancy or breastfeeding is safe. Hydroxyzine works by blocking the effects of histamine. It is a first-generation antihistamine in the piperazine family of chemicals.It was first made by Union Chimique Belge in 1956 and was approved for sale by Pfizer in the United States later that year. In 2019, it was the 75th most commonly prescribed medication in the United States, with more than 9 million prescriptions. Medical uses Hydroxyzine is used in the treatment of itchiness, anxiety, and nausea due to motion sickness.A systematic review concluded that hydroxyzine outperforms placebo in treating generalized anxiety disorder. Insufficient data were available to compare the drug with benzodiazepines and buspirone.Hydroxyzine can also be used for the treatment of allergic conditions, such as chronic urticaria, atopic or contact dermatoses, and histamine-mediated pruritus. These have also been confirmed in both recent and past studies to have no adverse effects on the liver, blood, nervous system, or urinary tract.Use of hydroxyzine for premedication as a sedative has no effects on tropane alkaloids, such as atropine, but may, following general anesthesia, potentiate meperidine and barbiturates, and use in pre-anesthetic adjunctive therapy should be modified depending upon the state of the individual.Hydroxyzine is used as a non-barbiturate tranquilizer and for the treatment of neurological disorders, such as psychoneurosis and other forms of anxiety or tension states.Doses of hydroxyzine hydrochloride used for sleep range from 25 to 100 mg. As with other antihistamine sleep aids, hydroxyzine is usually only prescribed for short term or "as-needed" use since tolerance to the CNS effects of hydroxyzine can develop in as little as a few days. Contraindications The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can cause fetal abnormalities. When administered to pregnant rats, mice and rabbits, hydroxyzine caused abnormalities such as hypogonadism with doses significantly above that of the human therapeutic range.In humans, a significant dose has not yet been established in studies and, by default, the Food and Drug Administration (FDA) has introduced contraindication guidelines in regard to hydroxyzine. Use by those at risk for or showing previous signs of hypersensitivity is also contraindicated. Hydroxyzine is contraindicated for intravenous (IV) injection, as it has shown to cause hemolysis. Other contraindications include the administration of hydroxyzine alongside depressants and other compounds which affect the central nervous system; if absolutely necessary, it should only be administered concomitantly in small doses. If administered in small doses with other substances, such as mentioned, then patients should refrain from using dangerous machinery, motor vehicles or any other practice requiring absolute concentration, in accordance with safety law.Studies have also been conducted which show that long-term prescription of hydroxyzine can lead to tardive dyskinesia after years of use, but effects related to dyskinesia have also anecdotally been reported after periods of 7.5 months, such as continual head rolling, lip licking and other forms of athetoid movement. In certain cases, elderly patients previous interactions with phenothiazine derivatives or pre-existing neuroleptic treatment may have contributed to dyskinesia at the administration of hydroxyzine due to hypersensitivity caused by prolonged treatment, and therefore some contraindication is given for short-term administration of hydroxyzine to those with previous phenothiazine use. Side effects Several reactions have been noted in manufacturer guidelines—deep sleep, incoordination, sedation, calmness, and dizziness have been reported in children and adults, as well as others such as hypotension, tinnitus, and headaches. Gastrointestinal effects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by the mild antimuscarinic properties of hydroxyzine.Central nervous system effects such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage. Such properties have been attributed to hydroxyzine in several cases, particularly in patients treated for neuropsychological disorders, as well as in cases where overdoses have been observed. While there are reports of the "hallucinogenic" or "hypnotic" properties of hydroxyzine, several clinical data trials have not reported such side effects from the sole consumption of hydroxyzine, but rather, have described its overall calming effect described through the stimulation of areas within the reticular formation. The hallucinogenic or hypnotic properties have been described as being an additional effect from overall central nervous system suppression by other CNS agents, such as lithium or ethanol.Hydroxyzine exhibits anxiolytic and sedative properties in many psychiatric patients. One study showed that patients reported very high levels of subjective sedation when first taking the drug, but that levels of reported sedation decreased markedly over 5-7 days, likely due to CNS receptor desensitization. Other studies have suggested that hydroxyzine acts as an acute hypnotic, reducing sleep onset latency and increasing sleep duration — also showing that some drowsiness did occur. This was observed more in female patients, who also had greater hypnotic response. The use of sedating drugs alongside hydroxyzine can cause oversedation and confusion if administered at high doses—any form of hydroxyzine treatment alongside sedatives should be done under supervision of a doctor.Because of the potential for more severe side effects, this drug is on the list to avoid in the elderly.In 2015, the European Medicines Agency (EMA) announced a small but definite risk of QT prolongation associated with the use of hydroxyzine. This side effect is more likely to occur in people with pre-existing cardiac disease, or with the use of other medicines known to prolong the QT interval. Pharmacology Pharmacodynamics Hydroxyzines predominant mechanism of action is as a potent and selective histamine H1 receptor inverse agonist. This action is responsible for its antihistamine and sedative effects. Unlike many other first-generation antihistamines, hydroxyzine has a lower affinity for the muscarinic acetylcholine receptors, and in accordance, has a lower risk of anticholinergic side effects. In addition to its antihistamine activity, hydroxyzine has also been shown to act more weakly as an antagonist of the serotonin 5-HT2A receptor, the dopamine D2 receptor, and the α1-adrenergic receptor. The weak antiserotonergic effects of hydroxyzine likely underlie its usefulness as an anxiolytic, as other antihistamines without such properties have not been found to be effective in the treatment of anxiety.Hydroxyzine crosses the blood–brain barrier easily and exerts effects in the central nervous system. A positron emission tomography (PET) study found that brain occupancy of the H1 receptor was 67.6% for a single 30 mg dose of hydroxyzine. In addition, subjective sleepiness correlated well with the brain H1 receptor occupancy. PET studies with antihistamines have found that brain H1 receptor occupancy of more than 50% is associated with a high prevalence of somnolence and cognitive decline, whereas brain H1 receptor occupancy of less than 20% is considered to be non-sedative. Pharmacokinetics Hydroxyzine can be administered orally or via intramuscular injection. When given orally, hydroxyzine is rapidly absorbed from the gastrointestinal tract. The effect of hydroxyzine is notable in 30 minutes.Hydroxyzine is rapidly absorbed and distributed with oral and intramuscular administration, and is metabolized in the liver; the main metabolite (45%), cetirizine, is formed through oxidation of the alcohol moiety to a carboxylic acid by alcohol dehydrogenase, and overall effects are observed within one hour of administration. Higher concentrations are found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzable and possesses similar antihistamine properties. The other metabolites identified include a N-dealkylated metabolite, and an O-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by CYP3A4 and CYP3A5. "In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination."The Tmax of hydroxyzine is about 2.0 hours in both adults and children and its elimination half-life is around 20.0 hours in adults (mean age 29.3 years) and 7.1 hours in children. Its elimination half-life is shorter in children compared to adults. In another study, the elimination half-life of hydroxyzine in elderly adults was 29.3 hours. One study found that the elimination half-life of hydroxyzine in adults was as short as 3 hours, but this may have just been due to methodological limitations. Although hydroxyzine has a long elimination half-life and produces antihistamine for as long as 24 hours, the CNS effects of hydroxyzine and other antihistamines with long half-lives seem to diminish after 8 hours.Administration in geriatrics differs from the administration of hydroxyzine in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, which provide a distinction between elderly aged patients and other younger groups. Hydroxyzine should be administered carefully in the elderly with consideration given to possible reduced elimination. Chemistry Hydroxyzine is a member of the diphenylmethylpiperazine class of antihistamines. Hydroxyzine is supplied mainly as a dihydrochloride salt (hydroxyzine hydrochloride) but also to a lesser extent as an embonate salt (hydroxyzine pamoate). The molecular weights of hydroxyzine, hydroxyzine dihydrochloride, and hydroxyzine pamoate are 374.9 g/mol, 447.8 g/mol, and 763.3 g/mol, respectively. Due to their differences in molecular weight, 1 mg hydroxyzine dihydrochloride is equivalent to about 1.7 mg hydroxyzine pamoate. Analogues Analogues of hydroxyzine include buclizine, cetirizine, cinnarizine, cyclizine, etodroxizine, meclizine, and pipoxizine among others. Synthesis Hydroxyzine is synthesized by the alkylation of 1-(4-chlorobenzhydryl)piperazine with 2-(2-chloroethoxy)ethanol: Society and culture Brand names Hydroxyzine preparations require a doctors prescription. The drug is available in two formulations, the pamoate (anxiolytic) and the dihydrochloride or hydrochloride salts (antihistamine). Vistaril, Equipose, Masmoran, and Paxistil are preparations of the pamoate salt, while Atarax, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, and Tranquizine are of the hydrochloride salt. References External links "Hydroxyzine". Drug Information Portal. U.S. National Library of Medicine.
Dapsone	Dapsone, also known as 4,4-sulfonyldianiline (SDA) or diaminodiphenyl sulfone (DDS), is an antibiotic commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is a second-line medication for the treatment and prevention of pneumocystis pneumonia and for the prevention of toxoplasmosis in those who have poor immune function. Additionally, it has been used for acne, dermatitis herpetiformis, and various other skin conditions. Dapsone is available both topically and by mouth.Severe side effects may include a decrease in blood cells, red blood cell breakdown especially in those with glucose-6-phosphate dehydrogenase deficiency (G-6-PD), or hypersensitivity. Common side effects include nausea and loss of appetite. Other side effects include liver inflammation, methemoglobinemia, and a number of types of skin rashes. While the safety of use during pregnancy is not entirely clear some physicians recommend that it be continued in those with leprosy. It is of the sulfone class.Dapsone was first studied as an antibiotic in 1937. Its use for leprosy began in 1945. It is on the World Health Organizations List of Essential Medicines. The form, which is taken by mouth, is available as a generic drug and not very expensive. Medical uses Infections Dapsone is commonly used in combination with rifampicin and clofazimine for the treatment of leprosy. It is also used to both treat and prevent pneumocystis pneumonia (PCP). It is also used for toxoplasmosis in people unable to tolerate trimethoprim with sulfamethoxazole.Dapsone by mouth was one of the first medications used to treat moderate to severe acne vulgaris, and is still occasionally prescribed for the treatment of severe cases. A topical form of dapsone is also effective with potentially less side effects.It is unclear if the combination with pyrimethamine is useful in the prevention of malaria. Autoimmune disease Cutaneous lupus erythematosis. Dapsone is effective and safe in persons with moderate, severe, or refractory cutaneous lupus erythematosis. Idiopathic thrombocytopenic purpura. Dapsone is effective and safe for adjunctive glucocorticoid-sparing treatment of persons with idiopathic thrombocytopenic purpura and is preferred over danazol or interferon alpha in those people with antinuclear antibodies. Chronic spontaneous urticaria. Dapsone is effective and safe for treatment of second-line therapy for people with chronic spontaneous urticaria in those for whom antihistamines and other first-line agents have failed. Relapsing polychondritis. There are no clinical trials but there are many case reports that dapsone is effective at doses of 25 mg/day to 200 mg/day for treatment of relapsing polychondritis. Other Dermatitis herpetiformis in combination with a gluten-free diet.Dapsone may be used to treat brown recluse spider bites that become necrotic.Dapsone is the recommended treatment for erythema elevatum diutinum, as a review found that using oral dapsone alone was effective in 80% of early cases of the disease. However, dapsone can potentially cause severe side effects, meaning that sometimes steroids or other antibiotics should be used instead, although these alternative treatments are much less effective.An August 2015 review notes that dapsone is reported to be effective against generalized granuloma annulare.Dapsone has been used as a monomer in the design of dye adsorbent polymers. Contraindications and precautions People with porphyria, anemia, cardiac disease, lung disease, HIV infection, G6PD deficiency, and liver impairment are at higher risks of adverse effects when using dapsone. Adverse effects Hypersensitivity reactions occur in 1.4% of persons treated with dapsone, and can be fatal in medical settings with low resources. It is a form of severe cutaneous adverse reactions (SCARs) in which a SCARs disorder, primarily the DRESS syndrome or a DRESS syndrome-like reaction occurs. Blood Hemolysis is the most prominent side-effect, occurring in about 20 % of patients treated with dapsone, although it is dose-related. It may lead to hemolytic anemia and methemoglobinemia. The side-effect is more common and severe in those with glucose-6-phosphate dehydrogenase deficiency, leading to the dapsone-containing antimalarial combination Lapdap being withdrawn from clinical use. A case of hemolysis in a neonate from dapsone in breast milk has been reported. Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis. Abnormalities in white blood cell formation, including aplastic anemia, are rare, yet are the cause of the majority of deaths attributable to dapsone therapy.Methemoglobinemia occurs in about 15 % of patients treated with long-term dapsone at standard doses (100 mg/day). Only special multi-wawelength oximeters (CO-oximeters) can detect methemoglobinemia directly. When there is a "saturation gap" between a low ordinary pulse oximeter reading and a high arterial blood gas analysis result, methemoglobinemia may be suspected. Liver Toxic hepatitis and cholestatic jaundice have been reported by the manufacturer. These toxic reactions may also occur as part of the dapsone hypersensitivity syndrome (a form of SCARs-see above) or dapsone syndrome (see below). Dapsone is metabolized by the Cytochrome P450 system, specifically isozymes CYP2D6, CYP2B6, CYP3A4, and CYP2C19. Dapsone metabolites produced by the cytochrome P450 2C19 isozyme are associated with the methemoglobinemia side effect of the drug. Skin When used topically, dapsone can cause mild skin irritation, redness, dry skin, burning, and itching. When used together with benzoyl peroxide products, temporary yellow or orange skin discolorations can occur. Dapsone hypersensitivity syndrome Hypersensitivity reactions occur in some patients. This reaction may be more frequent in patients receiving multiple-drug therapy.The reaction always involves a rash, may also include fever, jaundice, and eosinophilia, and is likely to be one manifestation of the SCARs reaction viz., the DRESS syndrome (see above). In general, these symptoms will occur within the first six weeks of therapy or not at all, and may be ameliorated by corticosteroid therapy. Other adverse effects Other adverse effects include nausea, headache, and rash (which are common), and insomnia, psychosis, and peripheral neuropathy. Effects on the lung occur rarely and may be serious, though are generally reversible. Mechanism of action As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthase, thereby inhibiting nucleic acid synthesis. Though structurally distinct from dapsone, the sulfonamide group of antibacterial drugs also work in this way. As an anti-inflammatory, dapsone inhibits the myeloperoxidase-H2O2-halide-mediated cytotoxic system in polymorphonucleocytes. As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation. Myeloperoxidase inhibition has also been suggested as a neuron-sparing mechanism for reducing inflammation in neurodegenerative diseases such as Alzheimers disease and stroke.Dapsones anti-inflammatory and immunomodulatory effects are thought to be its mechanism of action in treating dermatitis herpetiformis.Dapsone is an odorless white to creamy-white crystalline powder with a slightly bitter taste. History Discovery In the early 20th century, the German chemist Paul Ehrlich was developing theories of selective toxicity based largely on the ability of certain dyes to kill microbes. Gerhard Domagk, who would later win a Nobel Prize for his efforts, made a major breakthrough in 1932 with the discovery of the antibacterial prontosil red (sulfonamidochrysoidine). Further investigation into the involved chemicals opened the way to sulfa drug and sulfone therapy, first with the discovery of sulfanilamide, the active agent of prontosil, by Daniel Bovet and his team at Pasteur Institute (1935), then with that of dapsone independently by Ernest Fourneau in France and Gladwin Buttle in the United Kingdom. Proposed use in antimalarial drugs The spread of drug-resistant malaria in Africa has encouraged the development of new, low-cost antimalarial drugs. Plasmodium falciparum, one of the Plasmodium species that causes malaria, has developed resistance both to chloroquine and sulfadoxine/pyrimethamine, two of the most common treatments for malaria. Artemisinin, another antimalarial drug, had been developed in the 1980s but was too expensive for large-scale use. This led GlaxoSmithKline to develop Lapdap, a combination drug consisting of chlorproguanil and dapsone. Lapdap was licensed in the United Kingdom starting in October 2003.One advantage of Lapdap was that chlorproguanil and dapsone are both low-cost drugs. Another was that by virtue of being a combination drug, it was less likely to cause drug resistance. However, because dapsone causes hemolytic anemia in patients with G6PD deficiency, and because G6PD deficiency affects 10-25% of the population of sub-Saharan Africa, it was discovered that Lapdap is not safe for use in Africa. It was available in many African countries for four years before GlaxoSmithKline took it off the market in February 2008. Dapsone gel Dapsone had been reported in a few cases to effectively treat acne, but the risk of hemolytic anemia kept it from being widely used for this purpose. For many years scientists attempted to develop a topical formulation of dapsone that would be as effective against acne as oral dapsone, but without the hemolysis side effect. This was difficult to accomplish because dapsone is highly insoluble in aqueous solvents. In the early 2000s QLT USA developed Aczone, a 5% dapsone gel that was shown to be effective against acne without causing clinically significant declines in hemoglobin levels, even in subjects with G6PD deficiency. In February 2016, the FDA approved a 7.5% dapsone gel. This higher strength has the advantage of a once-daily application, versus twice-daily application of the 5% formulation. Other uses Dapsone also find uses as a curing agent in the manufacture of paints, adhesives, composites, powder coats, printed circuit boards, and imine-based vitrimers. See also Promin, a more-soluble derivative References External links "Dapsone". Drug Information Portal. U.S. National Library of Medicine.
