Split (1)

train · 7.32k rows

page_title stringlengths 1 91	page_text stringlengths 0 34.2k
Flutamide	Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.Side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes. Conversely, the medication has fewer side effects and is better-tolerated in women with the most common side effect being dry skin. Diarrhea and elevated liver enzymes can occur in both sexes. Rarely, flutamide can cause liver damage, lung disease, sensitivity to light, elevated methemoglobin, elevated sulfhemoglobin, and deficient neutrophils. Numerous cases of liver failure and death have been reported, which has limited the use of flutamide.Flutamide acts as a selective antagonist of the androgen receptor (AR), competing with androgens like testosterone and dihydrotestosterone (DHT) for binding to ARs in tissues like the prostate gland. By doing so, it prevents their effects and stops them from stimulating prostate cancer cells to grow. Flutamide is a prodrug to a more active form. Flutamide and its active form stay in the body for a relatively short time, which makes it necessary to take flutamide multiple times per day. Flutamide was first described in 1967 and was first introduced for medical use in 1983. It became available in the United States in 1989. The medication has largely been replaced by newer and improved NSAAs, namely bicalutamide and enzalutamide, due to their better efficacy, tolerability, safety, and dosing frequency (once per day), and is now relatively little-used. It is on the World Health Organizations List of Essential Medicines. Medical uses Prostate cancer GnRH is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase.DHT, and to a significantly smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are GnRH analogues, such as leuprorelin or cetrorelix. Although GnRH agonists stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary gland and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH agonist therapy to block this surge, and it and other NSAAs continue in this use. In contrast to GnRH agonists, GnRH antagonists dont cause an initial androgen surge, and are gradually replacing GnRH agonists in clinical use.There have been studies to investigate the benefit of adding an antiandrogen to surgical orchiectomy or its continued use with a GnRH analogue (combined androgen blockade (CAB)). Adding antiandrogens to orchiectomy showed no benefit, while a small benefit was shown with adding antiandrogens to GnRH analogues.Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment with antiandrogens exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life.Flutamide has been found to be similarly effective in the treatment of prostate cancer to bicalutamide, although indications of inferior efficacy, including greater compensatory increases in testosterone levels and greater reductions in PSA levels with bicalutamide, were observed. The medication, at a dosage of 750 mg/day (250 mg three times daily), has also been found to be equivalent in effectiveness to 250 mg/day oral cyproterone acetate as a monotherapy in the treatment of prostate cancer in a large-scale clinical trial of 310 patients, though its side effect and toxicity profiles (including gynecomastia, diarrhea, nausea, loss of appetite, and liver disturbances) were regarded as considerably worse than those of cyproterone acetate.A dosage of 750 mg/day flutamide (250 mg/three times a day) is roughly equivalent in terms of effectiveness to 50 mg/day bicalutamide when used as the antiandrogen component in combined androgen blockade in the treatment of advanced prostate cancer.Flutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.The combination of flutamide with an estrogen such as ethinylestradiol sulfonate has been used as a form of combined androgen blockade and as an alternative to the combination of flutamide with surgical or medical castration. Skin and hair conditions Flutamide has been researched and used extensively in the treatment of androgen-dependent skin and hair conditions in women including acne, seborrhea, hirsutism, and scalp hair loss, as well as in hyperandrogenism (e.g., in polycystic ovary syndrome or congenital adrenal hyperplasia), and is effective in improving the symptoms of these conditions. The dosages used are lower than those used in the treatment of prostate cancer. Although flutamide continues to be used for these indications, its use in recent years has been limited due to the risk of potentially fatal hepatotoxicity, and it is no longer recommended as a first- or second-line therapy. The related NSAA bicalutamide has also been found to be effective in the treatment of hirsutism in women and appears to have comparable effectiveness to that of flutamide, but has a far lower and only small risk of hepatotoxicity in comparison.Aside from its risk of liver toxicity and besides other nonsteroidal antiandrogens, it has been said that flutamide is likely the best typically used antiandrogen medication for the treatment of androgen-dependent symptoms in women. This is related to its high effectiveness and minimal side effects. Acne and seborrhea Flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies. In a long-term study of 230 women with acne, 211 of whom also had seborrhea, very-low-dose flutamide alone or in combination with an oral contraceptive caused a marked decrease in acne and seborrhea after 6 months of treatment, with maximal effect by 1 year of treatment and benefits maintained in the years thereafter. In the study, 97% of the women reported satisfaction with the control of their acne with flutamide. In another study, flutamide decreased acne and seborrhea scores by 80% in only 3 months. In contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications. Flutamide has, in general, been found to reduce symptoms of acne by as much as 90% even at low doses, with several studies showing complete acne clearance. Excessive hair growth Flutamide has been found to be effective in the treatment of hirsutism (excessive body/facial hair growth) in numerous studies. It possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate. The medication shows equivalent or superior effectiveness to other antiandrogens including spironolactone, cyproterone acetate, and finasteride in the treatment of hirsutism, although its relatively high risk of hepatotoxicity makes it unfavorable compared to these other options. It has been used to treat hirsutism at dosages ranging from 62.5 mg/day to 750 mg/day. A study found that multiple dosages of flutamide significantly reduced hirsutism in women with polycystic ovary syndrome and that there were no significant differences in the effectiveness for dosages of 125 mg/day, 250 mg/day, and 375 mg/day. In addition, a study found that combination of 125 mg/day flutamide with finasteride was no more effective than 125 mg/day flutamide alone in the treatment of hirsutism. These findings support the use of flutamide at lower doses for hirsutism without loss of effectiveness, which may help to lower the risk of hepatotoxicity. However, the risk has been found to remain even at very low doses. Scalp hair loss Flutamide has been found to be effective in the treatment of female pattern hair loss in a number of studies. In one study of 101 pre- and postmenopausal women, flutamide alone or in combination with an oral contraceptive produced a marked decrease in hair loss scores after 1 year of treatment, with maximum effect after 2 years of treatment and benefits maintained for another 2 years. In a small study of flutamide with an oral contraceptive, the medication caused an increase in cosmetically acceptance hair density in 6 of 7 women with diffuse scalp hair loss. In a comparative study, flutamide significantly improved scalp hair growth (21% reduction in Ludwig scores) in hyperandrogenic women after 1 year of treatment, whereas cyproterone acetate and finasteride were ineffective. Transgender hormone therapy Flutamide has been used as a component of feminizing hormone therapy for transgender women. At least two centers have been reported to use flutamide as an antiandrogen in transgender women. However, the use of flutamide for such purposes, as well as in biological women with androgen-dependent dermatological conditions, is discouraged due to reports of hepatotoxicity in men with prostate cancer at comparable doses. Other uses Flutamide has been used in case reports to decrease the frequency of spontaneous orgasms, for instance in men with post-orgasmic illness syndrome. Available forms Flutamide is available in the form of 125 mg oral capsules and 250 mg oral tablets. Side effects The side effects of flutamide are sex-dependent. In men, a variety of side effects related to androgen deprivation may occur, the most common being gynecomastia and breast tenderness. Others include hot flashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression, and sexual dysfunction including reduced libido and erectile dysfunction. In women, flutamide is, generally, relatively well tolerated, and does not interfere with ovulation. The only common side effect of flutamide in women is dry skin (75%), which can be attributed to a reduction of androgen-mediated sebum production. General side effects that may occur in either sex include dizziness, lack of appetite, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine, and hepatic changes. Because flutamide is a pure antiandrogen, unlike steroidal antiandrogens like cyproterone acetate and megestrol acetate (which additionally possess progestogenic activity), it does not appear to have a risk of cardiovascular side effects (e.g., thromboembolism) or fluid retention. Gynecomastia Flutamide, as a monotherapy, causes gynecomastia in 30 to 79% of men, and also produces breast tenderness. However, more than 90% of cases of gynecomastia with NSAAs including flutamide are mild to moderate. Tamoxifen, a selective estrogen receptor modulator (SERM) with predominantly antiestrogenic actions, can counteract flutamide-induced gynecomastia and breast pain in men. Diarrhea Diarrhea is more common and sometimes more severe with flutamide than with other NSAAs. In a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide. Moreover, 6% of flutamide-treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so. In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5 to 20% for flutamide, 2 to 5% for bicalutamide, and 2 to 4% for nilutamide. In contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications. Rare reactions Liver toxicity Although rare, flutamide has been associated with severe hepatotoxicity and death. By 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities. There have been continued case reports since, including liver transplants and death. A 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with flutamide, including 7 liver transplantations and 2 deaths.Based on the number of prescriptions written and the number of cases reported in the MedWatch database, the rate of serious hepatotoxicity associated with flutamide treatment was estimated in 1996 as approximately 0.03% (3 per 10,000). However, other research has suggested that the true incidence of significant hepatotoxicity with flutamide may be much greater, as high as 0.18 to 10%. Flutamide is also associated with liver enzyme elevations in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5 times upper normal limit) occur only in 3 to 5%. The risk of hepatotoxicity with flutamide is much higher than with nilutamide or bicalutamide. Lower doses of the medication appear to have a possibly reduced but still significant risk. Liver function should be monitored regularly with liver function tests during flutamide treatment. In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.The mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity. Specifically, flutamide and particularly its major metabolite hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes I (NADH ubiquinone oxidoreductase), II (succinate dehydrogenase), and V (ATP synthase), and thereby reduce cellular respiration via ATP depletion and hence decrease cell survival. Inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity. In contrast to flutamide and hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. It is thought that the nitroaromatic group of flutamide and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity.The hepatotoxicity of flutamide appears to depend on hydrolysis of flutamide catalyzed by an arylacetamide deacetalyse enzyme. This is analogous to the hepatotoxicity that occurs with the withdrawn paracetamol (acetominophen)-related medication phenacetin. In accordance, the combination of paracetamol (acetaminophen) and flutamide appears to result in additive to synergistic hepatotoxicity, indicating a potential drug interaction. Others Flutamide has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). The incidence of interstitial pneumonitis with flutamide was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients. A variety of case reports have associated flutamide with photosensitivity. Flutamide has been associated with several case reports of methemoglobinemia. Bicalutamide does not appear to share this risk with flutamide. Flutamide has also been associated with reports of sulfhemoglobinemia and neutropenia. Birth defects Out of the available endocrine-disrupting compounds looked at, flutamide has a notable effect on anogenital distance in rats.) Pharmacology Pharmacodynamics Antiandrogenic activity Flutamide acts as a selective, competitive, silent antagonist of the androgen receptor (AR). Its active form, hydroxyflutamide, has between 10- to 25-fold higher affinity for the AR than does flutamide, and hence is a much more potent AR antagonist in comparison. However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR. Flutamide has far lower affinity for the AR than do steroidal antiandrogens like spironolactone and cyproterone acetate, and it is a relatively weak antiandrogen in terms of potency by weight, but the large dosages at which flutamide is used appear to compensate for this. In accordance with its selectivity for the AR, flutamide does not interact with the progesterone, estrogen, glucocorticoid, or mineralocorticoid receptor, and possesses no intrinsic progestogenic, estrogenic, glucocorticoid, or antigonadotropic activity. However, it can have some indirect estrogenic effects via increased levels of estradiol secondary to AR blockade, and this involved in the gynecomastia it can produce. Because flutamide does not have any estrogenic, progestogenic, or antigonadotropic activity, the medication does not cause menstrual irregularities in women. This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate. Similarly to nilutamide, bicalutamide, and enzalutamide, flutamide crosses the blood–brain barrier and exerts central antiandrogen actions.Flutamide has been found to be equal to slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen in bioassays. This is in spite of the fact that hydroxyflutamide has on the order of 10-fold lower affinity for the AR relative to cyproterone acetate. Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide. In addition, whereas bicalutamide has an elimination half-life of around 6 days, hydroxyflutamide has an elimination half-life of only 8 to 10 hours, a roughly 17-fold difference. In accordance, at dosages of 50 mg/day bicalutamide and 750 mg/day flutamide (a 15-fold difference), circulating levels of flutamide at steady-state have been found to be approximately 7.5-fold lower than those of bicalutamide. Moreover, whereas flutamide at this dosage has been found to produce a 75% reduction in prostate-specific antigen levels in men with prostate cancer, a fall of 90% has been demonstrated with this dosage of bicalutamide. In accordance, 50 mg/day bicalutamide has been found to possess equivalent or superior effectiveness to 750 mg/day flutamide in a large clinical trial for prostate cancer. Also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs. Taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide.Dose-ranging studies of flutamide in men with benign prostatic hyperplasia and prostate cancer alone and in combination with a GnRH agonist have been performed.Flutamide increases testosterone levels by 5- to 10-fold in gonadally intact male rats. CYP17A1 inhibition Flutamide and hydroxyflutamide have been found in vitro to inhibit CYP17A1 (17α-hydroxylase/17,20-lyase), an enzyme which is required for the biosynthesis of androgens. In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients and women with polycystic ovary syndrome. In a directly comparative study of flutamide monotherapy (375 mg once daily) versus bicalutamide monotherapy (80 mg once daily) in Japanese men with prostate cancer, after 24 weeks of treatment flutamide decreased dehydroepiandrosterone (DHEA) levels by about 44% while bicalutamide increased them by about 4%. As such, flutamide is a weak inhibitor of androgen biosynthesis. However, the clinical significance of this action may be limited when flutamide is given without a GnRH analogue to non-castrated men, as the medication markedly elevates testosterone levels into the high normal male range via prevention of AR activation-mediated negative feedback on the hypothalamic–pituitary–gonadal axis in this context. Other activities Flutamide has been identified as an agonist of the aryl hydrocarbon receptor. This may be involved in the hepatotoxicity of flutamide. Pharmacokinetics The absorption of flutamide is complete upon oral ingestion. Food has no effect on the bioavailability of flutamide. Steady-state levels of hydroxyflutamide, the active form of flutamide, are achieved after 2 to 4 days administration. Levels of hydroxyflutamide are approximately 50-fold higher than those of flutamide at steady-state.The plasma protein binding of flutamide and hydroxyflutamide are high; 94 to 96% and 92 to 94%, respectively. Flutamide and its metabolite hydroxyflutamide are known to be transported by the multidrug resistance-associated protein 1 (MRP1; ABCC1).Flutamide is metabolized by CYP1A2 (via α-hydroxylation) in the liver during first-pass metabolism to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion), and to at least five other, minor metabolites. Flutamide has at least 10 inactive metabolites total, including 4-nitro-3-fluoro-methylaniline.Flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.Flutamide and hydroxyflutamide have elimination half-lives of 4.7 hours and 6 hours in adults, respectively. However, the half-life of hydroxyflutamide is extended to 8 hours after a single dose and to 9.6 hours at steady state) in elderly individuals. The elimination half-lives of flutamide and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and for this reason, flutamide is instead administered three times daily at 8-hour intervals. In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives, and this allows for once-daily administration in their cases. Chemistry Unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. Hence, it is described as nonsteroidal in order to distinguish it from older steroidal antiandrogens such as cyproterone acetate and megestrol acetate. Synthesis History Flutamide was first synthesized in 1967 by Neri and colleagues at Schering Plough Corporation. It was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity. The code name of flutamide during development was SCH-13521. Clinical research of the medication began in 1971, and it was first marketed in 1983, specifically in Chile under the brand name Drogenil and in West Germany under the brand name Flugerel. Flutamide was not introduced in the United States until 1989; it was specifically approved by the U.S. Food and Drug Administration for the treatment of metastatic prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue. The medication was first studied for the treatment of hirsutism in women in 1989. It was the first "pure antiandrogen" to be studied in the treatment of hirsutism. Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995. Society and culture Generic names Flutamide is the generic name of the drug and its INN, USAN, BAN, DCF, and JAN. Its names in Latin, German, and Spanish are flutamidum, flutamid, and flutamida, respectively. The medication has also been referred to by the name niftolide. Brand names Brand names of flutamide include or have included Cebatrol, Cytomid, Drogenil, Etaconil, Eulexin, Flucinom, Flumid, Flutacan, Flutamid, Flutamida, Flutamin, Flutan, Flutaplex, Flutasin, Fugerel, Profamid, and Sebatrol, among others. Availability Flutamide is marketed widely throughout the world, including in the United States, Canada, Europe, Australia, New Zealand, South Africa, Central and South America, East and Southeast Asia, India, and the Middle East. Research Prostate cancer The combination of an estrogen and flutamide as a form of combined androgen blockade for the treatment of prostate cancer has been researched. Enlarged prostate Flutamide has been studied in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate) in men in several clinical studies. It has been found to reduce prostate volume by about 25%, which is comparable to the reduction achieved with the 5α-reductase inhibitor finasteride. Unfortunately, it has been associated with side effects in these studies including gynecomastia and breast tenderness (in about 50% of patients), gastrointestinal disturbances such as nausea, diarrhea, and flatulence, and hepatotoxicity, although sexual function including libido and erectile potency were maintained. Breast cancer Flutamide was studied for the treatment of advanced breast cancer in two phase II clinical trials but was found to be ineffective. Out of a total of 47 patients, only three short-term responses occurred. However, the patients in the studies were selected irrespective of AR, ER, PR, or HER2 status, which were all unknown. Psychiatric disorders Flutamide has been studied in the treatment of bulimia nervosa in women.Flutamide was found to be effective in the treatment of obsessive–compulsive disorder (OCD) in men with comorbid Tourettes syndrome in one small randomized controlled trial. Conversely, it was ineffective in patients with OCD in another study. More research is necessary to determine whether flutamide is effective in the treatment of OCD. References Further reading Sogani PC, Whitmore WF (1988). "Flutamide and other antiandrogens in the treatment of advanced prostatic carcinoma". Cancer Treat. Res. Cancer Treatment and Research. 39: 131–45. doi:10.1007/978-1-4613-1731-9_9. ISBN 978-1-4612-8974-6. PMID 2908604. Brogden RN, Clissold SP (1989). "Flutamide. A preliminary review of its pharmacodynamic and pharmac
Flutamide	okinetic properties, and therapeutic efficacy in advanced prostatic cancer". Drugs. 38 (2): 185–203. doi:10.2165/00003495-198938020-00003. PMID 2670515. Neri R (1989). "Pharmacology and pharmacokinetics of flutamide". Urology. 34 (4 Suppl): 19–21, discussion 46–56. doi:10.1016/0090-4295(89)90230-6. PMID 2477934. Newling DW (1989). "The use of flutamide as monotherapy in the treatment of advanced prostate cancer". Prog. Clin. Biol. Res. 303: 117–21. PMID 2674980. Labrie F, Dupont A, Cusan L, Manhès G, Bergeron N, Lacourcière Y, Pineault S, Bélanger A, Monfette G, Emond J (1989). "Combination therapy with castration and flutamide: todays treatment of choice for prostate cancer". J. Steroid Biochem. 33 (4B): 817–21. doi:10.1016/0022-4731(89)90499-8. PMID 2689788. Goldspiel BR, Kohler DR (1990). "Flutamide: an antiandrogen for advanced prostate cancer". DICP. 24 (6): 616–23. doi:10.1177/106002809002400612. PMID 2193461. S2CID 26125621. Brogden RN, Chrisp P (1991). "Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer". Drugs Aging. 1 (2): 104–15. doi:10.2165/00002512-199101020-00003. PMID 1794008. Labrie F (1993). "Mechanism of action and pure antiandrogenic properties of flutamide". Cancer. 72 (12 Suppl): 3816–27. doi:10.1002/1097-0142(19931215)72:12+<3816::aid-cncr2820721711>3.0.co;2-3. PMID 8252497. S2CID 2195250. Iversen P, Melezinek I, Schmidt A (2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU Int. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992. S2CID 28215804. Ibáñez L, de Zegher F (2006). "Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women". Hum. Reprod. Update. 12 (3): 243–52. doi:10.1093/humupd/dmi054. PMID 16407452. Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, Buckel E, Contreras L (2011). "Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature". Ann Hepatol. 10 (1): 93–8. doi:10.1016/S1665-2681(19)31595-9. PMID 21301018. Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues". Eur Rev Med Pharmacol Sci. 21 (1 Suppl): 69–77. PMID 28379593.
Cefotaxime	Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in human it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.Common side effects include nausea, allergic reactions, and inflammation at the site of injection. Another side effect may include Clostridium difficile diarrhea. It is not recommended in people who have had previous anaphylaxis to a penicillin. It is relatively safe for use during pregnancy and breastfeeding. It is in the third-generation cephalosporin family of medications and works by interfering with the bacterias cell wall.Cefotaxime was discovered in 1976, and came into commercial use in 1980. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses It is a broad-spectrum antibiotic with activity against numerous gram-positive and gram-negative bacteria. Given its broad spectrum of activity, cefotaxime is used for a variety of infections, including: Lower respiratory tract infections – e.g. pneumonia (most commonly caused by S. pneumoniae) Genitourinary system infections – urinary tract infections (e.g. E. coli, S. epidermidis, P. mirabilis) and cervical/urethral gonorrhea Gynecologic infections – e.g. pelvic inflammatory disease, endometritis, and pelvic cellulitis Sepsis – secondary to Streptococcus spp., S. aureus, E. coli, and Klebsiella spp. Intra-abdominal infections – e.g. peritonitis Bone and joint infections – S. aureus, Streptococcus spp. CNS infections – e.g. meningitis/ventriculitis secondary to N. meningitidis, H. influenzae, S. pneumoniaeAlthough cefotaxime has demonstrated efficacy in these infections, it is not necessarily considered to be the first-line agent. In meningitis, cefotaxime crosses the blood–brain barrier better than cefuroxime. Spectrum of activity As a β-lactam antibiotic in the third-generation class of cephalosporins, cefotaxime is active against numerous Gram-positive and Gram-negative bacteria, including several with resistance to classic β-lactams such as penicillin. These bacteria often manifest as infections of the lower respiratory tract, skin, central nervous system, bone, and intra-abdominal cavity. While regional susceptibilities must always be considered, cefotaxime typically is effective against these organisms (in addition to many others): Staphylococcus aureus (not including MRSA) and S. epidermidis Streptococcus pneumoniae and S. pyogenes Escherichia coli Haemophilus influenzae Neisseria gonorrhoeae and N. meningitidis Klebsiella spp. Burkholderia cepacia Proteus mirabilis and P. vulgaris Enterobacter spp. Bacteroides spp. Fusobacterium spp.Notable organisms against which cefotaxime is not active include Pseudomonas and Enterococcus. As listed, it has modest activity against the anaerobic Bacteroides fragilis. The following represents MIC susceptibility data for a few medically significant microorganisms: H. influenzae: ≤0.007 – 0.5 µg/mL S. aureus: 0.781 – 172 µg/mL S. pneumoniae: ≤0.007 – 8 µg/mLHistorically, cefotaxime has been considered to be comparable to ceftriaxone (another third-generation cephalosporin) in safety and efficacy for the treatment of bacterial meningitis, lower respiratory tract infections, skin and soft tissue infections, genitourinary tract infections, and bloodstream infections, as well as prophylaxis for abdominal surgery. The majority of these infections are caused by organisms traditionally sensitive to both cephalosporins. However, ceftriaxone has the advantage of once-daily dosing, whereas the shorter half-life of cefotaxime necessitates two or three daily doses for efficacy. Changing patterns in microbial resistance suggest cefotaxime may be suffering greater resistance than ceftriaxone, whereas the two were previously considered comparable. Considering regional microbial sensitivities is also important when choosing any antimicrobial agent for the treatment of infection. Adverse reactions Cefotaxime is contraindicated in patients with a known hypersensitivity to cefotaxime or other cephalosporins. Caution should be used and risks weighed against potential benefits in patients with an allergy to penicillin, due to cross-reactivity between the classes. The most common adverse reactions experienced are: Pain and inflammation at the site of injection/infusion (4.3%) Rash, pruritus, or fever (2.4%) Colitis, diarrhea, nausea, vomiting (1.4%) Mechanism of action Cefotaxime is a β-lactam antibiotic (which refers to the structural components of the drug molecule itself). As a class, β-lactams inhibit bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs). This inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) in the absence of cell wall assembly. Due to the mechanism of their attack on bacterial cell wall synthesis, β-lactams are considered to be bactericidal.Unlike β-lactams such as penicillin and amoxicillin, which are highly susceptible to degradation by β-lactamase enzymes (produced, for example, nearly universally by S. aureus), cefotaxime boasts the additional benefit of resistance to β-lactamase degradation due to the structural configuration of the cefotaxime molecule. The syn-configuration of the methoxyimino moiety confers stability against β-lactamases. Consequently, the spectrum of activity is broadened to include several β-lactamase-producing organisms (which would otherwise be resistant to β-lactam antibiotics), as outlined below. Cefotaxime, like other β-lactam antibiotics, does not only block the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, it has no effect on the plastids of the vascular plants. This supports the endosymbiotic theory and indicates an evolution of plastid division in land plants. Administration Cefotaxime is administered by intramuscular injection or intravenous infusion. As cefotaxime is metabolized to both active and inactive metabolites by the liver and largely excreted in the urine, dose adjustments may be appropriate in people with renal or hepatic impairment. Plant tissue culture Cefotaxime is the only cephalosporin which has very low toxicity in plants, even at higher concentration (up to 500 mg/L). It is widely used to treat plant tissue infections with Gram-negative bacteria, while vancomycin is used to treat the plant tissue infections with Gram-positive bacteria. See also Ceftazidime References External links "Cefotaxime". Drug Information Portal. U.S. National Library of Medicine.