Magnesium salicylate	Magnesium salicylate is a common analgesic and nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate musculoskeletal pain such as in tendons and muscles. It is also used to treat joint pain like arthritis, general back pain, and headaches.It is found in a variety of over-the-counter (OTC) medications, most notably the brand Doans Pills, as an anti-inflammatory, primarily for back-pain relief. Magnesium salicylate can be an effective OTC alternative to prescription NSAIDs, with both anti-inflammatory and pain-relieving effects. Controversy While magnesium salicylate is sold as an alternative for pain relief, it is still a nonsteroidal anti-inflammatory drug and, like others in this class, can cause stomach ulcers, without any proven superiority to other over-the-counter pain relievers. Novartis, the company (formerly known as Ciba or Ciba-Geigy Corp.) that produces Doans Pills, has claimed that the product is superior in providing back pain relief. In June 1996, the US Federal Trade Commission (FTC) charged the company with violating federal law with its unsubstantiated claim. In March 1998, the court ruled in favor of the FTC, but there was no stipulation about how the company should or would have to amend its advertising/packaging. Thus, Doans was able to continue marketing as a "superior treatment for back pain". In May 1999, the FTC released a statement summarizing the proceedings and announced the commissions decision after a 4–0 vote imposing a penalty on Doans and its marketer, Novartis, to "run ads to correct misbeliefs resulting from their unsubstantiated claim that Doans Pills are superior to other over-the-counter analgesics for treating back pain" and to modify packaging to include the statement "Although Doans is an effective pain reliever, there is no evidence that Doans is more effective than other pain relievers for back pain." The ads were required to run for a period of one year. == References ==
Glibenclamide/metformin	Glibenclamide/metformin, also known as glyburide/metformin and sold under the brand name Glucovance, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes. It contains glibenclamide, a sulfonylureas, and metformin, a biguanide. References External links "Glyburide mixture with Metformin hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Primidone	Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures, as well as essential tremors. It is taken by mouth.Common side effects include sleepiness, poor coordination, nausea, and loss of appetite. Severe side effects may include suicide, psychosis, a lack of blood cells. Use during pregnancy may result in harm to the baby. Primidone is an anticonvulsant of the barbiturate class. How it works is not entirely clear.Primidone was approved for medical use in the United States in 1954. It is available as a generic medication. In 2017, it was the 238th most commonly prescribed medication in the United States, with more than two million prescriptions. Medical uses Epilepsy Licensed for generalized tonic-clonic and complex partial seizures in the United Kingdom. In the United States, primidone is approved for adjunctive (in combination with other drugs) and monotherapy (by itself) use in generalized tonic-clonic seizures, simple partial seizures, and complex partial seizures, and myoclonic seizures. In juvenile myoclonic epilepsy (JME), it is a second-line therapy, reserved for when the valproates or lamotrigine do not work and when other second-line therapies—acetazolamide work either.Open-label case series have suggested that primidone is effective in the treatment of epilepsy. Primidone has been compared to phenytoin, phenobarbital, mephobarbital, ethotoin, metharbital, and mephenytoin. In adult comparison trials, primidone has been found to be just as effective. Essential tremor Primidone is considered to be a first-line therapy for essential tremor along with propranolol. In terms of tremor amplitude reduction, it is just as effective as propranolol, reducing it by 50%. Both drugs are well studied for this condition, unlike other therapies, and are recommended for initial treatment. 250 mg/day (low-dose therapy) is just as good as 750 mg/day (high-dose therapy).Primidone is not the only anticonvulsant used for essential tremor; the others include topiramate and gabapentin. Other pharmacological agents include alprazolam, clonazepam, atenolol, sotalol, nadolol, clozapine, nimodipine, and botulinum toxin A. Many of these drugs were less effective (according to Table 1), but a few were not. Only propranolol has been compared to primidone in a clinical trial. Psychiatric disorders In 1965, Monroe and Wise reported using primidone along with a phenothiazine derivative antipsychotic and chlordiazepoxide in treatment-resistant psychosis. What is known is that ten years later, Monroe went on to publish the results of a meta-analysis of two controlled clinical trials on people displaying out-of-character and situationally inappropriate aggression, who had abnormal EEG readings, and who responded poorly to antipsychotics; one of the studies was specifically mentioned as involving psychosis patients. When they were given various anticonvulsants not only did their EEGs improve, but so did the aggression.In March 1993, S.G. Hayes of the University of Southern California School of Medicine reported that nine out of twenty-seven people (33%) with either treatment-resistant depression or treatment-resistant bipolar disorder had a permanent positive response to primidone. A plurality of subjects were also given methylphenobarbital in addition to or instead of primidone. Adverse effects Primidone can cause drowsiness, listlessness, ataxia, visual disturbances, nystagmus, headache, and dizziness. These side effects are the most common, occurring in more than 1% of users. Transient nausea and vomiting are also common side effects. Dupuytrens contracture, a disease of the fasciae in the palm and fingers that permanently bends the fingers (usually the little and ring fingers) toward the palm, was first noted to be highly prevalent in epileptic people in 1941 by a Dr. Lund, fourteen years before primidone was on the market. Lund also noted that it was equally prevalent in individuals with idiopathic and symptomatic epilepsy and that the severity of the epilepsy did not matter. However, only one quarter of the women were affected vs. half of the men. Thirty-five years later, Critcheley et al. reported a correlation between how long a patient had had epilepsy and his or her chance of getting Dupuytrens contracture. They suspected that this was due to phenobarbital therapy, and that the phenobarbital was stimulating peripheral tissue growth factors. Dupuytrens contracture is almost exclusively found in Caucasians, especially those of Viking descent, and highest rates are reported in Northern Scotland, Norway, Iceland, and Australia. It has also been associated with alcoholism, heavy smoking, diabetes mellitus, physical trauma (either penetrating in nature or due to manual labor), tuberculosis, and HIV. People with rheumatoid arthritis are less likely to get this, and Drs. Hart and Hooper speculate that this is also true of gout due to the use of allopurinol. This is the only susceptibility factor that is generally agreed upon. Anticonvulsants do not seem to increase the incidence of Dupuytrens contracture in non-whites.Primidone has other cardiovascular effects in beyond shortening the QT interval. Both it and phenobarbital are associated with elevated serum levels (both fasting and six hours after methionine loading) of homocysteine, an amino acid derived from methionine. This is almost certainly related to the low folate levels reported in primidone users. Elevated levels of homocysteine have been linked to coronary heart disease. In 1985, both drugs were also reported to increase serum levels of high density lipoprotein (HDL) cholesterol, total cholesterol, and apolipoproteins A and B.It was first reported to exacerbate hepatic porphyria in 1975. In 1981, it was shown that phenobarbital, one of primidones metabolites, only induced a significant porphyrin at high concentrations in vitro. It can also cause elevations in hepatic enzymes such as gamma-glutamyl transferase and alkaline phosphatase.Less than 1% of primidone users will experience a rash. Compared to carbamazepine, lamotrigine, and phenytoin, this is very low. The rate is comparable to that of felbamate, vigabatrin, and topiramate. Primidone also causes exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis. Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most heavily associated with bone diseases such as osteoporosis, osteopenia (which can precede osteoporosis), osteomalacia and fractures. The populations usually said to be most at risk are institutionalized people, postmenopausal women, older men, people taking more than one anticonvulsant, and children, who are also at risk of rickets. However, it has been suggested that bone demineralization is most pronounced in young people (25–44 years of age) and one 1987 study of institutionalized people found that the rate of osteomalacia in the ones taking anticonvulsants—one out of nineteen individuals taking an anticonvulsant (vs. none among the thirty-seven people taking none) —was similar to that expected in elderly people. The authors speculated that this was due to improvements in diet, sun exposure and exercise in response to earlier findings, and/or that this was because it was sunnier in London than in the Northern European countries which had earlier reported this effect. In any case, the use of more than one anticonvulsant has been associated with an increased prevalence of bone disease in institutionalized epilepsy patients versus institutionalized people who did not have epilepsy. Likewise, postmenopausal women taking anticonvulsants have a greater risk of fracture than their drug-naive counterparts.Anticonvulsants affect the bones in many ways. They cause hypophosphatemia, hypocalcemia, low Vitamin D levels, and increased parathyroid hormone. Anticonvulsants also contribute to the increased rate of fractures by causing somnolence, ataxia, and tremor which would cause gait disturbance, further increasing the risk of fractures on top of the increase due to seizures and the restrictions on activity placed on epileptic people. Increased fracture rate has also been reported for carbamazepine, valproate and clonazepam. The risk of fractures is higher for people taking enzyme-inducing anticonvulsants than for people taking non-enzyme-inducing anticonvulsants. In addition to all of the above, primidone can cause arthralgia.Granulocytopenia, agranulocytosis, and red-cell hypoplasia and aplasia, and megaloblastic anemia are rarely associated with the use of primidone. Megaloblastic anemia is actually a group of related disorders with different causes that share morphological characteristics—enlarged red blood cells with abnormally high nuclear-cytoplasmic ratios resulting from delayed maturation of nuclei combined with normal maturation of cytoplasm, into abnormal megakaryocytes and sometimes hypersegmented neutrophils; regardless of etiology, all of the megaloblastic anemias involve impaired DNA replication. The anticonvulsant users who get this also tend to eat monotonous diets devoid of fruits and vegetables.This antagonistic effect is not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.In addition to increasing the risk of megaloblastic anemia, primidone, like other older anticonvulsants also increases the risk of neural tube defects, and like other enzyme-inducing anticonvulsants, it increases the likelihood of cardiovascular defects, and cleft lip without cleft palate. Epileptic women are generally advised to take folic acid, but there is conflicting evidence regarding the effectiveness of vitamin supplementation in the prevention of such defects.Additionally, a coagulation defect resembling Vitamin K deficiency has been observed in newborns of mothers taking primidone. Because of this, primidone is a Category D medication.Primidone, like phenobarbital and the benzodiazepines, can also cause sedation in the newborn and also withdrawal within the first few days of life; phenobarbital is the most likely out of all of them to do that.In May 2005, Dr. M. Lopez-Gomezs team reported an association between the use of primidone and depression in epilepsy patients; this same study reported that inadequate seizure control, posttraumatic epilepsy, and polytherapy were also risk factors. Polytherapy was also associated with poor seizure control. Out of all of the risk factors, usage of primidone and inadequate seizure control were the greatest; with ORs of 4.089 and 3.084, respectively. They had been looking for factors associated with depression in epilepsy patients. Schaffer et al. 1999 reported that one of their treatment failures, a 45-year-old woman taking 50 mg a day along with lithium 600 mg/day, clozapine 12.5 mg/day, trazodone 50 mg/day, and alprazolam 4 mg/day for three and a half months experienced auditory hallucinations that led to discontinuation of primidone. It can also cause hyperactivity in children; this most commonly occurs at low serum levels. There is one case of an individual developing catatonic schizophrenia when her serum concentration of primidone went above normal.Primidone is one of the anticonvulsants associated with anticonvulsant hypersensitivity syndrome, others being carbamazepine, phenytoin, and phenobarbital. This syndrome consists of fever, rash, peripheral leukocytosis, lymphadenopathy, and occasionally hepatic necrosis.Hyperammonemic encephalopathy was reported by Katano Hiroyuki of the Nagoya City Higashi General Hospital in early 2002 in a patient who had been stable on primidone monotherapy for five years before undergoing surgery for astrocytoma, a type of brain tumor. Additionally, her phenobarbital levels were inexplicably elevated post-surgery. This is much more common with the valproates than with any of the barbiturates. A randomized controlled trial whose results were published in the July 1985 issue of The New England Journal of Medicine found that primidone was more likely to cause impotence than phenytoin, carbamazepine, or phenobarbital. Like phenytoin, primidone is rarely associated with lymphadenopathy. Primidone can also cause vomiting; this happens in 1.0–0.1% of users. Overdose The most common symptoms of primidone overdose are coma with loss of deep tendon reflexes and, during the recovery period, if the patient survives, disorientation, dysarthria, nystagmus, and ataxia, lethargy, somnolence, vomiting, nausea, and occasionally, focal neurological deficits which lessen over time. Complete recovery comes within five to seven days of ingestion. The symptoms of primidone poisoning have generally been attributed to its biotransformation to phenobarbital; however, primidone has toxic effects independent of its metabolites in humans. The massive crystalluria that sometimes occurs sets its symptom profile apart from that of phenobarbital. The crystals are white, needle-like, shimmering, hexagonal plates consisting mainly of primidone.In the Netherlands alone, there were thirty-four cases of suspected primidone poisoning between 1978 and 1982. Out of these, Primidone poisoning was much less common than phenobarbital poisoning. Twenty-seven of those adult cases were reported to the Dutch National Poison Control Center. Out of these, one person taking it with phenytoin and phenobarbital died, twelve became drowsy and four were comatose.Treatments for primidone overdose have included hemoperfusion with forced diuresis, a combination of bemegride and amiphenazole; and a combination of bemegride, spironolactone, caffeine, pentylenetetrazol, strophanthin, penicillin and streptomycin.In the three adults who are reported to have succumbed, the doses were 20–30 g. However, two adult survivors ingested 30 g 25 g, and 22.5 g. One woman experienced symptoms of primidone intoxication after ingesting 750 mg of her roommates primidone. Interactions Taking primidone with monoamine oxidase inhibitors (MAOIs) such as isocarboxazid (Marplan), phenelzine (Nardil), procarbazine (Matulane), selegiline (Eldepryl), tranylcypromine (Parnate) or within two weeks of stopping any one of them may potentiate the effects of primidone or change ones seizure patterns. Isoniazid, an antitubercular agent with MAOI properties, has been known to strongly inhibit the metabolism of primidone.Like many anticonvulsants, primidone interacts with other anticonvulsants. Clobazam decreases clearance of primidone,Mesuximide increases plasma levels of phenobarbital in primidone users, both primidone and phenobarbital accelerate the metabolism of carbamazepine via CYP3A4, and lamotrigines apparent clearance is increased by primidone. In addition to being an inducer of CYP3A4, it is also an inducer of CYP1A2, which causes it to interact with substrates such as fluvoxamine, clozapine, olanzapine, and tricyclic antidepressants. It also interacts with CYP2B6 substrates such as bupropion, efavirenz, promethazine, selegiline, and sertraline; CYP2C8 substrates such as amiodarone, paclitaxel, pioglitazone, repaglinide, and rosiglitazone; and CYP2C9 substrates such as bosentan, celecoxib, dapsone, fluoxetine, glimepiride, glipizide, losartan, montelukast, nateglinide, paclitaxel, phenytoin, sulfonamides, trimethoprim, warfarin, and zafirlukast. It also interacts with estrogens.Primidone and the other enzyme-inducing anticonvulsants can cut the half-life of antipyrine roughly in half (6.2 ± 1.9 h vs. 11.2 ± 4.2 h), and increases the clearance rate by almost 70%. Phenobarbital reduces the half-life to 4.8 ± 1.3 and increases the clearance by almost 109%. It also interferes with the metabolism of dexamethasone, a synthetic steroid hormone, to the point where its withdrawal from the regimen of a 14-year-old living in the United Kingdom made her hypercortisolemic. Tempelhoff and colleagues at the Washington University School of Medicines Department of Anesthesiology reported in 1990 that primidone and other anticonvulsant drugs increase the amount of fentanyl needed during craniotomy based on the patients heart rate. Mechanism of action The exact mechanism of primidones anticonvulsant action is still unknown after over fifty years. It is believed to work via interactions with voltage-gated sodium channels which inhibit high-frequency repetitive firing of action potentials. The effect of primidone in essential tremor is not mediated by PEMA. The major metabolite, phenobarbital, is also a potent anticonvulsant in its own right and likely contributes to primidones effects in many forms of epilepsy. According to Brenners Pharmacology textbook, Primidone also increases GABA-mediated chloride flux: thereby hyperpolarizing the membrane potential. Primidone was recently shown to directly inhibit the TRPM3 ion channel; whether this effect contributes to its anticonvulsant effect is not known, but gain of function mutations in TRPM3 were recently shown to be associated with epilepsy and intellectual disability. Pharmacokinetics Primidone converts to phenobarbital and PEMA; it is still unknown which exact cytochrome P450 enzymes are responsible. The phenobarbital, in turn, is metabolized to p-hydroxyphenobarbital. The rate of primidone metabolism was greatly accelerated by phenobarbital pretreatment, moderately accelerated by primidone pretreatment, and reduced by PEMA pretreatment. In 1983, a new minor metabolite, p-hydroxyprimidone, was discovered.Primidone, carbamazepine, phenobarbital and phenytoin are among the most potent hepatic enzyme inducing drugs in existence. This enzyme induction occurs at therapeutic doses. In fact, people taking these drugs have displayed the highest degree of hepatic enzyme induction on record. In addition to being an inducer of CYP3A4, it is also an inducer of CYP1A2, which causes it to interact with substrates such as fluvoxamine, clozapine, olanzapine, and tricyclic antidepressants, as well as potentially increasing the toxicity of tobacco products. Its metabolite, phenobarbital, is a substrate of CYP2C9, CYP2B6, CYP2C8, CYP2C19, CYP2A6, CYP3A5, CYP1E1, and the CYP2E subfamily. The gene expression of these isoenzymes is regulated by human pregnane receptor X (PXR) and constitutive androstane receptor (CAR). Phenobarbital induction of CYP2B6 is mediated by both. Primidone does not activate PXR.The rate of metabolism of primidone into phenobarbital was inversely related to age; the highest rates were in the oldest patients (the maximum age being 55). People aged 70–81, relative to people aged 18–26, have decreased renal clearance of primidone, phenobarbital, and PEMA, in ascending order of significance, and that there was a greater proportion of PEMA in the urine. The clinical significance is unknown. The percentage of primidone converted to phenobarbital has been estimated to be 5% in dogs and 15% in humans. Work done twelve years later found that the serum phenobarbital 0.111 mg/100 mL for every mg/kg of primidone ingested. Authors publishing a year earlier estimated that 24.5% of primidone was metabolized to phenobarbital. However, the patient reported by Kappy and Buckley would have had a serum level of 44.4 mg/100 mL instead of 8.5 mg/100 mL if this were true for individuals who have ingested large dose. The patient reported by Morley and Wynne would have had serum barbiturate levels of 50 mg/100 mL, which would have been fatal. History Primidone is a congener of phenobarbital where the carbonyl oxygen of the urea moiety is replaced by two hydrogen atoms. The effectiveness of Primidone for epilepsy was first demonstrated in 1949 by Yule Bogue. He found it to have a similar anticonvulsant effect to phenobarbitol, but more specific, i.e. with fewer associated sedative effects.It was brought to market a year later by the Imperial Chemical Industry (ICI), now known as AstraZeneca in the United Kingdom and Germany. In 1952, it was approved in the Netherlands.Also in 1952, Drs. Handley and Stewart demonstrated its effectiveness in the treatment of patients who failed to respond to other therapies; it was noted to be more effective in people with idiopathic generalized epilepsy than in people whose epilepsy had a known cause. Dr. Whitty noted in 1953 that it benefitted patients with psychomotor epilepsy, who were often treatment-resistant. Toxic effects were reported to be mild. That same year, it was approved in France. Primidone was introduced in 1954 under the brandname Mysoline by Wyeth in the United States. Association with megaloblastic anemia In 1954, Chalmers and Boheimer reported that the drug was associated with megaloblastic anemia. Between 1954 and 1957, twenty-one cases of megaloblastic anemia associated with primidone and/or phenytoin were reported. In most of these cases the anemia was due to vitamin deficiencies: usually folic acid deficiency; in one case Vitamin B12 deficiency and in one case Vitamin C deficiency. Some cases were associated with deficient diets: one patient ate mostly bread and butter, another ate bread, buns, and hard candy, and another could rarely be persuaded to eat in the hospital.The idea that folic acid deficiency could cause megaloblastic anemia was not new. What was new was the idea that drugs could cause this in well-nourished people with no intestinal abnormalities. In many cases, it was not clear which drug had caused it. It was speculated that this might be related to the structural similarity between folic acid, phenytoin, phenobarbital, and primidone. Folic acid had been found to alleviate the symptoms of megaloblastic anemia in the 1940s, not long after it was discovered, but the typical patient only made a full recovery—cessation of CNS and PNS symptoms as well as anemia—on B12 therapy. Five years earlier, folic acid deficiency was linked to birth defects in rats. Primidone was seen by some as too valuable to withhold based on the slight possibility of this rare side effect and by others as dangerous enough to be withheld unless phenobarbital or some other barbiturate failed to work for this and other reasons (i.e., reports of permanent psychosis). Available forms Primidone is available as a 250 mg/5mL suspension, and in the form of 50 mg, 125 mg, and 250 mg tablets. It is also available in a chewable tablet formulation in Canada.It is marketed as several different brands including Mysoline (Canada, Ireland, Japan, the United Kingdom, and the United States), Prysoline (Israel, Rekah Pharmaceutical Products, Ltd.), Apo-Primidone, Liskantin (Germany, Desitin), Resimatil (Germany, Sanofi-Synthélabo GmbH), Mylepsinum (Germany, AWD.pharma GmbH & Co., KG)., and Sertan (Hungary, 250 mg tablets, ICN Pharmaceuticals Inc.[1]) Other animals Primidone has veterinary uses, including the prevention of aggressive behavior and cannibalism in gilt pigs, and treatment of nervous disorders in dogs and other animals. References Further reading "Toxicology and Carcinogenesis Studies of Primidone in F344/N Rats and B6C3F1 Mice (Feed Studies)" (PDF). Department of Health and Human Services National Toxicology Program. September 2000. Lay summary. {{cite web}}: Cite uses deprecated parameter \|lay-url= (help) External links "Primidone". Drug Information Portal. U.S. National Library of Medicine. "Testing Status of Primidone (primaclone) 10270-A". National Toxicology Program.
Nimodipine	Nimodipine, sold under the brand name Nimotop among others, is calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage (a form of cerebral hemorrhage). It was originally developed within the calcium channel blocker class as it was used for the treatment of high blood pressure, but is not used for this indication. It was patented in 1971 and approved for medical use in the US in 1988. It was approved for medical use in Germany in 1985. Medical use Because it has some selectivity for cerebral vasculature, nimodipines main use is in the prevention of cerebral vasospasm and resultant ischemia, a complication of subarachnoid hemorrhage (a form of cerebral bleed), specifically from ruptured intracranial berry aneurysms irrespective of the patients post-ictus neurological condition. Its administration begins within 4 days of a subarachnoid hemorrhage and is continued for three weeks. If blood pressure drops by over 5%, dosage is adjusted. There is still controversy regarding the use of intravenous nimodipine on a routine basis.A 2003 trial (Belfort et al.) found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia.Nimodipine is not regularly used to treat head injury. Several investigations have been performed evaluating its use for traumatic subarachnoid hemorrhage; a systematic review of 4 trials did not suggest any significant benefit to the patients that receive nimodipine therapy. There was one report case of nimodipine being successfully used for treatment of ultradian bipolar cycling after brain injury and, later, amygdalohippocampectomy. Dosage The regular dosage is 60 mg tablets every four hours. If the patient is unable to take tablets orally, it was previously given via intravenous infusion at a rate of 1–2 mg/hour (lower dosage if the body weight is <70 kg or blood pressure is too low), but since the withdrawal of the IV preparation, administration by nasogastric tube is an alternative. Contraindications Nimodipine is associated with low blood pressure, flushing and sweating, edema, nausea and other gastrointestinal problems, most of which are known characteristics of calcium channel blockers. It is contraindicated in unstable angina or an episode of myocardial infarction more recently than one month.While nimodipine was occasionally administered intravenously in the past, the FDA released an alert in January 2006, warning that it had received reports of the approved oral preparation being used intravenously, leading to severe complications; this was despite warnings on the box that this should not be done. Side-effects The FDA has classified the side effects into groups based on dosages levels at q4h. For the high dosage group (90 mg) less than 1% of the group experienced adverse conditions including itching, gastrointestinal hemorrhage, thrombocytopenia, neurological deterioration, vomiting, diaphoresis, congestive heart failure, hyponatremia, decreasing platelet count, disseminated intravascular coagulation, deep vein thrombosis. Pharmacokinetics Absorption After oral administration, it reaches peak plasma concentrations within one and a half hours. Patients taking enzyme-inducing anticonvulsants have lower plasma concentrations, while patients taking sodium valproate were markedly higher. Metabolism Nimodipine is metabolized in the first pass metabolism. The dihydropyridine ring of the nimodipine is dehydrogenated in the hepatic cells of the liver, a process governed by cytochrome P450 isoform 3A (CYP3A). This can be completely inhibited however, by troleandomycin (an antibiotic) or ketoconazole (an antifungal drug). Excretion Studies in non-human mammals using radioactive labeling have found that 40–50% of the dose is excreted via urine. The residue level in the body was never more than 1.5% in monkeys. Mode of action Nimodipine binds specifically to L-type voltage-gated calcium channels. There are numerous theories about its mechanism in preventing vasospasm, but none are conclusive.Nimodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid. Synthesis The key acetoacetate (2) for the synthesis of nimodipine (5) is obtained by alkylation of sodium acetoacetate with 2-methoxyethyl chloride, Aldol condensation of meta-nitrobenzene (1) and the subsequent reaction of the intermediate with enamine (4) gives nimodipine. Stereochemistry Nimodipine contains a stereocenter and can exist as either of two enantiomers. The pharmaceutical drug is a racemate, an equal mixture of the (R)- and (S)- forms. References Further reading Pharmacology: R. Towart, S. Kazda, Br. J. Pharmacol. 67, 409P (1979). Use as cerebral vasodilator: H. Meyer et al., GB 2018134 ; eidem, U.S. Patent 4,406,906 (1979, 1983 to Bayer). Effect on associative learning in aging rabbits: R. A. Deyo et al., Science 243, 809 (1989). External links "Nimodipine". Drug Information Portal. U.S. National Library of Medicine.