Salbutamol	Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing relaxation of airway smooth muscle. It is used to treat asthma, including asthma attacks, exercise-induced bronchoconstriction, and chronic obstructive pulmonary disease (COPD). It may also be used to treat high blood potassium levels. Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution. Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.Common side effects include shakiness, headache, fast heart rate, dizziness, and feeling anxious. Serious side effects may include worsening bronchospasm, irregular heartbeat, and low blood potassium levels. It can be used during pregnancy and breastfeeding, but safety is not entirely clear.Salbutamol was patented in 1966 in Britain and became commercially available in the UK in 1969. It was approved for medical use in the United States in 1982. It is on the World Health Organizations List of Essential Medicines. Salbutamol is available as a generic medication. In 2020, it was the seventh most commonly prescribed medication in the United States, with more than 61 million prescriptions. Medical uses Salbutamol is typically used to treat bronchospasm (due to any cause—allergic asthma or exercise-induced), as well as chronic obstructive pulmonary disease. It is also one of the most common medicines used in rescue inhalers (short-term bronchodilators to alleviate asthma attacks).As a β2 agonist, salbutamol also has use in obstetrics. Intravenous salbutamol can be used as a tocolytic to relax the uterine smooth muscle to delay premature labor. While preferred over agents such as atosiban and ritodrine, its role has largely been replaced by the calcium channel blocker nifedipine, which is more effective and better tolerated.Salbutamol has been used to treat acute hyperkalemia, as it stimulates potassium flow into cells, thus lowering the potassium in the blood. Adverse effects The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation. Other symptoms may include tachycardia, arrhythmia, flushing of the skin, myocardial ischemia (rare), and disturbances of sleep and behaviour. Rarely occurring, but of importance, are allergic reactions of paradoxical bronchospasms, urticaria (hives), angioedema, hypotension, and collapse. High doses or prolonged use may cause hypokalemia, which is of concern especially in patients with kidney failure and those on certain diuretics and xanthine derivatives.Salbutamol metered dose inhalers have been described as the “single biggest source of carbon emissions from NHS medicines prescribing” due to the propellants used in the inhalers. Dry powder inhalers are recommended as a low-carbon alternative. Pharmacology The tertiary butyl group in salbutamol makes it more selective for β2 receptors, which are the predominant receptors on the bronchial smooth muscles. Activation of these receptors causes adenylyl cyclase to convert ATP to cAMP, beginning the signalling cascade that ends with the inhibition of myosin phosphorylation and lowering the intracellular concentration of calcium ions (myosin phosphorylation and calcium ions are necessary for muscle contractions). The increase in cAMP also inhibits inflammatory cells in the airway, such as basophils, eosinophils, and most especially mast cells, from releasing inflammatory mediators and cytokines. Salbutamol and other β2 receptor agonists also increase the conductance of channels sensitive to calcium and potassium ions, leading to hyperpolarization and relaxation of bronchial smooth muscles.Salbutamol is either filtered out by the kidneys directly or is first metabolized into the 4′-O-sulfate, which is excreted in the urine. Chemistry Salbutamol is sold as a racemic mixture. The (R)-(−)-enantiomer (CIP nomenclature) is shown in the image at right (top), and is responsible for the pharmacologic activity; the (S)-(+)-enantiomer (bottom) blocks metabolic pathways associated with elimination of itself and of the pharmacologically active enantiomer (R). The slower metabolism of the (S)-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation. Potential formulation of the R form as an enantiopure drug is complicated by the fact that the stereochemistry is not stable, but rather the compound undergoes racemization within a few days to weeks, depending on pH. History Salbutamol was discovered in 1966, by a team led by David Jack at the Allen and Hanburys laboratory (a subsidiary of Glaxo) in Ware, Hertfordshire, England, and was launched as Ventolin in 1969.The 1972 Munich Olympics were the first Olympics where anti-doping measures were deployed, and at that time β2 agonists were considered to be stimulants with high risk of abuse for doping. Inhaled salbutamol was banned from those games, but by 1986 was permitted (although oral β2 agonists were not). After a steep rise in the number of athletes taking β2 agonists for asthma in the 1990s, Olympic athletes were required to provide proof that they had asthma in order to be allowed to use inhaled β2 agonists.In February 2020, the U.S. Food and Drug Administration (FDA) approved the first generic of an albuterol sulfate inhalation aerosol for the treatment or prevention of bronchospasm in people four years of age and older with reversible obstructive airway disease and the prevention of exercise-induced bronchospasm in people four years of age and older. The FDA granted approval of the generic albuterol sulfate inhalation aerosol to Perrigo Pharmaceutical.In April 2020, the FDA approved the first generic of Proventil HFA (albuterol sulfate) metered dose inhaler, 90 μg per inhalation, for the treatment or prevention of bronchospasm in patients four years of age and older who have reversible obstructive airway disease, as well as the prevention of exercise-induced bronchospasm in this age group. The FDA granted approval of this generic albuterol sulfate inhalation aerosol to Cipla Limited. Society and culture In 2020, generic versions were approved in the United States. Names Salbutamol is the international nonproprietary name (INN) while albuterol is the United States Adopted Name (USAN). The drug is usually manufactured and distributed as the sulfate salt (salbutamol sulfate). It was first sold by Allen & Hanburys (UK) under the brand name Ventolin, and has been used for the treatment of asthma ever since. The drug is marketed under many names worldwide. Doping As of 2011 there was no evidence that an increase in physical performance occurs after inhaling salbutamol, but there are various reports for benefit when delivered orally or intravenously. In spite of this, salbutamol required "a declaration of Use in accordance with the International Standard for Therapeutic Use Exemptions" under the 2010 WADA prohibited list. This requirement was relaxed when the 2011 list was published to permit the use of "salbutamol (maximum 1600 micrograms over 24 hours) and salmeterol when taken by inhalation in accordance with the manufacturers recommended therapeutic regimen."Abuse of the drug may be confirmed by detection of its presence in plasma or urine, typically exceeding 1,000 ng/mL. The window of detection for urine testing is on the order of just 24 hours, given the relatively short elimination half-life of the drug, estimated at between 5 and 6 hours following oral administration of 4 mg. Research Salbutamol has been studied in subtypes of congenital myasthenic syndrome associated with mutations in Dok-7.It has also been tested in a trial aimed at treatment of spinal muscular atrophy; it is speculated to modulate the alternative splicing of the SMN2 gene, increasing the amount of the SMN protein, the deficiency of which is regarded as a cause of the disease. Veterinary use Salbutamols low toxicity makes it safe for other animals and thus is the medication of choice for treating acute airway obstruction in most species. It is usually used to treat bronchospasm or coughs in cats and dogs and used as a bronchodilator in horses with recurrent airway obstruction; it can also be used in emergencies to treat asthmatic cats.Toxic effects require an extremely high dose, and most overdoses are due to dogs chewing on and puncturing an inhaler or nebulizer vial. See also Ipratropium/salbutamol Isoprenaline Levosalbutamol – the (R)-(−)-enantiomer Salmeterol References External links "Albuterol". Drug Information Portal. U.S. National Library of Medicine. Salbutamol at The Periodic Table of Videos
Nasal spray	Nasal sprays are used to deliver medications locally in the nasal cavities or systemically. They are used locally for conditions such as nasal congestion and allergic rhinitis. In some situations, the nasal delivery route is preferred for systemic therapy because it provides an agreeable alternative to injection or pills. Substances can be assimilated extremely quickly and directly through the nose. Many pharmaceutical drugs exist as nasal sprays for systemic administration (e.g. sedative-analgesics, treatments for migraine, osteoporosis and nausea). Other applications include hormone replacement therapy, treatment of Alzheimers disease and Parkinsons disease. Nasal sprays are seen as a more efficient way of transporting drugs with potential use in crossing the blood–brain barrier. Antihistamines Antihistamines work by competing for receptor sites to block the function of histamine, thereby reducing the inflammatory effect. Antihistamine nasal sprays include: Azelastine hydrochloride Levocabastine hydrochloride Olopatadine hydrochloride Corticosteroids Corticosteroid nasal sprays can be used to relieve the symptoms of sinusitis, hay fever, allergic rhinitis and non-allergic (perennial) rhinitis. They can reduce inflammation and histamine production in the nasal passages, and have been shown to relieve nasal congestion, runny nose, itchy nose and sneezing. Side effects may include headaches, nausea and nose bleeds. Corticosteroid nasal sprays include: Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone furoate Fluticasone propionate Mometasone Triamcinolone acetonide Saline Saline sprays are typically non medicated. A mist of saline solution containing sodium chloride is delivered to help moisturize dry or irritated nostrils. This is a form of nasal irrigation. They can also relieve nasal congestion and remove airborne irritants such as pollen and dust thereby providing sinus allergy relief. Three types of nasal sprays preparations of sodium chloride are available including hypertonic (3% sodium chloride or sea water), isotonic (0.9% sodium chloride) and hypotonic (0.65% sodium chloride). Isotonic solutions have the same salt concentration as the human body, whereas hypertonic solutions have a higher salt content and hypotonic solutions have a lower salt content. Isotonic saline nasal sprays are commonly used in infants and children to wash out the thick mucus from the nose in case of allergic rhinitis. Hypertonic solutions may be more useful at drawing moisture from the mucous membrane and relieving nasal congestion. Natural nasal sprays that include chemical complexes derived from plant sources such as ginger, capsaicin and tea-tree oil are also available. There is however no trial-verified evidence that they have a measurable effect on symptoms. Topical decongestants Decongestant nasal sprays are available over-the-counter in many countries. They work to very quickly open up nasal passages by constricting blood vessels in the lining of the nose. Prolonged use of these types of sprays can damage the delicate mucous membranes in the nose. This causes increased inflammation, an effect known as rhinitis medicamentosa or the rebound effect. Decongestant nasal sprays are advised for short-term use only, preferably 5 to 7 days at maximum. Some doctors advise to use them 3 days at maximum. A recent clinical trial has shown that a corticosteroid nasal spray may be useful in reversing this condition. Topical nasal decongestants include: Oxymetazoline Phenylephrine Xylometazoline Allergy combinations Combination use of two medications as nasal spray preparation has been frequently prescribed by doctors. List of combination nasal sprays: Azelastine together with fluticasone propionate (trade names including Dymista) Xylometazoline together with cromoglicic acid See also Olopatadine/mometasone References External links Media related to Nasal sprays at Wikimedia Commons
Cariprazine	Cariprazine, sold under the brand names Vraylar and Reagila among others, is an on oral atypical antipsychotic originated by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, and bipolar depression. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. Positive Phase III study results were published for schizophrenia and mania in early 2012, and for bipolar disorder I depression from a Phase II trial in 2015.Cariprazine was approved for medical use in the United States in September 2015. Medical uses Cariprazine is used to treat schizophrenia and manic, depressive, or mixed episodes associated with bipolar I disorder. In the United States it is approved for schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and treatment of depressive episodes associated with bipolar I disorder (bipolar depression).Cariprazine consistently improved depressive symptoms across a spectrum of patients with bipolar I depression. In Australia, UK and Europe it is currently approved only for schizophrenia. Side effects Side effects may first appear on the first day after starting cariprazine. The most prevalent side effects for cariprazine include akathisia, and insomnia. Cariprazine does not appear to impact prolactin levels, and unlike many other antipsychotics, does not increase the QT interval on the electrocardiogram (ECG). In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as "not greatly different from that seen in patient treated with placebo" but a second called the incidence of movement-related disorders "rather high".Regarding side effects, the label of cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."Because cariprazine and its active metabolites have long half-lives, many healthcare professionals monitor for adverse effects up to several weeks after starting cariprazine. A longer monitoring period is also indicated for dosage changes, whether they represent an increase or a decrease, because elimination may take several weeks Pharmacology Pharmacodynamics Unlike many antipsychotics that are D2 and 5-HT2A receptor antagonists, cariprazine is a D2 and D3 partial agonist It also has a higher affinity for D3 receptors. The D2 and D3 receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia. Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazines high selectivity towards D3 receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D3 receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors. Cariprazine also acts on 5-HT1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies). In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D3 receptors, though further studies need to be conducted. This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits. Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity. In monkey studies, the administration of increasing doses of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D2/D3 receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied. Dopamine D2 and D3 receptor occupancy in humans has been summarized as, "In healthy volunteers, single-dose cariprazine of 0.5 mg occupied up to 12% of striatal D2/D3 receptors, while striatal D2/D3 occupancy after multiple dosing up to cariprazine 1.0 mg/d ranged from 63 to 79% [39]. In an open-label, fixed-dose, 2-week trial in eight males with schizophrenia, PET scans of dorsal striatal regions (caudate nucleus and putamen) and ventral striatum (nucleus accumbens) showed maximum occupancy (‡ 90%) at a 3-mg target dose of cariprazine following 14 d of treatment [40,41]. After 14 d of cariprazine 1.5 mg/d, receptor occupancy was 69% in the caudate nucleus, 69% in the nucleus accumbens, and 75% in the putamen". Pharmacokinetics Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic. In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).Cariprazine is metabolized primarily by the cytochrome P450 3A4 isoenzyme (CYP3A4), with some minor metabolism by CYP2D6. Cariprazine does not induce the production of CYP3A4 or CYP1A2 in the liver, and weakly, competitively inhibits CYP2D6 and CYP3A4. Research Cariprazine is also potentially useful as an add-on therapy in major depressive disorder. It is being developed jointly by AbbVie and Gedeon Richter Plc, with AbbVie responsible for commercialization in the U.S., Canada, Japan, Taiwan and certain Latin American countries (including Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru and Venezuela). In February 2022 AbbVie requested FDA approval for adjunctive treatment for major depressive disorder. References External links "Cariprazine". Drug Information Portal. U.S. National Library of Medicine.
Hydroxycarbamide	Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and decreases the number of attacks. It is taken by mouth.Common side effects include bone marrow suppression, fevers, loss of appetite, psychiatric problems, shortness of breath, and headaches. There is also concern that it increases the risk of later cancers. Use during pregnancy is typically harmful to the baby. Hydroxycarbamide is in the antineoplastic family of medications. It is believed to work by blocking the making of DNA.Hydroxycarbamide was approved for medical use in the United States in 1967. It is on the World Health Organizations List of Essential Medicines. Hydroxycarbamide is available as a generic medication. Medical uses Hydroxycarbamide is used for the following indications: Myeloproliferative disease (primarily essential thrombocythemia and polycythemia vera). It has been found to be superior to anagrelide for the control of ET. Sickle-cell disease (increases production of fetal hemoglobin that then interferes with the hemoglobin polymerisation as well as by reducing white blood cells that contribute to the general inflammatory state in sickle cell patients.) Second line treatment for psoriasis (slows down the rapid division of skin cells) Systemic mastocytosis Chronic myelogenous leukemia (largely replaced by imatinib, but still in use for its cost-effectiveness) Side effects Reported side effects are: neurological reactions (e.g., headache, dizziness, drowsiness, disorientation, hallucinations, and convulsions), nausea, vomiting, diarrhea, constipation, mucositis, anorexia, stomatitis, bone marrow toxicity (dose-limiting toxicity; may take 7–21 days to recover after the drug has been discontinued), megaloblastic anemia, thrombocytopenia, bleeding, hemorrhage, gastrointestinal ulceration and perforation, immunosuppression, leukopenia, alopecia (hair loss), skin rashes (e.g., maculopapular rash), erythema, pruritus, vesication or irritation of the skin and mucous membranes, pulmonary edema, abnormal liver enzymes, creatinine and blood urea nitrogen.Due to its negative effect on the bone marrow, regular monitoring of the full blood count is vital, as well as early response to possible infections. In addition, renal function, uric acid and electrolytes, as well as liver enzymes, are commonly checked. Moreover, because of this, its use in people with leukopenia, thrombocytopenia or severe anemia is contraindicated.Hydroxycarbamide has been used primarily for the treatment of myeloproliferative diseases, which has an inherent risk of transforming to acute myeloid leukemia. There has been a longstanding concern that hydroxycarbamide itself carries a leukemia risk, but large studies have shown that the risk is either absent or very small. Nevertheless, it has been a barrier for its wider use in patients with sickle-cell disease. Mechanism of action Hydroxycarbamide decreases the production of deoxyribonucleotides via inhibition of the enzyme ribonucleotide reductase by scavenging tyrosyl free radicals as they are involved in the reduction of nucleoside diphosphates (NDPs).In the treatment of sickle-cell disease, hydroxycarbamide increases the concentration of fetal hemoglobin. The precise mechanism of action is not yet clear, but it appears that hydroxycarbamide increases nitric oxide levels, causing soluble guanylyl cyclase activation with a resultant rise in cyclic GMP, and the activation of gamma globin gene expression and subsequent gamma chain synthesis necessary for fetal hemoglobin (HbF) production (which does not polymerize and deform red blood cells like the mutated HbS, responsible for sickle cell disease). Adult red cells containing more than 1% HbF are termed F cells. These cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF. Hydroxyurea also suppresses the production of granulocytes in the bone marrow which has a mild immunosuppressive effect particularly at vascular sites where sickle cells have occluded blood flow. Natural occurrence Hydroxyurea has been reported as endogenous in human blood plasma at concentrations of approximately 30 to 200 ng/ml. Chemistry Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869. Medical chemists, Dresler and Stein created Hydroxyurea from hydroxylamine, hydrochloric acid and potassium cyanide as a technical exercise in organic chemistry, as part of a series of experiments generating derivatives of urea. Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites. Due to its chemical properties hydroxyurea was explored as an antisickling agent in the treatment of hematological conditions. One common mechanism for synthesizing hydroxyurea is by the reaction of calcium cyanate with hydroxylamine nitrate in absolute ethanol and by the reaction of salt (i.e. sodium or potassium) cyanates and hydroxylamine hydrochloride in aqueous solution. Hydroxyurea has also been prepared by converting a quaternary ammonium anion exchange resin from the chloride form to the cyanate form with sodium cyanate and reacting the resin in the cyanate form with hydroxylamine hydrochloride. This method of hydroxyurea synthesis was patented by Hussain et al. (2015). Pharmacology Hydroxyurea is a monohydroxyl-substituted urea (hydroxycarbamate) antimetabolite. Similar to other antimetabolite anti-cancer drugs, it acts by disrupting the DNA replication process of dividing cancer cells in the body. Hydroxyurea selectively inhibits ribonucleoside diphosphate reductase, an enzyme required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates, thereby preventing cells from leaving the G1/S phase of the cell cycle. This agent also exhibits radiosensitizing activity by maintaining cells in the radiation-sensitive G1 phase and interfering with DNA repair.Biochemical research has explored its role as a DNA replication inhibitor which causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair). Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents.Hydroxyurea has many pharmacological applications under the Medical Subject Headings classification system: Antineoplastic Agents – Substances that inhibit or prevent the proliferation of neoplasms. Antisickling Agents – Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions. Nucleic Acid Synthesis Inhibitors – Compounds that inhibit cell production of DNA or RNA. Enzyme Inhibitors – Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Cytochrome P-450 CYP2D6 Inhibitors – Acts as an inhibitor to one of the most important enzymes involved in the metabolism of xenobiotics in the body, CYP2D6 a member of the cytochrome P450 mixed oxidase system. Society and culture Brand names Brand names include: Hydrea, Litalir, Droxia, and Siklos. References External links "Hydroxyurea". Drug Information Portal. U.S. National Library of Medicine.
Rifamycin	The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections. The rifamycin group includes the "classic" rifamycin drugs as well as the rifamycin derivatives rifampicin (or rifampin), rifabutin, rifapentine, rifalazil and rifaximin. Rifamycin, sold under the trade name Aemcolo, is approved in the United States for treatment of travelers diarrhea in some circumstances. Bacterium Streptomyces mediterranei was first isolated in 1957 from a soil sample collected near the beach-side town of St Raphael in southern France. The name was originally given by two microbiologists working with the Italian drug company Group Lepetit SpA in Milan, the Italian Grazia Beretta, and Pinhas Margalith of Israel.In 1969, the bacterium was renamed Nocardia mediterranei when another scientist named Thiemann found that it has a cell wall typical of the Nocardia species. Then, in 1986, the bacterium was renamed again Amycolatopsis mediterranei, as the first species of a new genus, because a scientist named Lechevalier discovered that the cell wall lacks mycolic acid and is not able to be infected by the Nocardia and Rhodococcus phages. Based on 16S ribosomal RNA sequences, Bala et al. renamed the species in 2004 Amycolatopsis rifamycinica. First drugs Rifamycins were first isolated in 1957 from a fermentation culture of Streptomyces mediterranei at the laboratory of Gruppo Lepetit SpA in Milan by two scientist named Piero Sensi and Maria Teresa Timbal, working with the Israeli scientist Pinhas Margalith. Initially, a family of closely related antibiotics was discovered referred to as Rifamycin A, B, C, D, E. The only component of this mixture sufficiently stable to isolate in a pure form was Rifamycin B, which unfortunately was poorly active. However, further studies showed that while Rifamycin B was essentially inactive, it was spontaneously oxidized and hydrolyzed in aqueous solutions to yield the highly active Rifamycin S. Simple reduction of Rifamycin S yielded the hydroquinone form called Rifamycin SV, which became the first member of this class to enter clinical use as an intravenous antibiotic. Further chemical modification of Rifamycin SV yielded an improved analog Rifamide, which was also introduced into clinical practice, but was similarly limited to intravenous use. After an extensive modification program, Rifampin was eventually produced, which is orally available and has become a mainstay of Tuberculosis therapy Lepetit filed for patent protection of Rifamycin B in the UK in August 1958, and in the US in March 1959. The British patent GB921045 was granted in March 1963, and U.S. Patent 3,150,046 was granted in September 1964. The drug is widely regarded as having helped conquer the issue of drug-resistant tuberculosis in the 1960s. Clinical trials Rifamycins have been used for the treatment of many diseases, the most important one being HIV-related tuberculosis. A systematic review of clinical trials on alternative regimens for prevention of active tuberculosis in HIV-negative individuals with latent TB found that a weekly, directly observed regimen of rifapentine with isoniazid for three months was as effective as a daily, self-administered regimen of isoniazid for nine months. But the rifapentine-isoniazid regimen had higher rates of treatment completion and lower rates of hepatotoxicity. However, the rate of treatment-limiting adverse events was higher in the rifapentine-isoniazid regimen.The rifamycins have a unique mechanism of action, selectively inhibiting bacterial DNA-dependent RNA polymerase, and show no cross-resistance with other antibiotics in clinical use. However, despite their activity against bacteria resistant to other antibiotics, the rifamycins themselves suffer from a rather high frequency of resistance. Because of this, Rifampin and other rifamycins are typically used in combination with other antibacterial drugs. This is routinely practiced in TB therapy and serves to prevent the formation of mutants that are resistant to any of the drugs in the combination. Rifampin rapidly kills fast-dividing bacilli strains as well as "persisters" cells, which remain biologically inactive for long periods of time that allow them to evade antibiotic activity. In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients. Although Tuberculosis therapy remains the most important use of Rifampin, an increasing problem with serious Multiple Drug Resistant bacterial infections has led to some use of antibiotic combinations containing Rifampin to treat them. Mechanism of action The antibacterial activity of rifamycins relies on the inhibition of bacterial DNA-dependent RNA synthesis. This is due to the high affinity of rifamycins for the prokaryotic RNA polymerase. The selectivity of the rifamycins depends on the fact that they have a very poor affinity for the analogous mammalian enzyme. Crystal structure data of the antibiotic bound to RNA polymerase indicates that rifamycin blocks synthesis by causing strong steric clashes with the growing oligonucleotide ("steric-occlusion" mechanism). If rifamycin binds the polymerase after the chain extension process has started, no inhibition is observed on the biosynthesis, consistent with a steric-occlusion mechanism. Single step high level resistance to the rifamycins occurs as the result of a single amino acid change in the bacterial DNA dependent RNA polymerase. Biosynthesis The first information on the biosynthesis of the rifamycins came from studies using the stable isotope Carbon-13 and NMR spectroscopy to establish the origin of the carbon skeleton. These studies showed that the ansa chain was derived from acetate and propionate, in common with other polyketide antibiotics. The naphthalenic chromophore was shown to derive from a propionate unit coupled with a seven carbon amino moiety of unknown origin. The general scheme of biosynthesis starts with the uncommon starting unit, 3-amino-5-hydroxybenzoic acid (AHBA), via type I polyketide pathway (PKS I) in which chain extension is performed using 2 acetate and 8 propionate units. AHBA is believed to have originated from the Shikimate pathway, however this was not incorporated into the biosynthetic mechanism. This is due to the observation that 3 amino-acid analogues converted into AHBA in cell-free extracts of A. mediterranei. The rif cluster is responsible for the biosynthesis of rifamycins. It contains genes rifG through rifN, which were shown to biosynthesize AHBA.[10] RifK, rifL, rifM, and rifN are believed to act as transaminases in order to form the AHBA precursor kanosamine. "RifH" encodes aminoDAHP synthase that catalyzes the condensation between 1-deoxy-1-imino-d-erythrose 4-phosphate and phosphoenolpyruvate. RifA through rifE encode a type I polyketide synthase module, with the loading module being a non-ribosomal peptide synthetase. In all, rifA-E assemble a linear undecaketide and are followed by rifF, which encodes an amide synthase and causes the undecaketide to release and form a macrolactam structure. Moreover, the rif cluster contains various regulatory proteins and glycosylating genes that appear to be silent. Other types of genes seem to perform post-synthase modifications of the original polyketide. Derivatives Lepetit introduced Rifampicin, an orally active rifamycin, around 1966. Rifabutin, a derivative of rifamycin S, was invented around 1975 and came onto the US market in 1993. Hoechst Marion Roussel (now part of Aventis) introduced rifapentine in 1999. Rifaximin is an oral rifamycin marketed in the US by Salix Pharmaceuticals that is poorly absorbed from the intestine. It has been used to treat hepatic encephalopathy and travelers diarrhea. Currently available rifamycins Rifampicin or Rifampin Rifabutin Rifapentine Rifaximin Aemcolo References Bibliography Sensi. et al., Farmaco Ed. Sci. (1959) 14, 146-147 - the paper announcing the discovery of the rifamycins. Thieman et al. Arch. Microbiol. (1969), 67 147-151 - the paper which renamed Streptomyces mediterranei as Nocardia mediterranei. Lechevalier et al., Int. J. Syst. Bacteriol. (1986), 36, 29) - the paper which renamed Nocardia mediterranei as Amycolatopsis mediterranei. Bala S (2004). "Reclassification of "Amycolatopsis mediterranei" DSM 46095 as "Amycolatopsis rifamycinica" sp. nov". International Journal of Systematic and Evolutionary Microbiology. 54 (4): 1145–1149. doi:10.1099/ijs.0.02901-0. PMID 15280283. - the paper with the latest name change External links "Rifamycin". Drug Information Portal. U.S. National Library of Medicine.
Alcaftadine	Alcaftadine is used to prevent eye irritation brought on by allergic conjunctivitis. It is a H1 histamine receptor antagonist.It was approved by the U.S. Food and Drug Administration (FDA) in July 2010, under the trade name Lastacaft. Pharmacology Alcaftadine is an antagonist at three of the histamine receptors (1, 2 and 4). The main indication for Alcaftadine is for prevention of allergic conjunctivitis. By blocking these three receptors, Alcaftadine has been shown to significantly reduce the effects of allergens. This effect on histamine receptors seems to show lower rates of itching, eosinophil recruitment and redness after exposure to an allergen. The effect of alcaftadine seemed to reduce the amount of eosinophil cells significantly as compared to olopatadine 0.1%. When animal models were used to test alcaftadine, alcaftadine 0.25% seemed to show superior results for decreasing E-cadherin expression as compared to placebo. The reduction of E-cadherin means decreased junctions which would lead to progression of allergic conjunctivitis. Clinical relevance When Alcaftadine was tested against placebo and olopatadine, only Alcaftadine 0.25% was shown to have a clinically significant reduction in conjunctival redness scores 7 and 15 minutes after administration. When clinical groups where compared to placebo, treatment with all three of the alcaftadine groups (0.05, 0.1 and 0.25%) showed a reduction in secondary endpoints of (lid swelling, conjunctival redness, ocular itching/tearing) as compared to placebo. Adverse effects In studies comparing the effectiveness of olopatadine to alcaftadine, there was not a dose response increase of adverse effects as alcaftadine doses increases for 0.05% to 0.1% to 0.25%. The most common seen side effect of alcaftadine administration was irritation or a stinging sensation at the administration site. Pharmacokinetics Alcaftadine is typically administrated as an eye drop which keeps its effects regional as compared to systemic effects. The main metabolite of alcaftadine is a carboxylic acid metabolite that has minimal systemic effects. The maximum concentration of its main active metabolite is 0.06 ng/ml at Tmax of 15 minutes. The minimal absorption of alcaftadine, leads to minimal systemic accumulation. The half life of the major metabolite of alcaftadine is two hours after ocular administration. Except for the metabolite, the rest of alcaftadine is excreted unchanged. Since alcaftadine is administrated at a small concentration and at a local site (the eye), it seems to have minimal systemic effects. Sales Sales for Alcaftadine from the company Allergan began in July 2010. Since the beginning of sales, Alcaftadine prescriptions have increased until at least March 2012. From the time period of July 2010 until March 2012, cumulative sales have reached 139,000 prescriptions. Out of these 139,000 prescriptions there have been 104,000 unique patients. In March 2012, Alcaftadine exceeded sales of Elestat and this trend may continue as prescribers see the benefit of Alcaftadine and become more comfortable prescribing it. See also Ketotifen References External links "Alcaftadine". Drug Information Portal. U.S. National Library of Medicine.
Sotorasib	Sotorasib, sold under the brand names Lumakras and Lumykras, is an anti-cancer medication used to treat non-small-cell lung cancer (NSCLC). It targets a specific mutation, G12C, in the protein K-Ras encoded by gene KRAS which is responsible for various forms of cancer.The most common side effects include diarrhea, musculoskeletal pain, nausea, fatigue, liver damage and cough.Sotorasib is an inhibitor of the RAS GTPase family.Sotorasib is the first approved targeted therapy for tumors with any KRAS mutation, which accounts for approximately 25% of mutations in non-small cell lung cancers. KRAS G12C mutations occur in about 13% of patients with non-small cell lung cancers. Sotorasib was approved for medical use in the United States in May 2021, and in the European Union in January 2022. Medical uses Sotorasib is indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. Clinical development Sotorasib is being developed by Amgen. Phase I clinical trials were completed in 2020. In December 2019, it was approved to begin Phase II clinical trials.Because the G12C KRAS mutation is relatively common in some cancer types, 14% of non-small-cell lung cancer adenocarcinoma patients and 5% of colorectal cancer patients, and sotorasib is the first drug candidate to target this mutation, there have been high expectations for the drug. The Food and Drug Administration has granted a fast track designation to sotorasib for the treatment of metastatic non-small-cell lung carcinoma with the G12C KRAS mutation. Chemistry and pharmacology Sotorasib can exist in either of two atropisomeric forms and one is more active than the other. It selectively forms an irreversible covalent bond to the sulfur atom in the cysteine residue that is present in the mutated form of KRAS, but not in the normal form. History Researchers evaluated the efficacy of sotorasib in a study of 124 participants with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy. The major outcomes measured were objective response rate (proportion of participants whose tumor is destroyed or reduced) and duration of response. The objective response rate was 36% and 58% of those participants had a duration of response of six months or longer.The U.S. Food and Drug Administration (FDA) granted the application for sotorasib orphan drug, fast track, priority review, and breakthrough therapy designations. The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), Health Canada and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.The FDA granted approval of Lumakras to Amgen Inc. Society and culture Economics At introduction, in the United States, Sotorasib costs US$17,900 per month. Legal status In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Lumykras, intended for the treatment of people with KRAS G12C mutation non-small cell lung cancer (NSCLC). The applicant for this medicinal product is Amgen Europe B.V. Sotorasib was approved for medical use in the European Union in January 2022. Names Sotorasib is the recommended international nonproprietary name (INN). References Further reading Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. (September 2020). "KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors". N Engl J Med. 383 (13): 1207–17. doi:10.1056/NEJMoa1917239. PMC 7571518. PMID 32955176. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, et al. (January 2020). "Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors". J Med Chem. 63 (1): 52–65. doi:10.1021/acs.jmedchem.9b01180. PMID 31820981. External links "Sotorasib". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03600883 for "A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)" at ClinicalTrials.gov
Beractant	Beractant, also known by the trade name of Survanta, is a modified bovine pulmonary surfactant containing bovine lung extract (phospholipids, neutral lipids, fatty acids, and bovine surfactant proteins), to which synthetic DPPC, tripalmitin and palmitic acid are added. The composition provides 25 mg/mL phospholipids, 0.5 to 1.75 mg/mL triglycerides, 1.4 to 3.5 mg/mL free fatty acids, and <1.0 mg/mL total surfactant proteins. As an intratracheal suspension, it can be used for the prevention and treatment of neonatal respiratory distress syndrome. Survanta is manufactured by Abbvie. Generic form Beraksurf is generic form of Survanta (Beractant) which is manufacturing by Tekzima. References External links "Beractant". Drug Information Portal. U.S. National Library of Medicine.
Lopinavir/ritonavir	Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution.Common side effects include diarrhea, vomiting, feeling tired, headaches, and muscle pains. Severe side effects may include pancreatitis, liver problems, and high blood sugar. It is commonly used in pregnancy and it appears to be safe. Both medications are HIV protease inhibitors. Ritonavir functions by slowing down the breakdown of lopinavir.Lopinavir/ritonavir as a single medication was approved for use in the United States in 2000. It is on the World Health Organizations List of Essential Medicines. Medical uses Lopinavir/ritonavir was once a preferred combination for HIV first-line therapy in the United States. But due its higher pill burden compared to than other protease inhibitor-based regimens and increased gastrointestinal intolerance, it is no longer recommended to treatment-naive patients. Adverse effects The most common adverse effects observed with lopinavir/ritonavir are diarrhea and nausea. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%. Other common adverse effects include abdominal pain, asthenia, headache, vomiting and, particularly in children, rash.Raised liver enzymes and hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) are also commonly observed during lopinavir/ritonavir treatment.Lopinavir/ritonavir is anticipated to have varying degrees of interaction with other medications that are also CYP3A and/or P-gp substrates.People with a structural heart disease, preexisting conduction system abnormalities, ischaemic heart disease, or cardiomyopathies should use lopinavir/ritonavir with caution.On 8 March 2011 the U.S. Food and Drug Administration notified healthcare professionals of serious health problems that have been reported in premature babies receiving lopinavir/ritonavir oral solution, probably because of its propylene glycol content. They recommend the use should be avoided in premature babies. History Abbott Laboratories (now, via spinoff, Abbvie) was one of the earliest users of the Advanced Photon Source (APS), a national synchrotron-radiation light source at Argonne National Laboratory. One of the early research projects undertaken at the APS focused on proteins from the human immunodeficiency virus (HIV). Using the APS beam line for X-ray crystallography, researchers determined viral protein structures that allowed them to determine their approach to the development of HIV protease inhibitors, a key enzyme target that processes HIV polyproteins after infection, the function of which allows the lifecycle of the virus to proceed. As a result of this structure-based drug design approach using the Argonne APS, Abbott was able to develop new products that inhibit the protease, and therefore stop virus replication.Lopinavir was developed by Abbott in an attempt to improve upon the companys earlier protease inhibitor, ritonavir, specifically with regard to its serum protein-binding properties (reducing the interference by serum on protease enzyme inhibition) and its HIV resistance profile (reducing the ability of virus to evolve resistance to the drug). Administered alone, lopinavir has insufficient bioavailability; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of intestinal and hepatic cytochrome P450 3A4, which would otherwise reduce drug levels through catabolism. Abbott, therefore, pursued a strategy of co-administering lopinavir with doses of ritonavir sub-therapeutic with respect to HIV inhibition; hence, lopinavir was only formulated and marketed as a fixed-dose combination medication with ritonavir.Lopinavir/ritonavir was approved by the US Food and Drug Administration (FDA) on 15 September 2000, and in Europe on 19 March 2001. Its patent was scheduled to expire in the US on 26 June 2016.In March 2020, during the COVID-19 pandemic, the Israeli government announced that it would force AbbVie to license its patents for lopinavir/ritonavir. In response, AbbVie announced that it would cease enforcing its patents on the drug entirely. Society and culture Cost As a result of high prices and the spread of HIV infection, the government of Thailand issued a compulsory license on 29 January 2007, to produce and/or import generic versions of lopinavir and ritonavir. In response, Abbott Laboratories withdrew its registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai governments lack of respect for patents. Abbotts attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to boycott all of Abbotts medicines by the French NGO AIDES. Available forms Heat-stable pellets that can be taken by mouth have been developed for children. Research While data for SARS-CoV-1 looked promising, the benefit in COVID-19 is unclear as of 23 March 2020. In 2020, a non-blinded, randomized trial found lopinavir/ritonavir was not useful to treat severe COVID-19. In this trial the medication was started typically around 13 days after the start of symptoms. References External links "Lopinavir mixture with ritonavir". Drug Information Portal. U.S. National Library of Medicine. "Fact sheet on lopinavir and ritonavir (Lpv/R) oral pellets". World Health Organization (WHO). Archived from the original on 21 November 2015.
PCE	PCE may stand for: Business and economics Personal consumption expenditure, or private consumption expenditure Personal consumption expenditures price index, a measure of inflation Chemistry and engineering PCE or eticyclidine, an illegal drug related to Phencyclidine (PCP) Tetrachloroethylene (perchloroethylene), widely used in dry-cleaning Pro-opiomelanocortin converting enzyme, an enzyme Pyrometric cone equivalent, measuring heat in the firing of pottery Power conversion efficiency, a near synonym for "Energy conversion efficiency" often used in the field of photovoltaics Computing Path computation element, a network element used for pathfinding Principle of computational equivalence, a concept developed by Stephen Wolfram published in the book A New Kind of Science PC Engine, a video game console Medicine Prenatal cocaine exposure, exposure of a fetus to cocaine when a pregnant woman uses the drug Eticyclidine, a dissociative anesthetic drug Organizations Paavai College of Engineering, Namakkal, Tamil Nadu, India Padmanava College of Engineering, Rourkela, an engineering college in Rourkela, Orissa state, India Parents for Choice in Education, an advocacy group in Utah, U.S. Parliamentary Commissioner for the Environment, New Zealand government agency Political parties Spain PCE, Communist Party of Spain or "Partido Comunista de España" PCE(i), Communist Party of Spain (International)(1975) or Partido Comunista de España(Internacional) PCE(m-l), Communist Party of Spain (Marxist–Leninist) or Partido Comunista de España (Marxista-Leninista) PCE(ML), Communist Party of Spain (Marxist–Leninist) (historical) or Partido Comunista de España (Marxista-Leninista) PCE(M-R), Workers Party of Spain–Communist Unity or Partido de los Trabajadores de España–Unidad Comunista PCE(R), Communist Party of Spain (Reconstituted) or Partido Comunista de España (Reconstituido) Other countries Parti Communautaire Européen, a political party in Belgium Partido Comunista del Ecuador, the Communist Party of Ecuador Other ISO 639:pce or Palaung language, spoken in Burma and neighboring countries Passenger car equivalent, a measure of traffic flow PCE-842-class patrol craft, U.S. Navy patrol craft escorts, many of which were transferred to the Philippine Navy Power cost equalization, a state subsidy in Alaska Parduice
Pacritinib	Pacritinib, sold under the brand name Vonjo, is an anti-cancer medication used to treat myelofibrosis. It is a macrocyclic protein kinase inhibitor. It mainly inhibits Janus kinase 2 (JAK2) and Fms-like tyrosine kinase 3\CD135 (FLT3). Common side effects include diarrhea, low platelet counts, nausea, anemia, and swelling in legs. Medical uses Pacritinib in indicated to treat adults who have a rare form of a bone marrow disorder known as intermediate or high-risk primary or secondary myelofibrosis and who have platelet (blood clotting cells) levels below 50,000/µL. History The effectiveness and safety of pacritinib were demonstrated in a study that included 63 participants with intermediate or high-risk primary or secondary myelofibrosis and low platelets who received pacritinib 200 mg twice daily or standard treatment. Effectiveness was determined based upon the proportion of participants who had a 35% or greater spleen volume reduction from baseline to week 24. Nine participants (29%) in the pacritinib treatment group had a 35% or greater spleen volume reduction, compared to one participant (3%) in the standard treatment group.The U.S. Food and Drug Administration (FDA) granted the application for pacritinib priority review, fast track, and orphan drug designations. Society and culture Names Pacritinib is the International nonproprietary name (INN). References External links "Pacritinib". Drug Information Portal. U.S. National Library of Medicine.
Isradipine	Isradipine (tradenames DynaCirc, Prescal) is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack. It was patented in 1978 and approved for medical use in 1989. Medical uses Isradipine is given as either a 2.5 mg or 5 mg capsule. Side effects Common side effects include: Dizziness Warmth, redness, or tingly feeling under your skin Headache Weakness, tired feeling Nausea, vomiting, diarrhea, upset stomach Skin rash or itchingSerious side effects include: Lightheadedness or fainting Shortness of breath, especially from minimal physical activity Swelling in the hands and feet Rapid and/or heavy heartbeat Chest pain Drug interactions It is advised that those using Isradipine not take Anzemet (Dolasetron), as both agents can cause a dose-dependent PR interval and QRS complex prolongation.Itraconazole exhibits a negative inotropic effect on the heart and thus could spur an additive effect when used concomitantly with Isradipine. Onmel/Sporanox also inhibits an important cytochrome liver enzyme (CYP 450 3A4) which is needed to metabolize Isradipine and other Calcium Channel Blockers. This will increase plasma levels of Isradipine and could cause an unintentional overdose of the medication. Caution is advised when administering both agents together.Tizanidine demonstrates anti-hypertensive effects and should be avoided in patients taking Isradipine due to the possibility of synergism between both medications.The anti-biotic Rifampin lowered plasma concentrations of Isradipine to below detectable limits.Cimetidine increased Isradipine mean peak plasma levels. A downward dose adjustment may be necessary with this particular instance of polypharmacy.Severe hypotension was reported with Fentanyl anesthesia when it was combined with other Calcium Channel Blockers. Even though Isradipine, another Calcium Channel Blocker, has not been used in conjunction with Fentanyl anesthesia in any studies, caution is advised.Note: There was no significant interaction between Isradipine and Warfarin (Coumadin), Isradipine and Microzide Hydrochlorothiazide, Isradipine and Lanoxin (Digoxin), and Isradipine and Nitrostat (Nitroglycerin). Overdose Symptoms of an Isradipine overdose include: Lethargy Sinus tachycardia Transient hypotension Stereochemistry Isradipine contains a stereocenter and consists of two enantiomers, more precisely atropisomers. This is a racemate, i.e. a 1: 1 mixture of ( R ) - and the ( S ) - Form: References Further reading External links MedlinePlus DrugInfo medmaster-a693048 Diseases Database (DDB): 30003 Drug offers hope for Parkinsons - BBC News, 11 June 2007. [1] - Commentary of Chan et al. publication [2] - ArsTechnica - Why neurons die in Parkinsons patients
Clascoterone	Clascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne. It is also under development in a higher concentration for the treatment of androgen-dependent scalp hair loss, under the brand name Breezula. The medication is used as a cream by application to the skin, for instance the face and scalp.Clascoterone is an antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone. It shows minimal systemic absorption when applied to skin.The medication, developed by Cassiopea and Intrepid Therapeutics, was approved by the US Food and Drug Administration (FDA) for acne in August 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Clascoterone is indicated for the topical treatment of acne vulgaris in females and males age 12 years and older. It is applied to the affected skin area in a dose of 1 g cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening. The medication should not be used ophthalmically, orally, or vaginally.Two large phase 3 randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks. Clascoterone decreased acne symptoms by about 8 to 18% more than placebo. The defined treatment success endpoint was achieved in about 18 to 20% of individuals with clascoterone relative to about 7 to 9% of individuals with placebo. The comparative effectiveness of clascoterone between males and females was not described.A small pilot randomized controlled trial in 2011 found that clascoterone cream decreased acne symptoms to a similar or significantly greater extent than tretinoin 0.05% cream. No active comparator was used in the phase III clinical trials of clascoterone for acne. Hence, its unclear how clascoterone compares to other therapies used in the treatment of acne. Available forms Clascoterone is available in the form of a 1% (10 mg/g) cream for topical use. Contraindications Clascoterone has no contraindications. Side effects The incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials. Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone metabolite. HPA axis suppression as measured by the cosyntropin stimulation test was observed to occur in 3 of 42 (7%) of adolescents and adults using clascoterone for acne. HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone. Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals. Pharmacology Pharmacodynamics Clascoterone is a steroidal antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT). In a bioassay, the topical potency of the medication was greater than that of progesterone, flutamide, and finasteride and was equivalent to that of cyproterone acetate. Likewise, it is significantly more efficacious as an antiandrogen than other AR antagonists such as enzalutamide and spironolactone in scalp dermal papilla cells and sebocytes in vitro. Pharmacokinetics Steady-state levels of clascoterone occur within 5 days of twice daily administration. At a dosage of 6 g clascoterone cream applied twice daily, maximal circulating levels of clascoterone were 4.5 ± 2.9 ng/mL, area-under-the-curve levels over the dosing interval were 37.1 ± 22.3 h*ng/mL, and average circulating levels of clascoterone were 3.1 ± 1.9 ng/mL. In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection. Along these lines, the medication is not progonadotropic in animals.The plasma protein binding of clascoterone is 84 to 89% regardless of concentration.Clascoterone is rapidly hydrolyzed into cortexolone (11-deoxycortisol) and this compound is a possible primary metabolite of clascoterone based on in-vitro studies in human liver cells. During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL). Clascoterone may also produce other metabolites, including conjugates.The elimination of clascoterone has not been fully characterized in humans. Chemistry Clascoterone, also known as cortexolone 17α-propionate or 11-deoxycortisol 17α-propionate, as well as 17α,21-dihydroxyprogesterone 17α-propionate or 17α,21-dihydroxypregn-4-en-3,20-dione 17α-propionate, is a synthetic pregnane steroid and a derivative of progesterone and 11-deoxycortisol (cortexolone). It is specifically the C17α propionate ester of 11-deoxycortisol.An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04).Corticosteroids related to clascoterone, for instance cortisone acetate and prednisolone acetate, show antiandrogenic activity in animals similarly to clascoterone. History C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity. Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile. The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020.The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1,440 participants 9 to 58 years of age with acne vulgaris. The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia. Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks. Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed. The benefit of clascoterone in comparison to placebo was assessed after 12 weeks of treatment using the Investigators Global Assessment (IGA) score that measures the severity of disease (on a scale from 0 to 4) and a decrease in the number of acne lesions. Society and culture Names Clascoterone is the generic name of the drug and its INN and USAN. Research Clascoterone has been suggested as a possible treatment for hidradenitis suppurativa (acne inversa), an androgen-dependent skin condition. References External links "Clascoterone". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02608450 for "A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (25)" at ClinicalTrials.gov Clinical trial number NCT02608476 for "A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (26)" at ClinicalTrials.gov
Levosalbutamol	Levosalbutamol, also known as levalbuterol, is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Evidence is inconclusive regarding the efficacy of levosalbutamol versus salbutamol or salbutamol-levosalbutamol combinations, however levosalbutamol is believed to have a better safety profile due to its more selective binding to β2 receptors (primarily in the lungs) versus β1 (primarily in heart muscle).The drug is the (R)-(−)-enantiomer of its prototype drug salbutamol. It is available in some countries in generic formulations from pharmaceutical companies including Cipla, Teva, and Dey, among others. Medical use Levosalbutamols bronchodilator properties give it indications in treatment of COPD (chronic obstructive pulmonary disease, also known as chronic obstructive lung disease) and asthma. Like other bronchodilators, it acts by relaxing smooth muscle in the bronchial tubes, and thus shortening or reversing an acute "attack" of shortness of breath or difficulty breathing. Unlike some slower-acting bronchodilators, it is not indicated as a preventative of chronic bronchial constriction. Comparison to salbutamol A 2013 systematic review of the drugs use as a treatment for acute asthma found that it "was not superior to albuterol regarding efficacy and safety in subjects with acute asthma." The review concluded: "We suggest that levalbuterol should not be used over albuterol for acute asthma." Levalbuterol is notably more costly. Adverse effects Generally, levosalbutamol is well tolerated. Common mild side-effects include an elevated heart rate, muscle cramps, and gastric upset (including heartburn and diarrhea).Symptoms of overdose in particular include: collapse into a seizure; chest pain (possible precursor of a heart attack); fast, pounding heartbeat, which may cause raised blood pressure (hypertension); irregular heartbeat (cardiac arrhythmia), which may cause paradoxical lowered blood pressure (hypotension); nervousness and tremor; headache; dizziness and nausea/vomiting; weakness or exhaustion (medical fatigue); dry mouth; and insomnia.Rarer side effects may indicate a dangerous allergic reaction. These include: paradoxical bronchospasm (shortness of breath and difficulty breathing); skin itching, rash, or hives (urticaria); swelling (angioedema) of any part of the face or throat (which can lead to voice hoarseness), or swelling of the extremities. Pharmacology Mechanism of action Activation of β2 adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of 3,5-cyclic adenosine monophosphate (cyclic AMP). The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn, inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Levosalbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways. Levosalbutamol acts as a functional agonist that relaxes the airway irrespective of the spasmogen involved, thereby protecting against all bronchoconstrictor challenges. While it is recognized that β2 adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta receptors in the human heart, 10–50% of which are β2 adrenergic receptors. The precise function of these receptors has not been established. However, all β adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, and restlessness symptoms, and/or electrocardiographic (ECG). Approval and names Levosalbutamol is the INN while levalbuterol is the USAN. Levalbuterol was approved in the United States as a solution to be used with a nebulizer device in March 1999 and in March 2015 became available in a formulation with a metered-dose inhaler under the trade name Xopenex HFA (levalbuterol tartrate inhalation aerosol). See also Salbutamol — the racemic mixture containing both (R)-(−)- and (S)-(+)-enantiomers References External links "Levalbuterol". Drug Information Portal. U.S. National Library of Medicine.
Cefdinir	Cefdinir, sold under the brand name Omnicef among others, is an antibiotic used to treat pneumonia, otitis media, strep throat, and cellulitis. It is a less preferred option for pneumonia, otitis media, and strep throat which may be used in those with a severe allergy to penicillin. It is taken by mouth.Common side effects include diarrhea, nausea, and a skin rash. Serious side effects may include Clostridioides difficile infection, anaphylaxis, and Stevens–Johnson syndrome. Use in pregnancy and breastfeeding is believed to be safe but has not been well studied. It is a third-generation cephalosporin and works by interfering with a bacterias ability to make a cell wall resulting in its death.It was patented in 1979 and approved for medical use in 1991. It is available as a generic medication. In 2019, it was the 159th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Medical uses Therapeutic uses of cefdinir include otitis media, soft tissue infections, and respiratory tract infections, including sinusitis, strep throat (note: no documented resistance of Group A Streptococcus to penicillin has ever been reported, and penicillin or amoxicillin is preferred except in penicillin allergic patients), community-acquired pneumonia, and acute exacerbations of bronchitis. Susceptible organisms Cefdinir is a bactericidal antibiotic of the cephalosporin class of antibiotics. It can be used to treat infections caused by several Gram-negative and Gram-positive bacteria. Bacterial susceptibility and resistance Cefdinir is a broad-spectrum antibiotic and has been used to treat infections of the respiratory tract including pneumonia, sinusitis, and bronchitis. The following represents MIC susceptibility data for a few medically significant microorganisms. Haemophilus influenzae: 0.05 - 4 μg/ml Streptococcus pneumoniae: 0.006 - 64 μg/ml Streptococcus pyogenes: ≤0.004 - 2 μg/ml Side effects Side effects include diarrhea, vaginal infections or inflammation, nausea, headache, and abdominal pain."It is also one of the medications that can cause toxic epidermal necrolysis or Stevens–Johnson syndrome.The pediatric version of cefdinir can bind to iron in the digestive tract; in rare cases, this causes a rust or red discoloration of the stool. Blood typically appears dark brown or black in stool, and testing may confirm which is present. If the reddish stool is accompanied by abdominal pain, weight loss, diarrhea, etc., a Clostridioides difficile infection caused by the antibiotic could be signified. Mechanism of action Society and culture Economics As of 2008, cefdinir was the highest-selling cephalosporin antibiotic in the United States, with more than US$585 million in retail sales of its generic versions. Available forms Cefdinir is administered orally. It is available as capsules and a suspension. Dosage, schedule, and duration of therapy varies according to the type of infection. Warner-Lambert licensed this cephalosporin for marketing in US from Fujisawa. Abbott obtained U.S. marketing rights to Omnicef (cefdinir) in December 1998 through an agreement with Warner-Lambert Company. It was approved by FDA on December 4, 1997. It is available in US as Omnicef by Abbott Laboratories and in India as Cednir by Abbott, Kefnir by Glenmark, Cefdair by Xalra Pharma and Cefdiel by Ranbaxy. Synthesis Acylation of the primary amine 1 with 4-bromo-3-oxobutanoyl bromide (2) leads to the amide (3). The active methylene group in that product is then nitrosated with sodium nitrite; the initial product spontaneously tautomerizes to afford the oxime (4). The bromoketone array in that intermediate constitutes a classical starting function for construction of thiazoles. Reaction of 4 with thiourea thus leads to formation of an aminothiazole moiety. Thus there is obtained the antibiotic cefdinir (5). References External links "Cefdinir". Drug Information Portal. U.S. National Library of Medicine.
Potassium iodide	Potassium iodide is a chemical compound, medication, and dietary supplement. It is a medication used for treating hyperthyroidism, in radiation emergencies, and for protecting the thyroid gland when certain types of radiopharmaceuticals are used. In the third world it is also used for treating skin sporotrichosis and phycomycosis. It is a supplement used by people with low dietary intake of iodine. It is administered orally.Common side effects include vomiting, diarrhea, abdominal pain, rash, and swelling of the salivary glands. Other side effects include allergic reactions, headache, goitre, and depression. While use during pregnancy may harm the baby, its use is still recommended in radiation emergencies. Potassium iodide has the chemical formula KI. Commercially it is made by mixing potassium hydroxide with iodine.Potassium iodide has been used medically since at least 1820. It is on the World Health Organizations List of Essential Medicines. Potassium iodide is available as a generic medication and over the counter. Potassium iodide is also used for the iodization of salt. Medical uses Dietary supplement Potassium-iodide is a nutritional-supplement in animal feeds and also in the human diet. In humans it is the most common additive used for "iodizing" table salt (a public health measure to prevent iodine deficiency in populations that get little seafood). The oxidation of iodide causes slow loss of iodine content from iodised salts that are exposed to excess air. The alkali metal iodide salt, over time and exposure to excess oxygen and carbon dioxide, slowly oxidizes to metal carbonate and elemental iodine, which then evaporates. Potassium iodate (KIO3) is used to iodize some salts so that the iodine is not lost by oxidation. Dextrose or sodium thiosulfate are often added to iodized table salt to stabilize potassium iodide thus reducing loss of the volatile chemical. Thyroid protection Thyroid iodine uptake blockade with potassium iodide is used in nuclear medicine scintigraphy and therapy with some radioiodinated compounds that are not targeted to the thyroid, such as iobenguane (MIBG), which is used to image or treat neural tissue tumors, or iodinated fibrinogen, which is used in fibrinogen scans to investigate clotting. These compounds contain iodine, but not in the iodide form. However, since they may be ultimately metabolized or break down to radioactive iodide, it is common to administer non-radioactive potassium iodide to ensure that iodide from these radiopharmaceuticals is not sequestered by the normal affinity of the thyroid for iodide. U.S. Food and Drug Administration-approved dosing of potassium iodide for this purpose with iobenguane, is as follows (per 24 hours): infants less than 1 month old, 16 mg; children 1 month to 3 years, 32 mg; children 3 years to 18 years, 65 mg; adults 130 mg. However, some sources recommend alternative dosing regimens.Not all sources are in agreement on the necessary duration of thyroid blockade, although agreement appears to have been reached about the necessity of blockade for both scintigraphic and therapeutic applications of iobenguane. Commercially available iobenguane is labeled with iodine-123, and product labeling recommends administration of potassium iodide 1 hour prior to administration of the radiopharmaceutical for all age groups, while the European Association of Nuclear Medicine recommends (for iobenguane labeled with either isotope), that potassium iodide administration begin one day prior to radiopharmaceutical administration, and continue until the day following the injection, with the exception of new-borns, who do not require potassium iodide doses following radiopharmaceutical injection.Product labeling for diagnostic iodine-131 iobenguane recommends potassium iodide administration one day before injection and continuing 5 to 7 days following administration, in keeping with the much longer half-life of this isotope and its greater danger to the thyroid. Iodine-131 iobenguane used for therapeutic purposes requires a different pre-medication duration, beginning 24–48 hours prior to iobenguane injection and continuing 10–15 days following injection. Nuclear accidents In 1982, the U.S. Food and Drug Administration approved potassium iodide to protect thyroid glands from radioactive iodine involving accidents or fission emergencies. In an accidental event or attack on a nuclear power plant, or in nuclear bomb fallout, volatile fission product radionuclides may be released. Of these products, 131I (Iodine-131) is one of the most common and is particularly dangerous to the thyroid gland because it may lead to thyroid cancer. By saturating the body with a source of stable iodide prior to exposure, inhaled or ingested 131I tends to be excreted, which prevents radioiodine uptake by the thyroid. According to one 2000 study "KI administered up to 48 h before 131I exposure can almost completely block thyroid uptake and therefore greatly reduce the thyroid absorbed dose. However, KI administration 96 h or more before 131I exposure has no significant protective effect. In contrast, KI administration after exposure to radioiodine induces a smaller and rapidly decreasing blockade effect." For optimal prevention, KI must be dosed daily until a risk of significant exposure to radioiodine by either inhalation or ingestion no longer exists.Emergency 130 milligrams potassium iodide doses provide 100 mg iodide (the other 30 mg is the potassium in the compound), which is roughly 700 times larger than the normal nutritional need (see recommended dietary allowance) for iodine, which is 150 micrograms (0.15 mg) of iodine (as iodide) per day for an adult. A typical tablet weighs 160 mg, with 130 mg of potassium iodide and 30 mg of excipients, such as binding agents. Potassium iodide cannot protect against any other mechanisms of radiation poisoning, nor can it provide any degree of protection against dirty bombs that produce radionuclides other than those of iodine. The potassium iodide in iodized salt is insufficient for this use. A likely lethal dose of salt (more than a kilogram) would be needed to equal the potassium iodide in one tablet.The World Health Organization does not recommend KI prophylaxis for adults over 40 years, unless the radiation dose from inhaled radioiodine is expected to threaten thyroid function, because the KI side effects increase with age and may exceed the KI protective effects; "...unless doses to the thyroid from inhalation rise to levels threatening thyroid function, that is of the order of about 5 Gy. Such radiation doses will not occur far away from an accident site."The U.S. Department of Health and Human Services restated these two years later as "The downward KI (potassium iodide) dose adjustment by age group, based on body size considerations, adheres to the principle of minimum effective dose. The recommended standard (daily) dose of KI for all school-age children is the same (65 mg). However, adolescents approaching adult size (i.e., >70 kg [154 lbs]) should receive the full adult dose (130 mg) for maximal block of thyroid radioiodine uptake. Neonates ideally should receive the lowest dose (16 mg) of KI."SSKI (i.e., the "saturated solution of KI" rather than tablets) may be used in radioiodine-contamination emergencies (i.e., nuclear accidents) to "block" the thyroids uptake of radioiodine, at a dose of two drops of SSKI per day for an adult. This is not the same as blocking the thyroids release of thyroid hormone, for which the adult dose is different (and is actually higher by a factor of 7 or 8), and for which KI anti-radiation pills (not a common medical treatment form of KI) are not usually available in pharmacies, or normally used in hospitals, or by physicians. Although the two forms of potassium iodide are completely interchangeable, normally in practice the SSKI solution, which is the historical medical form of high dose iodine, is generally used for all medical purposes save for radioiodine prophylaxis. For protection of the thyroid against radioiodine (iodine-131) contamination, the convenient standard 130 mg KI pill is used, if available. As noted, the equivalent two drops of SSKI (equaling the dose of one KI pill) may be used for this purpose, if the pills are not available. Side effects There is reason for caution with prescribing the ingestion of high doses of potassium iodide and iodate, because their unnecessary use can cause conditions such as the Jod-Basedow phenomena, trigger and/or worsen hyperthyroidism and hypothyroidism, and then cause temporary or even permanent thyroid conditions. It can also cause sialadenitis (an inflammation of the salivary gland), gastrointestinal disturbances, and rashes. Potassium iodide is also not recommended for people with dermatitis herpetiformis and hypocomplementemic vasculitis – conditions that are linked to a risk of iodine sensitivity.There have been some reports of potassium iodide treatment causing swelling of the parotid gland (one of the three glands that secrete saliva), due to its stimulatory effects on saliva production.A saturated solution of KI (SSKI) is typically given orally in adult doses several times a day (5 drops of SSKI assumed to be 1⁄3 mL) for thyroid blockade (to prevent the thyroid from excreting thyroid hormone) and occasionally this dose is also used, when iodide is used as an expectorant (the total dose is about one gram KI per day for an adult). The anti-radioiodine doses used for 131I uptake blockade are lower, and range downward from 100 mg a day for an adult, to less than this for children (see table). All of these doses should be compared with the far lower dose of iodine needed in normal nutrition, which is only 150 μg per day (150 micrograms, not milligrams). At maximal doses, and sometimes at much lower doses, side effects of iodide used for medical reasons, in doses of 1000 times the normal nutritional need, may include: acne, loss of appetite, or upset stomach (especially during the first several days, as the body adjusts to the medication). More severe side effects that require notification of a physician are: fever, weakness, unusual tiredness, swelling in the neck or throat, mouth sores, skin rash, nausea, vomiting, stomach pains, irregular heartbeat, numbness or tingling of the hands or feet, or a metallic taste in the mouth.In the event of a radioiodine release the ingestion of prophylaxis potassium iodide, if available, or even iodate, would rightly take precedence over perchlorate administration, and would be the first line of defence in protecting the population from a radioiodine release. However, in the event of a radioiodine release too massive and widespread to be controlled by the limited stock of iodide and iodate prophylaxis drugs, then the addition of perchlorate ions to the water supply, or distribution of perchlorate tablets would serve as a cheap, efficacious, second line of defense against carcinogenic radioiodine bioaccumulation. The ingestion of goitrogen drugs is, much like potassium iodide also not without its dangers, such as hypothyroidism. In all these cases however, despite the risks, the prophylaxis benefits of intervention with iodide, iodate or perchlorate outweigh the serious cancer risk from radioiodine bioaccumulation in regions where radioiodine has sufficiently contaminated the environment. Potassium iodide in its raw form is a mild irritant and should be handled with gloves. Chronic overexposure can have adverse effects on the thyroid. Potassium iodide is a possible teratogen. Industrial uses KI is used with silver nitrate to make silver iodide (AgI), an important chemical in film photography. KI is a component in some disinfectants and hair treatment chemicals. KI is also used as a fluorescence quenching agent in biomedical research, an application that takes advantage of collisional quenching of fluorescent substances by the iodide ion. However, for several fluorophores addition of KI in μM-mM concentrations results in increase of fluorescence intensity, and iodide acts as fluorescence enhancer.Potassium iodide is a component in the electrolyte of dye sensitised solar cells (DSSC) along with iodine. Potassium iodide finds its most important applications in organic synthesis mainly in the preparation of aryl iodides in the Sandmeyer reaction, starting from aryl amines. Aryl iodides are in turn used to attach aryl groups to other organics by nucleophilic substitution, with iodide ion as the leaving group. Chemistry Potassium iodide is an ionic compound which is made of the following ions: K+I−. It crystallises in the sodium chloride structure. It is produced industrially by treating KOH with iodine.It is a white salt, which is the most commercially significant iodide compound, with approximately 37,000 tons produced in 1985. It absorbs water less readily than sodium iodide, making it easier to work with. Aged and impure samples are yellow because of the slow oxidation of the salt to potassium carbonate and elemental iodine. 