Artesunate	Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of malaria. Artesunate can be given by injection into a vein, injection into a muscle, by mouth, and by rectum.The most common side effects include kidney failure requiring dialysis, hemoglobinuria (the presence of hemoglobin in urine) and jaundice.Artesunate is generally well tolerated. Side effects may include a slow heartbeat, allergic reaction, dizziness, and low white blood cell levels. During pregnancy it appears to be a safer option, even though animal studies have found harm to the baby. Use is likely fine during breastfeeding. It is in the artemisinin class of medication.Artesunate was developed by Liu Xu in 1977. It is on the World Health Organizations List of Essential Medicines. It was approved for medical use in the United States in May 2020. It is in the class of medications known as artemisinins, which are derivatives from "qinghao," or sweet wormwood plant (Artemisia annua). Medical uses Artesunate is the first-line treatment for children or adults with severe malaria, usually in combination with another antimalarial drug. There is moderate-quality evidence that treatment with artesunate plus mefloquine is superior to treatment with artesunate plus amodiaquine or artesunate plus sulfadoxine-pyrimethamine. Artemisinin-based combination therapy may be used by mouth in persons that can tolerate it after 24 hours by injection.Artesunate is preferred over parenteral quinine for severe malaria treatment. Artesunate was shown to prevent more deaths from severe malaria than quinine in two large multicentre randomized controlled trials from Africa and Asia. A subsequent systematic review of seven randomized controlled trials found this improvement in survival rates to be consistent across all trials.Artesunates efficacy is comparable to that of artemether, another artemisinin derivative, in treating adults for severe malaria caused by Plasmodium falciparum, though artesunate clears more parasites initially. Artesunate combination drugs have a number of advantages over artemether-based drugs in terms of its uptake and administration routes and may be more effective in treatment of severe and complicated malaria in children.Artesunate is also used to treat less severe forms of malaria when it can be given orally. It has activity against P. ovale, P. malariae, and severe P. knowlesi.Artesunate + sulfadoxine/pyrimethamine for treatment of P. vivax is not recommended due to high rates of resistance.While artesunate is used primarily as treatment for malaria, there is some evidence that it may also have some beneficial effects in Schistosoma haematobium infection, but has not been evaluated in large randomized trials. Artesunate is used as the treatment of choice for severe malaria by the World Health Organization (WHO) over quinine. Pregnancy When given in the second or third trimesters of pregnancy, no artesunate-related adverse pregnancy outcomes have been reported. However, there is insufficient evidence regarding the safety of artesunate use in the first trimester of pregnancy. The WHO recommends that artesunate use for severe malaria in the first trimester should be based on the individual risks versus benefits. In absence of other viable treatment options, artesunate may be used. Children Artesunate is safe for use in children. Artesunate + sulfadoxine/pyrimethamine should be avoided in the newborns due to sulfadoxine/pyrmethamine effects on bilirubin. Parenteral artesunate dosing for treatment of severe malaria in children less than 20 kg should be higher than that of adults in order to increase exposure. When artesunate cannot be given orally or intramuscularly due to an individuals weakness or inability to swallow, rectal administration may be given as pre-referral treatment as long as parenteral administration is initiated after transfer to a more advanced facility. Adverse effects Artesunate may cause serious side effects including hemolytic anemia (a condition in which red blood cells are destroyed), and severe allergic reactions.Artesunate is generally safe and well tolerated. Artesunate-based regimens are less likely to cause vomiting and tinnitus than quinine plus anti-malarial antibiotic therapy. The best recognised adverse effect of the artemisinins is that they lower reticulocyte counts. This is not usually of clinical relevance.With increased use of I.V. artesunate, there have been reports of post-artesunate delayed haemolysis (PADH). Delayed haemolysis (occurring around two weeks after treatment) has been observed in people treated with artesunate for severe malaria. Contraindications Artesunate is typically a well tolerated medicine. Known contraindications include a previous severe allergic reaction to artesunate.Drugs that should be avoided while on artesunate are the drugs that inhibit the liver enzyme CYP2A6. These drugs include amiodarone, desipramine, isoniazid, ketoconazole, letrozole, methoxsalen and tranylcypromine. Mechanisms of action The mechanisms of action of artesunate remains unclear and debatable. Artesunate is a prodrug that is rapidly converted to its active form dihydroartemisinin (DHA). This process involves hydrolysis of the 4-carbon ester group via plasma esterase enzyme. It is hypothesized that the cleavage of endoperoxide bridge in the pharmacophore of DHA generates reactive oxygen species (ROS), which increases oxidative stress and causes malarial protein damage via alkylation. In addition, Artesunate potently inhibits the essential Plasmodium falciparum exported protein 1 (EXP1), a membrane glutathione S-transferase. As a result, the amount of glutathione in the parasite is reduced.In 2016, artemisinin has been shown to bind to a large number targets, suggesting that it acts in a promiscuous manner. There is evidence suggesting DHA inhibition of calcium-dependent ATPase on endoplasmic membrane, which disrupts protein folding of parasites. Pharmacokinetics In infected individuals, the elimination half-life of artesunate is about 0.22 hours. Its active metabolite, DHA, has a slightly longer half-life of 0.34 hours. Overall, the average half-life ranges from 0.5 to 1.5 hours. Because of its short half-life, its use in malaria prevention is limited.DHA is metabolized to an inactive metabolite by the liver enzymes CYP2B6, CYP2C19, and CYP3A4. Chemical synthesis Artesunate is made from dihydroartemisinin (DHA) by reacting it with succinic acid anhydride in a basic medium. It is one of few semi-synthetic derivatives from artemisinin that is water-soluble. Research In 2007, the FDA approved an Investigational New Drug (IND) protocol for intravenous artesunate.Artesunate is under study for the treatment of cancer and COVID-19. History In May 2020, artesunate was approved for medical use in United States. Prior to this approval, intravenous (IV) artesunate was only available through the Expanded Access program of the U.S. Food and Drug Administration (FDA), which allowed the Centers for Disease Control and Prevention (CDC) to provide IV artesunate to people in the U.S. with severe malaria and to people with uncomplicated malaria who are unable to take oral medications under an investigational new drug (IND) protocol. There has been no FDA-approved drug for treatment of severe malaria in the United States since the marketing of quinidine was discontinued by the manufacturer in March 2019.The safety and efficacy of IV artesunate for the treatment of severe malaria was primarily evaluated in a randomized controlled trial in Asia (Trial 1) and a supportive published randomized controlled trial in Africa (Trial 2). Trial 1 was conducted at 10 sites in Myanmar, Bangladesh, India, and Indonesia.Trial 1 enrolled 1,461 participants who received either IV artesunate or the comparator drug quinine and included 202 pediatric participants younger than 15 years. Trial 2 included 5,425 randomized pediatric participants younger than 15 years of age with severe malaria who were treated with artesunate or quinine. In both trials, the number of participants treated with artesunate who died in the hospital was significantly lower than the number who died in the control group treated with quinine. Trial 2 was conducted during 2005–2010 in nine African countries. A third trial, Trial 3, was conducted during 2007–2008 in Gabon and Malawi.In Trial 1, the most common adverse reactions in participants with malaria treated with IV artesunate were acute renal failure requiring dialysis, hemoglobinuria and jaundice. The safety profile in Trial 2 was generally similar to Trial 1.One trial was used to evaluate both, safety and benefits of artesunate. The trial enrolled participants with severe malaria who needed hospitalization because of their condition. Participants received at random either artesunate or a medicine used to treat malaria (quinine). Participants and the health care providers knew which treatment was being given.The benefit of artesunate in comparison to quinine was evaluated by comparing the number of participants who died while in the hospital (in-hospital mortality).The benefit of artesunate was supported by the data from Trial 2 in which pediatric participants younger than 15 years of age with severe malaria were randomly assigned treatment with artesunate or quinine.The application for IV artesunate was granted priority review and orphan drug designations. The FDA granted approval of artesunate for injection to Amivas. References External links "Artesunate". Drug Information Portal. U.S. National Library of Medicine.
Nifedipine	Nifedipine (3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), sold under the brand name Adalat and Procardia, among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynauds phenomenon, and premature labor. It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the babys lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. It is a calcium channel blocker of the dihydropyridine type. Nifedipine is taken by mouth and comes in fast- and slow-release formulations.Common side effects include lightheadedness, headache, feeling tired, leg swelling, cough, and shortness of breath. Serious side effects may include low blood pressure and heart failure. There is tentative evidence that its use in pregnancy is safe; however, it is not recommended during breastfeeding.Nifedipine was patented in 1967, and approved for use in the United States in 1981. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 118th most commonly prescribed medication in the United States, with more than 5 million prescriptions. Medical uses High blood pressure The approved uses are for the long-term treatment of hypertension and angina pectoris. In hypertension, recent clinical guidelines generally favour diuretics and ACE inhibitors, although calcium channel antagonists, along with thiazide diuretics, are still favoured as primary treatment for patients over 55 and black patients.Nifedipine given as sublingual administration has previously been used in hypertensive emergencies. It was once frequently prescribed on an as-needed basis to patients taking MAOIs for real or perceived hypertensive crises. This was found to be dangerous, and has been abandoned. Sublingual administration of nifedipine promotes a hypotensive effect via peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, reflex tachycardia, and a steal phenomenon in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including cerebral ischemia/infarction, myocardial infarction, complete heart block, and death. As a result of this, in 1985 the FDA reviewed all data regarding the safety and effectiveness of sublingual nifedipine for the management of hypertensive emergencies, and concluded that the practice should be abandoned because it was neither safe nor effective. An exception to the avoidance of this practice is in the use of nifedipine for the treatment of hypertension associated with autonomic dysreflexia in spinal cord injury. Early labor Nifedipine has been used frequently as a tocolytic (agent that delays premature labor). A Cochrane review has concluded that it has benefits over placebo or no treatment for prolongation of pregnancy. It also has benefits over beta-agonists and may also have some benefits over atosiban and magnesium sulfate, although atosiban results in fewer maternal adverse effects. No difference was found in the rate of deaths among babies around the time of birth, while data on longer-term outcomes is lacking. Other Raynauds phenomenon is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine.Topical nifedipine has been shown to be as effective as topical nitrates for anal fissures.Nifedipine is also used in high-altitude medicine to treat high altitude pulmonary edema.Nifedipine is one of the main choices for the treatment of Prinzmetal angina due to its vasodilating effects on the coronary arteries.Other uses include painful spasms of the esophagus such as from cancer or tetanus. It is also used for the small subset of people with pulmonary hypertension.Finally, nifedipine can be used in the treatment of renal calculi, which are commonly referred to as kidney stones. Studies have indicated that it helps to relieve renal colic. However, alpha blockers (such as tamsulosin) have been described as being significantly better. Side effects Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. Tachycardia (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine.Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing grapefruit or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the inhibition of CYP3A4-mediated metabolism.As calcium channel blocker, nifedipine has a risk of causing gingival hyperplasia Overdose A number of persons have developed toxicity due to acute overdosage with nifedipine, either accidentally or intentionally, and via either oral or parenteral administration. The adverse effects include lethargy, bradycardia, marked hypotension and loss of consciousness. The drug may be quantified in blood or plasma to confirm a diagnosis of poisoning, or to assist in a medicolegal investigation following death. Analytical methods usually involve gas or liquid chromatography and specimen concentrations are usually in the 100-1000 μg/L range.[1] Mechanism of action Nifedipine is a calcium channel blocker. Although nifedipine and other dihydropyridines are commonly regarded as specific to the L-type calcium channel, they also possess nonspecific activity towards other voltage-dependent calcium channels.Nifedipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid. History Nifedipine (initially BAY a1040, then Adalat) was developed by the German pharmaceutical company Bayer, with most initial studies being performed in the early 1970s.The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery disease who took nifedipine. This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctuations in blood pressure) and at high doses of 80 mg a day and more. Adalat was the first German pharmaceutical to be awarded the highly prestigious Prix Galien in 1980. In the same year, Ahmed Hegazy submitted his invention (in collaboration with Klaus-Dieter Rämsch) of an extended release, solid medicinal preparation of nifedipine to the German Patent Office in Munich, patenting the “use of nifedipine crystals with a specific surface area of 1-4 m2/g for the production of solid medicinal formulations for achieving long-lasting blood levels for the oral treatment of hypertension by administration 1 to 2 times”, an invention that became known as Adalat retard from Bayer (see letter Dr Schauerte). In that formulation, the active ingredient is released over a period of up to 36 hours. With the increasing incidence of heart disease in that period—heart failure became the first cause of death in West Germany—and the new formulation, the medication replaced Aspirine in the 1990s as the biggest single product of Bayer. As Alexander Mey noted, "[d]iese Maßnahmen führten dazu, dass der Umsatz im Jahr 2000 auf 1,7 Mrd. US-$ stieg, obwohl das Präparat bereits ein Vierteljahrhundert am Markt war." On 14 October 1991, Hegazy was awarded the Otto Bayer Medal—no relation to the company founder—for his work solubilizing poorly soluble active ingredients such as nifedipine, a prize, that the Bayer Group has been using to honor excellent research since 1984. By 2020, 528 researchers had received the award. A 1995 US lawsuit, in which Hegazy defended his patent, found that Pfizers Procardia XL product was also based on his European patent No. 0047899, United States Patent 5264446. Society and culture Brand names In India, Nifedipine is manufactured by JB Chemicals, and comes in brands Nicardia Retard (Nifedipine 10 mg, 20 mg tablets) as well as Nicardia XL 30/60 which are Nifedipine Extended Release Tablets. See also Cilnidipine Felodipine Lacidipine Nilvadipine Nimodipine References External links "Nifedipine". Drug Information Portal. U.S. National Library of Medicine.