4 KI + 2 CO 2 + O 2 ⟶ 2 K 2 CO 3 + 2 I 2 {\displaystyle {\ce {4 KI + 2 CO2 + O2 -> 2 K2CO3 + 2 I2}}} Inorganic chemistry Since the iodide ion is a mild reducing agent, I− is easily oxidised to iodine (I2) by powerful oxidising agents such as chlorine: 2 KI ( aq ) + Cl 2 ( aq ) ⟶ 2 KCl ( aq ) + I 2 ( aq ) {\displaystyle {\ce {2 KI_{(aq)}{}+ Cl2_{(aq)}-> 2 KCl_{(aq)}{}+ I2_{(aq)}}}} This reaction is employed in the isolation of iodine from natural sources. Air will oxidize iodide, as evidenced by the observation of a purple extract when aged samples of KI are rinsed with dichloromethane. As formed under acidic conditions, hydriodic acid (HI) is a stronger reducing agent.Like other iodide salts, KI forms triiodide (I−3) when combined with elemental iodine. KI ( aq ) + I 2 ( s ) ⟶ KI 3 ( aq ) {\displaystyle {\ce {KI_{(aq)}{}+ I2_{(s)}-> KI3_{(aq)}}}} Unlike I2, I−3 salts can be highly water-soluble. Through this reaction, iodine is used in redox titrations. Aqueous KI3, "Lugols solution", is used as a disinfectant and as an etchant for gold surfaces. Potassium iodide and silver nitrate are used to make silver(I) iodide, which is used for high speed photographic film and for cloud seeding: KI ( aq ) + 9 AgNO 3 ( aq ) ⟶ AgI ( s ) + KNO 3 ( aq ) {\displaystyle {\ce {KI_{(aq)}{}+ 9AgNO3_{(aq)}-> AgI_{(s)}{}+ KNO3_{(aq)}}}} Organic chemistry KI serves as a source of iodide in organic synthesis. A useful application is in the preparation of aryl iodides from arenediazonium salts. KI, acting as a source of iodide, may also act as a nucleophilic catalyst for the alkylation of alkyl chlorides, bromides, or mesylates. History Potassium iodide has been used medically since at least 1820. Some of the earliest uses included for syphilis. Chernobyl Potassium iodides (KI) value as a radiation protective (thyroid blocking) agent was demonstrated following the Chernobyl nuclear reactor disaster in April, 1986. A saturated solution of potassium iodide (SSKI) was administered to 10.5 million children and 7 million adults in Poland as a preventative measure against accumulation of radioactive 131I in the thyroid gland. Reports differ concerning whether people in the areas immediately surrounding Chernobyl itself were given the supplement. However the US Nuclear Regulatory Commission (NRC) reported, "thousands of measurements of I-131 (radioactive iodine) activity...suggest that the observed levels were lower than would have been expected had this prophylactic measure not been taken. The use of KI...was credited with permissible iodine content in 97% of the evacuees tested."With the passage of time, people living in irradiated areas where KI was not available have developed thyroid cancer at epidemic levels, which is why the US Food and Drug Administration (FDA) reported "The data clearly demonstrate the risks of thyroid radiation... KI can be used [to] provide safe and effective protection against thyroid cancer caused by irradiation."Chernobyl also demonstrated that the need to protect the thyroid from radiation was greater than expected. Within ten years of the accident, it became clear that thyroid damage caused by released radioactive iodine was virtually the only adverse health effect that could be measured. As reported by the NRC, studies after the accident showed that "As of 1996, except for thyroid cancer, there has been no confirmed increase in the rates of other cancers, including leukemia, among the... public, that have been attributed to releases from the accident."But equally important to the question of KI is the fact that radioactivity releases are not "local" events. Researchers at the World Health Organization accurately located and counted the residents with cancer from Chernobyl and were startled to find that "the increase in incidence [of thyroid cancer] has been documented up to 500 km from the accident site... significant doses from radioactive iodine can occur hundreds of kilometers from the site, beyond emergency planning zones." Consequently, far more people than anticipated were affected by the radiation, which caused the United Nations to report in 2002 that "The number of people with thyroid cancer... has exceeded expectations. Over 11,000 cases have already been reported." Nagasaki These findings were consistent with studies of the effects of previous radioactivity releases. In 1945, millions of Japanese were exposed to radiation from nuclear weapons, and the effects can still be measured. Today, nearly half (44.8%) the survivors of Nagasaki studied have identifiable thyroid disease, with an editorial in The Journal of the American Medical Association reporting "it is remarkable that a biological effect from a single brief environmental exposure nearly 60 years in the past is still present and can be detected." Nuclear weapons testing The development of thyroid cancer among residents in the North Pacific from radioactive fallout following the United States nuclear weapons testing in the 1950s (on islands nearly 200 miles downwind of the tests) were instrumental in the 1978 decision by the FDA to issue a request for the availability of KI for thyroid protection in the event of a release from a commercial nuclear power plant or weapons-related nuclear incident. Noting that KIs effectiveness was "virtually complete" and finding that iodine in the form of KI was substantially superior to other forms including iodate (KIO3) in terms of safety, effectiveness, lack of side effects, and speed of onset, the FDA invited manufacturers to submit applications to produce and market KI. Fukushima It was reported on March 16, 2011, that potassium iodide tablets were given preventively to U.S. Naval air crew members flying within 70 nautical miles of the Fukushima Daiichi Nuclear Power Plant damaged in the earthquake (8.9/9.0 magnitude) and ensuing tsunami on March 11, 2011. The measures were seen as precautions, and the Pentagon said no U.S. forces have shown signs of radiation poisoning. By March 20, the US Navy instructed personnel coming within 100 miles of the reactor to take the pills. The Netherlands In the Netherlands, the central storage of iodine-pills is located in Zoetermeer, near The Hague. In 2017, the Dutch government distributed pills to hundreds of thousands of residents who lived within a certain distance of nuclear power plants and met some other criteria. Belgium By 2020, potassium iodide tablets are made available free of charge for all residents in all pharmacies throughout the country. Formulations Three companies (Anbex, Inc., Fleming Co, and Recipharm of Sweden) have met the strict FDA requirements for manufacturing and testing of KI, and they offer products (IOSAT, ThyroShield, and ThyroSafe, respectively) which are available for purchase. In 2012, Fleming Co. sold all its product rights and manufacturing facility to other companies and no longer exists. ThyroShield is currently not in production. The Swedish manufacturing facility for Thyrosafe, a half-strength potassium iodide tablet for thyroid protection from radiation, was mentioned on the secret US 2008 Critical Foreign Dependencies Initiative leaked by Wikileaks in 2010.Tablets of potassium iodide are supplied for emergency purposes related to blockade of radioiodine uptake, a common form of radiation poisoning due to environmental contamination by the short-lived fission product 131I. Potassium iodide may also be administered pharmaceutically for thyroid storm. For reasons noted above, therapeutic drops of SSKI, or 130 mg tablets of KI as used for nuclear fission accidents, are not used as nutritional supplements, since an SSKI drop or nuclear-emergency tablet provides 300 to 700 times more iodine than the daily adult nutritional requirement. Dedicated nutritional iodide tablets containing 0.15 mg (150 micrograms (μg)) of iodide, from KI or from various other sources (such as kelp extract) are marketed as supplements, but they are not to be confused with the much higher pharmaceutical dose preparations. Potassium iodide can be conveniently prepared in a saturated solution, abbreviated SSKI. This method of delivering potassium iodide doesnt require a method to weigh out the potassium iodide, thus allowing it to be used in an emergency situation. KI crystals are simply added to water until no more KI will dissolve and instead sits at the bottom of the container. With pure water, the concentration of KI in the solution depends only on the temperature. Potassium iodide is highly soluble in water thus SSKI is a concentrated source of KI. At 20 degrees Celsius the solubility of KI is 140-148 grams per 100 grams of water. Because the volumes of KI and water are approximately additive, the resulting SSKI solution will contain about 1.00 gram (1000 mg) KI per milliliter (mL) of solution. This is 100% weight/volume (note units of mass concentration) of KI (one gram KI per mL solution), which is possible because SSKI is significantly more dense than pure water—about 1.67 g/mL. Because KI is about 76.4% iodide by weight, SSKI contains about 764 mg iodide per mL. This concentration of iodide allows the calculation of the iodide dose per drop, if one knows the number of drops per milliliter. For SSKI, a solution more viscous than water, there are assumed to be 15 drops per mL; the iodide dose is therefore approximately 51 mg per drop. It is conventionally rounded to 50 mg per drop. The term SSKI is also used, especially by pharmacists, to refer to a U.S.P. pre-prepared solution formula, made by adding KI to water to prepare a solution containing 1000 mg KI per mL solution (100% wt/volume KI solution), to closely approximate the concentration of SSKI made by saturation. This is essentially interchangeable with SSKI made by saturation, and also contains about 50 mg iodide per drop. Saturated solutions of potassium iodide can be an emergency treatment for hyperthyroidism (so-called thyroid storm), as high amounts of iodide temporarily suppress secretion of thyroxine from the thyroid gland. The dose typically begins with a loading dose, then 1⁄3 mL SSKI (5 drops or 250 mg iodine as iodide), three times per day. Iodide solutions made from a few drops of SSKI added to drinks have also been used as expectorants to increase the water content of respiratory secretions and encourage effective coughing. SSKI has been proposed as a topical treatment for sporotrichosis, but no trials have been conducted to determine the efficacy or side effects of such treatment. Potassium iodide has been used for symptomatic treatment of erythema nodosum patients for persistent lesions whose cause remains unknown. It has been used in cases of erythema nodosum associated with Crohns disease. Due to its high potassium content, SSKI is extremely bitter, and if possible it is administered in a sugar cube or small ball of bread. It may also be mixed into much larger volumes of juices. Neither SSKI or KI tablets form nutritional supplements, since the nutritional requirement for iodine is only 150 micrograms (0.15 mg) of iodide per day. Thus, a drop of SSKI provides 50/0.15 = 333 times the daily iodine requirement, and a standard KI tablet provides twice this much. See also Elephant toothpaste References External links "Potassium iodide". Drug Information Portal. U.S. National Library of Medicine. World Health Organizations guidelines for iodine prophylaxis following a nuclear accident
Dolasetron	Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors. Dolasetron breaks down slowly, staying in the body for a long time. One dose is usually administered once or twice daily and lasts 4 to 9 hours. This drug is removed from the body by the liver and kidneys. It was patented in 1986 and approved for medical use in 2002. It is on the World Health Organizations List of Essential Medicines. Medical uses Chemotherapy-induced nausea and vomiting 5-HT3 receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting. Many times they are given intravenously about 30 minutes before beginning therapy. Post-operative and post-radiation nausea and vomiting Is a possible therapy for nausea and vomiting due to acute or chronic medical illness or acute gastroenteritis Unlike most other 5HT3 antagonists, data is lacking for use of dolasetron with aprepitant in chemotherapy-induced nausea and vomiting (CINV). It is also sometimes used as an antiemetic (anti-vomiting medication) in veterinary medicine for dogs and cats. Adverse effects Dolasetron is a well-tolerated drug with few side effects. Headache, dizziness, and constipation are the most commonly reported side effects associated with its use. There is a potential for prolonging of the QT interval to occur as well. There have been no significant drug interactions reported with this drugs use. Dolasetron is broken down by the livers cytochrome P450 system and has little effect on the metabolism of other drugs broken down by this system. Intravenous dolasetron is contraindicated in Chemotherapy-induced nausea and vomiting (CINV). Doxorubicin and cyclophosphamide are as emetogenic as cisplatin, and preventive drugs should always be considered. The 5HT3 agonists are the mainstays of prevention and are frequently used in combination with other drugs such as corticosteroids and the NK1 receptor antagonist aprepitant. However, the FDA recently issued a drug communication stating that the injection form of dolasetron, a 5HT3 agonist, should no longer be used in adult or pediatric patients with CINV. Dolasetron injection can increase the risk of developing torsade de pointes, a potentially fatal abnormal heart rhythm. Patients with underlying heart conditions or existing heart rate or rhythm problems are at increased risk. Although the oral form of this agent can still be used, careful monitoring and correction of potassium and magnesium levels should be initiated prior to and during treatment. In addition, in older patients and in patients with heart failure, a slow heart rate, underlying cardiac disease, and those with renal impairment, monitoring with electrocardiography is indicated when this drug is used. Congenital long-QT syndrome and drugs that prolong the PR or QRS interval are contraindications to dolasetron therapy. Dolasetron injection may still be used for the prevention and treatment of postoperative nausea and vomiting, per Food and Drug Administration guidelines. See also 5-HT3 receptor antagonist: Drug discovery and development References == Further reading ==
Finasteride/tadalafil	Finasteride/tadalafil, sold under the brand name Entadfi, is a fixed-dose combination medication used for the treatment of benign prostatic hyperplasia (BPH). It contains finasteride and tadalafil. It is taken by mouth.It was approved for medical use in the United States in December 2021. Medical uses Finasteride/tadalafil is indicated to treat benign prostatic hyperplasia (BPH) in men. References External links "Finasteride". Drug Information Portal. U.S. National Library of Medicine. "Tadalafil". Drug Information Portal. U.S. National Library of Medicine.
Entacapone	Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinsons disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinsons disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.Entacapone is a selective and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT). When taken together with levodopa (L-DOPA) and carbidopa, entacapone stops catechol-O-methyltransferase from breaking down and metabolizing levodopa, resulting in an overall increase of levodopa remaining in the brain and body.Carbidopa/levodopa/entacapone (Stalevo), a medication developed by Orion Pharma and marketed by Novartis, is a single tablet formulation that contains levodopa, carbidopa, and entacapone. Medical uses Entacapone is used in addition to levodopa and carbidopa for people with Parkinsons disease to treat the signs and symptoms of end-of-dose "wearing-off." "Wearing-off" is characterized by the re-appearance of both motor and non-motor symptoms of Parkinsons disease occurring towards the end of a previous levodopa and carbidopa dose. In clinical trials, entacapone has not been shown to slow progression or reverse Parkinsons disease.Entacapone is an orally active drug that can be taken with or without food. Pregnancy and breastfeeding Pregnancy category C: risk is not ruled out.Although there have been animal studies that showed that entacapone was excreted into maternal rat milk, there have been no studies with human breast milk. Caution is advised for mothers taking entacapone while breastfeeding or during pregnancy. Children Entacapone safety and efficacy have not been assessed in infants or children. Liver problems Biliary excretion is the major route of excretion for entacapone. People with liver dysfunction may require additional caution and more frequent liver function monitoring while taking entacapone. Kidney problems There are no significant considerations for people with poor kidney function taking entacapone. Contraindications There is a high risk for allergic reactions for people who are hypersensitive to entacapone.Potential limiting conditions to consider before starting entacapone include: History of allergic reaction to entacapone History of liver disease, liver dysfunction, or alcoholism Current or planned pregnancy Current or planned surgeries Side effects The following side effects have been reported by people with Parkinsons disease treated with entacapone: Abdominal pain Nausea Vomiting Fatigue Dry mouth Back ache Movement problems The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone. This drug may cause or worsen dyskinesia for people with Parkinsons disease treated together with levodopa and carbidopa. In particular, "peak-dose dyskinesias" may occur when levodopa levels are at its peak concentration in the serum plasma. Diarrhea 10% of patients taking entacapone have been shown to experience diarrhea. Diarrhea may occur within 4–12 weeks of initial entacapone use but resolves after discontinuation of the drug. Use of entacapone in the presence of diarrhea can also be associated with weight loss, low potassium levels, and dehydration. In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone. Urine color 10% of people taking entacapone experience a change in urine color to orange, red, brown, or black. This side effect is due to entacapone metabolism and excretion in the urine and shown to not be harmful. Sudden sleep onset People have reported sudden sleep onset while engaging in daily activities without prior warning of drowsiness. In controlled studies, patients on entacapone had a 2% increased risk of somnolence compared to placebo. Low blood pressure Episodes of orthostatic hypotension have been shown to be more common at the start of entacapone use due to increased levels of levodopa. Behavior problems Post-marketing data shows that entacapone may change or worsen mental status, leading to behaviors such as delusions, agitation, confusion, and delirium.People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors. Interactions In studies, entacapone has shown a low potential for interaction with other drugs. In theory, it could interact with MAO inhibitors, tricyclic antidepressants and noradrenaline reuptake inhibitors because they also increase catecholamine levels in the body, with drugs being metabolized by COMT (for example methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline), with iron because it could form chelates, with substances binding to the same albumin site in the blood plasma (for example diazepam and ibuprofen), and with drugs being metabolized by the liver enzyme CYP2C9 (for example warfarin). None of the medications tested in studies have shown clinically relevant interactions, except perhaps warfarin for which a 13% (CI90: 6–19%) increase in INR was seen when combined with entacapone. Pharmacology Mechanism of action Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). COMT eliminates biologically active catechols present in catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. When administered with a decarboxylase inhibitor, COMT acts as the major metabolizing enzyme for levodopa and metabolizes it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and in the periphery.For the treatment of Parkinsons disease, entacapone is given as an adjunct to levodopa and an aromatic amino acid decarboxylase inhibitor, carbidopa. Entacapone inhibits COMT in the periphery (but not, or at most marginally, in the brain) and the metabolism of levodopa, thus increasing plasma levels of levodopa and causing more constant dopaminergic stimulation in order to reduce the signs and symptoms presented in the disease. Pharmacokinetics Absorption The time to highest blood plasma concentrations is approximately one hour. The substance undergoes extensive first-pass metabolism. Absolute oral bioavailability (F) is 35%. Distribution The volume of distribution (Vd) after intravenous injection is approximately 20 liters. 98% of the circulating entacapone is bound to serum albumin, which limits its distribution into tissues. Metabolism and elimination Entacapone is primarily metabolized to its glucuronide in the liver, and 5% are converted into the Z-isomer. It has a half-life of approximately 0.3–0.7 hours, with only 0.2% being excreted unchanged in the urine. References External links "Entacapone". Drug Information Portal. U.S. National Library of Medicine.
Portia	Portia may refer to: Biology Portia (spider), a genus of jumping spiders Anaea troglodyta or Portia, a brush-footed butterfly Portia tree, a plant native to Polynesia Ctt. Portia, an orchid Cattlianthe Medication A form of birth control made of ethinylestradiol/levonorgestrel Other uses Portia (moon), a moon of Uranus Portia Club, a womens club in Payette, Idaho/USA Portia, Missouri, a community in the United States PORTIA portfolio-management software from Thomson Financial HMS Lennox (1914) or HMS Portia, a Laforey-class destroyer launched in 1914 People with the given name Portia Arthur (born 1990), Ghanaian author, writer and reporter Porcia Catonis, the wife of Roman senator Marcus Junius Brutus (fictionalized as a character in William Shakespeares play Julius Caesar as "Portia") Portia Dawson, American actress Portia de Rossi or Portia DeGeneres, Australian-born actress Portia Doubleday, American actress Portia Geach (1873–1959), Australian artist and feminist Portia Holman (1903–1983), Australian child psychiatrist Portia Mansfield (1887–1979), American dance educator and choreographer Portia Simpson-Miller, political leader of Jamaicas Peoples National Party and Prime Minister of Jamaica Portia White, Canadian singer Portia Zvavahera (born 1985), Zimbabwean painter Portia, pen name of Abigail Adams (1744-1818) Portia, pen name of Grizelda Elizabeth Cottnam Tonge (1803-1825) Fictional Portia (The Merchant of Venice), a character in William Shakespeares play The Merchant of Venice Portia Quayne, the protagonist in The Death of the Heart by Elizabeth Bowen Portia Gibbons, character on The Mighty B! Portia, a minor character in The Hunger Games Portia Copeland, a character in Carson McCullers novel The Heart Is a Lonely Hunter Portia Blake, the lead character in the American radio and television soap opera Portia Faces Life Portia, the name for the frequently changed spider protagonist in Children of Time (novel), a novel by Adrian Tchaikovsky Portia, Doors mother in Neverwhere, a novel by Neil Gaiman See also Porch Porcia (disambiguation) Porsche (disambiguation)
Abrocitinib	Abrocitinib, sold under the brand name Cibinqo, is a Janus kinase inhibitor medication used for the treatment of atopic dermatitis (eczema). It was developed by Pfizer. Medical uses Abrocitinib is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Side effects The most common adverse effects in studies were upper respiratory tract infection, headache, nausea, and diarrhea. Pharmacology Mechanism of action It is a selective inhibitor of the enzyme janus kinase 1 (JAK1). Pharmacokinetics Abrocitinib is quickly absorbed from the gut and generally reaches highest blood plasma concentrations within one hour. Only 1.0 to 4.4% of the dose are found unmetabolized in the urine. History April 2016: initiation of Phase 2b trial December 2017: initiation of JADE Mono-1 Phase 3 trial May 2018: Results of Phase 2b trial posted October 2019: Results of Phase 3 trial presented June 2020: Results of second Phase 3 trial published Society and culture Legal status In October 2021, 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 Cibinqo, intended for the treatment of atopic dermatitis. The applicant for this medicinal product is Pfizer Europe MA EEIG. In December 2021, the European Commission approved abrocitinib for the treatment of atopic dermatitis.In January 2022, the United States Food and Drug Administration (FDA) approved abrocitinib for adults with moderate-to-severe atopic dermatitis. References External links "Abrocitinib". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03349060 for "Study to Evaluate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-1)" at ClinicalTrials.gov Clinical trial number NCT03575871 for "Study Evaluating Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-2)" at ClinicalTrials.gov Clinical trial number NCT03720470 for "Study Evaluating Efficacy and Safety of PF-04965842 and Dupilumab in Adult Subjects With Moderate to Severe Atopic Dermatitis on Background Topical Therapy (JADE Compare)" at ClinicalTrials.gov
Treprostinil	Treprostinil, sold under the brand names Remodulin for infusion, Orenitram for oral, and Tyvaso for inhalation, is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Treprostinil is a synthetic analog of prostacyclin (PGI2). Treprostinil was approved for use in the United States in May 2002.The drug can be given in various forms: IV, subcutaneous injection, oral inhalation, as well as oral extended-release tablets. The subcutaneous administration tends to be very painful. Medical uses Treprostinil is indicated for the treatment of pulmonary arterial hypertension in people with NYHA Class II-IV symptoms to diminish symptoms associated with exercise. It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted. This medication is also available in inhaled and tablet forms. In people with pulmonary arterial hypertension requiring transition from epoprostenol sodium (Flolan), treprostinil is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. Treprostinil therapy may be effective in treating Degos disease. Adverse effects Since treprostinil is a vasodilator, its antihypertensive effect may be compounded by other medications that affect the blood pressure, including calcium channel blockers, diuretics, and other vasodilating agents. Because of treprostinils inhibiting effect on platelet aggregation, there is an increased risk of bleeding, especially among patients who are also taking anticoagulants. It is not known whether treprostinil is excreted in breast milk. Caution is advised when administering this medication to nursing women. Caution is advised when administering treprostinil to patients who have impaired kidney or liver function.Common side effects depending on route of administration: 85% of patients report pain or other reaction at the infusion site. Other side effects may include headache, cough, throat irritation, diarrhea, nausea, rash, jaw pain, vasodilatation, dizziness, edema (swelling), pruritus (itching), and hypotension.Warnings: Abrupt interruption of the treprostinil infusion can lead to worsening of pulmonary hypertension symptoms, and should be avoided. Pharmacology Mechanism of action Treprostinil binds to the IP receptor in the lung tissue which will cause G protein activation and lead to three major effects: vasodilation, decreased cell proliferation and inhibition of platelet aggregation. Pharmacokinetics The pharmacokinetics of continuous subcutaneous treprostinil are linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250 pg/m) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 ng/kg/min has not been studied. Treprostinil is substantially metabolized by the liver, but the involved enzymes are not currently known. Five metabolites (HU1 through HU5) have been described thus far. Based on the results of in vitro human hepatic cytochrome P450 studies, Remodulin does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether Remodulin induces these enzymes has not been studied. Dosage and administration For infusion Treprostinil may be administered as a continuous subcutaneous infusion or continuous intravenous infusion via a small infusion pump that the patient must wear at all times. Treprostinil can be given subcutaneously by continuous infusion using an infusion set connected to an infusion pump, but also may be given intravenously via a central venous catheter if the patient is unable to tolerate subcutaneous administration because of severe site pain or reaction. Remodulin is supplied in 20 mL vials, containing treprostinil in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10 mg/mL. Treprostinil can be administered subcutaneously as supplied. It must be diluted for intravenous infusion with either sterile water or a 0.9% sodium chloride solution prior to administration. The infusion rate is normally initiated at 1.25 ng/kg/min for new patients, but may be reduced to 0.625 ng/kg/min if the normal rate provokes unwanted side effects in the patient. The infusion rate of treprostinil should be increased no more than 1.25 ng/kg/min per week for the first month, then 2.5 ng/kg/min per week for the remaining duration of infusion. The infusion rate should ideally be high enough to improve symptoms of pulmonary hypertension, while minimizing unpleasant side effects (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction). Dosage adjustments may be undertaken more often if tolerated. There is little experience with doses >40 ng/kg/min. Abrupt cessation of infusion should be avoided. Restarting a Remodulin infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Remodulin to be re-titrated. In patients with mild or moderate liver dysfunction, the initial dose of Remodulin should be decreased to 0.625 ng/kg/min ideal body weight and should be increased cautiously. Remodulin has not been studied in patients with severe liver dysfunction. No studies have been performed in patients with kidney dysfunction. No specific advice about dosing in patients with renal impairment can be given. Inhaled form The inhaled form of treprostinil was approved by the FDA in July 2009 and is marketed as the trade name Tyvaso. The inhaled form is used with a proprietary inhalation device supplied by the manufacturer. Patients use one ampule with inhalation solution a day, four times a day at least four hours apart. Oral form The oral form of treprostinil was approved by the FDA in December 2013 and is marketed as the trade name Orenitram. Orenitram is taken 2 or 3 times daily with food. History During the 1960s a U.K. 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 worked by inhibiting the synthesis of prostaglandins. This finding opened the door to a broader understanding of the role of prostaglandins in the body. Vane and a team from the Wellcome Foundation had identified a lipid mediator they called “PG-X,” which inhibited platelet aggregation. PG-X, which later would become known as prostacyclin, was 30 times more potent than any other known anti-aggregatory agent.By 1976, Vane and fellow researcher Salvador Moncada published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthetic molecule which was given the name epoprostenol. But like native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, 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 was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogs.Remodulin was approved for use in the United States in May 2002, and again in July 2018. Tyvaso, the inhaled form of treprostinil, was approved for use in the United States in July 2009. Orenitram was approved in December 2013.Trepulmix was approved for use in the European Union in April 2020. Effect on PPARs Treprostinil has demonstrated an effect on PPAR-γ, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class. References Further reading External links "Treprostinil". Drug Information Portal. U.S. National Library of Medicine.
Angiotensin II (medication)	Angiotensin II (Ang II) is a medication that is used to treat hypotension resulting from septic shock or other distributive shock. It is a synthetic vasoconstrictor peptide that is identical to human hormone angiotensin II and is marketed under the brand name Giapreza. The Food and Drug Administration approved the use of angiotensin II in December 2017 to treat low blood pressure resulting from septic shock.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Angiotensin II is a vasoconstrictor used to increase blood pressure in adults with septic or other distributive shock. Angiotensin II is a naturally occurring hormone secreted as part of the renin-angiotensin system that results in powerful systemic vasoconstriction. The vasopressor effects of angiotensin have been studied since it was first isolated in the late 1930s. Vasopressors are defined as agents that combat vasodilatory shock by inducing peripheral vasoconstriction. Commonly used vasopressors include catecholamine (e.g., dopamine, norepinephrine, epinephrine) and non-catecholamine (e.g., vasopressin). but these agents are not always effective in reversing vasodilatory shock, and their use can be associated with significant side effects including limb ischemia and cardiac arrhythmia. Angiotensin II is as a treatment option that can increase blood pressure and allow catecholamine dose reductions. Angiotensin II must be administered as an intravenous infusion diluted in 0.9% sodium chloride prior to use. The recommended starting dosage of angiotensin II is 20 nanograms (ng)/kg/min via continuous intravenous infusion. Administration through a central venous line is recommended. Monitor blood pressure response and titrate angiotensin II every 5 minutes by increments of up to 15 ng/kg/min as needed to achieve or maintain target blood pressure. Adverse effects Angiotensin II treated patients are at an increased risk of thromboembolic events. There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received angiotensin II compared to placebo treated patients in the ATHOS-3 study [13% (21/163 patients) vs. 5% (8/158 patients)]. It is recommended that patients be on concurrent venous thromboembolism prophylaxis. Other adverse reactions include thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia.Angiotensin II acts on Angiotensin receptor (AT1) on presynaptic adrenergic nerves → release of catecholamine → excessive catecholamine can be harmful as it can cause myocyte necrosis. Interactions Angiotensin II receptor blockers, as their name implies, block the action of angiotensin II at its receptors and therefore may reduce its effects. References External links "Angiotensin II". Drug Information Portal. U.S. National Library of Medicine. "Angiotensin II acetate". Drug Information Portal. U.S. National Library of Medicine.