Doxapram	Doxapram hydrochloride (marketed as Dopram, Stimulex or Respiram) is a respiratory stimulant. Administered intravenously, doxapram stimulates an increase in tidal volume, and respiratory rate. Mechanism of action Doxapram stimulates chemoreceptors in the carotid bodies of the carotid arteries, which in turn, stimulates the respiratory centre in the brain stem. Appearance Doxapram is a white to off-white, odorless, crystalline powder that is stable in light and air. It is soluble in water, sparingly soluble in alcohol and practically insoluble in ether. Injectable products have a pH from 3.5-5. Benzyl alcohol or chlorobutanol is added as a preservative agent in the commercially available injections. Uses Doxapram is used in intensive care settings to stimulate the respiratory rate in patients with respiratory failure. It may be useful for treating respiratory depression in patients who have taken excessive doses of drugs such as buprenorphine or fentanyl analogues which may fail to respond adequately to treatment with naloxone.It is equally as effective as pethidine in suppressing shivering after surgery.Doxapram has been used as an anesthetic reversal agent when taking care of captive sharks but it must be used with caution since "animals can be extremely excitatory and dangerous under the influence of this drug". Side effects Side effects include high blood pressure, panic attacks, rapid heart rate, tremor, sweating, and vomiting. Convulsions have been reported. Its use is relatively contraindicated in people with coronary heart disease, epilepsy, and high blood pressure. It is also contraindicated in newborns and small children, mainly due to the presence of benzyl alcohol, which is included as a preservative. See also Pentethylcyclanone (similar structure) == References ==
Lubiprostone	Lubiprostone (rINN, marketed under the trade name Amitiza among others) is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company. The drug was developed by Sucampo Pharmaceuticals and approved by the Food and Drug Administration (FDA) in 2006. It was recommended for use in the UK by the National Institute for Health and Care Excellence (NICE) in July 2014. Health Canada approved the drug in 2015.The cost to the NHS was £29.68 per 24 mcg 28-cap pack as of April 2017. Lubiprostone received approval from the Food and Drug Administration in 2008 to treat irritable bowel syndrome with constipation (IBS-C), and in 2013 for the treatment of OIC in adults with chronic noncancer pain. It is available through prescription only.The drug is available in the United States, Japan, Switzerland, India, Bangladesh, United Kingdom, and Canada. In Bangladesh and India, lubiprostone is marketed under the trade name Lubigut by Ziska Pharmaceuticals, Lubilax by Beacon Pharmaceuticals, and under the trade name Lubowel by Sun Pharmaceutical. Medical uses Lubiprostone is a laxative used for the treatment of constipation, specifically: Chronic idiopathic constipation (difficult or infrequent passage of stools that lasts for 3 months or longer and is not caused by diet, disease, or drugs).Constipation caused by certain opioid (narcotic) pain medications in people with chronic (on-going), noncancer pain, or in patients with long-lasting pain caused by a previous cancer or its treatment who do not need weekly increases in opioid dosage.The effectiveness of lubiprostone has not been established in patients who are taking a diphenylheptane opioid (e.g., methadone).Irritable bowel syndrome with constipation (IBS-C; a condition that causes stomach pain or cramps, bloating, and infrequent or difficult passage of stools) in women who are at least 18 years of age.Lubiprostone has not been studied in children. There is current research under way to determine the safety and efficacy in postoperative bowel dysfunction. It comes in a liquid filled capsule and is available only with a doctors prescription. If one misses a dose it should be taken as soon as possible unless it is almost time for the next dose, in which case it should be skipped and the user should return to their regular dosing schedule. Adverse effects In clinical trials, the most common adverse event was nausea (31%) . Other adverse events (≥5% of patients) included diarrhea (13%), headache (13%), abdominal distension (5%), abdominal pain (5%), flatulence (6%), sinusitis (5%), vomiting (5%), and fecal incontinence (1%). The FDA lists the following:For subjects with chronic idiopathic constipation taking Amitiza: Nausea ~ 29% (4% were severe, and 9% of patients discontinued treatment due to nausea. The rate of nausea was lower among male (8%) and elderly (19%) patients. No patients in the clinical studies were hospitalized due to nausea.) Diarrhea: ~12% (2% were severe, and 2% of patients discontinued treatment due to diarrhea) Several less common adverse reactions (<1%).For opioid-induced constipation: Nausea: ~ 11%; 1% severe nausea and 2% discontinued treatment due to nausea. Diarrhea: ~ 8%; 2% severe diarrhea and 1% of patients discontinued treatment due to diarrhea. Less common adverse reactions (<1%): fecal incontinence, blood potassium decreased.For subjects with irritable bowel syndrome with constipation: Nausea: ~ 8%; 1% severe nausea and 1% discontinued treatment due to nausea. Diarrhea: ~ 7%; <1% of patients had severe diarrhea and <1% of patients discontinued treatment due to diarrhea. Less common adverse reactions: <1%A 2018 pooled analysis from three phase III, randomized, double-blind, placebo-controlled studies on usage for Opioid-Induced Constipation, found that the numbers of patients reporting adverse effects were similar in both the lubiprostone and placebo treatment groups for all opioid classes (P ≥ 0.125); however, gastrointestinal adverse effects were reported more frequently by those receiving lubiprostone than 2 of the 3 opioid groups. The most commonly reported TEAEs in the lubiprostone treatment groups were nausea (13.4%–18.1%), diarrhea (1.2%–13.9%), and abdominal pain (4.7%–5.6%). In the population overall, the greatest likelihood of experiencing the first episode of any of these three TEAEs was greatest in the first week of treatment and decreased thereafter.According to Medscape, the most common (>10%) were: Nausea , Diarrhea (7-12%), Headache (2-11%). Less common side effects (1-10%) included: Abdominal pain (4-8%), Abdominal distension (3-6%), Flatulence (4-6%), Vomiting (3%), Loose stools (3%), Edema (1-3%), Abdominal discomfort (1-3%), Dizziness (3%), Chest discomfort/pain (2%), Dyspnea (2%), Dyspepsia (2%), Fatigue (2%), Dry mouth (1%). Contraindications Known or suspected mechanical GI obstruction. Known hypersensitivity to lubiprostone or any ingredient in the formulation.There is no current data on use in people with liver or kidney complications. The effects on pregnancy have not been studied in humans but testing in guinea pigs resulted in fetal loss. Amitiza is not approved for use in children. Lubiprostone is contraindicated in patients exhibiting chronic diarrhea, bowel obstruction, or diarrhea-predominant irritable bowel syndrome. Mechanism of action Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 that acts by specifically activating ClC-2 chloride channels on the apical aspect of gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase motility, and promote spontaneous bowel movements (SBM). Symptoms of constipation such as pain and bloating are usually improved within one week, and SBM may occur within one day. Pharmacokinetics Unlike many laxative products, lubiprostone does not show signs of drug tolerance, chemical dependency, or altered serum electrolyte concentration. There was no rebound effect following withdrawal of treatment, but a gradual return to pre-treatment bowel movement frequency should be expected. Minimal distribution of the drug occurs beyond the immediate gastrointestinal tissues. Lubiprostone is rapidly metabolized by reduction/oxidation, mediated by carbonyl reductase. There is no metabolic involvement of the hepatic cytochrome P450 system. The measurable metabolite, M3, exists in very low levels in plasma and makes up less than 10% of the total administered dose. Data indicate that metabolism occurs locally in the stomach and jejunum. References External links Official website
Clindamycin	Clindamycin is an antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (middle ear infections), and endocarditis. It can also be used to treat acne, and some cases of methicillin-resistant Staphylococcus aureus (MRSA). In combination with quinine, it can be used to treat malaria. It is available by mouth, by injection into a vein, and as a cream or a gel to be applied to the skin or in the vagina.Common side effects include nausea and vomiting, diarrhea, rashes, and pain at the site of injection. It increases the risk of hospital-acquired Clostridium difficile colitis about fourfold and thus is only recommended when other antibiotics are not appropriate. Alternative antibiotics may be recommended as a result. It appears to be generally safe in pregnancy. It is of the lincosamide class and works by blocking bacteria from making protein.Clindamycin was first made in 1966 from lincomycin. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 119th most commonly prescribed medication in the United States, with more than 5 million prescriptions. Medical uses Clindamycin is used primarily to treat anaerobic infections caused by susceptible anaerobic bacteria, including dental infections, and infections of the respiratory tract, skin, and soft tissue, and peritonitis. In people with hypersensitivity to penicillins, clindamycin may be used to treat infections caused by susceptible aerobic bacteria, as well. It is also used to treat bone and joint infections, particularly those caused by Staphylococcus aureus. Topical application of clindamycin phosphate can be used to treat mild to moderate acne. Acne For the treatment of acne, in the long term, the combined use of topical clindamycin and benzoyl peroxide was similar to salicylic acid plus benzoyl peroxide. Topical clindamycin plus topical benzoyl peroxide is more effective than topical clindamycin alone. Susceptible bacteria It is most effective against infections involving the following types of organisms: Aerobic Gram-positive cocci, including some members of the Staphylococcus and Streptococcus (e.g. pneumococcus) genera, but not enterococci. Anaerobic, Gram-negative rod-shaped bacteria, including some Bacteroides, Fusobacterium, and Prevotella, although resistance is increasing in Bacteroides fragilis.Most aerobic Gram-negative bacteria (such as Pseudomonas, Legionella, Haemophilus influenzae and Moraxella) are resistant to clindamycin, as are the facultative anaerobic Enterobacteriaceae. A notable exception is Capnocytophaga canimorsus, for which clindamycin is a first-line drug of choice.The following represents MIC susceptibility data for a few medically significant pathogens. Staphylococcus aureus: 0.016 μg/ml - >256 μg/ml Streptococcus pneumoniae: 0.002 μg/ml - >256 μg/ml Streptococcus pyogenes: <0.015 μg/ml - >64 μg/ml D-test When testing a gram-positive culture for sensitivity to clindamycin, it is common to perform a "D-test" to determine if there is a sub-population of bacteria present with the phenotype known as iMLSB. This phenotype of bacteria are resistant to the macrolide-lincosamide-streptogramin B group of antibiotics, however, the resistance mechanism is only induced by the presence of 14-membered ring macrolides, such as erythromycin. During a D-test, bacteria of the iMLSB phenotype demonstrate in vitro erythromycin-induced in vitro resistance to clindamycin. This is because of the activity of the macrolide-inducible plasmid-encoded erm gene.To perform a D-test, an agar plate is inoculated with the bacteria in question and two drug-impregnated disks (one with erythromycin, one with clindamycin) are placed 15–20 mm apart on the plate. If the area of inhibition around the clindamycin disk is "D" shaped, the test result is positive. Despite the apparent susceptibility to clindamycin in the absence of erythromycin, a positive D-test precludes therapeutic use of clindamycin. This is because the erythromycin-inducible erm gene is prone to mutations causing the inducible activity to switch to constitutive (permanently switched on). This in turn, may lead to the therapeutic failure of clindamycin. If the area of inhibition around the clindamycin disk is circular, the test result is negative and clindamycin can be used. Malaria Given with chloroquine or quinine, clindamycin is effective and well tolerated in treating Plasmodium falciparum malaria; the latter combination is particularly useful for children, and is the treatment of choice for pregnant women who become infected in areas where resistance to chloroquine is common. Clindamycin should not be used as an antimalarial by itself, although it appears to be very effective as such, because of its slow action. Patient-derived isolates of Plasmodium falciparum from the Peruvian Amazon have been reported to be resistant to clindamycin as evidenced by in vitro drug susceptibility testing. Other Clindamycin may be useful in skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Many strains of MRSA are still susceptible to clindamycin; however, in the United States spreading from the West Coast eastwards, MRSA is becoming increasingly resistant.While it has been used in intraabdominal infections, such use is generally not recommended due to resistance.Clindamycin is used in cases of suspected toxic shock syndrome, often in combination with a bactericidal agent such as vancomycin. The rationale for this approach is a presumed synergy between vancomycin, which causes the death of the bacteria by breakdown of the cell wall, and clindamycin, which is a powerful inhibitor of toxin synthesis. Both in vitro and in vivo studies have shown clindamycin reduces the production of exotoxins by staphylococci; it may also induce changes in the surface structure of bacteria that make them more sensitive to immune system attack (opsonization and phagocytosis).Clindamycin has been proven to decrease the risk of premature births in women diagnosed with bacterial vaginosis during early pregnancy to about a third of the risk of untreated women.The combination of clindamycin and quinine is the standard treatment for severe babesiosis.Clindamycin may also be used to treat toxoplasmosis, and, in combination with primaquine, is effective in treating mild to moderate Pneumocystis jirovecii pneumonia.Clindamycin, either applied to skin or taken by mouth, may also be used in hidradenitis suppurativa. Side effects Common adverse drug reactions associated with systemic clindamycin therapy – found in over 1% of people – include: diarrhea, pseudomembranous colitis, nausea, vomiting, abdominal pain or cramps and/or rash. High doses (both intravenous and oral) may cause a metallic taste. Common adverse drug reactions associated with topical formulations – found in over 10% of people – include: dryness, burning, itching, scaliness, or peeling of skin (lotion, solution); erythema (foam, lotion, solution); oiliness (gel, lotion). Additional side effects include contact dermatitis. Common side effects – found in over 10% of people – in vaginal applications include fungal infection.Rarely – in less than 0.1% of people – clindamycin therapy has been associated with anaphylaxis, blood dyscrasias, polyarthritis, jaundice, raised liver enzyme levels, renal dysfunction, cardiac arrest, and/or hepatotoxicity. Clostridioides difficile Pseudomembranous colitis is a potentially lethal condition commonly associated with clindamycin, but which also occurs with other antibiotics. Overgrowth of Clostridioides difficile, which is inherently resistant to clindamycin, results in the production of a toxin that causes a range of adverse effects, from diarrhea to colitis and toxic megacolon. Pregnancy and breastfeeding Use of clindamycin during pregnancy is generally considered safe.Clindamycin is classified as compatible with breastfeeding by the American Academy of Pediatrics, however, the WHO categorizes it as "avoid if possible". It is classified as L2 probably compatible with breastfeeding according to Medications and Mothers Milk. A 2009 review found it was likely safe in breastfeeding mothers, but did find one complication (hematochezia) in a breastfed infant which might be attributable to clindamycin. LactMed lists potentially negative gastrointestinal effects in babies whose mothers take it while breastfeeding but did not see that as justification to stop breastfeeding. Interactions Clindamycin may prolong the effects of neuromuscular-blocking drugs, such as succinylcholine and vecuronium. Its similarity to the mechanism of action of macrolides and chloramphenicol means they should not be given simultaneously, as this causes antagonism and possible cross-resistance. Chemistry Clindamycin is a semisynthetic derivative of lincomycin, a natural antibiotic produced by the actinobacterium Streptomyces lincolnensis. It is obtained by 7(S)-chloro-substitution of the 7(R)-hydroxyl group of lincomycin. The synthesis of clindamycin was first announced by BJ Magerlein, RD Birkenmeyer, and F Kagan on the fifth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in 1966. It has been on the market since 1968.Clindamycin is white or yellow. It is very soluble in water. The topically used clindamycin phosphate is a phosphate-ester prodrug of clindamycin. Mechanism of action Clindamycin has a primarily bacteriostatic effect. At higher concentrations, it may be bactericidal. It is a bacterial protein synthesis inhibitor by inhibiting ribosomal translocation, in a similar way to macrolides. It does so by binding to the rRNA of the bacterial 50S ribosome subunit, overlapping with the binding sites of the oxazolidinone, pleuromutilin, and macrolide antibiotics, among others. The binding is reversible. Clindamycin is more effective than lincomycin.The X-ray crystal structures of clindamycin bound to ribosomes (or ribosomal subunits) derived from Escherichia coli, Deinococcus radiodurans, and Haloarcura marismortui have been determined; the structure of the closely related antibiotic lincomycin bound to the 50S ribosomal subunit of Staphylococcus aureus has also been reported. Society and culture Economics Clindamycin is available as a generic medication and is relatively inexpensive. Available forms Clindamycin preparations that are taken by mouth include capsules (containing clindamycin hydrochloride) and oral suspensions (containing clindamycin palmitate hydrochloride). Oral suspension is not favored for administration of clindamycin to children, due to its extremely foul taste and odor. Clindamycin is formulated in a vaginal cream and as vaginal ovules for treatment of bacterial vaginosis. It is also available for topical administration in gel form, as a lotion, and in a foam delivery system (each containing clindamycin phosphate) and a solution in ethanol (containing clindamycin hydrochloride) and is used primarily as a prescription acne treatment.Several combination acne treatments containing clindamycin are also marketed, such as single-product formulations of clindamycin with benzoyl peroxide—sold as BenzaClin (Sanofi-Aventis), Duac (a gel form made by Stiefel), and Acanya, among other trade names—and, in the United States, a combination of clindamycin and tretinoin, sold as Ziana. In India, vaginal suppositories containing clindamycin in combination with clotrimazole are manufactured by Olive Health Care and sold as Clinsup-V. In Egypt, vaginal cream containing clindamycin produced by Biopharmgroup sold as Vagiclind indicated for vaginosis.Clindamycin is available as a generic drug, for both systemic (oral and intravenous) and topical use. (The exception is the vaginal suppository, which is not available as a generic in the US). Veterinary use The veterinary uses of clindamycin are quite similar to its human indications, and include treatment of osteomyelitis, skin infections, and toxoplasmosis, for which it is the preferred drug in dogs and cats. They can be used both by mouth and topically. A disadvantage is that bacterial resistance can develop fairly quickly. Gastrointestinal upset may also occur. Toxoplasmosis rarely causes symptoms in cats, but can do so in very young or immunocompromised kittens and cats. References External links "Clindamycin". Drug Information Portal. U.S. National Library of Medicine. "Clindamycin hydrochloride". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT04370548 for "DARE-BV1 in the Treatment of Bacterial Vaginosis (DARE-BVFREE)" at ClinicalTrials.gov
Fedratinib	Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.Myelofibrosis is a myeloid cancer associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor mutations which activate the JAK-STAT signaling pathway and which are sensitive to fedratinib. Phase I trial results focused on safety and efficacy of fedratinib in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011. Medical uses In the United States, fedratinib is indicated for the treatment of adults with intermediate-2 or high-risk primary or secondary (following polycythemia vera or essential thrombocythemia) myelofibrosis.In the European Union, fedratinib is indicated for the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis, following polycythaemia vera or essential thrombocythaemia, who are Janus kinase (JAK) inhibitor naïve or have been treated with ruxolitinib. Pharmacology Mechanism of action Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM). In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis. History Fedratinib was originally discovered at TargeGen. In 2010, Sanofi-Aventis acquired TargeGen and continued development of fedratinib until 2013. In 2016, Impact Biomedicines acquired the rights to fedratinib from Sanofi and continued its development for the treatment of myelofibrosis and polycythemia vera. In January 2018, the drugs rights were transferred to Celgene with their purchase of Impact Biomedicines.Fedratinib was approved for medical use in the United States in August 2019.The U.S. Food and Drug Administration (FDA) granted the application for fedratinib priority review and orphan drug designations. The FDA granted the approval of Inrebic to Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation. References External links "Fedratinib". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT01437787 for "Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis (JAKARTA)" at ClinicalTrials.gov
Prostacyclin	Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprostenol. The terms are sometimes used interchangeably. Function Prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). It does this by inhibiting platelet activation. It is also an effective vasodilator. Prostacyclins interactions contrast with those of thromboxane (TXA2), another eicosanoid. Both molecules are derived from arachidonic acid, and work together with opposite platelet aggregatory effects. These strongly suggest a mechanism of cardiovascular homeostasis between these two hormones in relation to vascular damage. Medical uses It is used to treat pulmonary arterial hypertension (PAH), pulmonary fibrosis, as well as atherosclerosis. Specifically, epoprostenol is given to patients with class III or class IV PAH. Degradation Prostacyclin, which has a half-life of 42 seconds, is broken down into 6-keto-PGF1, which is a much weaker vasodilator. A way to stabilize prostacyclin in its active form, especially during drug delivery, is to prepare prostacyclin in alkaline buffer. Even at physiological pH, prostacyclin can rapidly form the inactive hydration product 6-keto-prostaglandin F1α. Mechanism As mentioned above, prostacyclin (PGI2) is released by healthy endothelial cells and performs its function through a paracrine signaling cascade that involves G protein-coupled receptors on nearby platelets and endothelial cells. The platelet Gs protein-coupled receptor (prostacyclin receptor) is activated when it binds to PGI2. This activation, in turn, signals adenylyl cyclase to produce cAMP. cAMP goes on to inhibit any undue platelet activation (in order to promote circulation) and also counteracts any increase in cytosolic calcium levels that would result from thromboxane A2 (TXA2) binding (leading to platelet activation and subsequent coagulation). PGI2 also binds to endothelial prostacyclin receptors, and in the same manner, raises cAMP levels in the cytosol. This cAMP then goes on to activate protein kinase A (PKA). PKA then continues the cascade by promoting the phosphorylation of the myosin light chain kinase, which inhibits it and leads to smooth muscle relaxation and vasodilation. It can be noted that PGI2 and TXA2 work as physiological antagonists. Members Pharmacology Synthetic prostacyclin analogues (iloprost, cisaprost) are used intravenously, subcutaneously or by inhalation: as a vasodilator in severe Raynauds phenomenon or ischemia of a limb; in pulmonary hypertension. in primary pulmonary hypertension (PPH)The production of prostacyclin is inhibited by the action of NSAIDs on cyclooxygenase enzymes COX1 and COX2. These convert arachidonic acid to prostaglandin H2 (PGH2), the immediate precursor of prostacyclin. Since thromboxane (an eicosanoid stimulator of platelet aggregation) is also downstream of COX enzymes, one might think that the effect of NSAIDs would act to balance. However, prostacyclin concentrations recover much faster than thromboxane levels, so aspirin administration initially has little to no effect but eventually prevents platelet aggregation (the effect of prostaglandins predominates as they are regenerated). This is explained by understanding the cells that produce each molecule, TXA2 and PGI2. Since PGI2 is primarily produced in a nucleated endothelial cell, the COX inhibition by NSAID can be overcome with time by increased COX gene activation and subsequent production of more COX enzymes to catalyze the formation of PGI2. In contrast, TXA2 is released primarily by anucleated platelets, which are unable to respond to NSAID COX inhibition with additional transcription of the COX gene because they lack DNA material necessary to perform such a task. This allows NSAIDs to result in PGI2 dominance that promotes circulation and retards thrombosis. In patients with pulmonary hypertension, inhaled epoprostenol reduces pulmonary pressure, and improves right ventricular stroke volume in patients undergoing cardiac surgery. A dose of 60 μg is hemodynamically safe, and its effect is completely reversed after 25 minutes. No evidence of platelet dysfunction or an increase in surgical bleeding after administration of inhaled epoprostenol has been found. The drug has been known to cause flushing, headaches and hypotension. Synthesis Biosynthesis Prostacyclin is produced in endothelial cells, which line the walls of arteries and veins, from prostaglandin H2 (PGH2) by the action of the enzyme prostacyclin synthase. Although prostacyclin is considered an independent mediator, it is called PGI2 (prostaglandin I2) in eicosanoid nomenclature, and is a member of the prostanoids (together with the prostaglandins and thromboxane). PGI2, derived primarily from COX-2 in humans, is the major arachidonate metabolite released from the vascular endothelium. This is a controversial point, some assign COX 1 as the major prostacyclin producing cyclooxygenase in the endothelial cells of the blood vessels.The series-3 prostaglandin PGH3 also follows the prostacyclin synthase pathway, yielding another prostacyclin, PGI3. The unqualified term prostacyclin usually refers to PGI2. PGI2 is derived from the ω-6 arachidonic acid. PGI3 is derived from the ω-3 EPA. Artificial synthesis Prostacyclin can be synthesized from the methyl ester of prostaglandin F2α. After its synthesis, the drug is reconstituted in saline and glycerin.Because prostacyclin is so chemically labile, quantitation of their inactive metabolites, rather than the active compounds, is used to assess their rate of synthesis. History During the 1960s, a UK research team, headed by Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Vane discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of prostaglandins. This critical finding opened the door to a broader understanding of the role of prostaglandins in the body. A team at The Wellcome Foundation led by Salvador Moncada had identified a lipid mediator they called "PG-X," which inhibits platelet aggregation. PG-X, later known as prostacyclin, is 30 times more potent than any other then-known anti-aggregatory agent. They did this while searching for an enzyme that generates a fellow unstable prostanoid, Thromboxane A2In 1976, Vane and fellow researchers Salvador Moncada, Ryszard Gryglewski, and Stuart Bunting published the first paper on prostacyclin in Nature. The collaboration produced a synthesized molecule, which was named epoprostenol. But, as with native prostacyclin, the epoprostenol molecule is unstable in solution and prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. To overcome this challenge, the research team that discovered prostacyclin continued the research. The research team synthesized nearly 1,000 analogues. References External links "Epoprostenol". Drug Information Portal. U.S. National Library of Medicine. "Epoprostenol sodium". Drug Information Portal. U.S. National Library of Medicine.
Ropivacaine	Ropivacaine (rINN) is a local anaesthetic drug belonging to the amino amide group. The name ropivacaine refers to both the racemate and the marketed S-enantiomer. Ropivacaine hydrochloride is commonly marketed by AstraZeneca under the brand name Naropin. History Ropivacaine was developed after bupivacaine was noted to be associated with cardiac arrest, particularly in pregnant women. Ropivacaine was found to have less cardiotoxicity than bupivacaine in animal models. Clinical use Contraindications Ropivacaine is contraindicated for intravenous regional anaesthesia (IVRA). However, new data suggested both ropivacaine (1.2-1.8 mg/kg in 40ml) and levobupivacaine (40 ml of 0.125% solution) can be used, because they have less cardiovascular and central nervous system toxicity than racemic bupivacaine. Adverse effects Adverse drug reactions (ADRs) are rare when it is administered correctly. Most ADRs relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, however allergic reactions can rarely occur. Systemic exposure to excessive quantities of ropivacaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures followed by depression (drowsiness, loss of consciousness), respiratory depression and apnea). Cardiovascular effects include hypotension, bradycardia, arrhythmias, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression. Postarthroscopic glenohumeral chondrolysis Ropivacaine is toxic to cartilage and their intra-articular infusions can lead to Postarthroscopic glenohumeral chondrolysis. Treatment of overdose As for bupivacaine, Celepid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose in animal experiments and in humans in a process called lipid rescue. References External links "Ropivacaine". Drug Information Portal. U.S. National Library of Medicine. "Ropivacaine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Delafloxacin	Delafloxacin sold under the brand name Baxdela among others, is a fluoroquinolone antibiotic used to treat acute bacterial skin and skin structure infections. Medical use Delafloxacin is indicated to treat adults with acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible bacteria or adults with community-acquired bacterial pneumonia (CABP) caused by designated susceptible bacteria.Susceptible bacteria for ABSSSI are: Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, and Enterococcus faecalis Gram-negative organisms: Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.Susceptible bacteria for CABP are:Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible [MSSA] isolates only), Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae. It has not been tested in pregnant women.In the European Union it is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults when it is considered inappropriate to use other antibacterial agents that are commonly recommended for the initial treatment of these infections. Adverse effects Like other drugs in the fluoroquinolone class, delafloxacin contains a black box warning about the risk of tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis. The label also warns against the risk of hypersensitivity reactions and Clostridium difficile-associated diarrhea.Adverse effects occurring in more than 2% of clinical trial subjects included nausea, diarrhea, headache, elevated transaminases, and vomiting. Interactions Like other fluoroquinolones, delafloxacin chelates metals including aluminum, magnesium, sucralfate, iron, zinc, and divalent and trivalent cations like didanosine; using this drugs with antacids, some dietary supplements, or drugs buffered with any of these ions will interfere with available amounts of delafloxacin. Pharmacology The half-life varies in around 8 hours at normal doses. Excretion is 65% through urine, mostly in unmetabolized form, and 28% via feces. Clearance is reduced in people with severe kidney disease.Delafloxacin is more active (lower MIC90) than other quinolones against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In contrast to most approved fluoroquinolones, which are zwitterionic, delafloxacin has an anionic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. This property is believed to confer to delafloxacin an advantage for the eradication of Staphylococcus aureus in acidic environments, including intracellular infections and biofilms. Chemistry The chemical name is 1-deoxy-1 (methylamino)-D-glucitol, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (salt).The injectable form of delafloxacin is sold as the meglumine salt of the active ingredient and its United States Adopted Name, delafloxacin meglumine, reflects that; the injection formulation also includes EDTA and sulfobutylether-β-cyclodextrin. The tablet is made of delafloxacin, citric acid anhydrous, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, sodium bicarbonate, and sodium phosphate monobasic monohydrate. History Delafloxacin was known as ABT-492, RX-3341, and WQ-3034 while it was under development.Rib-X Pharmaceuticals acquired delafloxacin from Wakunaga Pharmaceutical in 2006. Rib-X was renamed to Melinta Therapeutics in 2013. It was developed and marketed by Melinta Therapeutics (formerly Rib-X Pharmaceuticals), which subsequently merged with Cempra.Key clinical trials for delafloxacin have been performed by Melinta regarding indications for skin and skin structure infections as well as complicated bacterial infections and uncomplicated gonorrhea. The trial on gonorrhea was terminated before data was released.Delafloxacin was approved by the FDA in June 2017, after it was noninferior to vancomycin plus aztreonam in two trials on 1042 patients with acute bacterial skin and skin structure infection. New Drug Applications (NDA) for delafloxacin (Baxdela) 450 mg tablets and 300 mg injections were approved by the FDA in June 2017.The FDA obligated Melinta to conduct further studies as follows: a 5-year surveillance study to determine if resistance emerges, with the final report due in December 2022 a study of the IV form in pregnant rats to determine distribution to the reproductive tract, due June 2018, with further studies required if there is significant distribution.Melinta merged with Cempra in August, 2017.Melinta has entered into commercialization and distribution agreements with both Menarini Therapeutics (March 2017) and Eurofarma Laboratórios (January 2015) for international commercialization of delafloxacin. The agreement with Menarini allows them to commercialize and distribute in 68 countries, including Europe, China, and South Korea among others. A similar agreement with Eurofarma allows for commercialization in Brazil. References External links "Delafloxacin". Drug Information Portal. U.S. National Library of Medicine. "Delafloxacin meglumine". Drug Information Portal. U.S. National Library of Medicine.
Ibuprofen	Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used by mouth or intravenously. It typically begins working within an hour.Common side effects include heartburn and a rash. Compared to other NSAIDs, it may have other side effects such as gastrointestinal bleeding. It increases the risk of heart failure, kidney failure, and liver failure. At low doses, it does not appear to increase the risk of heart attack; however, at higher doses it may. Ibuprofen can also worsen asthma. While it is unclear whether it is safe in early pregnancy, it appears to be harmful in later pregnancy and therefore is not recommended. Like other NSAIDs, it works by inhibiting the production of prostaglandins by decreasing the activity of the enzyme cyclooxygenase (COX). Ibuprofen is a weaker anti-inflammatory agent than other NSAIDs.Ibuprofen was discovered in 1961 by Stewart Adams and John Nicholson while working at Boots UK Limited and initially marketed as Brufen. It is available under a number of trade names, including Nurofen, Advil and Motrin. Ibuprofen was first marketed in 1969 in the United Kingdom and in 1974 in the United States. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 38th most commonly prescribed medication in the United States, with more than 16 million prescriptions. Medical uses Ibuprofen is used primarily to treat fever (including post-vaccination fever), mild to moderate pain (including pain relief after surgery), painful menstruation, osteoarthritis, dental pain, headaches, and pain from kidney stones. About 60% of people respond to any nonsteroidal anti-inflammatory drug; those who do not respond well to a particular one may respond to another.It is used for inflammatory diseases such as juvenile idiopathic arthritis and rheumatoid arthritis. It is also used for pericarditis and patent ductus arteriosus.If a patient is self-treating with over-the-counter Ibuprofen, it should not be taken for more than 10 days, unless the patient has spoken with their doctor. Lysine In some countries, ibuprofen lysine (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate") is licensed for treatment of the same conditions as ibuprofen; the lysine salt is used because it is more water-soluble.Ibuprofen lysine is sold for rapid pain relief; given in form of a lysine salt, absorption is much quicker (35 minutes compared to 90–120 minutes). However, a clinical trial with 351 participants in 2020, funded by Sanofi, found no significant difference between ibuprofen and ibuprofen lysine concerning the eventual onset of action or analgesic efficacy.In 2006, ibuprofen lysine was approved in the U.S. by the Food and Drug Administration (FDA) for closure of patent ductus arteriosus in premature infants weighing between 500 and 1,500 g (1 and 3 lb), who are no more than 32 weeks gestational age when usual medical management (such as fluid restriction, diuretics, and respiratory support) is not effective. Adverse effects Adverse effects include nausea, dyspepsia, diarrhea, constipation, gastrointestinal ulceration/bleeding, headache, dizziness, rash, salt and fluid retention, and high blood pressure.Infrequent adverse effects include esophageal ulceration, heart failure, high blood levels of potassium, kidney impairment, confusion, and bronchospasm. Ibuprofen can exacerbate asthma, sometimes fatally.Allergic reactions, including anaphylaxis and anaphylactic shock, may occur. Ibuprofen may be quantified in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in people who are hospitalized, or assist in a medicolegal death investigation. A monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in people who have overdosed has been published.In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. Cardiovascular risk Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of progression to hypertension in women, though less than for acetaminophen, and myocardial infarction (heart attack), particularly among those chronically using higher doses. On 9 July 2015, the U.S. Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with ibuprofen and related NSAIDs; the NSAID aspirin is not included in this warning. The European Medicines Agency (EMA) issued similar warnings in 2015. Skin Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid or pemphigoid-like blistering. As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent, but it is considered a weak photosensitising agent compared to other members of the 2-arylpropionic acid class. Like other NSAIDs, ibuprofen is an extremely rare cause of the autoimmune disease Stevens–Johnson syndrome (SJS). Ibuprofen is also an extremely rare cause of toxic epidermal necrolysis. Interactions Alcohol Drinking alcohol when taking ibuprofen may increase the risk of stomach bleeding. Aspirin According to the Food and Drug Administration (FDA), "ibuprofen can interfere with the antiplatelet effect of low-dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention". Allowing sufficient time between doses of ibuprofen and immediate-release (IR) aspirin can avoid this problem. The recommended elapsed time between a dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after IR aspirin, and 8 hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for enteric-coated aspirin. But, if ibuprofen is taken only occasionally without the recommended timing, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal. Paracetamol Ibuprofen combined with paracetamol is considered generally safe in children for short-term usage. Overdose Ibuprofen overdose has become common since it was licensed for OTC use. Many overdose experiences are reported in the medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low. Human response in cases of overdose ranges from an absence of symptoms to a fatal outcome despite intensive-care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen, and include abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, ear ringing, and nystagmus. Rarely, more severe symptoms, such as gastrointestinal bleeding, seizures, metabolic acidosis, high blood levels of potassium, low blood pressure, slow heart rate, fast heart rate, atrial fibrillation, coma, liver dysfunction, acute kidney failure, cyanosis, respiratory depression, and cardiac arrest have been reported. The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs. Correlation between severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg (around 150 tablets of 200 mg units for an average man); however, large doses do not indicate the clinical course is likely to be lethal. A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant conditions of the individual person. Treatment to address an ibuprofen overdose is based on how the symptoms present. In cases presenting early, decontamination of the stomach is recommended. This is achieved using activated charcoal; charcoal adsorbs the drug before it can enter the bloodstream. Gastric lavage is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Purposeful vomiting is not recommended. The majority of ibuprofen ingestions produce only mild effects, and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and kidney function monitored. Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, the kidneys excretion of unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit. Miscarriage A Canadian study of pregnant women suggests that those taking any type or amount of NSAIDs (including ibuprofen, diclofenac and naproxen) were 2.4 times more likely to miscarry than those not taking the medications. However, an Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs. Pharmacology NSAIDs such as ibuprofen work by inhibiting the cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and to thromboxane A2 (which stimulates platelet aggregation, leading to the formation of blood clots). Like aspirin and indomethacin, ibuprofen is a nonselective COX inhibitor, in that it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The analgesic, antipyretic, and anti-inflammatory activity of NSAIDs appears to operate mainly through inhibition of COX-2, which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 instead would be responsible for unwanted effects on the gastrointestinal tract. However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain, and different compounds cause different degrees of analgesia and gastric damage.Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer. The R-enantiomer is converted through a series of three main enzymes. These enzymes include acyl-CoA-synthetase, which converts the R-enantiomer to (−)-R-ibuprofen I-CoA; 2-arylpropionyl-CoA epimerase, which converts (−)-R-ibuprofen I-CoA to (+)-S-ibuprofen I-CoA; and hydrolase, which converts (+)-S-ibuprofen I-CoA to the S-enantiomer. In addition to the conversion of ibuprofen to the S-enantiomer, the body can metabolize ibuprofen to several other compounds, including numerous hydroxyl, carboxyl and glucuronyl metabolites. Virtually all of these have no pharmacological effects.Unlike most other NSAIDs, ibuprofen also acts as an inhibitor of Rho kinase and may be useful in recovery from spinal-cord injury. Pharmacokinetics After oral administration, peak serum concentration is reached after 1–2 hours, and up to 99% of the drug is bound to plasma proteins. The majority of ibuprofen is metabolized and eliminated within 24 hours in the urine; however, 1% of the unchanged drug is removed through biliary excretion. Chemistry Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like ethanol (66.18 g/100 mL at 40 °C for 90% EtOH), methanol, acetone and dichloromethane.The original synthesis of ibuprofen by the Boots Group started with the compound 2-methylpropylbenzene. The synthesis took six steps. A modern, greener technique for the synthesis involves only three steps. Stereochemistry Ibuprofen, like other 2-arylpropionate derivatives such as ketoprofen, flurbiprofen and naproxen, contains a stereocenter in the α-position of the propionate moiety. The product sold in pharmacies is a racemic mixture of the S and R-isomers. The S (dextrorotatory) isomer is the more biologically active; this isomer has been isolated and used medically (see dexibuprofen for details).The isomerase enzyme, alpha-methylacyl-CoA racemase, converts (R)-ibuprofen into the (S)-enantiomer.The (S)- ibuprofen, the eutomer, harbors the desired therapeutic activity. Interestingly, the inactive (R)-enantiomer, the distomer, undergoes a unidirectional chiral inversion to offer the active (S)-enantiomer. That is, when the ibuprofen is administered as a racemate the distomer is converted in vivo into the eutomer while the latter is unaffected. History Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s. The name is derived from the 3 functional groups: isobutyl (ibu) propionic acid (pro) phenyl (fen). Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to aspirin. The molecule was discovered and synthesized by a team led by Stewart Adams, with a patent application filed in 1961. Adams initially tested the drug as treatment for his hangover. In 1985, Boots worldwide patent for ibuprofen expired and generic products were launched.The drug was launched as a treatment for rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Later, in 1983 and 1984, it became the first NSAID (other than aspirin) to be available over the counter (OTC) in these two countries. Boots was awarded the Queens Award for Technical Achievement in 1985 for the development of the drug. Dr. Adams was subsequently awarded an Order of the British Empire (OBE) in 1987. In November 2013, work on ibuprofen was recognized by the erection of a Royal Society of Chemistry blue plaque at Boots Beeston Factory site in Nottingham, which reads: In recognition of the work during the 1980s by The Boots Company PLC on the development of ibuprofen which resulted in its move from prescription only status to over the counter sale, therefore expanding its use to millions of people worldwide and another at BioCity Nottingham, the site of the original laboratory, which reads: In recognition of the pioneering research work, here on Pennyfoot Street, by Dr Stewart Adams and Dr John Nicholson in the Research Department of Boots which led to the discovery of ibuprofen used by millions worldwide for the relief of pain. Society and culture Availability Ibuprofen was made available under prescription in the United Kingdom in 1969, and in the United States in 1974. In the years since, the good tolerability profile, along with extensive experience in the population, as well as in so-called phase-IV trials (postapproval studies), have resulted in the availability of ibuprofen OTC in pharmacies worldwide, as well as in supermarkets and other general retailers. Ibuprofen is its International nonproprietary name (INN), British Approved Name (BAN), Australian Approved Name (AAN) and United States Adopted Name (USAN). In the U.S., Motrin has been on the market since 1974, and Advil has been on the market since 1984. Ibuprofen is commonly available in the United States up to the FDAs 1984 dose limit OTC, rarely used higher by prescription.In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor. Route It can be used by mouth, as a tablet, capsule or suspension, or intravenously. Research Ibuprofen is sometimes used for the treatment of acne because of its anti-inflammatory properties, and has been sold in Japan in topical form for adult acne. As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up). NSAIDs are of unclear utility in the prevention and treatment of Alzheimers disease.Ibuprofen has been associated with a lower risk of Parkinsons disease and may delay or prevent it. Aspirin, other NSAIDs, and paracetamol (acetaminophen) had no effect on the risk for Parkinsons. In March 2011, researchers at Harvard Medical School announced in Neurology that ibuprofen had a neuroprotective effect against the risk of developing Parkinsons disease. People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinsons disease, but no such effect was found for other pain relievers, such as aspirin and paracetamol. Use of ibuprofen to lower the risk of Parkinsons disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems.Some dietary supplements might be dangerous to take along with ibuprofen and other NSAIDs, but as of 2016 more research needs to be conducted to be certain. These supplements include those that can prevent platelet aggregation, including ginkgo, garlic, ginger, bilberry, dong quai, feverfew, ginseng, turmeric, meadowsweet (Filipendula ulmaria), and willow (Salix spp.); those that contain coumarin, including chamomile, horse chestnut, fenugreek and red clover; and those that increase the risk of bleeding, like tamarind. References External links "Ibuprofen". Drug Information Portal. U.S. National Library of Medicine. GB patent 971700, Stewart Sanders Adams & John Stuart Nicholson, "Anti-Inflammatory Agents", published 1964-09-30, assigned to BOOTS PURE DRUG CO LTD "Evidence for the efficacy of pain medications" (PDF). National Safety Council (NSC). 26 August 2020.