Thalidomide	Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications of leprosy. While it has been used in a number of HIV-associated conditions, such use is associated with increased levels of the virus. It is administered orally.Common side effects include sleepiness, rash, and dizziness. Severe side effects include tumor lysis syndrome, blood clots, and peripheral neuropathy. Use in pregnancy may harm the fetus, including resulting in malformation of the limbs. In males who are taking the medication, contraception is essential if a partner could become pregnant. It is an immunomodulatory medication and works by a number of mechanisms, including stimulating T cells and decreasing TNF-α production.Thalidomide was first marketed in 1957 in West Germany, where it was available over the counter. When first released, thalidomide was promoted for anxiety, trouble sleeping, "tension", and morning sickness. While it was initially thought to be safe in pregnancy, concerns regarding birth defects arose until the medication was removed from the market in Europe in 1961. The total number of infants affected by use during pregnancy is estimated at 10,000, of whom about 40% died around the time of birth. Those who survived had limb, eye, urinary tract, and heart problems. Its initial entry into the US market was prevented by Frances Kelsey, a reviewer at the FDA. The birth defects caused by thalidomide led to the development of greater drug regulation and monitoring in many countries.It was approved in the United States in 1998 for use as a treatment for cancer. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses Thalidomide is used as a first-line treatment in multiple myeloma in combination with dexamethasone or with melphalan and prednisone to treat acute episodes of erythema nodosum leprosum and for maintenance therapy.The bacterium that causes tuberculosis (TB) is related to leprosy. Thalidomide may be helpful in some cases where standard TB drugs and corticosteroids are not sufficient to resolve severe inflammation in the brain.It is used as a second-line treatment to manage graft versus host disease and aphthous stomatitis in children and has been prescribed for other conditions in children, including actinic prurigo and epidermolysis bullosa; the evidence for these uses is weak. It is recommended only as a third line treatment in graft-versus-host-disease in adults because of lack of efficacy and side effects observed in clinical trials. Contraindications Thalidomide should not be used by men or women who are trying to father or conceive a child, or who cannot or will not follow the risk management program to prevent pregnancies, or by women who are breastfeeding or pregnant. The prescribing doctor is required to ensure that contraception is being used, and regular pregnancy tests are taken. Those allergic to thalidomide should not take it. It should be used with caution in people with chronic infections like HIV or hepatitis B. Adverse effects Thalidomide causes birth defects. The U.S. Food and Drug Administration (FDA) and other regulatory agencies have approved marketing of the drug only with an auditable risk evaluation and mitigation strategy that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to both men and women, as the drug can be transmitted in semen.There is a high risk that thalidomide can cause excessive blood clots. There is also a high risk that thalidomide can interfere with formation of various kinds of new blood cells, creating a risk of infection via neutropenia, leukopenia, and lymphopenia, and risks that blood will not clot via thrombocytopenia. There is also a risk of anemia via lack of red blood cells. The drug can also damage nerves, causing potentially irreversible peripheral neuropathy.Thalidomide has several adverse cardiovascular effects, including risk of heart attacks, pulmonary hypertension, and changes in heart rhythm, such as syncope, bradycardia, and atrioventricular block.Thalidomide can cause liver damage and severe skin reactions like Stevens–Johnson syndrome. It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause tumor lysis syndrome. Thalidomide can prevent menstruation.In addition, very common (reported in more than 10% of people) adverse effects include tremor, dizziness, tingling, numbness, constipation, and peripheral edema.Common adverse effects (reported by 1–10% of people) include confusion, depressed mood, reduced coordination, heart failure, difficulty breathing, interstitial lung disease, lung inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness, and a sense of unwellness. Interactions There are no expected pharmacokinetic interactions between thalidomide and other medicines due to its neutral effects on P-glycoprotein and the cytochrome P450 family. It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, due to its bradycardia-inducing effects. The risk of peripheral neuropathy may be increased by concomitant treatment with other agents known to cause peripheral neuropathy. The risk of venous thromboembolisms with thalidomide seems to be increased when patients are treated with oral contraceptives or other cytotoxic agents (including doxorubicin and melphalan) concurrently. Thalidomide may interfere with various contraceptives, and hence it is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are taking thalidomide. Overdose As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4 grams, none of them fatal. No specific antidote for overdose exists and treatment is purely supportive. Pharmacology The precise mechanism of action for thalidomide is not known, although efforts to identify thalidomides teratogenic action generated 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000. As of 2015, the main theories were inhibition of the process of angiogenesis, its inhibition of cereblon, a ubiquitin ligase, and its ability to generate reactive oxygen species which in turn kills cells. In 2018, results were first published which suggested that thalidomides teratogenic effects are mediated through degradation of the transcription factor, SALL4, an as yet unverified finding.Thalidomide also binds to and acts as an antagonist of the androgen receptor (AR) and hence is a nonsteroidal antiandrogen (NSAA) of some capacity. In accordance, it can produce gynecomastia and sexual dysfunction as side effects in men. Chirality and biological activity Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood. The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effect. The hypothesis that the tragedy could be avoided in this case by using a single enantiomer is misleading and pointless, because it was later demonstrated that the “safe” R-thalidomide undergoes an in vivo chiral inversion to the “teratogenic” S-thalidomide. Under biological conditions, the enantiomers interconvert [bidirectional chiral inversion - (R)- to (S)- and vice versa]. Chemistry Thalidomide is racemic; while S-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent. The racemization process can occur in vivo. The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion.Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L-glutamic acid treatment, but this has since been reformed by the use of L-glutamine. As shown in the image below, N-carbethoxyphthalimide (1) can react with L-glutamine to yield N-phthaloyl-L-glutamine (2). Cyclization of N-phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide (3). Celgene Corporations original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure. History In 1952, thalidomide was synthesised by Chemical Industry Basel (CIBA), but was found "to have no effect on animals and was discarded" on that basis. In 1957, it was acquired by Chemie Grünenthal in Germany. The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics. Heinrich Mückter was appointed to head the discovery program based on his experience working with the German armys antiviral research. While preparing reagents for the work, Mueckters assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of glutethimide, a sedative. The medicinal chemistry work turned to improving the lead compound into a suitable drug: the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women.Researchers at Chemie Grünenthal found that thalidomide was a particularly effective antiemetic that had an inhibitory effect on morning sickness. On 1 October 1957, the company launched thalidomide and began marketing it under the trade name Contergan. It was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches.During that period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus. Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drugs development, scientists did not believe any drug taken by a pregnant woman could pass across the placental barrier and harm the developing fetus. There soon appeared reports of abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that peripheral neuritis developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over the counter.While initially considered safe, the drug was responsible for teratogenic deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany. The regulatory authorities in East Germany never approved thalidomide. One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested for toxicity on rodents only, as was usual at the time.In the UK, the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of Diageo plc), marketed thalidomide throughout the UK, Australia and New Zealand, under the brand name Distaval, as a remedy for morning sickness. Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child ... Outstandingly safe Distaval has been prescribed for nearly three years in this country." Globally, more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. By the mid-1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least 37 different trade names. In the US, representatives from Chemie Grünenthal approached Smith, Kline & French (SKF), now GlaxoSmithKline (GSK), with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in the archives of the FDA, shows that in 1956–57, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women. In 1956, researchers involved in clinical trials at SKF noted that, even when used in very high doses, thalidomide could not induce sleep in mice. And when administered at doses 50 to 650 times larger than that claimed by Chemie Grünenthal to be "sleep inducing", the researchers could still not achieve the hypnotic effect in animals that it had on humans. After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. In 1958, Chemie Grünenthal reached an agreement with William S Merrell Company in Cincinnati, Ohio (later Richardson-Merrell, now part of Sanofi), to market and distribute thalidomide throughout the US.The US FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes, after the American distributor and manufacturer Richardson-Merrell had applied for its approval in September 1960. The official in charge of the FDA review, Frances Oldham Kelsey, did not rely on information from the company, which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company demanded approval six times, and was refused each time. Nevertheless, a total of 17 children with thalidomide-induced malformations were born in the US. Oldham Kelsey was given a Presidential award for distinguished service from the federal government for not allowing thalidomide to be approved for sale in the U.S.In Canada, the history of thalidomide dates back to April 1961. There were many different forms sold, with the most common variant being called Talimol. Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects. It was not until March 1962, that both drugs were banned from the Canadian market by the FDD and, soon afterward, physicians were warned to destroy their supplies. Leprosy treatment In 1964, Israeli physician Jacob Sheskin administered thalidomide to a patient critically ill with leprosy. The patient exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. The treatment was attempted despite the ban on thalidomides use, and results were favourable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed.Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965. Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue, with at least 100 cases identified in Brazil between 2005 and 2010. 5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with poor access to healthcare, and these cases have occurred despite the controls. In 1998, the FDA approved the drugs use in the treatment of ENL. Because of thalidomides potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name Thalomid, establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under the program include limiting prescription and dispensing rights to authorized prescribers and pharmacies only, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug.In 2010, the World Health Organization (WHO) stated that it did not recommend thalidomide for leprosy due to the difficulty of adequately controlling its use, and due to the availability of clofazimine. Cancer treatment Shortly after the teratogenic properties of thalidomide were recognized in the mid-1960s, its anti-cancer potential was explored and two clinical trials were conducted in people with advanced cancer, including some people with multiple myeloma; the trials were inconclusive.Little further work was done with thalidomide in cancer until the 1990s.Judah Folkman pioneered studies into the role of angiogenesis (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that solid tumors could not expand without it. In 1993 he surprised the scientific world by hypothesizing the same was true of blood cancers, and the next year he published work showing that a biomarker of angiogenesis was higher in all people with cancer, but especially high in people with blood cancers, and other evidence emerged as well. Meanwhile, a member of his lab, Robert DAmato, who was looking for angiogenesis inhibitors, discovered in 1994 that thalidomide inhibited angiogenesis and was effective in suppressing tumor growth in rabbits. Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas. Folkman persuaded the patients doctor to try thalidomide, and that doctor conducted a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment. The results of that trial were published in the New England Journal of Medicine in 1999.After further work was done by Celgene and others, in 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.It was also evaluated whether thalidomide can be combined with melphalan and prednisone for patients with multiple myeloma. This combination of drugs probably results in an increase of the overall survival. Society and culture Birth defect crisis In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as phocomelia, as a consequence of thalidomide use. The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment; thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28. Thalidomide did not damage the fetus if taken after 42 days gestation.It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000. Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962. Notable cases Lorraine Mercer MBE of the United Kingdom, born with phocomelia of both arms and legs, is the only thalidomide survivor to carry the Olympic Torch. Thomas Quasthoff, an internationally acclaimed bass-baritone, who describes himself: "1.34 meters tall, short arms, seven fingers — four right, three left — large, relatively well-formed head, brown eyes, distinctive lips; profession: singer". Niko von Glasow produced a documentary called NoBodys Perfect, based on the lives of 12 people affected by the drug, which was released in 2008. Mercédes Benegbi, born with phocomelia of both arms, drove the successful campaign for compensation from her government for Canadians who were affected by thalidomide. Mat Fraser, born with phocomelia of both arms, is an English rock musician, actor, writer and performance artist. He produced a 2002 television documentary "Born Freak", which looked at this historical tradition and its relevance to modern disabled performers. This work has become the subject of academic analysis in the field of disability studies. Change in drug regulations The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962 Kefauver Harris Amendment (U.S.), 1965 Directive 65/65/EEC1 (E.U.), and the Medicines Act 1968 (UK). In the United States, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all side effects encountered in testing. The FDA subsequently initiated the Drug Efficacy Study Implementation to reclassify drugs already on the market. Quality of life In the 1960s, thalidomide was successfully marketed as a safer alternative to barbiturates. Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a teratogenic substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE). Of these babies born with TE, "about 40% of them died before their first birthday". The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE. Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. Access to health care services can also be a challenge for these people, and women in particular have experienced difficulty in locating healthcare professionals who can understand and embrace their needs. Brand names Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval and many others. Research Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide. Thalidomide analogs The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression. In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide, is now FDA approved. Additionally, apremilast was approved by the FDA in March 2014. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.Interest turned to pomalidomide, a derivative of thalidomide marketed by Celgene. It is a very active anti-angiogenic agent and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma. It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand name Imnovid. Clinical research There is no conclusive evidence that thalidomide or lenalidomide is useful to bring about or maintain remission in Crohns disease.Thalidomide was studied in a Phase II trial for Kaposis sarcoma, a rare soft-tissue cancer most commonly seen in the immunocompromised, that is caused by the Kaposis sarcoma-associated herpesvirus (KSHV). References Further reading External links "Thalidomide". Drug Information Portal. U.S. National Library of Medicine. Daemmrich A (7 December 2015). "Remind me again, what is thalidomide and how did it cause so much harm". The Conversation.
Sulfadiazine	Sulfadiazine is an antibiotic. Used together with pyrimethamine, a dihydrofolate reductase inhibitor, it is the treatment of choice for toxoplasmosis, which is caused by a protozoan parasite. It is a second-line treatment for otitis media, prophylaxis of rheumatic fever, chancroid, chlamydia, and infections by Haemophilus influenzae. It is also used as adjunct therapy for chloroquine-resistant malaria and several forms of bacterial meningitis. It is taken by mouth. Sulfadiazine is available in multiple generic tablets of 500 mg. For urinary tract infections, the usual dose is 4 to 6 grams daily in 3 to 6 divided doses.Common side effects include nausea, diarrhea, headache, fever, rash, depression, and pancreatitis. It should not be used in people who have severe liver problems, kidney problems, or porphyria. If used during pregnancy, it may increase the risk of kernicterus in the baby. While the company that makes it does not recommend use during breastfeeding, use is believed to be safe if the baby is otherwise healthy. It is in the sulfonamide class of medications.Sulfadiazine was approved for medical use in the United States in 1941. It is on the World Health Organizations List of Essential Medicines. Sulfadiazine is available as a generic medication. Medical uses It eliminates bacteria that cause infections by stopping the production of folate inside the bacterial cell, and is commonly used to treat urinary tract infections and burns. In combination, sulfadiazine and pyrimethamine can be used to treat toxoplasmosis, the disease caused by Toxoplasma gondii. Mechanism of action Sulfadiazine works by inhibiting the enzyme dihydropteroate synthetase. Side effects Side effects reported for sulfadiazine include nausea, loss of appetite, dizziness, gastrointestinal upset, rash and fever. Brand names This drug is sold branded as Lantrisul, Neotrizine, Sulfa-Triple #2, Sulfadiazine, Sulfaloid, Sulfonamides Duplex, Sulfose, Terfonyl, Triple Sulfa, Triple Sulfas, and Triple Sulfoid. See also Silver sulfadiazine References External links "Sulfadiazine". Drug Information Portal. U.S. National Library of Medicine.
Damoctocog alfa pegol	Damoctocog alfa pegol, sold under the brand name Jivi is a recombinant DNA-derived, Factor VIII concentrate medication used to treat hemophilia A.The most common side effects include headache, cough, nausea and fever.Damoctocog alfa pegol (antihemophilic factor- recombinant pegylated-aucl) was approved for medical use in the United States in August 2018, and in the European Union in November 2018. Medical uses In the United States damoctocog alfa pegol is indicated for use in previously treated adults and adolescents (twelve years of age and older) with hemophilia A (congenital Factor VIII deficiency) for: (1) On-demand treatment and control of bleeding episodes ; (2) Perioperative management of bleeding; (3) Routine prophylaxis to reduce the frequency of bleeding episodes.In the European Union, damoctocog alfa pegol is indicated for the treatment and prophylaxis of bleeding in previously treated people twelve years of age and older with haemophilia A (congenital factor VIII deficiency). References External links "Damoctocog alfa pegol". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT01184820 for "Trial to Evaluate the Pharmacokinetics and Safety Profile of BAY94-9027 Following Single and Multiple Dose Administration" at ClinicalTrials.gov Clinical trial number NCT01580293 for "A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A (PROTECT-VIII)" at ClinicalTrials.gov Clinical trial number NCT01775618 for "Safety and Efficacy of BAY94-9027 in Previously Treated Male Children With Haemophilia A" at ClinicalTrials.gov
Necitumumab	Necitumumab (INN) is a recombinant human IgG1 monoclonal antibody used as an antineoplastic, which is manufactured by Eli Lilly. It binds to the epidermal growth factor receptor (EGFR). The US FDA approved necitumumab under the brand name Portrazza for use with gemcitabine and cisplatin in previously untreated metastatic squamous non-small-cell lung carcinoma (NSCLC). It was counterproductive in non-squamous non-small-cell lung carcinoma. == References ==
Caffeine citrate	Caffeine citrate, sold under the brand name Cafcit among others, is a medication used to treat a lack of breathing in premature babies. Specifically it is given to babies who are born at less than 35 weeks or weigh less than 2 kilograms (4.4 lb) once other causes are ruled out. It is given by mouth or slow injection into a vein.Side effects can include problems feeding, increased heart rate, low blood sugar, necrotizing enterocolitis, and kidney problems. Testing blood caffeine levels is occasionally recommended. Although it is often referred to as a citric acid salt of caffeine, as implied by its name, caffeine citrate in fact consists of cocrystals of the two components. Caffeine citrate is in the xanthine family of medication. It works by stimulating the respiratory centers in the brain.Caffeine was discovered in 1819. It is on the World Health Organizations List of Essential Medicines. The intravenous form may also be taken by mouth.In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Gencebok. It was approved for use in the European Union in August 2020. Medical uses Caffeine citrate is generally the preferred treatment for apnea of prematurity for infants born 28 to 32 weeks or earlier than 28 weeks. It has fewer side effects as compared to theophylline.Caffeine improves airway function in asthma, increasing forced expiratory volume (FEV1) by 5% to 18%, with this effect lasting for up to four hours. Mechanism In method of action, the preparation is identical to that of caffeine base as the citrate counter ion dissociates in water. Doses of caffeine citrate, due to the added weight of the citrate moiety, are understandably higher than with caffeine base, i.e., it takes a larger dose to get the same amount of caffeine. The ratio of therapeutic doses of caffeine base to its citrate salt is typically 1:2. Dosing should therefore be clearly distinguished. Manufacture The drug is prepared by combining anhydrous caffeine with citric acid monohydrate and sodium citrate dihydrate. Caffeine citrate cocrystals can take on at least two anhydrous polymorphs. References External links "Caffeine citrate". Drug Information Portal. U.S. National Library of Medicine. "Caffeine Citrate (CUI C0054436)". NCI Metathesaurus.
Zoledronic acid	Zoledronic acid, also known as zoledronate and sold under the brand name Zometa by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Pagets disease of bone and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.Common side effects include fever, joint pain, high blood pressure, diarrhea, and feeling tired. Serious side effects may include kidney problems, low blood calcium, and osteonecrosis of the jaw. Use during pregnancy may result in harm to the baby. It is in the bisphosphonate family of medications. It works by blocking the activity of osteoclast cells and thus decreases the breakdown of bone.Zoledronic acid was patented in 1986 and approved for medical use in the United States in 2001. It is on the World Health Organizations List of Essential Medicines. Medical uses Bone complications of cancer Zoledronic acid is used to prevent bone fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis. It can also be used to treat hypercalcaemia of malignancy and can be helpful for treating pain from bone metastases.It can be given at home rather than in hospital. Such use has shown safety and quality-of-life benefits in people with breast cancer and bone metastases. Osteoporosis Zoledronic acid, in brand name products Aclasta and Reclast among others, may be given as a 5 mg infusion once per year for treatment of osteoporosis in men and post-menopausal women at increased risk of fracture.In 2007, the U.S. Food and Drug Administration (FDA) also approved it for the treatment of postmenopausal osteoporosis. Other Zoledronic acid may be used for treatment of osteogenesis imperfecta.A single 5 mg dose of zoledronic acid is used for the treatment of Pagets disease. Contraindications Poor kidney function (e.g. estimated glomerular filtration rate less than 30 mL/min) Hypocalcaemia Pregnancy Paralysis Side effects Side effects can include fatigue, anemia, muscle aches, fever, and/or swelling in the feet or legs. Flu-like symptoms are common after the first infusion, although not subsequent infusions, and are thought to occur because of its potential to activate human gamma delta T cell (γδ T cells). Kidneys There is a risk of severe renal impairment. Appropriate hydration is important before administration, as is adequate calcium and vitamin D intake before Aclasta therapy in patients with hypocalcaemia, and for ten days following Aclasta in patients with Pagets disease of the bone. Monitoring for other mineral metabolism disorders and the avoidance of invasive dental procedures for those who develop osteonecrosis of the jaw is recommended.Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease. Some cases of acute kidney injury either requiring dialysis or having a fatal outcome following Reclast use have been reported to the U.S. Food and Drug Administration (FDA). This assessment was confirmed by the European Medicines Agency (EMA), whose Committee for Medicinal Products for Human Use (CHMP) specified new contraindications for the medication on 15 December 2011, which include hypocalcaemia and severe renal impairment with a creatinine clearance of less than 35 ml/min. Bone Osteonecrosis of the jaw A rare complication that has been recently observed in cancer patients being treated with bisphosphonates is osteonecrosis of the jaw. This has mainly been seen in patients with multiple myeloma treated with zoledronic acid who have had dental extractions. Atypical fractures After approving the drug on 8 July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including zoledronic acid, after several cases of atypical fractures were reported. In 2008, the EMAs Pharmacovigilance Working Party (PhVWP) noted that alendronic acid was associated with an increased risk of atypical fracture of the femur that developed with low or no trauma. In April 2010, the PhVWP noted that further data from both the published literature and post-marketing reports were now available which suggested that atypical stress fractures of the femur may be a class effect. The European Medicines Agency then reviewed all case reports of stress fractures in patients treated with bisphosphonates, relevant data from the published literature, and data provided by the companies which market bisphosphonates. The Agency recommended that doctors who prescribe bisphosphonate-containing medicines should be aware that atypical fractures may occur rarely in the femur, especially after long-term use, and that doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use. Pharmacology As a nitrogenous bisphosphonate, Zoledronic acid is a potent inhibitor of bone resorption, allowing the bone-forming cells time to rebuild normal bone and allowing bone remodeling. Research Zoledronic acid has been found to have a direct antitumor effect and to synergistically augment the effects of other antitumor agents in osteosarcoma cells.Zoledronic acid has shown significant benefits versus placebo over three years, with a reduced number of vertebral fractures and improved markers of bone density. An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.Zoledronic acid also attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function. With hormone therapy for breast cancer An increase in disease-free survival (DFS) was found in the ABCSG-12 trial, in which 1,803 premenopausal women with endocrine-responsive early breast cancer received anastrozole with zoledronic acid. A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.In a meta-analysis of trials where upfront zoledronic acid was given to prevent aromatase inhibitor-associated bone loss, active cancer recurrence appeared to be reduced.As of 2010 "The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanism of action and antitumoral activity of bisphosphonates."A 2010 review concluded that "adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer ... is cost-effective from a US health care system perspective". References External links "Zoledronic acid". Drug Information Portal. U.S. National Library of Medicine.
Insulin (medication)	As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin is also used along with glucose to treat hyperkalemia (high blood potassium levels). Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle. There are various types of insulin, suitable for various time spans. The types are often all called insulin in the broad sense, although in a more precise sense, insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action. It is on the World Health Organizations List of Essential Medicines. In 2019, regular human insulin was the 298th most commonly prescribed medication in the United States, with more than 1 million prescriptions.Insulin can be made from the pancreas of pigs or cows. Human versions can be made either by modifying pig versions or recombinant technology. It comes in three main types: short–acting (such as regular insulin), intermediate-acting (such as neutral protamine Hagedorn (NPH) insulin), and longer-acting (such as insulin glargine). History Insulin was first used as a medication in Canada by Charles Best and Frederick Banting in 1922.This is a chronology of key milestones in the history of the medical use of insulin. For more details on the discovery, extraction, purification, clinical use, and synthesis of insulin, see Insulin 1921 Research on the role of pancreas in the nutritive assimilation 1922 Frederick Banting, Charles Best and James Collip use bovine insulin extract in humans at Connaught Laboratories in Toronto, Canada. 1922 Leonard Thompson becomes the first human to be treated with insulin. 1922 James D. Havens, son of former congressman James S. Havens, becomes the first American to be treated with insulin. 1922 Elizabeth Hughes Gossett, daughter of the U.S. Secretary of State, becomes the first American to be (officially) treated in Toronto. 1923 Eli Lilly produces commercial quantities of much purer bovine insulin than Banting et al. had used 1923 Farbwerke Hoechst, one of the forerunners of todays Sanofi Aventis, produces commercial quantities of bovine insulin in Germany 1923 Hans Christian Hagedorn founds the Nordisk Insulinlaboratorium in Denmark – forerunner of todays Novo Nordisk 1923 Constance Collier returns to health after being successfully treated with insulin in Strasbourg 1926 Nordisk receives a Danish charter to produce insulin as a non-profit 1936 Canadians David M. Scott and Albert M. Fisher formulate a zinc insulin mixture at Connaught Laboratories in Toronto and license it to Novo 1936 Hagedorn discovers that adding protamine to insulin prolongs the duration of action of insulin 1946 Nordisk formulates Isophane porcine insulin aka Neutral Protamine Hagedorn or NPH insulin 1946 Nordisk crystallizes a protamine and insulin mixture 1950 Nordisk markets NPH insulin 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer lasting insulin 1955 Frederick Sanger determines the amino acid sequence of insulin 1965 Synthesized by total synthesis by Wang Yinglai, Chen-Lu Tsou, et al. 1969 Dorothy Crowfoot Hodgkin solves the crystal structure of insulin by X-ray crystallography 1973 Purified monocomponent (MC) insulin is introduced 1973 The U.S. officially "standardized" insulin sold for human use in the U.S. to U-100 (100 units per milliliter). Prior to that, insulin was sold in different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so the effort to "standardize" the potency aimed to reduce dosage errors and ease doctors job of prescribing insulin for people. Other countries also followed suit. 1978 Genentech produces biosynthetic human insulin in Escherichia coli bacteria using recombinant DNA techniques, licenses to Eli Lilly 1981 Novo Nordisk chemically and enzymatically converts porcine to human insulin 1982 Genentech synthetic human insulin (above) approved 1983 Eli Lilly and Company produces biosynthetic human insulin with recombinant DNA technology, Humulin 1985 Axel Ullrich sequences a human cell membrane insulin receptor. 1988 Novo Nordisk produces recombinant biosynthetic human insulin 1996 Lilly Humalog "lispro" insulin analogue approved. 2000 Sanofi Aventis Lantus insulin "glargine" analogue approved for clinical use in the US and Europe. 2004 Sanofi Aventis Apidra insulin "glulisine" insulin analogue approved for clinical use in the US. 2006 Novo Nordisk Levemir "detemir" insulin analogue approved for clinical use in the US. Medical uses Insulin is used to treat a number of diseases including diabetes and its acute complications such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. It is also used along with glucose to treat high blood potassium levels. Use during pregnancy is relatively safe for the baby. Insulin was formerly used in a psychiatric treatment called insulin shock therapy. Side effects Some side effects are hypoglycemia (low blood sugar), hypokalemia (low blood potassium), and allergic reactions. Allergy to insulin affected about 2% of people, of which most reactions are not due to the insulin itself but to preservatives added to insulin such as zinc, protamine, and meta-cresol. Most reactions are Type I hypersensitivity reactions and rarely cause anaphylaxis. A suspected allergy to insulin can be confirmed by skin prick testing, patch testing and occasionally skin biopsy. First line therapy against insulin hypersensitivity reactions include symptomatic therapy with antihistamines. The affected persons are then switched to a preparation that does not contain the specific agent they are reacting to or undergo desensitization.Cutaneous adverse effects Other side effects may include pain or skin changes at the sites of injection. Repeated subcutaneous injection without site rotation can lead to lipohypertrophy and amyloidomas, which manifest as firm palpable nodules under the skin. Principles Insulin is an endogenous hormone, which is produced by the pancreas. The insulin protein has been highly conserved across evolutionary time, and is present in both mammals and invertebrates. The insulin/insulin-like growth factor signalling pathway (IIS) has been extensively studied in species including nematode worms (e.g.C. elegans), flies (Drosophila melanogaster) and mice (Mus musculus). Its mechanisms of action are highly similar across species.Both type 1 diabetes and type 2 diabetes are marked by a loss of pancreatic function, though to differing degrees. People who are affected with diabetes are referred to as diabetics. Many diabetics require an exogenous source of insulin to keep their blood sugar levels within a safe target range.In 1916, Nicolae C. Paulescu (1869-1931) succeeded in developing an aqueous pancreatic extract that normalized a diabetic dog. In 1921, he published 4 papers in the Society of Biology in Paris centering on the successful effects of the pancreatic extract in diabetic dogs. Research on the Role of the Pancreas in Food Assimilation by Paulescu was published in August 1921 in the Archives Internationales de Physiologie, Liège, Belgium. Initially, the only way to obtain insulin for clinical use was to extract it from the pancreas of another creature. Animal glands were obtainable as a waste product of the meatpacking industry. Insulin was derived primarily from cows (Eli Lilly and Company) and pigs (Nordisk Insulinlaboratorium). The making of eight ounces of purified insulin could require as much as two tons of pig parts. Insulin from these sources is effective in humans as it is highly similar to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Initially, lower preparation purity resulted in allergic reactions to the presence of non-insulin substances. Purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods. Minor allergic reactions still occur occasionally, even to synthetic "human" insulin varieties.Beginning in 1982, biosynthetic "human" insulin has been manufactured for clinical use through genetic engineering techniques using recombinant DNA technology. Genentech developed the technique used to produce the first such insulin, Humulin, but did not commercially market the product themselves. Eli Lilly marketed Humulin in 1982. Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin. Manufacturers claim this reduces the presence of many impurities. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of C-peptide which has in recent years been shown to have systemic effects itself. Novo Nordisk has also developed a genetically engineered insulin independently using a yeast process.According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic human insulin. A majority of insulin used clinically today is produced this way, although clinical experience has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Adverse reactions have been reported; these include loss of warning signs that patients may slip into a coma through hypoglycemia, convulsions, memory lapse and loss of concentration. However, the International Diabetes Federations position statement from 2005 is very clear in stating that "there is NO overwhelming evidence to prefer one species of insulin over another" and "[modern, highly purified] animal insulins remain a perfectly acceptable alternative."Since January 2006, all insulins distributed in the U.S. and some other countries are synthetic "human" insulins or their analogues. A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U.S., although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier, and porcine lente insulin is also sold and marketed under the brand name Vetsulin(SM) in the U.S. for veterinary usage in the treatment of companion animals with diabetes. Basal insulin In type 1 diabetes, insulin production is extremely low, and as such the body requires exogenous insulin. Some people with type 2 diabetes, particularly those with very high hemoglobin A1c values, may also require a baseline rate of insulin, as their body is desensitized to the level of insulin being produced. Basal insulin regulates the bodys blood glucose between mealtimes, as well as overnight. This basal rate of insulin action is generally achieved via the use of an intermediate-acting insulin (such as NPH) or a long-acting insulin analog. In type 1 diabetics, it may also be achieved via continuous infusion of rapid-acting insulin using an insulin pump. Approximately half of a persons daily insulin requirement is administered as a basal insulin, usually administered once per day at night. Prandial insulin When a person eats food containing carbohydrates and glucose, insulin helps regulate the bodys metabolism of the food. Prandial insulin, also called mealtime or bolus insulin, is designed as a bolus dose of insulin prior to a meal to regulate the spike in blood glucose that occurs following a meal. The dose of prandial insulin may be static, or may be calculated by the patient using either their current blood sugar, planned carbohydrate intake, or both. This calculation may also be performed by an insulin pump in patients using a pump. Insulin regiments that consist of doses calculated in this manner are considered intensive insulin regimens. Prandial insulin is usually administered no more than 15–30 minutes prior to a meal using a rapid-acting insulin or a regular insulin. In some patients, a combination insulin may be used that contains both NPH (long acting) insulin and a rapid/regular insulin to provide both a basal insulin and prandial insulin. Challenges in treatment There are several challenges involved in the use of insulin as a clinical treatment for diabetes: Mode of administration. Selecting the right dose and timing. The amount of carbohydrates one unit of insulin handles varies widely between persons and over the day but values between 7 and 20 grams per 1 IE is typical. Selecting an appropriate insulin preparation (typically on speed of onset and duration of action grounds). Adjusting dosage and timing to fit food intake timing, amounts, and types. Adjusting dosage and timing to fit exercise undertaken. Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness. Variability in absorption into the bloodstream via subcutaneous delivery The dosage is non-physiological in that a subcutaneous bolus dose of insulin alone is administered instead of combination of insulin and C-peptide being released gradually and directly into the portal vein. It is simply a nuisance for people to inject whenever they eat carbohydrate or have a high blood glucose reading. It is dangerous in case of mistake (most especially too much insulin). Types Medical preparations of insulin are never just insulin in water (with nothing else). Clinical insulins are mixtures of insulin plus other substances including preservatives. These prevent the protein from spoiling or denaturing too rapidly, delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on.Slight variations of the human insulin molecule are called insulin analogues, (technically "insulin receptor ligands") so named because they are not technically insulin, rather they are analogues which retain the hormones glucose management functionality. They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin (as with insulin lispro, insulin aspart, and insulin glulisine), or steadily absorbed after injection instead of having a peak followed by a more or less rapid decline in insulin action (as with insulin detemir and insulin glargine), all while retaining insulins glucose-lowering action in the human body. However, a number of meta-analyses, including those done by the Cochrane Collaboration in 2005, Germanys Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007, and the Canadian Agency for Drugs and Technology in Health (CADTH) also released in 2007 have shown no unequivocal advantages in clinical use of insulin analogues over more conventional insulin types.Choosing insulin type and dosage/timing should be done by an experienced medical professional working closely with people who are diabetic.The commonly used types of insulin are as follows. Fast-acting Includes the insulin analogues aspart, lispro, and glulisine. These begin to work within 5 to 15 minutes and are active for 3 to 4 hours. Most insulins form hexamers, which delay entry into the blood in active form; these analog insulins do not but have normal insulin activity. Newer varieties are now pending regulatory approval in the U.S. which are designed to work rapidly, but retain the same genetic structure as regular human insulin. Short-acting Includes regular insulin, which begins working within 30 minutes and is active about 5 to 8 hours. Intermediate-acting Includes NPH insulin, which begins working in 1 to 3 hours and is active for 16 to 24 hours. Long-acting Includes the analogues glargine U100 and detemir, each of which begins working within 1 to 2 hours and continues to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals. Ultra-long acting Includes the analogues insulin glargine U300 and degludec, which begin working within 30 to 90 minutes and continues to be active for greater than 24 hours. Combination insulin products Includes a combination of either fast-acting or short-acting insulin with a longer acting insulin, typically an NPH insulin. The combination products begin to work with the shorter acting insulin (5–15 minutes for fast-acting, and 30 minutes for short acting), and remain active for 16 to 24 hours. There are several variations with different proportions of the mixed insulins (e.g. Novolog Mix 70/30 contains 70% aspart protamine [akin to NPH], and 30% aspart.) Methods of administration Unlike many medicines, insulin cannot be taken orally at the present time. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (single amino acid components), whereupon all activity is lost. There has been some research into ways to protect insulin from the digestive tract, so that it can be administered in a pill. So far this is entirely experimental. Subcutaneous Insulin is usually taken as subcutaneous injections by single-use syringes with needles, an insulin pump, or by repeated-use insulin pens with needles. People who wish to reduce repeated skin puncture of insulin injections often use an injection port in conjunction with syringes.The use of subcutaneous injections of insulin is designed to mimic the natural physiological cycle of insulin secretion, while taking into account the various properties of the formulations used such as half-life, onset of action, and duration of action. In many people, both a rapid- or short-acting insulin product as well as an intermediate- or long-acting product are used to decrease the amount of injections per day. In some, insulin injections may be combined with other injection therapy such as GLP-1 agonists. Cleansing of the injection site and injection technique are required to ensure effective insulin therapy. Insulin pump Insulin pumps are a reasonable solution for some. Advantages to the person are better control over background or basal insulin dosage, bolus doses calculated to fractions of a unit, and calculators in the pump that may help with determining bolus infusion dosages. The limitations are cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no "closed loop" means of controlling insulin delivery based on current blood glucose levels.Insulin pumps may be like electrical injectors attached to a temporarily implanted catheter or cannula. Some who cannot achieve adequate glucose control by conventional (or jet) injection are able to do so with the appropriate pump.Indwelling catheters pose the risk of infection and ulceration, and some peoples may also develop lipodystrophy due to the infusion sets. These risks can often be minimized by keeping infusion sites clean. Insulin pumps require care and effort to use correctly. Dosage and timing Dosage units One international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 μg pure crystalline insulin. The first definition of a unit of insulin was the amount required to induce hypoglycemia in a rabbit. This was set by James Collip at the University of Toronto in 1922. Of course, this was dependent on the size and diet of the rabbits. The unit of insulin was set by the insulin committee at the University of Toronto. The unit evolved eventually to the old USP insulin unit, where one unit (U) of insulin was set equal to the amount of insulin required to reduce the concentration of blood glucose in a fasting rabbit to 45 m g/d l (2.5 m mol/L). Once the chemical structure and mass of insulin was known, the unit of insulin was defined by the mass of pure crystalline insulin required to obtain the USP unit. The unit of measurement used in insulin therapy is not part of the International System of Units (abbreviated SI) which is the modern form of the metric system. Instead the pharmacological international unit (IU) is defined by the WHO Expert Committee on Biological Standardization. Potential complications The central problem for those requiring external insulin is picking the right dose of insulin and the right timing. Physiological regulation of blood glucose, as in the non-diabetic, would be best. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage in cells, reduces glycogen to glucose conversion, reducing blood glucose levels, and so reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so, returns to the normal fasting level. Even the best diabetic treatment with synthetic human insulin or even insulin analogs, however administered, falls far short of normal glucose control in the non-diabetic.Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. In addition, fats and proteins cause delays in absorption of glucose from carbohydrates eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same, since working muscle has some ability to take up glucose without the help of insulin.Because of the complex and interacting factors, it is, in principle, impossible to know for certain how much insulin (and which type) is needed to cover a particular meal to achieve a reasonable blood glucose level within an hour or two after eating. Non-diabetics beta cells routinely and automatically manage this by continual glucose level monitoring and insulin release. All such decisions by a diabetic must be based on experience and training (i.e., at the direction of a physician, PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the person. But it is not straightforward and should never be done by habit or routine. With some care however, it can be done reasonably well in clinical practice. For example, some people with diabetes require more insulin after drinking skim milk than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Their particular reaction to skimmed milk is different from other people with diabetes, but the same amount of whole milk is likely to cause a still different reaction even in that person. Whole milk contains considerable fat while skimmed milk has much less. It is a continual balancing act for all people with diabetes, especially for those taking insulin. People with insulin-dependent diabetes typically require some base level of insulin (basal insulin), as well as short-acting insulin to cover meals (bolus also known as mealtime or prandial insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that people with insulin-dependent diabetes must manage each day. This is normally achieved through regular blood tests, although continuous blood sugar testing equipment (Continuous Glucose Monitors or CGMs) are now becoming available which could help to refine this balancing act once widespread usage becomes common. Strategies A long-acting insulin is used to approximate the basal secretion of insulin by the pancreas, which varies in the course of the day. NPH/isophane, lente, ultralente, glargine, and detemir may be used for this purpose. The advantage of NPH is its low cost, the fact that you can mix it with short-acting forms of insulin, thereby minimizing the number of injections that must be administered, and that the activity of NPH will peak 4–6 hours after administration, allowing a bedtime dose to balance the tendency of glucose to rise with the dawn, along with a smaller morning dose to balance the lower afternoon basal need and possibly an afternoon dose to cover evening need. A disadvantage of bedtime NPH is that if not taken late enough (near midnight) to place its peak shortly before dawn, it has the potential of causing hypoglycemia. One theoretical advantage of glargine and detemir is that they only need to be administered once a day, although in practice many people find that neither lasts a full 24 hours. They can be administered at any time during the day as well, provided that they are given at the same time every day. Another advantage of long-acting insulins is that the basal component of an insulin regimen (providing a minimum level of insulin throughout the day) can be decoupled from the prandial or bolus component (providing mealtime coverage via ultra-short-acting insulins), while regimens using NPH and regular insulin have the disadvantage that any dose adjustment affects both basal and prandial coverage. Glargine and detemir are significantly more expensive than NPH, lente and ultralente, and they cannot be mixed with other forms of insulin.A short-acting insulin is used to simulate the endogenous insulin surge produced in anticipation of eating. Regular insulin, lispro, aspart and glulisine can be used for this purpose. Regular insulin should be given with about a 30-minute lead-time prior to the meal to be maximally effective and to minimize the possibility of hypoglycemia. Lispro, aspart and glulisine are approved for dosage with the first bite of the meal, and may even be effective if given after completing the meal. The short-acting insulin is also used to correct hyperglycemia.The usual schedule for checking fingerstick blood glucose and administering insulin is before all meals and sometimes also at bedtime. More recent guidelines also call for a check 2 hours after a meal to ensure the meal has been covered effectively. Sliding scales First described in 1934, what physicians typically refer to as sliding-scale insulin (SSI) is fast- or rapid-acting insulin only, given subcutaneously, typically at meal times and sometimes bedtime, but only when blood glucose is above a threshold (e.g. 10 mmol/L, 180 mg/dL). The so-called "sliding-scale" method is widely taught, although it has been heavily criticized. Sliding scale insulin (SSI) is not an effective way of managing long-term diabetes in individuals residing in nursing homes. Sliding scale insulin leads to greater discomfort and increased nursing time. Sample regimen using insulin glargine and insulin lispro: Insulin glargine: 20 units at bedtime Carb counting and DAFNE A more complicated method that allows greater freedom with meal times and snacks is "carb counting." This approach is taught to people who are diabetic in the UK and elsewhere as "Dose Adjustment For Normal Eating" or DAFNE. In Europe, people who are not familiar with the DAFNE regime can take an educational course where the basic starting insulin dose guideline is "for every 10g of carbohydrates you eat, take 1 unit of insulin". DAFNE courses also cover topics that naturally work alongside this regime, such as blood glucose monitoring, exercise and carbohydrate estimation to help the person work out their personal control requirements. People can also use their total daily dose (TDD) of insulin to estimate how many grams of carbohydrates will be "covered" by 1 unit of insulin, and using this result, estimate how many units of insulin should be administered depending on the carbohydrate content of their meal. For example, if the person determines that 1 unit of insulin will cover 15 grams of carbohydrates, then they must administer 5 units of insulin before consuming a meal that contains 75 grams of carbohydrates. Some alternative methods also consider the protein content of the meal (since excess dietary protein can be converted to glucose via gluconeogenesis). With DAFNE, most dosages involve a fair degree of guesswork, especially with non-labeled foods, and will only work fairly consistently from one dosage to the next if the person is aware of their bodys requirements. For example, a person finds they can take 1 unit of insulin to 10g of carbohydrates in the morning and the evening, but find that their body requires more insulin for a meal in the middle of the day so they have to adjust to 1 unit per 8.5g of carbohydrates. Other less obvious factors that affect the bodys use of insulin must also
Insulin (medication)	be taken into account. For example, some people may find that their bodies process insulin better on hot days so require less insulin. With this, the person again has to adjust their dose to the best of their understanding from their past experiences. The DAFNE regime requires the person to learn about their bodys needs through experience, which takes time and patience, but it can then become effective. Closed-loop predictive modeling People with fluctuating insulin requirements may benefit from a closed-loop predictive modeling approach. As an extension on "carb counting", in this closed-loop predictive modeling approach, the four daily insulin dosages needed to reach the target blood sugar levels for the "normal" daily carbohydrate consumption and amount of physical activity, are continuously adjusted based on the pre-meal and pre-night blood sugar level readings. Each new blood sugar reading provides the feedback to fine-tune and track the bodys insulin requirements. Within this strategy, the key specific factors, which have to be determined experimentally, are the blood sugar correction factor and the carbohydrate ratio. The blood sugar correction factor sets both the "proportional gain" and "integral gain" factors for the four feedback loops. When taken too low, deviations from the target blood sugar level are not corrected for effectively, when taken too high, the blood sugar regulation will become unstable. Since in this approach, the carbohydrate ratio is only used to account for non-standard carbohydrate intakes, it is usually not required to work with meal specific ratios. Dose calculation Insulin dosage is given by the formula i n s u l i n = g l u c o s e − T R C F + c a r b o h y d r a t e s K F = ( K F × ( g l u c o s e − T R ) ) + ( C F × c a r b o h y d r a t e s ) C F × K F {\displaystyle \mathrm {insulin} ={\frac {\mathrm {glucose} -{\mathit {TR}}}{\mathit {CF}}}+{\frac {\mathrm {carbohydrates} }{\mathit {KF}}}={\frac {{({\mathit {KF}}}\times (\mathrm {glucose} -{\mathit {TR}}))+({\mathit {CF}}\times \mathrm {carbohydrates} )}{{\mathit {CF}}\times {\mathit {KF}}}}} based on the persons blood glucose and carbohydrate intake and these constants: TR = target rate CF = corrective factor KF = carbohydrate factorBlood glucose and target rate are expressed in mg/dL or mmol/L. Constants should be set by a physician or clinical pharmacist. Abuse The abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death when the amount used is in excess of that required to handle ingested carbohydrate. Acute risks include brain damage, paralysis, and death. Symptoms may include dizziness, weakness, trembling, palpitations, seizures, confusion, headache, drowsiness, coma, diaphoresis and nausea. All persons with overdoses should be referred for medical assessment and treatment, which may last for hours or days.Data from the US National Poison Data System (2013) indicates that 89.3% of insulin cases reported to poison centers are unintentional, as a result of therapeutic error. Another 10% of cases are intentional, and may reflect attempted suicide, abuse, criminal intent, secondary gain or other unknown reasons. Hypoglycemia that has been induced by exogenous insulin can be chemically detected by examining the ratio of insulin to C-peptide in peripheral circulation. It has been suggested that this type of approach could be used to detect exogenous insulin abuse by athletes.The possibility of using insulin in an attempt to improve athletic performance was suggested as early as the 1998 Winter Olympics in Nagano, Japan, as reported by Peter Sönksen in the July 2001 issue of Journal of Endocrinology. The question of whether non-diabetic athletes could legally use insulin was raised by a Russian medical officer. Whether insulin would actually improve athletic performance is unclear, but concerns about its use led the International Olympic Committee to ban use of the hormone by non-diabetic athletes in 1998.The book Game of Shadows (2001), by reporters Mark Fainaru-Wada and Lance Williams, included allegations that baseball player Barry Bonds used insulin (as well as other drugs) in the apparent belief that it would increase the effectiveness of the growth hormone he was alleged to be taking. Bonds eventually testified in front of a federal grand jury as part of a government investigation of BALCO.Bodybuilders in particular are claimed to be using exogenous insulin and other drugs in the belief that they will increase muscle mass. Bodybuilders have been described as injecting up to 10 IU of regular synthetic insulin before eating sugary meals. A 2008 report suggested that insulin is sometimes used in combination with anabolic steroids and growth hormone (GH), and that "Athletes are exposing themselves to potential harm by self‐administering large doses of GH, IGF‐I and insulin". Insulin abuse has been mentioned as a possible factor in the deaths of bodybuilders Ghent Wakefield and Rich Piana.Insulin, human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) are self-administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone. Their rationale is that since insulin and HGH act synergistically to promote growth, and since IGF-1 is a primary mediator of musculoskeletal growth, the stacking of insulin, HGH and IGF-1 should offer a synergistic growth effect on skeletal muscle. This theory has been supported in recent years by top-level bodybuilders whose competition weight is in excess of 50 lb (23 kg) of muscle, larger than that of competitors in the past, and with even lower levels of body fat. Detection in biological fluids Insulin is often measured in serum, plasma or blood in order to monitor therapy in people who are diabetic, confirm a diagnosis of poisoning in hospitalized persons or assist in a medicolegal investigation of suspicious death. Interpretation of the resulting insulin concentrations is complex, given the numerous types of insulin available, various routes of administration, the presence of anti-insulin antibodies in insulin-dependent diabetics and the ex vivo instability of the drug. Other potential confounding factors include the wide-ranging cross-reactivity of commercial insulin immunoassays for the biosynthetic insulin analogs, the use of high-dose intravenous insulin as an antidote to antihypertensive drug overdosage and postmortem redistribution of insulin within the body. The use of a chromatographic technique for insulin assay may be preferable to immunoassay in some circumstances, to avoid the issue of cross-reactivity affecting the quantitative result and also to assist identifying the specific type of insulin in the specimen. Combination with other antidiabetic drugs A combination therapy of insulin and other antidiabetic drugs appears to be most beneficial in people who are diabetic, who still have residual insulin secretory capacity. A combination of insulin therapy and sulfonylurea is more effective than insulin alone in treating people with type 2 diabetes after secondary failure to oral drugs, leading to better glucose profiles and/or decreased insulin needs. Society and culture Economics In the United States the unit price of insulin has increased steadily from 1991 to 2019. It rose threefold from 2002 to 2013. Costs can be as high as US$900 per month. Concerns were raised in 2016 of pharmaceutical companies working together to increase prices. In January 2019, lawmakers from the United States House of Representatives sent letters to insulin manufacturers Eli Lilly and Co., Sanofi and Novo Nordisk asking for explanations for their rapidly raising insulin prices. The annual cost of insulin for people with type 1 diabetes in the U.S. almost doubled from $2,900 to $5,700 over the period from 2012 to 2016.People in the U.S. pay two to six times more than the rest of the world, including Canada, for brand name prescription medicine, according to the International Federation of Health Plans. Canada, like many other industrialized countries, has price controls on the cost of pharmaceuticals.California, in July 2022, approved a budget that allocates $100 million for the state to create its own insulin at a close-to-cost price. Regulatory status In March 2020, the FDA changed the regulatory pathway for approval of new insulin products. Insulin is regulated as a biologic rather than as a drug. The changed status gives the FDA more flexibility for approval and labeling. In July 2021, the FDA approved insulin glargine-yfgn (Semglee), a biosimilar product that contains the long acting analog insulin glargine. Insulin glargine-yfgn is interchangeable and less expensive than the reference product, insulin glargine (Lantus), which had been approved in 2000. The FDA requires that new insulin products are non-inferior to existing insulin products with respect to reduction in hemoglobin A1c. See Misbin, RI (February 2022). Insulin - History from an FDA Insider. Politics and Prose Publishing, Washington DC. Text ISBN 978-I-62429-391-7 Research Inhalation In 2006 the U.S. Food and Drug Administration (FDA) approved the use of Exubera, the first inhalable insulin. It was withdrawn from the market by its maker as of third quarter 2007, due to lack of acceptance. Inhaled insulin claimed to have similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. Currently, inhaled insulin is short acting and is typically taken before meals; an injection of long-acting insulin at night is often still required. When people were switched from injected to inhaled insulin, no significant difference was observed in HbA1c levels over three months. Accurate dosing was a particular problem, although people showed no significant weight gain or pulmonary function decline over the length of the trial, when compared to the baseline.Following its commercial launch in 2005 in the United Kingdom, it was not (as of July 2006) recommended by National Institute for Health and Clinical Excellence for routine use, except in cases where there is "proven injection phobia diagnosed by a psychiatrist or psychologist".In January 2008, the worlds largest insulin manufacturer, Novo Nordisk, also announced that the company was discontinuing all further development of the companys own version of inhalable insulin, known as the AERx iDMS inhaled insulin system. Similarly, Eli Lilly and Company ended its efforts to develop its inhaled Air Insulin in March 2008. However, MannKind Corp. (majority owner, Alfred E. Mann) remains optimistic about the concept. Transdermal There are several methods for transdermal delivery of insulin. Pulsatile insulin uses microjets to pulse insulin into the person, mimicking the physiological secretions of insulin by the pancreas. Jet injection had different insulin delivery peaks and durations as compared to needle injection. Some diabetics may prefer jet injectors to hypodermic injection.Both electricity using iontophoresis and ultrasound have been found to make the skin temporarily porous. The insulin administration aspect remains experimental, but the blood glucose test aspect of "wrist appliances" is commercially available. Researchers have produced a watch-like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through pores in the skin. A similar device, but relying on skin-penetrating "microneedles", was in the animal testing stage in 2015. Intranasal Intranasal insulin is being investigated. A randomized controlled trial that will determine whether intranasal insulin can delay or prevent the onset of type 1 diabetes in at-risk children and young adults is expected to yield results in 2016. By mouth The basic appeal of hypoglycemic agents by mouth is that most people would prefer a pill or an oral liquid to an injection. However, insulin is a peptide hormone, which is digested in the stomach and gut and in order to be effective at controlling blood sugar, cannot be taken orally in its current form. The potential market for an oral form of insulin is assumed to be enormous, thus many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar.A number of derivatization and formulation strategies are currently being pursued to in an attempt to develop an orally available insulin. Many of these approaches employ nanoparticle delivery systems and several are being tested in clinical trials. Pancreatic transplantation Another improvement would be a transplantation of the pancreas or beta cell to avoid periodic insulin administration. This would result in a self-regulating insulin source. Transplantation of an entire pancreas (as an individual organ) is difficult and relatively uncommon. It is often performed in conjunction with liver or kidney transplant, although it can be done by itself. It is also possible to do a transplantation of only the pancreatic beta cells. However, islet transplants had been highly experimental for many years, but some researchers in Alberta, Canada, have developed techniques with a high initial success rate (about 90% in one group). Nearly half of those who got an islet cell transplant were insulin-free one year after the operation; by the end of the second year that number drops to about one in seven. However, researchers at the University of Illinois at Chicago (UIC) have slightly modified the Edmonton Protocol procedure for islet cell transplantation and achieved insulin independence in diabetic people, with fewer but better-functioning pancreatic islet cells. Longer-term studies are needed to validate whether it improves the rate of insulin-independence. Beta cell transplant may become practical in the near future. Additionally, some researchers have explored the possibility of transplanting genetically engineered non-beta cells to secrete insulin. Clinically testable results are far from realization at this time. Several other non-transplant methods of automatic insulin delivery are being developed in research labs, but none is close to clinical approval. References External links "Insulin". Drug Information Portal. U.S. National Library of Medicine. "Insulin regular". Drug Information Portal. U.S. National Library of Medicine. "Insulin [Injection], biphasic". Drug Information Portal. U.S. National Library of Medicine.
Tafasitamab	Tafasitamab, sold under the brand name Monjuvi, is a medication used in combination with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).Tafasitamab may cause serious side effects including infusion related reactions, bone marrow suppression, infections, and harm to an unborn baby. The most common side effects of tafasitamab are low blood cell counts, fatigue, diarrhea, cough, fever, limb swelling, upper respiratory infection, and decreased appetite.Tafasitamab is a humanized Fc-modified cytolytic CD19 antibody.Tafasitamab was approved for medical use in the United States in July 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Tafasitamab represents an option for patients ineligible for CAR-T cell therapy. Medical uses Tafasitamab, in combination with lenalidomide, is indicated for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). History The FDA approved tafasitamab based primarily on evidence from one clinical trial (NCT02399085) of 81 participants 42 to 86 years old. Participants in the trial had lymphoma that relapsed or did not improve after prior treatments. The trial was conducted at 35 sites in the United States and Europe. At first, participants received tafasitamab in combination with lenalidomide and later tafasitamab alone following a specific schedule during each 28-day treatment cycle. Treatment continued until disease progression or unacceptable side effects. Both participants and health care providers knew which treatment had been given. The benefit of tafasitamab was evaluated by measuring how many participants had a complete or partial tumor shrinkage and how long that response lasted (called best overall response rate). Society and culture Names Tafasitamab is the international nonproprietary name (INN). References External links "Tafasitamab". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02399085 for "A Study to Evaluate the Safety and Efficacy of Lenalidomide With MOR00208 in Patients With R-R DLBCL (L-MIND)" at ClinicalTrials.gov
Calcipotriol	Calcipotriol, also known as calcipotriene, is a synthetic derivative of calcitriol, a form of vitamin D. It is used in the treatment of psoriasis. It is safe for long-term application in psoriatic skin conditions.It was patented in 1985 and approved for medical use in 1991. It is marketed under the trade name "Dovonex" in the United States, "Daivonex" outside North America, and "Psorcutan" in Germany.It is on the World Health Organizations List of Essential Medicines.Calcipotriol is also available as Calcipotriol/betamethasone dipropionate, a fixed-dose combination medication with the synthetic corticosteroid betamethasone dipropionate for the treatment of plaque psoriasis. Medical uses Chronic plaque psoriasis is the chief medical use of calcipotriol. It has also been used successfully in the treatment of alopecia areata. Contraindications Hypersensitivity, use on face, hypercalcaemia, or evidence of vitamin D toxicity are the only contraindications for calcipotriol use.Cautions include exposure to excessive natural or artificial light, due to the potential for calcipotriol to cause photosensitivity. Adverse effects Adverse effects by frequency: Very common (> 10% frequency) Burning Itchiness Skin irritationCommon (1–10% frequency) Uncommon (0.1–1% frequency) Exacerbation of psoriasisRare (< 0.1% frequency) Interactions No drug interactions are known. Pharmacology Mechanism of action The efficacy of calcipotriol in the treatment of psoriasis was first noticed by the observation of patients receiving various forms of vitamin D in an osteoporosis study. Unexpectedly, some patients who also had psoriasis experienced dramatic reductions in lesion counts.The precise mechanism of calcipotriol in remitting psoriasis is not well understood. However, it has been shown to have comparable affinity with calcitriol for the vitamin D receptor (VDR), while being less than 1% as active as the calcitriol in regulating calcium metabolism. The vitamin D receptor belongs to the steroid/thyroid receptor superfamily, and is found on the cells of many different tissues including the thyroid, bone, kidney, and T cells of the immune system. T cells are known to play a role in psoriasis, and it is thought that the binding of calcipotriol to the VDR modulates the T cells gene transcription of cell differentiation and proliferation related genes. In mouse studies, topical calcipotriol administration to the ear and dorsal skin led to a dose-dependent increase in the production of the epithelial cell-derived cytokine TSLP by keratinocytes, and triggered atopic dermatitis at high concentrations. This upregulation of TSLP production due to calcipotriol application is thought to be mediated through the coactivation of vitamin D receptor/RXRα and vitamin D receptor/RXRβ heterodimers. As psoriasis is typically thought to be partially driven by Th1/Th17 inflammatory cytokines, calcipotriol treatment at appropriate concentrations may alleviate psoriasis symptoms by repressing Th1/Th17 inflammation through TSLP production, which is linked to a Th2 response. However, it is important to note that this has not yet been confirmed. Pharmacokinetics After application and systemic uptake, calcipotriol undergoes rapid hepatic metabolism. Calcipotriol is metabolized to MC1046 (the α,β−unsaturated ketone analog), which is subsequently metabolized to its primary metabolite, the saturated ketone analog MC1080. MC1080 is then slowly metabolized to calcitroic acid.The metabolites of calcipotriol are less potent than the parent compound. Chemistry Calcipotriol is a white to almost white crystalline compound. References External links "Calcipotriene". Drug Information Portal. U.S. National Library of Medicine.