Infliximab	Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohns disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçets disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.Common side effects include infections, acute infusion reactions, and abdominal pain. Infliximab is a chimeric monoclonal antibody biologic. It seems to work by binding to and neutralizing TNF-α, preventing it from interacting with its receptors on the cell. TNF-α is a chemical messenger (cytokine) and a key part of the autoimmune reaction. Infliximab was originally developed in mice as a mouse antibody. Because humans have immune reactions to mouse proteins, the mouse common domains were replaced with similar human antibody domains. They are monoclonal antibodies and have identical structures and affinities to the target. Because they are a combination of mouse and human antibody amino acid sequences, they are called a "chimeric monoclonal antibody".Infliximab was approved for medical use in the United States in 1998, and in the European Union in August 1999. Infliximab biosimilars have been approved in the EU (2013), in Japan (2014), and in the United States (2016, 2017, 2019). It is on the World Health Organizations List of Essential Medicines. Medical uses Crohns disease Three phenotypes, or categories of disease, are present in Crohns disease: stricturing disease (which causes narrowing of the bowel), penetrating disease (which causes fistulae or abnormal connections of the bowel), and inflammatory disease (which primarily causes inflammation). Fistulizing disease Infliximab was first used for closure of fistulae in Crohns disease in 1999. In a 94-patient, phase II clinical trial, the researchers showed Infliximab was effective in closing fistulae between the skin and bowel in 56-68% of patients. A large, 296-patient Phase III clinical trial called the ACCENT 2 trial showed infliximab was additionally beneficial in maintaining closure of fistulae, with almost two-thirds of all patients treated with the three initial doses of infliximab having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistulae after a year, compared with 19% who received placebo therapy. This final trial resulted in the FDA approval of the drug to treat fistulizing disease. Inflammatory disease Infliximab has been used to induce and maintain remission in inflammatory Crohns disease. The ACCENT 1 trial, a large, multicentre trial, found 39 to 45% of patients treated with infliximab, who had an initial response to it, maintained remission after 30 weeks, compared with 21% who received placebo treatment. It also showed a mean maintenance of remission from 38 to 54 weeks compared with 21 weeks for patients who received placebo treatment.Crohns patients have flares of their disease between periods of disease quiescence. Severe flares are usually treated with steroid medications to obtain remission, but steroids have many undesirable side effects, so some gastroenterologists are now advocating the use of infliximab as the first drug to try to get patients into remission. This has been called the top-down approach to treatment. Ulcerative colitis Infliximab targets TNF, thought to be more related to Th1 cytokines. Ulcerative colitis was thought to be a Th2 disease, and infliximab would be of limited use. However, patients with ulcerative colitis have begun to be treated with infliximab on the basis of two large clinical trials conducted in 2005 by Paul Rutgeerts and William Sandborn. The Acute ulcerative Colitis Treatment trials (ACT1 and ACT2) to evaluate the utility of infliximab in ulcerative colitis showed 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared with 21% of patients who were treated with placebo medication. At two months, the response was 61-69% for patients treated with infliximab, and 31% for those treated with placebo.Newer drugs such as Etrolizumab have similar efficacy to Infliximab with fewer adverse effects for treatment of ulcerative colitis. Psoriatic arthritis In psoriatic arthritis (PsA), inhibitors of TNF, such as infliximab, improve the signs and symptoms. Several therapies with modest efficacy have been studied in nail psoriasis. Among available agents, higher quality data are available to support the efficacy of cyclosporine and infliximab. Based on studies in AS, the results suggest infliximab, etanercept, and adalimumab have the potential to reduce the signs and symptoms of moderate to severely active axial involvement in PsA in patients who have had an inadequate response to NSAID (level 1a, grade A). The anti-TNF agents (infliximab and etanercept; level 1b, grade A) are more effective for the treatment of enthesitis than traditional agents. Results suggest infliximab is effective for the treatment of dactylitis in PsA. Other It was approved for treating ankylosing spondylitis, psoriatic arthritis, psoriasis, rheumatoid arthritis.Infliximab is also prescribed (out of indication) for the treatment of Behçets disease.Infliximab is the most frequently used biological agent in treating relapsing polychondritis. Half of the patients saw benefit from this treatment, and a few other patients experienced infections that in some cases lead to death.There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases; the FDA approved infliximab for chronic severe plaque psoriasis in adults in September 2006.Infliximab has been used off-label in treating refractory sarcoidosis, where other treatments have not been effective.Infliximab has been tested in chronic obstructive pulmonary disease (COPD) but there was no evidence of benefit with the possibility of harm.Infliximab is indicated for steroid refractory checkpoint inhibitor induced colitis, at a dose of 5 to 10 mg/kg. Adverse effects Infliximab has adverse effects, some life-threatening, common to drugs in the class of TNF inhibiting immunosuppressants (which also includes etanercept (Enbrel) and adalimumab (Humira)). Some of the most severe are: serious infections reactivation of hepatitis B reactivation of tuberculosis lethal hepatosplenic T-cell lymphoma (generally only when combined with 6-mercaptopurine) drug-induced lupus demyelinating central nervous system disorders psoriasis and psoriasiform skin lesions new-onset vitiligoCases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported with infliximab. The FDA issued a warning to doctors appearing in the respective product labeling of infliximab instructing them to screen and monitor potential patients more carefully. The FDA issued a warning to doctors that there is an increased risk of lymphoma and other cancers associated with the use of infliximab and other tumor necrosis factor blockers in children and adolescents.Maintenance therapy with the drug (versus intermittent or sporadic therapy) lessens the likelihood of developing antibodies to infliximab which are known to reduce the efficacy of the drug. Combination treatment with methotrexate (an antifolate drug which suppresses the immune system) has been shown to reduce the formation of these antibodies in patients with rheumatoid arthritis and combination therapy with other immunosuppressants has been shown to reduce the likelihood of these antibodies being formed in Crohns disease. The use of immunosuppressants may not be necessary in all diseases for which infliximab is indicated, and indiscriminant uses of these other immunosuppressants carry their own risks. Infliximab was studied in monotherapy (without concomitant immunosuppressants such as methotrexate or azathioprine) in psoriasis, psoriatic arthritis, and ankylosing spondylitis. Only its use in rheumatoid arthritis requires the concomitant use of methotrexate by the U.S. Food and Drug Administration (FDA) product labeling; however, the concomitant use of methotrexate in other disease states may help to reduce the bodys immune response to the infliximab and increase its duration of efficacy. Pharmacology Infliximab is a purified, recombinant DNA-derived chimeric human-mouse IgG monoclonal antibody that consists of mouse heavy and light chain variable regions combined with human heavy and light chain constant regions. It has a serum half-life of 9.5 days and can be detected in serum 8 weeks after infusion treatment.Infliximab neutralizes the biological activity of TNF-α by binding with high affinity to the soluble (free floating in the blood) and transmembrane (located on the outer membranes of T cells and similar immune cells) forms of TNF-α, and inhibits or prevents the effective binding of TNF-α with its receptors. Infliximab and adalimumab (another TNF antagonist) are in the subclass of "anti-TNF antibodies" (they are in the form of naturally occurring antibodies), and are capable of neutralizing all forms (extracellular-, transmembrane-, and receptor-bound) of TNF-α. Etanercept, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and, because of its modified form, cannot neutralize receptor-bound TNF-α. Additionally, the anti-TNF antibodies adalimumab and infliximab have the capability of lysing cells involved in the inflammatory process, whereas the receptor fusion protein apparently lacks this capability. Although the clinical significance of these differences have not been absolutely proven, etanercept, has been shown to perform worse than placebo for Crohns disease. These differences may account for the differential actions of these drugs in both efficacy and side effects.Infliximab has high specificity for TNF-α, and does not neutralize TNF beta (TNFβ, also called lymphotoxin α), an unrelated cytokine that uses different receptors from TNF-α. Biological activities attributed to TNF-α include induction of proinflammatory cytokines (such as interleukins IL-1 and IL-6), enhancement of leukocyte movement or migration from the blood vessels into the tissues (by increasing the permeability of endothelial layer of blood vessels), and increasing the release of adhesion molecules. Infliximab prevents disease in transgenic mice (a special type of mice biologically engineered to produce a human form of TNF-α and which are used to test the results of these drugs that might be expected in humans). These experimental mice develop arthritis as a result of their production of human TNF-α, and when administered after disease onset, infliximab allows eroded joints to heal.Other monoclonal antibodies targeting TNF-α are golimumab, adalimumab, and certolizumab pegol. Etanercept also binds and inhibits the action of TNF-α, but is not a monoclonal antibody (it is instead a fusion of TNF-receptor and an antibody constant region). History The importance of TNF in the development of rheumatoid arthritis was originally demonstrated by George Kollias and colleagues in proof of principle studies in transgenic animal models.Infliximab was developed by Junming Le (b.1940) and Jan Vilček (b.1933) at New York University School of Medicine and in collaboration with Centocor, (now Janssen Biotech, Inc.) Society and culture Marketing Remicade is marketed by Janssen Biotech, Inc. (formerly Centocor Biotech, Inc.) in the United States, Mitsubishi Tanabe Pharma in Japan, Xian Janssen in China, and Schering-Plough (now part of Merck & Co) elsewhere. Biosimilars In June 2013, two biosimilar versions (Inflectra and Remsima) were submitted for approval in Europe, by Hospira and Celltrion Healthcare respectively. Both had a positive opinion from European Medicines Agencys (EMA) Committee for Medicinal Products for Human Use (CHMP) for sale in the European Union (EU). Celltrion obtained marketing authorization approval (MAA) from 27 EU countries and 3 EEA (European Economic Area) countries by September 2013. Inflectra was approved for use in the European Union in September 2013, and Remsima was approved for use in the European Union in October 2013.In Japan, Celltrion received marketing authorization for Remsima from Japans Ministry of Health, Labour and Welfare (MHLW) in July 2014.In India, Epirus Biopharmaceuticals obtained approval to produce biosimilar infliximab under the brand name "Infimab" (trail name BOW015).The U.S. Food and Drug Administration (FDA) approved Celltrion/Hospira/Pfizers Inflectra (infliximab-dyyb) in April 2016. Although the US brand name is Inflectra, it is marketed in the European Union as Remsima.The FDA approved Samsung Bioepis Co., Ltd.s Renflexis (infliximab-abda) in April 2017.Biogen released another biosimilar, Flixabi, which was approved in Germany, the UK, and the Netherlands. Flixabi was approved for use in the European Union in May 2016.In December 2017, Ixifi (infliximab-qbtx) was approved in the United States.Zessly was approved for use in the European Union in May 2018.In December 2019, Avsola (infliximab-axxq) was approved in the United States.Avsola was approved for medical use in Canada in March 2020.In December 2021, Ixifi was approved for medical use in Canada. Availability/affordability In the United States, infliximab is an expensive medication, costing about US$900 for a 100 mg dose, and is covered by almost every US medical insurance plan (though caps on many plans make it possible to be covered for only a subset of treatments in the course of a year). Infliximab is supplied as a sterile, white, lyophilized (freeze-dried) powder, so must be reconstituted and administered by a health care professional, usually in a hospital or office setting. For this reason, it is usually covered under major medical insurance rather than prescription drug coverage. The loading regimen for all approved indications occurs at weeks 0, 2, and 6 at the above dosages.In the UK, infliximab is available from the NHS for Crohns disease treatment provided three criteria are met. Patients should have severe active Crohns disease with a CDAI score of 300 or more, have not responded to immunomodulating drugs and corticosteroids, and for whom surgery is inappropriate. Since February 2015, it is also approved for the treatment of ulcerative colitis where other treatments have not worked.In Australia, infliximab is available through the PBS for Crohns disease treatment provided the patient has not responded to conventional treatment and has a severe case of the condition.Infliximab is available in the Republic of Ireland through the HSEs Medical Card and Drug Payment Scheme.Johnson & Johnson reported in its 2013 annual report, "Remicade (infliximab), accounted for approximately 9.4% of the Companys total revenues for fiscal 2013." References External links "Infliximab". Drug Information Portal. U.S. National Library of Medicine.
Fosdenopterin	Fosdenopterin (or cyclic pyranopterin monophosphate, cPMP), sold under the brand name Nulibry, is a medication used to reduce the risk of death due to a rare genetic disease known as molybdenum cofactor deficiency type A.The most common side effects include complications related to the intravenous line, fever, respiratory infections, vomiting, gastroenteritis, and diarrhea.Fosdenopterin was approved for medical use in the United States in February 2021, It is the first medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of molybdenum cofactor deficiency type A. and in the European Union in September 2022. Medical uses Fosdenopterin is indicated to reduce the risk of mortality in people with molybdenum cofactor deficiency (MoCD) type A. Mechanism of action People with molybdenum cofactor deficiency type A cannot produce cyclic pyranopterin monophosphate (cPMP) in their body. Fosdenopterin is an intravenous medication that replaces the missing cPMP. cPMP is a precursor to molybdopterin, which is required for the enzyme activity of sulfite oxidase, xanthine dehydrogenase/oxidase and aldehyde oxidase. History Fosdenopterin was developed at the German universities TU Braunschweig and the University of Cologne.The effectiveness of fosdenopterin for the treatment of MoCD-A was demonstrated in thirteen treated participants compared to eighteen matched, untreated participants. The participants treated with fosdenopterin had a survival rate of 84% at three years, compared to 55% for the untreated participants.The U.S. Food and Drug Administration (FDA) granted the application for fosdenopterin priority review, breakthrough therapy, and orphan drug designations along with a rare pediatric disease priority review voucher. The FDA granted the approval of Nulibry to Origin Biosciences, Inc., in February 2021. Society and culture Legal status On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Nulibry, intended for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A. The applicant for this medicinal product is Comharsa Life Sciences Ltd. Fosdenopterin was approved for medical use in the European Union in September 2022. References External links "Fosdenopterin". Drug Information Portal. U.S. National Library of Medicine.
Mesna	Mesna, sold under the brand name Mesnex among others, is a medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder. It is used either by mouth or injection into a vein.Common side effects include headache, vomiting, sleepiness, loss of appetite, cough, rash, and joint pain. Serious side effects include allergic reactions. Use during pregnancy appears to be safe for the baby but this use has not been well studied. Mesna is an organosulfur compound. It works by altering the breakdown products of cyclophosphamide and ifosfamide found in the urine making them less toxic.Mesna was approved for medical use in the United States in 1988. It is on the World Health Organizations List of Essential Medicines. Medical uses Chemotherapy adjuvant Mesna is used therapeutically to reduce the incidence of haemorrhagic cystitis and haematuria when a patient receives ifosfamide or cyclophosphamide for cancer chemotherapy. These two anticancer agents, in vivo, may be converted to urotoxic metabolites, such as acrolein. Mesna assists to detoxify these metabolites by reaction of its sulfhydryl group with α,β-unsaturated carbonyl containing compounds such as acrolein. This reaction is known as a Michael addition. Mesna also increases urinary excretion of cysteine. Other Outside North America, mesna is also used as a mucolytic agent, working in the same way as acetylcysteine; it is sold for this indication as Mistabron and Mistabronco. Administration It is administered intravenously or orally (through the mouth). The IV mesna infusions would be given with IV ifosfamide, while oral mesna would be given with oral cyclophosphamide. The oral doses must be double the intravenous (IV) mesna dose due to bioavailability issues. The oral preparation allows patients to leave the hospital sooner, instead of staying four to five days for all the IV mesna infusions. Mechanism of action Mesna reduces the toxicity of urotoxic compounds that may form after chemotherapy administration. Mesna is a water-soluble compound with antioxidant properties, and is given concomitantly with the chemotherapeutic agents cyclophosphamide and ifosfamide. Mesna concentrates in the bladder where acrolein accumulates after administration of chemotherapy and through a Michael addition, forms a conjugate with acrolein and other urotoxic metabolites. This conjugation reaction inactivates the urotoxic compounds to harmless metabolites. The metabolites are then excreted in the urine. Names It is marketed by Baxter as Uromitexan and Mesnex. The name of the substance is an acronym for 2-mercaptoethane sulfonate Na (Na being the chemical symbol for sodium). See also Coenzyme M—a coenzyme with the same structure used by methanogenic bacteria References External links BC Cancer Agency NIH/MedlinePlus patient information Mesna at the US National Library of Medicine Medical Subject Headings (MeSH)
Acitretin	Acitretin (trade names Soriatane and Neotigason) is a second-generation retinoid. It is taken orally, and is typically used for psoriasis.Acitretin is an oral retinoid used in the treatment of severe resistant psoriasis. Because of the potential for problems and severe side effects it is generally used in only very severe cases of psoriasis that have been unresponsive to other treatments. It binds to nuclear receptors that regulates gene transcription. They induce keratinocyte differentiation and reduce epidermal hyperplasia, leading to the slowing of cell reproduction. Acitretin is readily absorbed and widely distributed after oral administration. A therapeutic effect occurs after two to four weeks or longer. Patients who have received the medication are advised against giving blood for at least three years due to the risk of birth defects. Adverse effects Acitretin is highly teratogenic and noted for the possibility of severe birth defects. It should not be used by pregnant women or women planning to get pregnant within 3 years following the use of acitretin. Sexually active women of childbearing age who use acitretin should also use at least two forms of birth control concurrently. Men and women who use it should not donate blood for three years after using it, because of the possibility that the blood might be used in a pregnant patient and cause birth defects. In addition, it may cause nausea, headache, itching, dry, red or flaky skin, dry or red eyes, dry or chapped lips, swollen lips, dry mouth, thirst, cystic acne or hair loss. Pharmacokinetics It is a metabolite of etretinate, which was used prior to the introduction of acitretin. Etretinate was discontinued because it had a narrow therapeutic index as well as a long elimination half-life (t1/2=120 days), making dosing difficult. In contrast, acitretins half-life is approximately 2 days. However, because acitretin can be reverse metabolised into etretinate which has an extremely long half-life, women must avoid becoming pregnant for at least three years after discontinuing acitretin. Therefore, acitretin is generally not recommended for women of child-bearing age with a risk of becoming pregnant. References External links "Acitretin". Drug Information Portal. U.S. National Library of Medicine.
Ciclesonide	Ciclesonide is a glucocorticoid used to treat asthma and allergic rhinitis. It is marketed under the brand names Alvesco for asthma and Omnaris, Omniair, Zetonna, and Alvesco for hay fever in the US and Canada. Side effects of the medication include headache, nosebleeds, and inflammation of the nose and throat linings.It was patented in 1990 and approved for medical use in 2005. The drug was approved for adults and children 12 and over by the US Food and Drug Administration in October 2006. It is on the World Health Organizations List of Essential Medicines. See also Beclomethasone dipropionate References == Further reading ==
Trandolapril/verapamil	Trandolapril/verapamil (Tarka) is an oral antihypertensive medication that combines a slow release formulation of verapamil hydrochloride, a calcium channel blocker, and an immediate release formulation of trandolapril, an ACE inhibitor. The patent, held by Abbott Laboratories, expired on February 24, 2015. This combination medication contains angiotensin-converting enzyme (ACE) inhibitor and calcium channel blocker and is prescribed for high blood pressure. References External links "Trandolapril mixture with verapamil hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Diazepam	Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken by mouth, inserted into the rectum, injected into muscle, injected into a vein or used as a nasal spray. When given into a vein, effects begin in one to five minutes and last up to an hour. By mouth, effects begin after 15 to 60 minutes.Common side effects include sleepiness and trouble with coordination. Serious side effects are rare. They include increased risk of suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy. Occasionally, excitement or agitation may occur. Long-term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer. It is not recommended during pregnancy or breastfeeding. Its mechanism of action works by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).Diazepam was patented in 1959 by Hoffmann-La Roche. It has been one of the most frequently prescribed medications in the world since its launch in 1963. In the United States it was the best-selling medication between 1968 and 1982, selling more than 2 billion tablets in 1978 alone. In 2019, it was the 117th most commonly prescribed medication in the United States, with more than 5 million prescriptions. In 1985 the patent ended, and there are now more than 500 brands available on the market. It is on the World Health Organizations List of Essential Medicines. Medical uses Diazepam is mainly used to treat anxiety, insomnia, panic attacks and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures (e.g., endoscopy). In 2020, it was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy. Diazepam is the most commonly used benzodiazepine for "tapering" benzodiazepine dependence due to the drugs comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose.Diazepam has a number of uses including: Treatment of anxiety, panic attacks, and states of agitation Treatment of neurovegetative symptoms associated with vertigo Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal Short-term treatment of insomnia Treatment of muscle spasms Treatment of tetanus, together with other measures of intensive treatment Adjunctive treatment of spastic muscular paresis (paraplegia/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, or spinal cord injury (long-term treatment is coupled with other rehabilitative measures) Palliative treatment of stiff person syndrome Pre- or postoperative sedation, anxiolysis or amnesia (e.g., before endoscopic or surgical procedures) Treatment of complications with stimulant overdoses and psychosis, such as cocaine or methamphetamineUsed in treatment of organophosphate poisoning and reduces the risk of seizure induced brain and cardiac damage. Preventive treatment of oxygen toxicity during hyperbaric oxygen therapyDosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have. Seizures Intravenous diazepam or lorazepam are first-line treatments for status epilepticus. However, intravenous lorazepam has advantages over intravenous diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose.The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, or soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids.Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age. Recurrence rates are reduced, but side effects are common so the decision to treat febrile seizures (which are benign in nature) with medication should use this as part of the evaluation. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of individuals with treatment-resistant epilepsy benefit from long-term benzodiazepines, and for such individuals, clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects. Alcohol withdrawal Because of its relatively long duration of action, and evidence of safety and efficacy, diazepam is preferred over other benzodiazepines for treatment of persons experiencing moderate to severe alcohol withdrawal. An exception to this is when a medication is required intramuscular in which case either lorazepam or midazolam is recommended. Other Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed. Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm. Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen is sometimes used as an alternative to diazepam. Availability Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation, and rectal forms.The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent (CANA), which contains diazepam. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care. Contraindications Use of diazepam should be avoided, when possible, in individuals with: Ataxia Severe hypoventilation Acute narrow-angle glaucoma Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two) Severe renal deficiencies (for example, patients on dialysis) Liver disorders Severe sleep apnea Severe depression, particularly when accompanied by suicidal tendencies Psychosis Pregnancy or breast feeding Caution required in elderly or debilitated patients Coma or shock Abrupt discontinuation of therapy Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of hallucinogens or some stimulants, where it is occasionally used as a treatment for overdose) History of alcohol or drug dependence Myasthenia gravis, an autoimmune disorder causing marked fatiguability Hypersensitivity or allergy to any drug in the benzodiazepine class Caution Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders. Pediatric patients Less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment. The smallest possible effective dose should be used for this group of patients. Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to those in this age group. Elderly and very ill patients can possibly experience apnea or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of people. The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger people, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam can also be dangerous in geriatric patients owing to a significant increased risk of falls. Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored. Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, can result in floppy infant syndrome. Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Adverse effects Adverse effects of benzodiazepines such as diazepam include anterograde amnesia, confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia, and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with drug tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before using benzodiazepines is not impaired. Tolerance to the cognitively impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them. Additionally, after cessation of benzodiazepines, cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation and hypotension. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.Diazepam has a range of side effects common to most benzodiazepines, including: Suppression of REM sleep and Slow wave sleep Impaired motor function Impaired coordination Impaired balance Dizziness Reflex tachycardiaLess commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of a substance use disorder, such as an alcohol use disorder, or a history of aggressive behavior. In some people, diazepam may increase the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely dystonia can occur.Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.Patients with severe attacks of apnea during sleep may experience respiratory depression (hypoventilation), leading to respiratory arrest and death.Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness. Tolerance and withdrawal Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms.Withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life.Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation.Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%.Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer. In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently. Dependence Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, substance use disorder or dependence are: People with a history of a substance use disorder or substance dependence Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers. People with severe personality disorders, such as borderline personality disorderPatients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended.People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.Diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable. The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately. Overdose An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose: Drowsiness Mental confusion Hypotension Impaired motor functions Impaired reflexes Impaired coordination Impaired balance Dizziness ComaAlthough not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.Overdoses of diazepam with alcohol, opiates or other depressants may be fatal. Interactions If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants.Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable. Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), other muscle relaxants, certain antidepressants, sedative antihistamines, opioids, and antipsychotics, as well as anticonvulsants such as phenobarbital, phenytoin, and carbamazepine. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence. Cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine, and valproic acid prolong the action of diazepam by inhibiting its elimination. Alcohol in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol. Oral contraceptives significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam. Rifampin, phenytoin, carbamazepine, and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects. Dexamethasone and St Johns wort also increase the metabolism of diazepam. Diazepam increases the serum levels of phenobarbital. Nefazodone can cause increased blood levels of benzodiazepines. Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam. Small doses of theophylline may inhibit the action of diazepam. Diazepam may block the action of levodopa (used in the treatment of Parkinsons disease). Diazepam may alter digoxin serum concentrations. Other drugs that may have interactions with diazepam include antipsychotics (e.g. chlorpromazine), MAO inhibitors, and ranitidine. Because it acts on the GABA receptor, the herb valerian may produce an adverse effect. Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity. Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity. Reports conflict as to whether food in general has any effects on the absorption and activity of orally administered diazepam. Pharmacology Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. Diazepam has anticonvulsant properties. Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat nerve cell preparations.Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepams anticonvulsant properties.Diazepam binds with high affinity to glial cells in animal cell cultures. Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepams action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release in rats. Mechanism of action Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes the binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarizes the neurons membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines. Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects.Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord. Pharmacokinetics Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepams peak pharmacological effects is 15 minutes to one hour for both routes of administration. The half-life of diazepam in general is 30–56 hours. Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly protein-bound, with 96 to 99% of the absorbed drug being protein-bound. The distribution half-life of diazepam is two to 13 minutes.Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day.Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam. Most of the drug is metabolised; very little diazepam is excreted unchanged. The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration. Physical and chemical properties Diazepam is a 1
Diazepam	,4-benzodiazepine. Diazepam occurs as solid white or yellow crystals with a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists it as being very slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Due to additives such as benzoic acid/benzoate in the injectable form. (Plumbs, 6th edition page 372) Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions. Diazepam should be stored at room temperature (15–30 °C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.Diazepam can absorb into plastics, so liquid preparations should not be kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve. Detection in body fluids Diazepam may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma diazepam concentrations are usually in a range of 0.1–1.0 mg/L in persons receiving the drug therapeutically. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation are usually performed using chromatographic techniques. History Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the companys Nutley, New Jersey, facility following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or opioids). Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler, diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion tablets. Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome. Society and culture Recreational use Diazepam is a medication with a high risk of misuse and can cause drug dependence. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways. Between 50 and 64% of rats will self-administer diazepam. Diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study. Diazepam has been found as an adulterant in heroin.Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice.Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge. These users often escalate dosage from 2 to 25 times the therapeutic dose of 5 to 10 mg.A large-scale study in the US, conducted by SAMHSA, using data from 2011, determined benzodiazepines were present in 28.7% of emergency department visits involving nonmedical use of pharmaceuticals. In this regard, benzodiazepines are second only to opiates, the study found in 39.2% of visits. About 29.3% of drug-related suicide attempts involve benzodiazepines, making them the most frequently represented class in drug-related suicide attempts. Males misuse benzodiazepines as commonly as females.Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden, and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range, suggesting a high degree of potential for misuse for benzodiazepines, zolpidem, and zopiclone. In Northern Ireland, in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine. Legal status Diazepam is regulated in most countries as a prescription drug: International Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances. UK Classified as a controlled drug, listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription, and for such purposes it is classified as a Class C drug. Germany Classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anlage III). Australia Diazepam is Schedule 4 substance under the Poisons Standard (June 2018). A schedule 4 drug is outlined in the Poisons Act 1964 as, "Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription." United States Diazepam is controlled as a Schedule IV substance under the Controlled Substances Act of 1970. Judicial executions The states of California and Florida offer diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program, although the state of California has not executed a prisoner since 2006. In August 2018, Nebraska used diazepam as part of the drug combination used to execute Carey Dean Moore, the first death row inmate executed in Nebraska in over 21 years. Veterinary uses Diazepam is used as a short-term sedative and anxiolytic for cats and dogs, sometimes used as an appetite stimulant. It can also be used to stop seizures in dogs and cats. References Further reading Dean L (2016). "Diazepam Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520370. Bookshelf ID: NBK379740. Thomas Hardman (April, 2021) "Valium FAQ- 20 Frequently Asked Questions" Pharmacologist at GenZen Laboratories. External links "Diazepam". Drug Information Portal. U.S. National Library of Medicine. "Diazepam Nasal Spray". MedlinePlus. "Diazepam". Resource Center. Chemwatch.