DTaP-IPV-HepB vaccine	DTaP-IPV-HepB vaccine is a combination vaccine whose generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated polio vaccine or DTaP-IPV-Hep B. It protects against the infectious diseases diphtheria, tetanus, pertussis, poliomyelitis, and hepatitis B.A branded formulation is marketed in the U.S. as Pediarix by GlaxoSmithKline. == References ==
Nicotine replacement therapy	Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine by means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting tobacco smoking by about 55%. Often it is used along with other behavioral techniques. NRT has also been used to treat ulcerative colitis. Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler. The use of multiple types of NRT at a time may increase effectiveness.Common side effects depend on the formulation of nicotine. Common side effects with the gum include nausea, hiccups, and irritation of the mouth. Common side effects with the patch include skin irritation and a dry mouth while the inhaler commonly results in a cough, runny nose, or headaches. Serious risks include nicotine poisoning and continued addiction. They do not appear to increase the risk of heart attacks. There are possible harms to the baby if used during pregnancy. Nicotine replacement therapy works by reducing cravings caused by nicotine addiction.They were first approved for use in 1984, in the United States. Nicotine replacement products are on the World Health Organizations List of Essential Medicines. They are available as generic medications. Medical uses Nicotine replacement therapy, in the form of gum, patches, nasal spray, inhaler and lozenges all improve the ability of people trying to quit tobacco products. Nicotine replacement therapy is as effective as medications, such as bupropion, in helping people quit smoking for at least six months. All forms of nicotine replacement therapy, including nicotine gum, patches, nasal spray, inhalers, and lozenges, have similar success rates in terms of helping people stop smoking. However, the likelihood that someone will stick to a certain treatment varies, with compliance being the highest with nicotine patches, followed by nicotine gum, inhalers, and nasal sprays. Using a few different nicotine replacement methods in combination may improve success rates in stopping tobacco use. Additionally, using nicotine replacement with counseling has been proven to improve tobacco abstinence rates. These other strategies include: creating a plan to quit and utilizing quit programs, a quit phone line, or app that provides tips and inspiration to help quit.Using nicotine replacement therapy to quit smoking should be considered for people who are severely dependent on nicotine. People who are severely dependent include those who smoke: more than one pack per day, within five minutes of awakening, while ill, when they wake up in the middle of the night, to ease withdrawal signs and symptoms.Nicotine replacement products are most beneficial for heavy smokers who smoke more than 15 cigarettes per day. There are not enough studies to show whether NRT helps those who smoke fewer than 10 cigarettes per day. Effectiveness Evaluation of NRT in real-world studies produces more modest outcomes than efficacy studies conducted by industry-funded trials. The National Health Service (NHS) in England has a smoking cessation service based on pharmacotherapy in combination with counseling support. An Action on Smoking and Health (UK) (ASH) report claims that the average cost per life-year gained for every smoker successfully treated by these services is less than £1,000 (below the NICE guidelines of £20,000 per QALY (quality-adjusted life year). However, the investment in NHS stop smoking services is relatively low. A comparison with treatment costs for illicit drug users shows that £585 million is committed for 350,000 problem drug users compared to £56 million for 9 million users of tobacco. This is £6.20 for each smoker, compared to £1,670 per illegal drug user.The claims for high efficacy and cost-effectiveness of NRT have not been substantiated in real-world effectiveness studies. Pierce and Gilpin (2002) stated their conclusion as follows: “Since becoming available over the counter, NRT appears no longer effective in increasing long-term successful cessation” (p. 1260). Efficacy studies, which are conducted using randomized controlled trials, do not transfer very well to real-world effectiveness. Bauld, Bell, McCullough, Richardson and Greaves (2009) reviewed 20 studies on the effectiveness of intensive NHS treatments for smoking cessation published between 1990 and 2007. Quit rates showed a dramatic decrease between 4-weeks and one year. A quit rate of 53% at four weeks fell to only 15% at one year. Younger smokers, females, pregnant smokers and more deprived smokers had lower quit rates than other groups. The efficacy for each of the formulations alone (lozenges, nasal spray, gum, and transdermal patch) to aid in smoking cessation is equal. Efficacy increases 15% to 36% with combining treatments such as gum and lozenges. Higher doses increase the chance of stopping smoking for a period of six months and more. For patches, the most efficient doses were 25 mg worn over 16 hours or 21 mg worn over 24 hours. The evidence suggests that 4 mg nicotine gum leads to higher quit rates compared with 2 mg in heavy smokers.E-cigarettes are twice as effective as NRT in helping people quit smoking. Toxicity N-Nitrosonornicotine, a strong carcinogen present in unburned tobacco and cigarette smoke, has been found in the urine of some users of oral NRT products. Nicotine patches is an alternative. Side effects Some side effects are caused by the nicotine, and are common to NRT products. Other common side effects depend on the formulation of nicotine. Common side effects with the gum include nausea, hiccups, and irritation of the mouth. Common side effects with the patch include skin irritation and a dry mouth while the inhaler commonly results in a cough, runny nose, or headaches. To minimize local skin reactions from the patch, the application site should be moved daily. The nicotine patch can also cause strange dreams if worn while asleep. Nasal sprays commonly cause nasal irritation, watering eyes, and coughing.Serious risks include nicotine poisoning, which includes symptoms like visual disturbances, hyper-salivation, nausea, and vomiting; and continued addiction to nicotine products. Avoiding smoking and other products with nicotine are recommended since it may lead to nicotine overdose. Although overdose is rare, it can be problematic, especially in children and pets. The symptoms of nicotine overdose include headache, pale skin and mouth, belly pain, weakness, diarrhea, tremors or seizures, agitation, confusion, restlessness, high or low blood pressure, fast or irregular heartbeat, fast breathing, and cold sweats.Limited evidence exists regarding long-term NRT use. Safety Pregnancy Nicotine is not safe to use in any amount during pregnancy. Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke. There are possible harms to the baby if NRT is used during pregnancy. Thus, pregnant women and those who are breastfeeding should also consult a physician before initiating NRT. The gum, lozenge, and nasal spray are pregnancy category C. The transdermal patch is pregnancy category D. The transdermal patch is considered less safe for the fetus because it delivers continuous nicotine exposure, as opposed to the gum or lozenge, which delivers intermittent and thus lower nicotine exposure.Strong evidence suggests that nicotine cannot be regarded as a safe substance of cigarette use. Nicotine itself could be at least partly responsible for many of the adverse after birth health results related to cigarette use while the mother was pregnant. There is evidence that nicotine negatively affects fetal brain development and pregnancy outcomes. There is also risk of stillbirth and pre-term birth. Nicotine use will probably harm fetal neurological development. Risks to the child later in life from nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility. Nicotine exposure during pregnancy can result in attention deficit hyperactivity disorder (ADHD) and learning disabilities in the child. It also puts the child at increased risk for nicotine addiction in the future.Pregnant women should consider behavioral therapy before NRT is considered. Youth In people under the age of eighteen, a physician is often consulted before starting NRT. The evidence suggests that exposure to nicotine between the ages of 10 and 25 years causes lasting harm to the brain and cognitive ability. Evidence is unclear whether adolescents gain benefit from cognitive-behavioral therapy or smoking cessation over the long-term as of 2017. Most tobacco users are under-eighteens when they start, and almost no-one over the age of 25 starts using. Cardiovascular conditions While there is no evidence that NRT can increase the risk of heart attacks, individuals with pre-existing cardiovascular conditions or recent heart attacks should consult a physician before initiating NRT.Smoking is known to cause cardiovascular diseases such as coronary heart disease, hypertension, heart attack, stroke, and peripheral artery disease. Cigarette smoking is the cause of 20% of all cardiovascular deaths in the United States, which is the leading cause of mortality. Other conditions Nicotine replacement therapies should be used cautiously in individuals with the following conditions: severe reactive airway diseases (for nasal spray), chronic nasal disorders such as sinusitis, polyps, rhinitis, or allergy (for nasal spray), diabetes (insulin-dependent), gastrointestinal diseases such as esophagitis, active gastric or peptic ulcer disease, liver problems, hyperthyroidism,pheochromocytoma, phenylketonuria (for lozenges), renal problems, and skin conditions such as psoriasis or dermatitis (for the transdermal patch). Mechanism of action Nicotine replacement therapy works by reducing cravings due to nicotine addiction. Smoking cigarettes releases high doses of nicotine to the brain in a matter of seconds as opposed to low doses released over a period of minutes to hours by the various forms of nicotine replacement therapy. Nicotine from NRT does not reach as high a concentration in the blood as does nicotine from smoke inhalation due to different absorption methods. NRT relies on systemic venous absorption, whereas nicotine from cigarettes reaches the arterial system. Nicotine replacement products vary in the time it takes for the nicotine to enter the body and the total time nicotine stays in the body. The more quickly a dose of nicotine is delivered and absorbed, the higher the addiction risk. It is possible to become dependent on some NRTs.Nicotine patches are applied to the skin and continuously administer a stable dose of nicotine slowly over 16–24 hours. Nicotine gum, nicotine sprays, nicotine toothpicks, nicotine sublingual tablets, and nicotine lozenges administer nicotine orally with quicker nicotine uptake into the body but lasting a shorter amount of time. Nicotine inhalers are metered-dose inhalers that administer nicotine through the lungs and mucous membranes of the throat quickly, lasting for a short amount of time. For example, blood nicotine levels are the highest 5–10 minutes after using the nicotine nasal spray, 20 minutes after using a nicotine inhaler or chewing nicotine gum, and 2–4 hours after using a nicotine patch. Society and culture NRT products were first approved for use in the United States in 1984. Nicotine replacement products are on the World Health Organizations List of Essential Medicines.. They are available as generic medication. Formulations The nicotine patch is a once-daily, longer-acting form of NRT. An advantage of the nicotine patch is its simple compliance; it does not require active use throughout the day. The gum, lozenge, sublingual tablet, oral inhaler, oral spray, and nasal spray are acutely dosed products, providing the user with the benefit and ability of self-titrating based on cravings.Brand names include Commit Lozenge, Nicoderm, Nicogum, Nicorette, Nicotex, Nicotinell, and Thrive. NRT products contain similar pharmaceutical grade nicotine as is used in e-cigarettes. Medicines In 2015, the United States Public Health Service listed seven agents for the stopping of tobacco, which included five nicotine replacement treatments (nicotine patches, gum, lozenges, inhalers, and nasal sprays) and two oral medications (bupropion and varenicline). Other NRT options are available, including nicotine mouth sprays and sublingual tablets. Dosing The dose of nicotine replacement therapy products is generally based on if the user is considered a heavy, average, or light smoker. A cigarette delivers an average of 1 mg to 3 mg of the nicotine contained in it. NRT products typically aim to parallel this, but the amount of nicotine absorbed by the user is less than the original dose. Nicotine nasal sprays are formulated in doses of lowest strength, available in 0.5 mg and 1 mg strengths. Nicotine lozenges deliver doses as low as 1 mg up to 4 mg. It is not chewed as the gum would be, and dissolves in approximately 30 minutes. This formulation may be preferred by those individuals who do not find gum chewing to be acceptable. Nicotine gum is available in doses of 2 mg and 4 mg. Using 4 mg nicotine gum versus 2 mg gum increases the likelihood of successful smoking cessation. When using the gum, acidic beverages like soda, coffee, or beer should be avoided fifteen minutes prior and during use because they can impede proper absorption of nicotine.Nicotine inhalers come in 10 mg and 15 mg cartridge strengths and typically deliver around 4 mg in one dose. The inhaler may be preferred in individuals who want to satisfy the hand-to-mouth ritual that smoking provides.Transdermal patches deliver between 5 mg and 52.5 mg of nicotine, which results in plasma levels similar to that of heavy smokers. Combining nicotine patch treatment with a faster nicotine-delivery means, like nicotine gum or spray, improves the likelihood of successful treatment. Not approved as NRTs Some smokeless consumer products available can function as alternative nicotine delivery systems (ANDS) but they have not received FDA approval as smoking-cessation therapy aids that are safe and effective. Snus and nasal snuff also allow for nicotine administration outside of tobacco smoking. Nicotine pouches are described as similar to or a tobacco-free variant of snus. They are pre-portioned and are held in the users lip or cheek allowing for sublingual or buccal delivery of flavors and high doses of nicotine. The small pouches are not like chewing tobacco, as the user does not need to spit since the contents of the pouches stay inside during use. Swedish pouches have been available on the American consumer market since at least 2016 but their popularity and controversy surged in 2019 & 2020. In the US and UK concerns have been raised that nicotine pouches are seemingly too similar to banned snus products, is aimed at teenagers, further complicating the youth vaping trend, falling into the hands of adolescents easily, and are discrete enough to easily pass for regular gums or lozenges.Nicotine infused toothpicks are another product that has been available in the United States since at least 2013. They can have a total nicotine delivery that is comparable to that of nicotine gum. Nicotine toothpicks generally are infused with food-grade flavorings and 1–3 mg of nicotine, which is similar to that of other oral-delivery nicotine products and some cigarettes. In spite of these similarities, as of 2018 they have been a subject of controversy. Online retailers have been under scrutiny for allowing their products to be too easily purchased by youth. Various news outlets and school districts have expressed the concern that these products have a high appeal to minors wanting to experiment with nicotine due to; the multitude of sweet flavors offered, ease & speed of use, seeming innocuous, and having a discrete nature. In 2015, NRT sales fell for the first time since 2008 while sales for e-cigarettes or electronic nicotine delivery systems (ENDS) continued to increase at a substantial rate. The evidence is that UK smokers are trying to quit with e-cigarettes rather than NRT methods.E-cigarettes are often, although not always, designed to look and feel like cigarettes. They have been marketed as less harmful alternatives to cigarettes, but very few are as yet approved as NRTs in any jurisdiction. Some electronic cigarettes have coarsely adjustable nicotine levels. Some healthcare groups have hesitated to recommend e-cigarettes for quitting smoking, because of limited evidence of effectiveness and safety. E-cigarettes are more effective than NRT in terms of abstinence from smoking at twelve months.The U.S. Food and Drug Administration (FDA) has a list of additional tobacco products they are seeking to regulate, including electronic cigarettes. Most approved NRT products have been approved for over 20 years, however the FDA has also approved nicotine inhalers as a form of NRT.Future approaches of NRT could include nicotine preloading, a true pulmonary inhaler, and nicotine vaccines. Nicotine preloading, otherwise known as pre-cessation or pre-quitting NRT, has found that using the patch for a few weeks before the quit date produces significantly higher quit rates than if it was started on the quit day. The true pulmonary inhaler would deliver nicotine to the lungs in a manner that more resembles cigarette smoking, which would provide better relief of background cravings as well as acute cravings. Nicotine vaccines are under investigation as a method to treat tobacco dependence through priming the body to mount an immune response against nicotine. References External links "Nicotine". Drug Information Portal. U.S. National Library of Medicine. University of Wisconsin Center for Tobacco Research and Intervention Recommendations for special populations "Nicotine Lozenges". MedlinePlus. 2018-08-15. "Nicotine Nasal Spray". MedlinePlus. 2016-07-15. "Nicotine Oral Inhalation". MedlinePlus. 2016-07-15. "Nicotine Gum". MedlinePlus. 2017-10-15.
Fexinidazole	Fexinidazole is a medication used to treat African trypanosomiasis (sleeping sickness) caused by Trypanosoma brucei gambiense. It is effective against both first and second stage disease. Some evidence also supports its use in Chagas disease. It is taken by mouth.Common side effects include nausea, vomiting, headache, and trouble sleeping. Other side effects may include QT prolongation, psychosis, and low white blood cells. It is unclear if use during pregnancy or breast feeding is safe. Fexinidazole is in the antiparasitic and the nitroimidazole family of medications. It is believed to work by turning on certain enzymes within the parasites that result in their death.Fexinidazole was first described in 1978. It was given a positive opinion by the European Medicines Agency in 2018. It is on the World Health Organizations List of Essential Medicines. Development for sleeping sickness was funded by the Drugs for Neglected Diseases initiative in collaboration with Sanofi. Fexinidazole was approved for medical use in the United States in July 2021. Medical use Sleeping sickness A trial in Africa found fexinidazole to be 91% effective at treating sleeping sickness. Though less effective than nifurtimox with eflornithine in severe disease, fexinidazole has the benefit that it can be taken by mouth.Fexinidazole is the first drug candidate for the treatment of advanced-stage sleeping sickness in thirty years. Other It has activity against Trypanosoma cruzi, Tritrichomonas foetus, Trichomonas vaginalis, Entamoeba histolytica, and Trypanosoma brucei. It has not been found to be useful for visceral leishmaniasis. Mechanism of action The biologically relevant active metabolites in vivo are the sulfoxide and sulfone. History Fexinidazole was discovered by the German pharmaceutical company Hoechst AG, but its development as a pharmaceutical was halted in the 1980s. Society and culture Fexinidazole Winthrop, a Sanofi-Aventis product developed with the Drugs for Neglected Diseases Initiative (DNDi), received a positive endorsement from the European Medicines Agency in 2018, for use in non-European markets. It was approved for the treatment of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC) in December 2018. Fexinidazole was included in the role of honour in Préscrire magazines 2020 prize list.[1] Veterinary use Fexinidazole is promising in African animal trypanosomiasis. Torreele et al. 2010 found the drug to be effective against T. b. gambiense infection of mice, rats, rabbits and beagles. They also found no toxicity in any of them, including a lack of mutagenicity despite in vitro mutagenicity. References External links "Fexinidazole". Drug Information Portal. U.S. National Library of Medicine.
Estazolam	Estazolam, sold under the brand name Prosom among others, is a tranquilizer medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring . It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia. It was patented in 1968 and came into medical use in 1975. Medical uses Estazolam is prescribed for the short-term treatment of certain sleep disorders. It is an effective hypnotic drug showing efficacy in increasing the time spent asleep as well as reducing awakenings during the night. Combination with non-pharmacological options for sleep management results in long-term improvements in sleep quality after discontinuation of short-term estazolam therapy. Estazolam is also sometimes used as a preoperative sleep aid. It was found to be superior to triazolam in side effect profile in preoperative patients in a trial. Estazolam also has anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with anxiety. Side effects A hang-over effect commonly occurs with next day impairments of mental and physical performance. Other side effects of estazolam include somnolence, dizziness, hypokinesia, and abnormal coordination.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. Tolerance and dependence The main safety concern of benzodiazepines such as estazolam is a benzodiazepine dependence and the subsequent benzodiazepine withdrawal syndrome which can occur upon discontinuation of the estazolam. A review of the literature found that long-term use of benzodiazepines such as estazolam is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. Estazolam should only be used short term and at the lowest effective dose to avoid complications related to long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. The short-term benefits of benzodiazepines on sleep begin to reduce after a few days due to tolerance to the hypnotic effects of benzodiazepines in the elderly. Contraindications and special caution Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. Elderly An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including estazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia. Pharmacology Estazolam is classed as a "triazolo" benzodiazepine drug. Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties. Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains. Pharmacokinetics Peak plasma levels are achieved within 1–6 hours. Estazolam is an intermediate acting benzodiazepine. The elimination half life of estazolam is an average of 19 hours, with a range of 8–31 hours. The major metabolite of estazolam is 4-hydroxyestazolam. Other identified metabolites include 1-oxo-estazolam, 4-hydroxy-estazolam, and benzophenone. Interactions Alcohol enhances the sedative hypnotic properties of estazolam. In package inserts, the manufacturer clearly warns about an interaction with Ritonavir, and although clinical interactions of Ritonavir with estazolam have not yet been described, the lack of clinical descriptions of the interactions does not negate the seriousness of the interaction. EEG effects in rabbits An animal study in rabbits demonstrated that estazolam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is significantly suppressed by estazolam. Abuse A primate study found that estazolam has abuse potential. Estazolam is a drug with the potential for misuse. Two types of drug misuse can occur; recreational misuse, where the drug is taken to achieve a high or when the drug is continued long term against medical advice. Estazolam became notorious in 1998 when a large amount of an herbal sleeping mix called Sleeping Buddha was recalled from the shelves after the FDA discovered that it contained estazolam. In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam. See also Alprazolam Benzodiazepine Benzodiazepine dependence Benzodiazepine withdrawal syndrome Long-term effects of benzodiazepines Brotizolam Midazolam Triazolam References External links "Estazolam". Drug Information Portal. U.S. National Library of Medicine.
Givosiran	Givosiran, sold under the brand name Givlaari, is a medication used for the treatment of adults with acute hepatic porphyria. Givosiran is a small interfering RNA (siRNA) directed towards delta-aminolevulinate synthase 1 (ALAS1), an important enzyme in the production of heme. The most common side effects include nausea and injection site reactions.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Givosiran is indicated for the treatment of adults with acute hepatic porphyria, a genetic disorder resulting in the buildup of toxic porphyrin molecules which are formed during the production of heme (which helps bind oxygen in the blood). History In November 2019, givosiran was approved in the United States for the treatment of adults with acute hepatic porphyria (AHP).Efficacy was evaluated in ENVISION (NCT03338816), a randomized, double‑blind, placebo‑controlled, multinational trial enrolling 94 participants with acute hepatic porphyria. Participants were randomized (1:1) to receive once monthly subcutaneous injections of givosiran 2.5 mg/kg or placebo during a six‑month double‑blind period. The performance of givosiran was measured by the rate of porphyria attacks that required hospitalizations, urgent health care visits or intravenous infusion of hemin at home. Participants who received givosiran experienced 70% fewer porphyria attacks compared to patients receiving a placebo.The U.S. Food and Drug Administration (FDA) granted the application for givosiran breakthrough therapy designation, priority review designation, and orphan drug designation. The FDA granted the approval of Givlaari to Alnylam Pharmaceuticals. References External links "Givosiran". Drug Information Portal. U.S. National Library of Medicine (NLM). Clinical trial number NCT03338816 for "ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)" at ClinicalTrials.gov
Methyl cellulose	Methyl cellulose (or methylcellulose) is a chemical compound derived from cellulose. It is sold under a variety of trade names and is used as a thickener and emulsifier in various food and cosmetic products, and also as a bulk-forming laxative. Like cellulose, it is not digestible, not toxic, and not an allergen. In 2017, it was the 272nd most commonly prescribed medication in the United States, with more than one million prescriptions. Uses Methyl cellulose has a wide range of uses. Medical Constipation Methyl cellulose is used to treat constipation. Effects generally occur within three days. It is taken by mouth and is recommended with sufficient water. Side effects may include abdominal pain. It is classified as a bulk forming laxative. It works by increasing the amount of stool present which improves intestinal contractions.It is available over the counter. It is sold under the brand name Citrucel among others. Artificial tears and saliva The lubricating property of methylcellulose is of particular benefit in the treatment of dry eyes. Solutions containing methyl cellulose or similar cellulose derivatives are used as substitute for tears or saliva if the natural production of these fluids is disturbed. Medication manufacturing Methyl cellulose is used in the manufacture of drug capsules; its edible and nontoxic properties provide a vegetarian alternative to the use of gelatin. Consumer products Thickener and emulsifier Methyl cellulose is occasionally added to hair shampoos, tooth pastes and liquid soaps, to generate their characteristic thick consistency. This is also done for foods, for example ice cream or croquette. Methyl cellulose is also an important emulsifier, preventing the separation of two mixed liquids because it is an emulsion stabilizer. Food The E number of methyl cellulose as food additive is E461. E464 is hydroxypropylcellulose and more soluble in water.Methyl cellulose, as a gel, has the unique property of setting when hot and melting when cold.Methyl cellulose is used as an ingredient in some meat analogues that are intended to replicate the texture of meat. Lubricant Methyl cellulose may be used in personal lubricant. Construction materials Methyl cellulose finds a major application as a performance additive in construction materials. It is added to mortar dry mixes to improve the mortars properties such as workability, open and adjustment time, water retention, viscosity, adhesion to surfaces etc. Construction grade methyl cellulose is not to be identified with food and pharmaceutical grade methyl cellulose and hydroxypropyl methyl cellulose, as it may be cross-linked with glyoxal for easy dispersion in water. The construction materials can be cement-based or gypsum-based. Notable examples of dry mixture mortars which utilize methyl cellulose include tile adhesives, EIFS, insulating plasters, hand-trowelled and machine-sprayed plaster, stucco, self-leveling flooring, extruded cement panels, skim coats, joint & crack fillers, and tile grouts. Typical usage is about 0.2% – 0.5% of total dry powder weight for dry mixtures. Derivatives of methyl cellulose which improve performance characteristics include hydroxypropyl methyl cellulose (HPMC) and hydroxyethyl methyl cellulose (HEMC). These derivatives typically improve the characteristics such as water retention, vertical surface slip resistance, open time, etc. Glue and binder Methyl cellulose can be employed as a mild glue which can be washed away with water. This may be used in the fixing of delicate pieces of art as well as in book conservation to loosen and clean off old glue from spines and bookboards. Methyl cellulose is the main ingredient in many wallpaper pastes. It is also used as a binder in pastel crayons and also as a binder in medications. Hydroxypropyl methylcellulose (HPMC) is an FDA-approved water-soluble adhesive, has been used in various wet-adhesion applications in construction products, paints, and drug delivery for 70 years.HPMC adheres strongly to all wet surfaces, regardless of hydrophobicity. Paint Methyl cellulose is used as a rheological modifier in paint to prevent sagging. Paper and textile sizing Methyl cellulose is used as sizing in the production of papers and textiles as it protects the fibers from absorbing water or oil. When applied to several pieces of paper, methyl cellulose will bind the layers together, often to create a more durable or multicolored sheet. In addition, origami artists use it to coat their origami models, as the compound will stiffen and protect the paper against time. Dust control Hydroxypropyl methyl cellulose (HPMC) and hydroxyethyl methyl cellulose (HEMC) is used as a binder in dust control technologies. They mitigate fugitive dust released from arid/semi-arid area as well as improve commercial face mask when used as a filtering material. Cell culture Methyl cellulose is also used in cell culture to study viral replication. It is dissolved in the same nutrient-containing medium in which cells are normally grown. A single layer of cells is grown on a flat surface, then infected with a virus for a short time. The strength of the viral sample used will determine how many cells get infected during this time. The thick methyl cellulose medium is then added on top of the cells in place of normal liquid medium. As the viruses replicate in the infected cells, they are able to spread between cells whose membranes touch each other, but are trapped when they enter the methyl cellulose. Only cells closely neighboring an infected cell will become infected and die. This leaves small regions of dead cells called plaques in a larger background of living uninfected cells. The number of plaques formed is determined by the strength of the original sample. Bacterial and protozoal motility inhibitor Aqueous methyl cellulose solutions have been used to slow bacterial and protozoal cell motility for closer inspection. Changing the amount of methyl cellulose in solution permits the adjustment of the solutions viscosity. Stem cell differentiation Methyl cellulose is used in the most common approaches to quantify multiple or single lineage-committed hematopoietic progenitors, called colony-forming cells (CFCs) or colony-forming units (CFUs), in combination with culture supplements that promote their proliferation and differentiation, and allow the clonal progeny of a single progenitor cell to stay together and thus form a colony of more mature cells. Chemistry It is a hydrophilic white powder in pure form and dissolves in cold (but not in hot) water, forming a clear viscous solution or gel. Methyl cellulose is used as a buffer additive in capillary electrophoresis to control electroosmotic flow for improved separations. Special effects The slimy, gooey appearance of an appropriate preparation of methyl cellulose with water, in addition to its nontoxic, nonallergenic, and edible properties, makes it popular for use in special effects for motion pictures and television wherever vile slimes must be simulated. In the film Ghostbusters, the gooey substance the supernatural entities used to "slime" the Ghostbusters was mostly a thick water solution of methyl cellulose. The Aliens ooze and drip a great deal of methyl cellulose—especially the queen.Methyl cellulose has been used to safely simulate molten materials, as well. In several of the Terminator films, it was back-lit with colored gels and films to reproduce the heated glow of iron in the large pouring ladles used to transport the metal from the smelting ovens to the various molds and forms. Methyl cellulose was also a stand-in for the lava flows in Los Angeles in Volcano and on the volcanic surface of Mustafar, in Star Wars: Episode III – Revenge of the Sith. Chemistry Methyl cellulose does not occur naturally and is synthetically produced by heating cellulose with caustic solution (e.g. a solution of sodium hydroxide) and treating it with methyl chloride. In the substitution reaction that follows, the hydroxyl residues (-OH functional groups) are replaced by methoxide (-OCH3 groups). Different kinds of methyl cellulose can be prepared depending on the number of hydroxyl groups substituted. Cellulose is a polymer consisting of numerous linked glucose molecules, each of which exposes three hydroxyl groups. The Degree of Substitution (DS) of a given form of methyl cellulose is defined as the average number of substituted hydroxyl groups per glucose. The theoretical maximum is thus a DS of 3.0, however more typical values are 1.3–2.6. Different methyl cellulose preparations can also differ in the average length of their polymer backbones. Solubility and temperature Methyl cellulose has a lower critical solution temperature (LCST) between 40 °C and 50 °C. At temperatures below the LCST, it is readily soluble in water; above the LCST, it is not soluble, which has a paradoxical effect that heating a saturated solution of methyl cellulose will turn it solid, because methyl cellulose will precipitate out. The temperature at which this occurs depends on DS-value, with higher DS-values giving lower solubility and lower precipitation temperatures because the polar hydroxyl groups are masked. Preparing a solution of methyl cellulose with cold water is difficult however: as the powder comes into contact with water, a gel layer forms around it, dramatically slowing the diffusion of water into the powder; hence, the inside remains dry. A better way is to first mix the powder with hot water, so that the methyl cellulose particles are well dispersed (and so have a much higher effective surface area) in the water, and cool down this dispersion while stirring, leading to the much more rapid dissolution of those particles. See also Carboxymethyl cellulose Ethyl cellulose Ethyl methyl cellulose Hydroxypropyl cellulose Hydroxyethyl cellulose References Further reading Cathleen Baker (1984). Methylcellulose & Sodium Carboxymethylcellulose: An Evaluation for Use in Paper Conservation through Accelerated Aging. Preprints of the Contributions to the Paris Congress, 2–8 September 1984: Adhesives and Consolidants, pp. 55–59. International Institute of Conservation. Robert L. Feller and Myron H. Wilt (1990). Evaluation of Cellulose Ethers for Conservation (free fulltext). Getty Conservation Institute. Pijper A (March 1947). "Methylcellulose and Bacterial Motility". J. Bacteriol. 53 (3): 257–69. doi:10.1128/JB.53.3.257-269.1947. PMC 518306. PMID 16561270.