Buprenorphine	Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal), or as an implant. For opioid use disorder, it is typically started when withdrawal symptoms have begun and for the first two days of treatment under direct observation of a health-care provider. In the United States, the combination formulation of buprenorphine/naloxone (Suboxone) is usually prescribed to discourage misuse by injection. Maximum pain relief is generally within an hour with effects up to 24 hours. Buprenorphine affects different types of opioid receptors in different ways. Depending on the type of receptor, it may be an agonist, partial agonist, or antagonist. In the treatment of opioid use disorder buprenorphine is an agonist/antagonist, meaning that it relieves withdrawal symptoms from other opioids and induces some euphoria, but also blocks the ability for many other opioids, including heroin, to cause an effect. Unlike full agonists like heroin or methadone, buprenorphine has a ceiling effect, such that taking more medicine will not increase the effects of the drug.Side effects may include respiratory depression (decreased breathing), sleepiness, adrenal insufficiency, QT prolongation, low blood pressure, allergic reactions, constipation, and opioid addiction. Among those with a history of seizures, a risk exists of further seizures. Opioid withdrawal following stopping buprenorphine is generally less severe than with other opioids. Whether use during pregnancy is safe is unclear, but use while breastfeeding is probably safe, since the dose the infant receives is 1-2% that of the maternal dose, on a weight basis.Buprenorphine was patented in 1965, and approved for medical use in the United States in 1981. It is on the World Health Organizations List of Essential Medicines. In addition to prescription as an analgesic it is a common medication used to treat opioid use disorders, such as addiction to heroin. In 2017, 14.6 million prescriptions for the medication were written in the United States. Buprenorphine may also be used recreationally for the high it produces, and in the US sublingual formulations are marketed as a film or mixed with naloxone to discourage injection. In the United States, buprenorphine is a schedule III controlled substance. Medical uses Opioid use disorder Buprenorphine is used to treat people with opioid use disorder.: 84–7 In the U.S., the combination formulation of buprenorphine/naloxone is generally prescribed to deter injection, since naloxone, an opioid antagonist, causes acute withdrawal if the formulation is crushed and injected.: 99 However, taken orally, the nalaxone has virtually no effect, due to the drugs extremely high first-pass metabolism and low bioavailability (2%). Before starting buprenorphine, individuals are generally advised to wait long enough after their last dose of opioid until they have some withdrawal symptoms to allow for the medication to bind the receptors,since if taken too soon, buprenorphine can displace other opioids bound to the receptors and precipitate an acute withdrawal. The dose of buprenorphine is then adjusted until symptoms improve, and individuals remain on a maintenance dose of 8–16 mg.: 99–100 Because withdrawal is uncomfortable and a deterrent for many patients, many have begun to call for different means of treatment initiation. Some providers have begun to use the Bernese method, also known as microdosing, in which very small doses of buprenorphine are given while patients are still using street opioids, and without precipitating withdrawal, with medicine levels slowly titrated upward. Buprenorphine versus methadone Both buprenorphine and methadone are medications used for detoxification and opioid replacement therapy, and appear to have similar effectiveness based on limited data. Both are safe for pregnant women with opioid use disorder,: 101 although preliminary evidence suggests that methadone is more likely to cause neonatal abstinence syndrome. In the US and European Union, only designated clinics can prescribe methadone for opioid use disorder, requiring patients to travel to the clinic daily. If patients are drug free for a period they may be permitted to receive "take home doses," reducing their visits to as little as once a week. Alternatively, up to a months supply of buprenorphine has been able to be prescribed by clinicians in the US or Europe who have completed a basic training (8–24 hours in the US) and received a waiver/licence allowing prescription of the medicine.: 84–5 In France, buprenorphine prescription for opioid use disorder has been permitted without any special training or restrictions since 1995, resulting in treatment of approximately ten times more patients per year with buprenorphine than with methadone in the following decade. In 2021, seeking to address record levels of opioid overdose, the United States also removed the requirement for a special waiver for prescribing physicians. Whether this change will be sufficient to impact prescription is unclear, since even before the change as many as half of physicians with a waiver permitting them to prescribe buprenorphine did not do so, and one third of non-waivered physicians reported that nothing would induce them to prescripe buprenorphine for opioid use disorder. Chronic pain A transdermal patch is available for the treatment of chronic pain. These patches are not indicated for use in acute pain, pain that is expected to last only for a short period of time, or pain after surgery, nor are they recommended for opioid addiction. Potency With respect to equianalgesic dosing, when used sublingually, the potency of buprenorphine is about 40 to 70 times that of morphine. When used as a transdermal patch, the potency of buprenorphine may be 100 to 115 times that of morphine. Veterinary uses Veterinarians frequently administer buprenorphine for perioperative pain, particularly in cats, where its effects are similar to morphine. The drugs legal status and lower potential for human abuse makes it an attractive alternative to other opioids. Adverse effects Common adverse drug reactions associated with the use of buprenorphine, similar to those of other opioids, include nausea and vomiting, drowsiness, dizziness, headache, memory loss, cognitive and neural inhibition, perspiration, itchiness, dry mouth, shrinking of the pupils of the eyes (miosis), orthostatic hypotension, male ejaculatory difficulty, decreased libido, and urinary retention. Constipation and central nervous system (CNS) effects are seen less frequently than with morphine. Respiratory effects The most severe side effect associated with buprenorphine is respiratory depression (insufficient breathing). It occurs more often in those who are also taking benzodiazepines or alcohol, or have underlying lung disease. The usual reversal agents for opioids, such as naloxone, may be only partially effective, and additional efforts to support breathing may be required. Respiratory depression may be less than with other opioids, particularly with chronic use. In the setting of acute pain management, though, buprenorphine appears to cause the same rate of respiratory depression as other opioids such as morphine. Buprenorphine dependence Buprenorphine treatment carries the risk of causing psychological or physiological (physical) dependencies. It has a slow onset of activity, with a long duration of action, and a long half-life of 24 to 60 hours. Once a patient has stabilised on the (buprenorphine) medication and programme, three options remain - continual use (buprenorphine-only medication), switching to a buprenorphine/naloxone combination, or a medically supervised withdrawal. Pain management Achieving acute opioid analgesia is difficult in persons using buprenorphine for pain management. Pharmacology Pharmacodynamics Opioid receptor modulator Buprenorphine has been reported to possess these following pharmacological activities: μ-Opioid receptor (MOR): Very high affinity partial agonist: at low doses, the MOR-mediated effects of buprenorphine are comparable to those of other narcotics, but these effects reach a "ceiling" as the receptor population is saturated. This behavior is responsible for several unique properties: buprenorphine greatly reduces the effect of most other MOR agonists, can cause precipitated withdrawal when used in actively opioid dependent persons, and has a lower incidence of respiratory depression and fatal overdose relative to full MOR agonists. κ-Opioid receptor (KOR): High affinity antagonist—this activity is hypothesized to underlie some of the effects of buprenorphine on mood disorders and addiction. δ-Opioid receptor (DOR): High affinity antagonist Nociceptin receptor (NOP, ORL-1): Weak affinity, very weak partial agonistIn simplified terms, buprenorphine can essentially be thought of as a nonselective, mixed agonist–antagonist opioid receptor modulator, acting as an unusually high affinity weak partial agonist of the MOR, a high affinity antagonist of the KOR and DOR, and a relatively low affinity, very weak partial agonist of the ORL-1/NOP.Although buprenorphine is a partial agonist of the MOR, human studies have found that it acts like a full agonist with respect to analgesia in opioid-intolerant individuals. Conversely, buprenorphine behaves like a partial agonist of the MOR with respect to respiratory depression.Buprenorphine is also known to bind to with high affinity and antagonize the putative ε-opioid receptor.Full analgesic efficacy of buprenorphine requires both exon 11- and exon 1-associated μ-opioid receptor splice variants.The active metabolites of buprenorphine are not thought to be clinically important in its CNS effects.In positron emission tomography (PET) imaging studies, buprenorphine was found to decrease whole-brain MOR availability due to receptor occupancy by 41% (i.e., 59% availability) at 2 mg, 80% (i.e., 20% availability) at 16 mg, and 84% (i.e., 16% availability) at 32 mg. Other actions Unlike some other opioids and opioid antagonists, buprenorphine binds only weakly to and possesses little if any activity at the sigma receptor.Buprenorphine also blocks voltage-gated sodium channels via the local anesthetic binding site, and this underlies its potent local anesthetic properties.Similarly to various other opioids, buprenorphine has also been found to act as an agonist of the toll-like receptor 4, albeit with very low affinity. Pharmacokinetics Buprenorphine is metabolized by the liver, via CYP3A4 (also CYP2C8 seems to be involved) isozymes of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation). The glucuronidation of buprenorphine is primarily carried out by UGT1A1 and UGT2B7, and that of norbuprenorphine by UGT1A1 and UGT1A3. These glucuronides are then eliminated mainly through excretion into bile. The elimination half-life of buprenorphine is 20 to 73 hours (mean 37 hours). Due to the mainly hepatic elimination, no risk of accumulation exists in people with renal impairment.One of the major active metabolites of buprenorphine is norbuprenorphine, which, in contrast to buprenorphine itself, is a full agonist of the MOR, DOR, and ORL-1, and a partial agonist at the KOR. However, relative to buprenorphine, norbuprenorphine has extremely little antinociceptive potency (1/50th that of buprenorphine), but markedly depresses respiration (10-fold more than buprenorphine). This may be explained by very poor brain penetration of norbuprenorphine due to a high affinity of the compound for P-glycoprotein. In contrast to norbuprenorphine, buprenorphine and its glucuronide metabolites are negligibly transported by P-glycoprotein.The glucuronides of buprenorphine and norbuprenorphine are also biologically active, and represent major active metabolites of buprenorphine. Buprenorphine-3-glucuronide has affinity for the MOR (Ki = 4.9 pM), DOR (Ki = 270 nM) and ORL-1 (Ki = 36 μM), and no affinity for the KOR. It has a small antinociceptive effect and no effect on respiration. Norbuprenorphine-3-glucuronide has no affinity for the MOR or DOR, but does bind to the KOR (Ki = 300 nM) and ORL-1 (Ki = 18 μM). It has a sedative effect but no effect on respiration. Chemistry Buprenorphine is a semisynthetic derivative of thebaine, and is fairly soluble in water, as its hydrochloride salt. It degrades in the presence of light. Detection in body fluids Buprenorphine and norbuprenorphine may be quantified in blood or urine to monitor use or non-medical recreational use, confirm a diagnosis of poisoning, or assist in a medicolegal investigation. A significant overlap of drug concentrations exists in body fluids within the possible spectrum of physiological reactions ranging from asymptomatic to comatose. Therefore, having knowledge of both the route of administration of the drug and the level of tolerance to opioids of the individual is critical when results are interpreted. History In 1969, researchers at Reckitt and Colman (now Reckitt Benckiser) had spent 10 years attempting to synthesize an opioid compound "with structures substantially more complex than morphine [that] could retain the desirable actions whilst shedding the undesirable side effects". Physical dependence and withdrawal from buprenorphine itself remain important issues, since buprenorphine is a long-acting opioid. Reckitt found success when researchers synthesized RX6029 which had showed success in reducing dependence in test animals. RX6029 was named buprenorphine and began trials on humans in 1971. By 1978, buprenorphine was first launched in the UK as an injection to treat severe pain, with a sublingual formulation released in 1982. Society and culture Regulation United States In the United States, buprenorphine and buprenorphine with naloxone were approved for opioid use disorder by the Food and Drug Administration in October 2002. The DEA rescheduled buprenorphine from a schedule V drug to a schedule III drug just before approval. The ACSCN for buprenorphine is 9064, and being a schedule III substance, it does not have an annual manufacturing quota imposed by the DEA. The salt in use is the hydrochloride, which has a free-base conversion ratio of 0.928. In the years before buprenorphine/naloxone was approved, Reckitt Benckiser had lobbied Congress to help craft the Drug Addiction Treatment Act of 2000, which gave authority to the Secretary of Health and Human Services to grant a waiver to physicians with certain training to prescribe and administer schedule III, IV, or V narcotic drugs for the treatment of addiction or detoxification. Before this law was passed, such treatment was permitted only in clinics designed specifically for drug addiction.The waiver, which can be granted after the completion of an eight-hour course, was required for outpatient treatment of opioid addiction with buprenorphine from 2000 to 2021. Initially, the number of people each approved physician could treat was limited to 10. This was eventually modified to allow approved physicians to treat up to 100 people with buprenorphine for opioid addiction in an outpatient setting. This limit was increased by the Obama administration, raising the number of patients to which doctors can prescribe to 275. On 14 January 2021, the US Department of Health and Human Services announced that the waiver would no longer be required to prescribe buprenorphine to treat up to 30 people concurrently.New Jersey authorized paramedics to give buprenorphine to people at the scene after they have recovered from an overdose. Europe In the European Union, Subutex and Suboxone, buprenorphines high-dose sublingual tablet preparations, were approved for opioid use disorder treatment in September 2006. In the Netherlands, buprenorphine is a list II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In France, where buprenorphine prescription by general practitioners and dispensed by pharmacies has been permitted since the mid-1990s as a response to HIV and overdose risk. Deaths caused by heroin overdose were reduced by four-fifths between 1994 and 2002, and incidence of AIDS among people who inject drugs in France fell from 25% in the mid-1990s to 6% in 2010. Brand names Buprenorphine is available under the trade names Cizdol, Brixadi (weekly and monthly depot injections approved in the US by FDA for addiction treatment in 2020), Suboxone (with naloxone), Subutex (typically used for opioid use disorder), Zubsolv, Bunavail, Buvidal (weekly and monthly depot injections, approved in the UK, Europe and Australia for addiction treatment in 2018), Sublocade (monthly injection, approved in the US in 2018), Probuphine, Temgesic (sublingual tablets for moderate to severe pain), Buprenex (solutions for injection often used for acute pain in primary-care settings), Norspan, and Butrans (transdermal preparations used for chronic pain). In Poland buprenorphine is available under the trade names Bunondol (for paint treatment, when morphine is too little; amounts of 0.2mg and 0.4mg) and Bunorfin (for addicts substitution in amount of 2 and 8mg). Buprenorphine has been introduced in most European countries as a transdermal formulation (marketed as Transtec) for the treatment of chronic pain not responding to nonopioids. Veterinary medicine It has veterinary medical use for treatment of pain in dogs and cats. Research Depression Some evidence supports the use of buprenorphine for depression. Buprenorphine/samidorphan, a combination product of buprenorphine and samidorphan (a preferential μ-opioid receptor antagonist), appears useful for treatment-resistant depression. Cocaine dependence In combination with samidorphan or naltrexone (μ-opioid receptor antagonists), buprenorphine is under investigation for the treatment of cocaine dependence, and recently demonstrated effectiveness for this indication in a large-scale (n = 302) clinical trial (at a high buprenorphine dose of 16 mg, but not a low dose of 4 mg). Neonatal abstinence Buprenorphine has been used in the treatment of the neonatal abstinence syndrome, a condition in which newborns exposed to opioids during pregnancy demonstrate signs of withdrawal. In the United States, use currently is limited to infants enrolled in a clinical trial conducted under an FDA-approved investigational new drug (IND) application. Preliminary research suggests that buprenorphine is associated with shorter time in hospital for neonates, compared to methadone. An ethanolic formulation used in neonates is stable at room temperature for at least 30 days. Obsessive–compulsive disorder In one study, buprenorphine was found to be effective in a subset of individuals with treatment-refractory obsessive–compulsive disorder. References External links "Buprenorphine". Drug Information Portal. U.S. National Library of Medicine. U.S. Federal government buprenorphine program for opioid addiction Australian national buprenorphine policy "The bitter pill": A Wired article on Suboxone "Subu Must Die – How a nation of junkies went cold turkey": A New Republic article on Subutex abuse in the nation of Georgia
Human chorionic gonadotropin	Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation. The presence of hCG is detected in some pregnancy tests (HCG pregnancy strip tests). Some cancerous tumors produce this hormone; therefore, elevated levels measured when the patient is not pregnant may lead to a cancer diagnosis and, if high enough, paraneoplastic syndromes, however, it is not known whether this production is a contributing cause, or an effect of carcinogenesis. The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary gland of males and females of all ages.Various endogenous forms of hCG exist. The measurement of these diverse forms is used in the diagnosis of pregnancy and a variety of disease states. Preparations of hCG from various sources have also been used therapeutically, by both medicine and quackery. As of December 6, 2011, the United States Food and Drug Administration has prohibited the sale of "homeopathic" and over-the-counter hCG diet products and declared them fraudulent and illegal.Beta-hCG is initially secreted by the syncytiotrophoblast. Structure Human chorionic gonadotropin is a glycoprotein composed of 237 amino acids with a molecular mass of 36.7 kDa, approximately 14.5kDa αhCG and 22.2kDa βhCG.It is heterodimeric, with an α (alpha) subunit identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and β (beta) subunit that is unique to hCG. The α (alpha) subunit is 92 amino acids long. The β-subunit of hCG gonadotropin (beta-hCG) contains 145 amino acids, encoded by six highly homologous genes that are arranged in tandem and inverted pairs on chromosome 19q13.3 - CGB (1, 2, 3, 5, 7, 8). It is known that CGB7 has a sequence slightly different from that of the others.The two subunits create a small hydrophobic core surrounded by a high surface area-to-volume ratio: 2.8 times that of a sphere. The vast majority of the outer amino acids are hydrophilic.beta-hCG is mostly similar to beta-LH, with the exception of a Carboxy Terminus Peptide (beta-CTP) containing four glycosylated serine residues that is responsible for hCGs longer half-life. Function Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum for the maternal recognition of pregnancy at the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus.It has been hypothesized that hCG may be a placental link for the development of local maternal immunotolerance. For example, hCG-treated endometrial cells induce an increase in T cell apoptosis (dissolution of T cells). These results suggest that hCG may be a link in the development of peritrophoblastic immune tolerance, and may facilitate the trophoblast invasion, which is known to expedite fetal development in the endometrium. It has also been suggested that hCG levels are linked to the severity of morning sickness or Hyperemesis gravidarum in pregnant women.Because of its similarity to LH, hCG can also be used clinically to induce ovulation in the ovaries as well as testosterone production in the testes. As the most abundant biological source is in women who are presently pregnant, some organizations collect urine from pregnant women to extract hCG for use in fertility treatment. Human chorionic gonadotropin also plays a role in cellular differentiation/proliferation and may activate apoptosis. Production Naturally, it is produced in the human placenta by the syncytiotrophoblast. Like any other gonadotropins, it can be extracted from the urine of pregnant women or produced from cultures of genetically modified cells using recombinant DNA technology. In Pubergen, Pregnyl, Follutein, Profasi, Choragon and Novarel, it is extracted from the urine of pregnant women. In Ovidrel, it is produced with recombinant DNA technology. hCG forms Three major forms of hCG are produced by humans, with each having distinct physiological roles. These include regular hCG, hyperglycosylated hCG, and the free beta-subunit of hCG. Degradation products of hCG have also been detected, including nicked hCG, hCG missing the C-terminal peptide from the beta-subunit, and free alpha-subunit, which has no known biological function. Some hCG is also made by the pituitary gland with a pattern of glycosylation that differs from placental forms of hCG.Regular hCG is the main form of hCG associated with the majority of pregnancy and in non-invasive molar pregnancies. This is produced in the trophoblast cells of the placental tissue. Hyperglycosylated hCG is the main form of hCG during the implantation phase of pregnancy, with invasive molar pregnancies, and with choriocarcinoma.Gonadotropin preparations of hCG can be produced for pharmaceutical use from animal or synthetic sources. Some of these are medically justified, whereas others are of a quack nature. Testing Blood or urine tests measure hCG. These can be pregnancy tests. hCG-positive can indicate an implanted blastocyst and mammalian embryogenesis or can be detected for a short time following childbirth or pregnancy loss. Tests can be done to diagnose and monitor germ cell tumors and gestational trophoblastic diseases. Concentrations are commonly reported in thousandth international units per milliliter (mIU/mL). The international unit of hCG was originally established in 1938 and has been redefined in 1964 and in 1980. At the present time, 1 international unit is equal to approximately 2.35×10−12 moles, or about 6×10−8 grams.It is also possible to test for hCG to have an approximation of the gestational age. Methodology Most tests employ a monoclonal antibody, which is specific to the β-subunit of hCG (β-hCG). This procedure is employed to ensure that tests do not make false positives by confusing hCG with LH and FSH. (The latter two are always present at varying levels in the body, whereas the presence of hCG almost always indicates pregnancy.) Many hCG immunoassays are based on the sandwich principle, which uses antibodies to hCG labeled with an enzyme or a conventional or luminescent dye. Pregnancy urine dipstick tests are based on the lateral flow technique. The urine test may be a chromatographic immunoassay or any of several other test formats, home-, physicians office-, or laboratory-based. Published detection thresholds range from 20 to 100 mIU/mL, depending on the brand of test. Early in pregnancy, more accurate results may be obtained by using the first urine of the morning (when urine is most concentrated). When the urine is dilute (specific gravity less than 1.015), the hCG concentration may not be representative of the blood concentration, and the test may be falsely negative. The serum test, using 2-4 mL of venous blood, is typically a chemiluminescent or fluorimetric immunoassay that can detect βhCG levels as low as 5 mIU/mL and allows quantification of the βhCG concentration. Reference levels in normal pregnancy The following is a list of serum hCG levels. (LMP is the last menstrual period dated from the first day of the last menstrual period.) The levels grow exponentially after conception and implantation. Interpretation The ability to quantitate the βhCG level is useful in monitoring germ cell and trophoblastic tumors, follow-up care after miscarriage, and diagnosis of and follow-up care after treatment of ectopic pregnancy. The lack of a visible fetus on vaginal ultrasound after βhCG levels reach 1500 mIU/mL is strongly indicative of an ectopic pregnancy. Still, even an hCG over 2000 IU/L does not necessarily exclude the presence of a viable intrauterine pregnancy in such cases.As pregnancy tests, quantitative blood tests and the most sensitive urine tests usually detect hCG between 6 and 12 days after ovulation. It must be taken into account, however, that total hCG levels may vary in a very wide range within the first 4 weeks of gestation, leading to false results during this period. A rise of 35% over 48 hours is proposed as the minimal rise consistent with a viable intrauterine pregnancy.Gestational trophoblastic disease like hydatidiform moles ("molar pregnancy") or choriocarcinoma may produce high levels of βhCG (due to the presence of syncytiotrophoblasts - part of the villi that make up the placenta) despite the absence of an embryo. This, as well as several other conditions, can lead to elevated hCG readings in the absence of pregnancy. hCG levels are also a component of the triple test, a screening test for certain fetal chromosomal abnormalities/birth defects. A study of 32 normal pregnancies came to the result that a gestational sac of 1–3 mm was detected at a mean hCG level of 1150 IU/L (range 800–1500), a yolk sac was detected at a mean level of 6000 IU/L (range 4500–7500) and fetal heartbeat was visible at a mean hCG level of 10,000 IU/L (range 8650–12,200). Uses Tumor marker Human chorionic gonadotropin can be used as a tumor marker, as its β subunit is secreted by some cancers including seminoma, choriocarcinoma, germ cell tumors, hydatidiform mole, teratoma with elements of choriocarcinoma, and islet cell tumor. For this reason, a positive result in males can be a test for testicular cancer. The normal range for men is between 0-5 mIU/mL. Combined with alpha-fetoprotein, β-HCG is an excellent tumor marker for the monitoring of germ cell tumors. Fertility Human chorionic gonadotropin injection is extensively used for final maturation induction in lieu of luteinizing hormone. In the presence of one or more mature ovarian follicles, ovulation can be triggered by the administration of HCG. As ovulation will happen between 38 and 40 hours after a single HCG injection, procedures can be scheduled to take advantage of this time sequence, such as intrauterine insemination or sexual intercourse. Also, patients that undergo IVF, in general, receive HCG to trigger the ovulation process, but have an oocyte retrieval performed at about 34 to 36 hours after injection, a few hours before the eggs actually would be released from the ovary. As HCG supports the corpus luteum, administration of HCG is used in certain circumstances to enhance the production of progesterone. In the male, HCG injections are used to stimulate the Leydig cells to synthesize testosterone. The intratesticular testosterone is necessary for spermatogenesis from the sertoli cells. Typical uses for HCG in men include hypogonadism and fertility treatment, including during testosterone replacement therapy to restore or maintain fertility and prevent testicular atrophy. Several vaccines against human chorionic gonadotropin (hCG) for the prevention of pregnancy are currently in clinical trials. HCG Pubergen, Pregnyl warnings In the case of female patients who want to be treated with HCG Pubergen, Pregnyl: a) Since infertile female patients who undergo medically assisted reproduction (especially those who need in vitro fertilization), are known to often be suffering from tubal abnormalities, after a treatment with this drug they might experience many more ectopic pregnancies. This is why early ultrasound confirmation at the beginning of a pregnancy (to see whether the pregnancy is intrauterine or not) is crucial. Pregnancies that have occurred after a treatment with this drug have a higher risk of multiple pregnancy. Female patients who have thrombosis, severe obesity, or thrombophilia should not be prescribed this medicine as they have a higher risk of arterial or venous thromboembolic events after or during a treatment with HCG Pubergen, Pregnyl. b)Female patients who have been treated with this medicine are usually more prone to pregnancy losses. In the case of male patients: A prolonged treatment with HCG Pubergen, Pregnyl is known to regularly lead to increased production of androgen. Therefore: Patients who have overt or latent cardiac failure, hypertension, renal dysfunction, migraines, or epilepsy might not be allowed to start using this medicine or may require a lower dose of HCG Pubergen, Pregnyl. This drug should be used with extreme caution in the treatment of prepubescent teenagers in order to reduce the risk of precocious sexual development or premature epiphyseal closure. This type of patients skeletal maturation should be closely and regularly monitored. Both male and female patients who have the following medical conditions must not start a treatment with HCG Pubergen, Pregnyl: (1) Hypersensitivity to this drug or to any of its main ingredients. (2) Known or possible androgen-dependent tumors for example male breast carcinoma or prostatic carcinoma. Anabolic steroid adjunct In the world of performance-enhancing drugs, HCG is increasingly used in combination with various anabolic-androgenic steroid (AAS) cycles. As a result, HCG is included in some sports illegal drug lists. When exogenous AAS are put into the male body, natural negative-feedback loops cause the body to shut down its own production of testosterone via shutdown of the hypothalamic-pituitary-gonadal axis (HPGA). This causes testicular atrophy, among other things. HCG is commonly used during and after steroid cycles to maintain and restore testicular size as well as normal testosterone production.High levels of AASs, that mimic the bodys natural testosterone, trigger the hypothalamus to shut down its production of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Without GnRH, the pituitary gland stops releasing luteinizing hormone (LH). LH normally travels from the pituitary via the blood stream to the testes, where it triggers the production and release of testosterone. Without LH, the testes shut down their production of testosterone. In males, HCG helps restore and maintain testosterone production in the testes by mimicking LH and triggering the production and release of testosterone. If HCG is used for too long and in too high a dose, the resulting rise in natural testosterone and estrogen would eventually inhibit endogenous production of luteinizing hormone via negative feedback on the hypothalamus and pituitary gland.Professional athletes who have tested positive for HCG have been temporarily banned from their sport, including a 50-game ban from MLB for Manny Ramirez in 2009 and a 4-game ban from the NFL for Brian Cushing for a positive urine test for HCG. Mixed Martial Arts fighter Dennis Siver was fined $19,800 and suspended 9 months for being tested positive after his bout at UFC 168. HCG diet British endocrinologist Albert T. W. Simeons proposed HCG as an adjunct to an ultra-low-calorie weight-loss diet (fewer than 500 calories). Simeons, while studying pregnant women in India on a calorie-deficient diet, and "fat boys" with pituitary problems (Frölichs syndrome) treated with low-dose HCG, observed that both lost fat rather than lean (muscle) tissue. He reasoned that HCG must be programming the hypothalamus to do this in the former cases in order to protect the developing fetus by promoting mobilization and consumption of abnormal, excessive adipose deposits. Simeons in 1954 published a book entitled Pounds and Inches, designed to combat obesity. Simeons, practicing at Salvator Mundi International Hospital in Rome, Italy, recommended low-dose daily HCG injections (125 IU) in combination with a customized ultra-low-calorie (500 cal/day, high-protein, low-carbohydrate/fat) diet, which was supposed to result in a loss of adipose tissue without loss of lean tissue.Other researchers did not find the same results when attempting experiments to confirm Simeons conclusions, and in 1976 in response to complaints the FDA required Simeons and others to include the following disclaimer on all advertisements: These weight reduction treatments include the injection of HCG, a drug which has not been approved by the Food and Drug Administration as safe and effective in the treatment of obesity or weight control. There is no substantial evidence that HCG increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or "normal" distribution of fat, or that it decreases the hunger and discomfort associated with calorie-restrictive diets. There was a resurgence of interest in the "HCG diet" following promotion by Kevin Trudeau, who was banned from making HCG diet weight-loss claims by the U.S. Federal Trade Commission in 2008, and eventually jailed over such claims.A 1976 study in the American Journal of Clinical Nutrition concluded that HCG is not more effective as a weight-loss aid than dietary restriction alone.A 1995 meta analysis found that studies supporting HCG for weight loss were of poor methodological quality and concluded that "there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight-loss or fat-redistribution, nor does it reduce hunger or induce a feeling of well-being".On November 15, 2016, the American Medical Association (AMA) passed policy that "The use of human chorionic gonadotropin (HCG) for weight loss is inappropriate." There is no scientific evidence that HCG is effective in the treatment of obesity. The meta-analysis found insufficient evidence supporting the claims that HCG is effective in altering fat-distribution, hunger reduction, or in inducing a feeling of well-being. The authors stated "…the use of HCG should be regarded as an inappropriate therapy for weight reduction…" In the authors opinion, "Pharmacists and physicians should be alert on the use of HCG for Simeons therapy. The results of this meta-analysis support a firm standpoint against this improper indication. Restraints on physicians practicing this therapy can be based on our findings." According to the American Society of Bariatric Physicians, no new clinical trials have been published since the definitive 1995 meta-analysis.The scientific consensus is that any weight loss reported by individuals on an "HCG diet" may be attributed entirely to the fact that such diets prescribe calorie intake of between 500 and 1,000 calories per day, substantially below recommended levels for an adult, to the point that this may risk health effects associated with malnutrition. Homeopathic HCG for weight control Controversy about, and shortages of, injected HCG for weight loss have led to substantial Internet promotion of "homeopathic HCG" for weight control. The ingredients in these products are often obscure, but if prepared from true HCG via homeopathic dilution, they contain either no HCG at all or only trace amounts. Moreover, it is highly unlikely that oral HCG is bioavailable due to the fact that digestive protease enzymes and hepatic metabolism renders peptide-based molecules (such as insulin and human growth hormone) biologically inert. HCG can likely only enter the bloodstream through injection. The United States Food and Drug Administration has stated that over-the-counter products containing HCG are fraudulent and ineffective for weight loss. They are also not protected as homeopathic drugs and have been deemed illegal substances. HCG is classified as a prescription drug in the United States and it has not been approved for over-the-counter sales by the FDA as a weight loss product or for any other purposes, and therefore neither HCG in its pure form nor any preparations containing HCG may be sold legally in the country except by prescription. In December 2011, FDA and FTC started to take actions to pull unapproved HCG products from the market. In the aftermath, some suppliers started to switch to "hormone-free" versions of their weight loss products, where the hormone is replaced with an unproven mixture of free amino acids or where radionics is used to transfer the "energy" to the final product. Tetanus vaccine conspiracy theory Catholic Bishops in Kenya are among those who have spread a conspiracy theory asserting that HCG forms part of a covert sterilization program, forcing denials from the Kenyan government.In order to induce a stronger immune response, some versions of human chorionic gonadotropin-based anti-fertility vaccines were designed as conjugates of the β subunit of HCG covalently linked to tetanus toxoid. It was alleged that a non-conjugated tetanus vaccine used in developing countries was laced with a human chorionic gonadotropin-based anti-fertility drug and was distributed as a means of mass sterilization. This charge has been vigorously denied by the World Health Organization (WHO) and UNICEF. Others have argued that a hCG-laced vaccine could not possibly be used for sterilization, since the effects of the anti-fertility vaccines are reversible (requiring booster doses to maintain infertility) and a non-conjugated vaccine is likely to be ineffective. Finally, independent testing of the tetanus vaccine by Kenyas health authorities revealed no traces of the human chorionic gonadotropin hormone. See also Equine chorionic gonadotropin Gonadotropin preparations Human placental lactogen Triple test - a screening test in pregnancy The Weight-Loss Cure "They" Dont Want You to Know About - Kevin Trudeaus book References External links Chorionic+Gonadotropin at the US National Library of Medicine Medical Subject Headings (MeSH) History of pregnancy test (NIH)
Dipyridamole	Dipyridamole (trademarked as Persantine and others) is a nucleoside transport inhibitor and a PDE3 inhibitor medication that inhibits blood clot formation when given chronically and causes blood vessel dilation when given at high doses over a short time. Medical uses Dipyridamole is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease Dipyridamole has been shown to lower pulmonary hypertension without significant drop of systemic blood pressure It inhibits formation of pro-inflammatory cytokines (MCP-1, MMP-9) in vitro and results in reduction of hsCRP in patients. It inhibits proliferation of smooth muscle cells in vivo and modestly increases unassisted patency of synthetic arteriovenous hemodialysis grafts. It increases the release of tissue plasminogen activator from brain microvascular endothelial cells. It results in an increase of 13-hydroxyoctadecadienoic acid and decrease of 12-hydroxyeicosatetraenoic acid in the subendothelial matrix and reduced thrombogenicity of the subendothelial matrix. Pretreatment it reduced reperfusion injury in volunteers. It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy. It results in a reduction of the number of thrombin and PECAM-1 receptors on platelets in stroke patients. Cyclic adenosine monophosphate impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Chronic therapy did not show significant drop of systemic blood pressure. It inhibits the replication of mengovirus RNA. It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills. Stroke A combination of dipyridamole and aspirin (acetylsalicylic acid/dipyridamole) is FDA-approved for the secondary prevention of stroke and has a bleeding risk equal to that of aspirin use alone. Dipyridamole absorption is pH-dependent and concomitant treatment with gastric acid suppressors (such as a proton pump inhibitor) will inhibit the absorption of liquid and plain tablets. Modified release preparations are buffered and absorption is not affected.However, it is not licensed as monotherapy for stroke prophylaxis, although a Cochrane review suggested that dipyridamole may reduce the risk of further vascular events in patients presenting after cerebral ischemia.A triple therapy of aspirin, clopidogrel, and dipyridamole has been investigated, but this combination led to an increase in adverse bleeding events. Vasodilation occurs in healthy arteries, whereas stenosed arteries remain narrowed. This creates a "steal" phenomenon where the coronary blood supply will increase to the dilated healthy vessels compared to the stenosed arteries which can then be detected by clinical symptoms of chest pain, electrocardiogram and echocardiography when it causes ischemia. Flow heterogeneity (a necessary precursor to ischemia) can be detected with gamma cameras and SPECT using nuclear imaging agents such as Thallium-201, Tc99m-Tetrofosmin and Tc99m-Sestamibi. However, relative differences in perfusion do not necessarily imply any absolute decrease in blood supply in the tissue supplied by a stenosed artery. Other uses Dipyridamole also has non-medicinal uses in a laboratory context, such as the inhibition of cardiovirus growth in cell culture. Drug interactions Due to its action as a phosphodiesterase inhibitor, dipyridamole is likely to potentiate the effects of adenosine. This occurs by blocking the nucleoside transporter (ENT1) through which adenosine enters erythrocyte and endothelial cells.According to Association of Anaesthetists of Great Britain and Ireland 2016 guidelines, dipyridamole is considered to not cause risk of bleeding when receiving neuroaxial anaesthesia and deep nerve blocks. It does not therefore require cessation prior to anaesthesia with these techniques, and can continue to be taken with nerve block catheters in place. Overdose Dipyridamole overdose can be treated with aminophylline: 6 or caffeine which reverses its dilating effect on the blood vessels. Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit. Mechanisms of action Dipyridamole has two known effects, acting via different mechanisms of action: Dipyridamole inhibits the phosphodiesterase enzymes that normally break down cAMP (increasing cellular cAMP levels and blocking the platelet aggregation, response to ADP) and/or cGMP. Dipyridamole inhibits the cellular reuptake of adenosine into platelets, red blood cells, and endothelial cells, leading to increased extracellular concentrations of adenosine. Experimental studies Dipyridamole is currently undergoing repurposing for treatment of ocular surface disorders. These include pterygium and dry eye disease. The first report of topical dipyridamoles benefit in treating pterygium was published in 2014. A subsequent report of outcomes in 25 patients using topical dipyridamole was presented in 2016. See also Acetylsalicylic acid/dipyridamole Cilostazol == References ==
Antara	Antara may refer to: Antara (music) Antara (musical instrument) Antara (news agency), Indonesian news agency Antara (Peru), a mountain in Peru Antara Polanco, upscale shopping mall in Polanco, Mexico City Antara Gange, a mountain in Karnataka, India Opel Antara, a sport utility vehicle developed by GM Korea, and sold as Opel and Vauxhall Fenofibrate, a prescription drug used for lowering triglycerides and cholesterol Antara (hospital), a mental hospital located in Kolkata, India People Antara Chowdhury (born 1991), singer and composer of Bengali songs Antarah ibn Shaddad (525–608), pre-Islamic Arabian poet Antara Mali (born 1979), Indian actress Antara Mitra (born 1987), Indian playback singer Antara Dev Sen (born 1963), British–Indian journalist

Subsets and Splits

No saved queries yet

Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.