Sutimlimab	Sutimlimab, sold under the brand name Enjaymo, is a monoclonal antibody that is used to treat adults with cold agglutinin disease (CAD). It is given by intravenous infusion. Sutimlimab prevents complement-enhanced activation of autoimmune human B cells in vitro.This drug is being developed by Bioverativ, a Sanofi company. Sutimlimab was approved for medical use in the United States in February 2022. Medical uses Sutimlimab is indicated to decrease the need for red blood cell transfusion due to hemolysis (red blood cell destruction) in adults with cold agglutinin disease (CAD). Adverse effects The most common side effects include respiratory tract infection, viral infection, diarrhea, dyspepsia (indigestion), cough, arthralgia (joint stiffness), arthritis, and swelling in the lower legs and hands. Pharmacology Mechanism of action Sutimlimab targets the C1s enzyme and inhibits its enzymatic propagation of the classical complement pathway, thereby, preventing the formation of the C3-convertase enzyme. History The effectiveness of sutimlimab was assessed in a study of 24 adults with cold agglutinin disease who had a blood transfusion within the past six months. All participants received sutimlimab for up to six months and could choose to continue therapy in a second part of the trial. Based on body weight, participants received either a 6.5g or 7.5g infusion of sutimlimab into their vein on day 0, day 7, and every 14 days through week 25.In total, 54% of participants responded to sutimlimab. The response was defined in the study as an increase in hemoglobin (an indirect measurement of the amount of red blood cells that are not destroyed) of 2 g/dL or greater (or to 12 g/dL or greater), and no red blood cell transfusions after the first five weeks of treatment; and no other therapies for cold agglutinin disease as defined in the study.The application for sutimlimab received orphan drug, breakthrough therapy, and priority review designations. 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 Enjaymo, intended for the treatment of hemolytic anemia in adults with cold agglutinin disease (CAD). The applicant for this medicinal product is Genzyme Europe BV. Names Sutimlimab is the International nonproprietary name (INN). References External links "Sutimlimab". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03347396 for "A Study to Assess the Efficacy and Safety of BIVV009 (Sutimlimab) in Participants With Primary Cold Agglutinin Disease Who Have a Recent History of Blood Transfusion (Cardinal Study)" at ClinicalTrials.gov
Fostamatinib	Fostamatinib, sold under the brand names Tavalisse and Tavlesse, is a tyrosine kinase inhibitor medication for the treatment of chronic immune thrombocytopenia (ITP). The drug is administered by mouth.Fostamatinib blocks the activity of the enzyme spleen tyrosine kinase (SYK). This enzyme is involved in stimulating parts of the immune system. By blocking SYKs activity, fostamatinib reduces the immune systems destruction of platelets, so allowing the platelet count to rise, which reduces the likelihood of excessive bleeding.The most commonly reported side effects are diarrhea, high blood pressure, nausea, respiratory infection, dizziness, increased liver enzymes, rash, abdominal pain, fatigue, chest pain and decreased white blood cell count.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Fostamatinib is a drug used to treat adults with low platelet count due to chronic immune thrombocytopenia (ITP) when a prior treatment for ITP has not worked well enough. Chronic immune thrombocytopenia is an autoimmune bleeding disorder where the blood doesnt clot as it should because of a low platelet count. Pharmacology Mechanism of action The tablets are formulated as fostamatinib disodium hexahydrate, a disodium hexahydrate salt, and is a prodrug of the active compound tamatinib (R-406), which is an inhibitor of the enzyme spleen tyrosine kinase (Syk), hence it is an syk inhibitor. Syk is a protein tyrosine kinase associated with various inflammatory cells, including macrophages, which are presumed to be the cells responsible for ITP platelet clearance. When FcγRs I, IIA, and IIIA bind to their ligands, the receptor complex becomes activated and triggers the phosphorylation of the immunoreceptor-activating motifs (ITAMs). This leads to various genes becoming activated, which causes a cytoskeletal rearrangement that mediates phagocytosis in cells of the monocyte/macrophage lineage. Because Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation, it is considered a good target for the inhibition of various autoimmune conditions, including rheumatoid arthritis and lymphoma. Clinical trials Fostamatinib has been in clinical trials for rheumatoid arthritis, autoimmune thrombocytopenia, autoimmune hemolytic anemia, IgA nephropathy, and lymphoma. The drug is currently being used in a Phase 1 trail to test the safety of the combination of the study drugs fostamatinib and paclitaxel for patients with ovarian cancer.The investigation of fostamatinib began with studies involving the treatment of mouse models with cytopenia. Mice were used to measure the effectiveness of R788, a small molecule prodrug of the biologically active R406, a Syk inhibitor. In animal models, treatment with R406/R788 was shown to be safe and effective in reducing inflammation and joint damage in immune-mediated rheumatoid arthritis. The models responded favorably to treatment so the study progressed to Phase 2 trials involving humans. Human studies have shown that R788 has good oral bioavailability, biologic activity, is well tolerated, and does not exhibit collagen or ADP-induced platelet aggregation. In NCT00706342, 16 adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trials beginning with 75 mg and rising to 175 mg twice a day. The dose was increased until a persistent response was evident, toxicity was reached, or 175 mg twice a day was met. 8 patients achieved persistent responses with platelet counts greater than 50,000 mm3/L on more than 67% of their visits. 3 of these patients had not persistently responded to thrombopoietic agents. 4 others had nonsustained responses. Mean peak platelet count exceeded 100,000 mm3/L in these 12 patients. Toxicity was evidenced primarily in GI-related side effects, notable diarrhea, urgency, and vomiting. 2 patients developed transaminitis.Fostamatinib as a treatment for severe COVID19 complications has finished a Phase 2 trial, and is entering a Phase 3 trial. Rheumatoid arthritis A phase II study of rheumatoid arthritis patients failing to respond to a biologic agent showed little efficacy as compared to placebo, but the drug was well tolerated. In patients with high inflammatory burden, measured by levels of C-reactive protein, ACR20 was achieved by a significantly higher portion of those in the fostamatinib group (42%) versus the placebo group (26%). Autoimmune thrombocytopenia Immune thrombocytopenic purpura (ITP) is an autoimmune disease where the immune system attacks and destroys platelets in the blood, causing abnormally low platelet counts. It is characterized by the antibody-mediated destruction of platelets. Patients with ITP have accelerated clearance of circulating IgG-coated platelets via Fcγ receptor-bearing macrophages in the spleen and liver, leading to different levels of thrombocytopenia and variable degrees of mucocutaneous bleeding. Recent studies of ITP pathophysiology suggest decreased platelet production may also be an important component of the thrombocytopenia. Many patients exhibit responses to established therapies, including corticosteroids, IV immunoglobulin, anti-D, splenectomy, and rituximab. However, there are a significant minority of patients who retain persistently low platelet counts despite treatment. These patients are consistently at risk of intracranial hemorrhage and other bleeding complications. Several thrombopoiesis-stimulating therapies including eltrombopag and romiplostim are being investigated to help combat low platelet counts in ITP patients. Rigel reported results from two Phase III clinical trials for fostamatinib as an ITP treatment in August and October 2016. The study is the second Phase 3, multi-center, randomized, double-blind, placebo controlled, study of fostamatinib disodium in the treatment of persistent/chronic immune thrombocytopenic purpura that Rigel has conducted. Primary outcome measures are defined as a stable platelet response by the end of the study (week 24) of at least 50,000/μL on at least 4 of the 6 visits between weeks 14–24. Participants received either a placebo, 100 mg, or 150 mg of the drug in the morning and evening for 24 full weeks. The first study, FIT 1 (047) met the primary endpoint in a statistically significant manner, with 18% of patients hitting the 50,000 platelets/μL of blood and no patients receiving the placebo meeting that criteria. As of June 2016, the open-label, long term extension study (049) is currently tracking 118 patients who opted to receive fostamatinib after completing either study 047 or 048. Autoimmune hemolytic anemia Approval for treatment of autoimmune hemolytic anemia (AIHA) is in Stage 1 of Phase II trials. This study is a Phase 2, multi-center, open label, Simon two-stage study to evaluate the safety and efficacy of fostamatinib disodium in the treatment of warm antibody autoimmune hemolytic anemia. Primary outcome measures examined include a hemoglobin response measured by levels higher than 10 g/dL and 2 g/dL higher than the baseline hemoglobin. Responses were studied for a period of 12 weeks and for a dose of 150 mg in the morning and evening. The study began in April 2016 and is estimated to conclude in September 2017. The study is currently recruiting participants from U.S. states including Arizona, California, D.C., Massachusetts, New York, North Carolina, and Texas. Subjects must have had a diagnosis of primary or secondary warm antibody AIHA, and must have failed at least 1 prior treatment regimen for AIHA. Subjects cannot have a platelet count less than 30,000/μL, have AIHA secondary to autoimmune disease, have uncontrolled or poorly controlled hypertension, or have cold antibody AIHA, cold agglutinin syndrome, mixed type AIHA, or paroxysmal cold hemoglobinuria. Immunoglobulin A nephropathy Fostamatinib as a treatment for IgA nephropathy (IgAN) is in Phase II trials, which will conclude at the end of 2016. IgAN is a chronic autoimmune disease associated with inflammation in the kidneys that reduces their ability to successfully filter blood. There are currently no disease-targeted therapies for IgAN. Participants are currently being recruited from the US, Austria, Germany, Hong Kong, Taiwan, and the UK. Patients must be between 18 and 70 years old, have renal biopsy findings consistent with IgA nephropathy, have been treated with an Angiotensin Converting Enzyme inhibitor (ACEi) and/or an Angiotensin II Receptor Blocker (ARB) for at least 90 days at the maximum approved dose, have a proteinuria > 1 gm/day at diagnosis of IgA nephropathy and a level > 0.5 gm/day at the second screening visit, and a blood pressure controlled to ≤ 1302/80 with angiotensin blockade. Eligible candidates cannot have recently used cyclophosphamide, mycophenolate mofetil, azathioprine, Rituximab, or > 15 mg/day of prednisone or any other corticosteroid equivalent. The study investigates whether fostamatinib is a safe and effective treatment for IgAN. It is a Phase 2, multi-center, randomized, double-blind, ascending-dose, placebo-controlled clinical study. Primary outcome measures include the mean change in proteinuria as measured by spot urine protein/creatinine ratio (sPCR). Effects were evaluated for 100 mg, 150 mg, and placebo formulations taken twice daily by mouth for 24 weeks. The study began in October 2014 and is expected to complete by June 2017. History Fostamatinib was approved for medical use in the United States in April 2018.The U.S. Food and Drug Administration (FDA) approved fostamatinib based on evidence from two identical, double-blind, placebo-controlled clinical trials, FIT-1 (NCT02076399) and FIT-2 (NCT02076412) of 150 adults with persistent or chronic ITP who had an insufficient response to previous treatment, which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonist. Participants were allowed to continue previous ITP treatment during the trial. Patients were randomized 2:1 to fostamatinib (100 mg orally twice daily) or placebo twice daily for 24 weeks. Dose could be escalated to 150 mg orally twice daily after one month. The benefit of fostamatinib was assessed based on the percentage of participants who achieved and maintained the pre-determined platelet count between treatment weeks 14 to 24 in fostamatinib and placebo groups respectively. The FIT-1 trial was conducted at 35 sites in Australia, Canada, Denmark, Hungary, Italy, Netherlands, the United Kingdom, and the United States. The FIT-2 trial was conducted at 23 sites in Austria, Bulgaria, Czech Republic, Germany, Norway, Poland, Romania, and Spain.The FDA granted the application for fostamatinib an orphan drug designation and granted the approval of Tavalisse to Rigel Pharmaceuticals.Fostamatinib was approved for medical use in the European Union in January 2020. References External links "Fostamatinib". Drug Information Portal. U.S. National Library of Medicine. "Fostamatinib disodium". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT02076399 for "A Efficacy and Safety Study of R935788 in the Treatment of Persistent/Chronic Immune Thrombocytopenic Purpura (ITP) (FIT)" at ClinicalTrials.gov
Budesonide	Budesonide, sold under the brand name Pulmicort among others, is a medication of the corticosteroid type. It is available as an inhaler, nebulization solution, pill, nasal spray, and rectal forms. The inhaled form is used in the long-term management of asthma and chronic obstructive pulmonary disease (COPD). The nasal spray is used for allergic rhinitis and nasal polyps. The pills in a delayed release form and rectal forms may be used for inflammatory bowel disease including Crohns disease, ulcerative colitis, and microscopic colitis.Common side effects with the inhaled form include respiratory infections, cough, and headaches. Common side effects with the pills include feeling tired, vomiting, and joint pains. Serious side effects include an increased risk of infection, loss of bone strength, and cataracts. Long-term use of the pill form may cause adrenal insufficiency. Stopping the pills suddenly following long-term use may therefore be dangerous. The inhaled form is generally safe in pregnancy. Budesonide chiefly acts as a glucocorticoid.Budesonide was initially patented in 1973. Commercial use as an asthma medication began in 1981. It is on the World Health Organizations List of Essential Medicines. Some forms are available as a generic medication. In 2019, generic budesonide was listed as involved in Tevas price fixing scheme in the United States. In 2019, it was the 201st most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses Asthma Budesonide is given by metered-dose inhaler or nebulizer for maintenance and prophylactic treatment of asthma, including patients who require oral corticosteroids and those who may benefit from a systemic dose reduction. Inflammatory bowel disease Formulations of delayed-release budesonide are an effective treatment for mild-to-moderately active Crohns disease involving the ileum and/or ascending colon. A Cochrane review found evidence for up to three months (but not longer) of maintenance of remission in Crohns disease.Budesonide assists in the induction of remission in people with active ulcerative colitis.Budesonide is highly effective and recommended as the drug of choice in microscopic colitis, for induction and maintenance of remission, and for both the lymphocytic colitis and collagenous colitis forms. Allergic rhinitis Budesonide in the form of nasal sprays is a treatment for allergic rhinitis. Eosinophilic esophagitis Topical budesonide has considerable effects in eosinophilic esophagitis. For this use, it is formulated as a tablet that disperses in the mouth, and sold under the trade name Jorveza. Bergers disease Budesonide (Tarpeyo) is indicated to reduce proteinuria (increased protein levels in the urine) in adults with primary immunoglobulin A (IgA) nephropathy (Bergers disease) at risk of rapid disease progression. Side effects Nasal budesonide inhalers have been associated with a number of side effects. These include nose irritation or burning, bleeding or sores in the nose, lightheadedness, upset stomach, cough, hoarseness, dry mouth, rash, sore throat, bad taste in mouth, change in mucus, and blurred vision. Other symptoms which should be reported immediately include difficulty in breathing, swelling of the face, white patches in the throat, mouth, or nose, irregular menstrual periods, severe acne, and on rare occasions, behavioral changes (mostly affecting children) Contraindications Budesonide is contraindicated as a primary treatment of status asthmaticus or other acute episode of asthma where intensive measures are required. It is also contraindicated for patients who have hypersensitivity to budesonide. Interactions Those taking tablets or capsules orally should avoid grapefruit and grapefruit juice and echinacea.: 160 Grapefruit juice may double bioavailability of oral budesonide. Echinacea diminishes bioavailability.Also, high-fat meals delay absorption but do not impede absorption. Pharmacology Budesonide is an agonist of glucocorticoid receptors. Among its effects are: Controls the rate of protein synthesis. Depresses the migration of polymorphonuclear leukocytes and fibroblasts. Reverses capillary permeability and lysosomal stabilization at the cellular level to prevent or control inflammation. Has a potent glucocorticoid activity and weak mineralocorticoid activity. Pharmacokinetics Onset of action: Nebulization: 2–8 days; Inhalation: 24 hours; Nasal: 10 hours Peak effect: Nebulization: 4–6 weeks; Inhalation: 1–2 weeks Distribution: 2.2-3.9 L/kg Protein binding: 85% to 90% Metabolism: Hepatic via CYP3A4 to two metabolites: 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide; minor activity Budesonide is extensively metabolized in first pass, resulting in a low bioavailability and systemic effects Bioavailability: Capsule: 9% to 21%; Nebulization: 6%; Inhalation: 6% to 13% Half-life elimination: 2–3.6 hours Time to peak: Capsule: 0.5–10 hours (variable in Crohns disease); Nebulization: 10–30 minutes; Inhalation: 1–2 hours; Tablet: 7.4-19.2 hours Excretion: urine (60%) and feces as metabolites. Chemistry Budesonide, also known as 11β,21-dihydroxy-16α,17α-(butylidenebis(oxy))pregna-1,4-diene-3,20-dione, is a synthetic pregnane steroid and non-halogenated cyclic ketal corticosteroid. It is the C16α hydroxyl, C16α,17α cyclic ketal with butyraldehyde derivative of prednisolone (11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione). Stereoisomerism Society and culture Legal status On 19 May 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 conditional marketing authorization for the medicinal product Kinpeygo, intended for the treatment of primary immunoglobulin A nephropathy. The applicant for this medicinal product is Calliditas Therapeutics AB. Kinpeygo is a hybrid medicine of Entocort which has been authorised in the EU since 2 April 1992. Kinpeygo contains the same active substance as Entocort but has a different formulation and a different indication. Brand names Aeronide (TH); Aquacort (DE); B Cort (CO); Bronex (PH); Budair (MY); Budecort DP (MY); Budenofalk (DE, GB, HK, KP, PH, SG); Budeson (AR); Budeson Aqua (AR); BudeSpray (TH); Budiair (KP); Budicort Respules (IL); Budinide (KSA); Bunase (TH); Clebudan (CN); Cortiment (CA, GB, AU); Cycortide (HK); Denecort (PH); Duasma (TW); Eltair (MY); Entocort (AR, AT, BE, BR, CH, CZ, DK, FI, FR, GB, HK, IE, IL, IT, KP, NL, NO, PL, PT, SE, TR);: 13 Giona Easyhaler (MY, SG, TH); Inflammide (PE); Miflonid (CZ); Miflonide (BE, DE, IL, IT, NZ, PT); Neumocort (PY); Novopulmon (DE, FR); Pulmicon Susp for Nebulizer (KP); Pulmicort (AT, BE, BG, BR, CH, CL, CN, CO, CR, CZ, DE, DK, DO, EE, FI, FR, GB, GR, GT, HN, ID, IN, NI, NL, NO, PA, PK, PL, PT, RU, SE, SV, TR, TW, UY, VE, ZA);: 13 Pulmicort Nasal Turbohaler (CL, KE, MU, NG); Pulmicort Turbuhaler (KE, MU, NG); Rafton (FR); Rhinocort (AU); Rhinocort Aqua (HK); Rhinoside (GR); Symbicort (FR, UK, US, ZA) Uceris (US). Research COVID-19 Budesonide was recommended in April 2021 by the UKs NHS to treat COVID-19 on a case-by-case basis for those aged 50 years of age and older. After a University of Oxford research team found in a trial with 1,700 patients that budesonide could benefit many people over 50 with COVID-19 symptoms, it was recommended from 12 April 2021, by the National Health Service in the UK for general practitioners (GPs) to treat COVID-19 on a case-by-case basis. Results of a large-scale trial published in August 2021 suggest that inhaled budesonide improves the time of recovery and peoples well-being during the recovery process. The recommendation was withdrawn in December 2021 citing the need for more research.Inhalational budesonide was added to the recommended treatment for cases of COVID-19 in India in April 2021. References External links "Budesonide". Drug Information Portal. U.S. National Library of Medicine. "Budesonide Nasal Spray". MedlinePlus. "Budesonide Oral Inhalation". MedlinePlus.
Etodolac	Etodolac is a nonsteroidal anti-inflammatory drug (NSAID). It was patented in 1971 and approved for medical use in 1985. It was approved in the U.S. in 1991. Medical uses NSAIDs are used for the management of mild to moderate pain, fever, and inflammation. They work by reducing the levels of prostaglandins, which are chemicals that are responsible for pain and the fever and tenderness that occur with inflammation. Etodolac blocks the cyclooxygenase (abbrev. COX) enzymes which form prostanoids, resulting in lower concentrations of prostaglandins. As a consequence, inflammation, pain and fever are reduced. Post-marketing studies demonstrated that etodolac inhibition of cyclooxygenase is somewhat COX-2 selective similar to celecoxib and other "COX-2 inhibitors." Unlike rofecoxib, both etodolac and celecoxib can fully inhibit COX-1 and are designated as having "preferential selectivity" toward COX-2. The R-enantiomer of etodolac is inactive against COX enzymes, but inhibits beta-catenin levels in hepatoma cells.In the UK, Etodolac is licensed for the treatment of inflammation and pain caused by osteoarthritis and rheumatoid arthritis. Interactions Etodolac should be avoided by patients with a history of asthma attacks, hives, or other allergic reactions to aspirin or other NSAIDs. Rare but severe allergic reactions have been reported in such individuals. It also should be avoided by patients with peptic ulcer disease or poor kidney function, since this medication can worsen both conditions. Etodolac is used with caution in patients taking blood thinning medications (anticoagulants), such as warfarin (Coumadin), because it increases the risk of bleeding. Patients taking both lithium and etodolac may develop toxic blood lithium levels. Additionally, etodolac has been found to interact with certain anti-depressant medications, such as sertraline or fluoxetine, which can increase risks of stroke, heart attack, and other cardiovascular conditions. Patients also taking ciclosporin (Sandimmune) can develop kidney toxicity. Use in children has not been adequately studied. Etodolac is not habit-forming. NSAIDs should be discontinued prior to elective surgery because of a mild interference with clotting that is characteristic of this group of medicines. Etodolac is best discontinued at least four days in advance of surgery. Etodolac metabolites may also cause a false positive bilirubin result on a urinalysis test. [1] Pregnancy and nursing Etodolac is generally avoided during pregnancy and nursing. NSAIDs may cause adverse cardiovascular effects in the fetus during pregnancy. 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. Brand names Etodolac is manufactured by Almirall Limited under the trade name Lodine SR and by Meda Pharmaceuticals under the name Eccoxolac. Generic etodolac is also available.The drug is also sold under several other brand names, including: "Etogesic" (India) Etova (India) Dualgan (Portugal) Etodin (South Korea) Etofree (India) Etopan (Israel) Flancox® (Brazil) Haipen (Japan) Lodine (France, Switzerland, United States) Proxym (S Etodolac) (India) Etol (Turkey) Lonine (Taiwan) Etodine (Egypt) Dolarit (Turkey) "Etodin Fort" (Bulgaria) References External links DrugBank info Medicinenet.com
Eliglustat	Eliglustat, sold under the brand name Cerdelga, is a medication used for the treatment of Gauchers disease. It was discovered at the University of Michigan, developed by Genzyme Corp, and was approved by the FDA in August 2014. Commonly used as the tartrate salt, the compound is believed to work by inhibition of glucosylceramide synthase. According to an article in Journal of the American Medical Association the oral substrate reduction therapy resulted in "significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count" in untreated adults with Gaucher disease Type 1. History Norman Radin began exploring the possibility of inhibiting the synthesis of lipid substrates involved in Gauchers disease as early as 1982, and, in collaboration with the laboratory of Jim Shayman, found several candidate inhibitors in the mid-1990s. Genzyme initially rejected the candidates developed by Radin and Shayman, but after a news broke of a competitor developing a new treatment for Gauchers disease, licensed the Radin/Shayman patents in 2000. Eliglustat did not receive FDA approval for another 14 years, a delay that Shayman speculated was due to some company leaders not being fully committed to developing a drug that would compete with imiglucerase (brand name Cerezyme), Genzymes flagship treatment for Gauchers disease. Society and culture Economics In 2014, the annual cost of eliglustat taken orally twice a day was $310,250. Cerezyme cost about $300,000 for the intravenous medication if taken twice a month. Manufacturing costs for eliglustat are slightly lower than for imiglucerase. Genzyme maintains higher prices for orphan drugs—most often paid for by insurers—in order to remain financially sustainable. References External links "Eliglustat". Drug Information Portal. U.S. National Library of Medicine.
Voriconazole	Voriconazole, sold under the brand name Vfend among others, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, candidiasis, coccidioidomycosis, histoplasmosis, penicilliosis, and infections by Scedosporium or Fusarium. It can be taken by mouth or used by injection into a vein.Common side effects include vision problems, nausea, abdominal pain, rash, headache, and seeing or hearing things that are not present. Use during pregnancy may result in harm to the baby. It is in the triazole family of medications. It works by affecting fungal metabolism and fungal cell membranes.Voriconazole was patented in 1990 and approved for medical use in the United States in 2002. It is on the World Health Organizations List of Essential Medicines. Medical uses Voriconazole is used to treat invasive aspergillosis and candidiasis and fungal infections caused by Scedosporium and Fusarium species, which may occur in immunocompromised patients, including people undergoing allogeneic bone marrow transplant (BMT), who have hematologic cancers or who undergo organ transplants.It is also used to prevent fungal infection in people as they undergo BMT.It is also the recommended treatment for the CNS fungal infections transmitted by epidural injection of contaminated steroids.It can be taken by mouth or given in a doctors office or clinic by intravenous infusion. Contraindications It is toxic to the fetus; pregnant women should not take it and women taking it should not become pregnant.People who have hereditary intolerance for galactose, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug. It should be used with caution in people with arrhythmias or long QT.No dose adjustment is necessary for renal impairment or advanced age, but children seem to clear voriconazole faster than adults and drug levels may need monitoring. Side effects The labels carry several warnings of the risk of injection site reactions, hypersensitivity reactions; kidney, liver, and pancreas damage; trouble with vision; and adverse effects in skin including damage due to phototoxicity, squamous cell skin cancer, and Stevens–Johnson syndrome; in long-term use there is a warning of the risk of bone fluorosis and periostitis.Additionally, very common adverse effects, occurring in more than 10% of people, include peripheral edema, headaches, trouble breathing, diarrhea, vomiting, abdominal pain, nausea, rashes, and fever.Common adverse effects, occurring in between 1 and 10% of people, include sinus infections, low numbers of white and red blood cells (agranulocytosis, pancytopenia, thrombocytopenia, leukopenia, and anemia), low blood sugar, reduced amount of potassium and sodium, depression, hallucinations, anxiety, insomnia, agitation, confusion, convulsions, fainting, tremor, weakness, tingling, sleepiness, dizziness, bleeding retina, irregular heart beats, slow or fast heart beats, low blood pressure, inflamed veins, acute respiratory distress syndrome, pulmonary edema, inflamed lips, swollen face, stomach upset, constipation, gingivitis, jaundice, hair loss, flaky skin, itchiness, red skin, back pain, chest pain, and chills. Interactions Being metabolized by hepatic cytochrome P450, voriconazole interacts with many drugs. Voriconazole should not be used in conjunction with many drugs (including sirolimus, rifampicin, rifabutin, carbamazepine, quinidine and ergot alkaloids) and dose adjustments and/or monitoring should be done when coadministered with others (including fluconazole, warfarin, ciclosporin, tacrolimus, omeprazole, and phenytoin). Voriconazole may be safely administered with cimetidine, ranitidine, indinavir, macrolide antibiotics, mycophenolate, digoxin and prednisolone. Pharmacology Pharmacokinetics Voriconazole is well absorbed orally with a bioavailability of 96%, allowing patients to be switched between intravenous and oral administration. History Pfizer brought the drug to market as Vfend. A generic version of the tablet form of voriconazole was introduced in the US in 2011 after Pfizer and Mylan settled litigation under the Hatch-Waxman Act; a generic version of the injectable form was introduced in 2012. In Europe patent protection expired in 2011 and pediatric administrative exclusivity expired in Europe in 2016. Society and culture Brand names As of July 2017, the medication is marketed under the following names worldwide: Cantex, Pinup, Vedilozin, Vfend, Vodask, Volric, Voramol, Voriconazol, Voriconazole, Voriconazolum, Voricostad, Vorikonazol, Voritek, Voriz, Vornal, and Vosicaz. References Further reading Dean L (December 2019). "Voriconazole Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 31886997. External links "Voriconazole". Drug Information Portal. U.S. National Library of Medicine.
Nebivolol	Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.Common side effects include dizziness, feeling tired, nausea, and headaches. Serious side effects may include heart failure and bronchospasm. Its use in pregnancy and breastfeeding is not recommended. It works by blocking β1-adrenergic receptors in the heart and dilating blood vessels.Nebivolol was patented in 1983 and came into medical use in 1997. It is available as a generic medication in the United Kingdom. In 2019, it was the 191st most commonly prescribed medication in the United States, with more than 3 million prescriptions. Medical uses It is used to treat high blood pressure and heart failure. Nebivolol is used in the treatment of angina, to decrease the heart rate and contractile force. This is relevant in patients who need to decrease the oxygen demand of the heart so that the blood supplied from stenosed or constricted arteries is adequate. ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics are generally preferred over beta blockers for the treatment of primary hypertension in the absence of co-morbidities. Pharmacology and biochemistry β1-selectivity Beta blockers help patients with cardiovascular disease by blocking β1 receptors, while many of the side-effects of these medications are caused by their blockade of β2 receptors. For this reason, beta blockers that selectively block β1 adrenergic receptors (termed cardioselective or β1-selective beta blockers) produce fewer adverse effects (for instance, bronchoconstriction) than those drugs that non-selectively block both β1 and β2 receptors. In a laboratory experiment conducted on biopsied heart tissue, nebivolol proved to be the most β1-selective of the β-blockers tested, being approximately 3.5 times more β1-selective than bisoprolol. However, the drugs receptor selectivity in humans is more complex and depends on the drug dose and the genetic profile of the patient taking the medication. The drug is highly cardioselective at 5 mg. In addition, at doses above 10 mg, nebivolol loses its cardioselectivity and blocks both β1 and β2 receptors, while the recommended starting dose of nebivolol is 5 mg, sufficient control of blood pressure may require doses up to 40 mg. Furthermore, nebivolol is also not cardioselective when taken by patients with a genetic makeup that makes them "poor metabolizers" of nebivolol (and other drugs) or with CYP2D6 inhibitors. As many as 1 in 10 Caucasian people and even more black people are poor CYP2D6 metabolizers and therefore might benefit less from nebivolols cardioselectivity although currently there are no directly comparable studies.Nebivolol while selectively blocking beta(1) receptor acts as a beta(3)-agonist. β3 receptors are found in the gallbladder, urinary bladder, and in brown adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat. In the urinary bladder it is thought to cause relaxation of the bladder and prevention of urination.Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) in healthy volunteers. Vasodilator action Nebivolol is unique as a beta-blocker. Unlike carvedilol, it has a nitric oxide (NO)-potentiating, vasodilatory effect via stimulation of β3 receptors. Along with labetalol, celiprolol and carvedilol, it is one of four beta blockers to cause dilation of blood vessels in addition to effects on the heart. Antihypertensive effect Nebivolol lowers blood pressure (BP) by reducing peripheral vascular resistance, and significantly increases stroke volume with preservation of cardiac output. The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of beta-blockade and an action that maintains cardiac output. Antihypertensive responses were significantly higher with nebivolol than with placebo in trials enrolling patient groups considered representative of the U.S. hypertensive population, in black people, and in those receiving concurrent treatment with other antihypertensive drugs. Pharmacokinetics Nebivolol plasma protein binding is approximately 98%, mostly to albumin and its half-life of low doses is 12 hours in extensive CYP2D6 metabolizers and 19 hours in poor metabolizers. Contraindications Severe bradycardia Heart block greater than first degree Patients with cardiogenic shock Decompensated cardiac failure Sick sinus syndrome (unless a permanent pacemaker is in place) Patients with severe hepatic impairment (Child-Pugh class B) Patients who are hypersensitive to any component of this product. Side effects Side effects might include headache, tiredness, dizziness, lightheadedness, reduced blood flow to extremities, bradycardia. Controversies Pharmacology of side-effects Several studies have suggested that nebivolol has reduced typical beta-blocker-related side effects, such as fatigue, clinical depression, bradycardia, or impotence. However, according to the FDABystolic is associated with a number of serious risks. Bystolic is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh > B) and in patients who are hypersensitive to any component of the product. Bystolic therapy is also associated with warnings regarding abrupt cessation of therapy, cardiac failure, angina and acute myocardial infarction, bronchospastic diseases, anesthesia and major surgery, diabetes and hypoglycemia, thyrotoxicosis, peripheral vascular disease, non-dihydropyridine calcium channel blockers use, as well as precautions regarding use with CYP2D6 inhibitors, impaired renal and hepatic function, and anaphylactic reactions. Finally, Bystolic is associated with other risks as described in the Adverse Reactions section of its PI. For example, a number of treatment-emergent adverse events with an incidence greater than or equal to 1 percent in Bystolic-treated patients and at a higher frequency than placebo-treated patients were identified in clinical studies, including headache, fatigue, and dizziness. FDA warning letter about advertising claims In late August 2008, the FDA issued a Warning Letter to Forest Laboratories citing exaggerated and misleading claims in their launch journal ad, in particular over claims of superiority and novelty of action. History Mylan Laboratories licensed the U.S. and Canadian rights to nebivolol from Janssen Pharmaceutica N.V. in 2001. Nebivolol is already registered and successfully marketed in more than 50 countries, including the United States where it is marketed under the brand name Bystolic from Mylan Laboratories and Forest Laboratories. Nebivolol is manufactured by Forest Laboratories. In India, nebivolol is available as Nebula (Zydus Healthcare Ltd), Nebizok (Eris life-sciences), Nebicip (Cipla ltd), Nebilong (Micro Labs), Nebistar (Lupin ltd), Nebicard (Torrent), Nubeta (Abbott Healthcare Pvt Ltd – India), and Nodon (Cadila Pharmaceuticals). In Greece and Italy, nebivolol is marketed by Menarini as Lobivon. In Germany its marketed as Nebilet by Berlin Chemie. In the Middle East, Russia and in Australia, it is marketed under the name Nebilet and in Pakistan it is marketed by The Searle Company Limited as Byscard. References External links "Nebivolol". Drug Information Portal. U.S. National Library of Medicine. "Nebivolol hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Asenapine	Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder.It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.It was initially approved in the United States in 2009 and approved as a generic medication in 2020. Medical uses Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In Australia asenapines approved (and also listed on the PBS) indications include the following: Schizophrenia Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder Maintenance treatment, as monotherapy, of bipolar I disorderIn the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed. A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado. Schizophrenia A Cochrane systematic review found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of Asenapine for the treatment of schizophrenia. Acute mania As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs (with the exception of ziprasidone) such as risperidone and olanzapine. Drop-out rates (in clinical trials) were also unusually high with asenapine. According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes. Adverse effects Adverse effect incidenceVery common (>10% incidence) adverse effects include: SomnolenceCommon (1-10% incidence) adverse effects include: Weight gain Increased appetite Extrapyramidal side effects (EPS; such as dystonia, akathisia, dyskinesia, muscle rigidity, parkinsonism) Sedation Dizziness Dysgeusia Oral hypoaesthesia Increased alanine aminotransferase FatigueUncommon (0.1-1% incidence) adverse effects include: Hyperglycaemia — elevated blood glucose (sugar) Syncope Seizure Dysarthria sinus bradycardia Bundle branch block QTc interval prolongation (has a relatively low risk for causing QTc interval prolongation.) sinus tachycardia Orthostatic hypotension Hypotension Swollen tongue Dysphagia (difficulty swallowing) Glossodynia Oral paraesthesiaRare (0.01-0.1% incidence) adverse effects include: Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate) Tardive dyskinesia Speech disturbance Rhabdomyolysis Angioedema Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia Accommodation disorder Pulmonary embolism Gynaecomastia GalactorrhoeaUnknown incidence adverse effects Allergic reaction Restless legs syndrome Nausea Oral mucosal lesions (ulcerations, blistering and inflammation) Salivary hypersecretion HyperprolactinaemiaAsenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22). Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis. This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic. The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics. Discontinuation For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing 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 recurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped. Pharmacology Pharmacodynamics Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors. At all other targets asenapine is an antagonist. As of November 2010 asenapine is also in clinical trials at UC Irvine to treat stuttering. Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors. References External links "Asenapine". Drug Information Portal. U.S. National Library of Medicine. "Asenapine maleate". Drug Information Portal. U.S. National Library of Medicine.
Enalapril/hydrochlorothiazide	Enalapril/hydrochlorothiazide, sold under the brand name Vaseretic among others, is a fixed-dose combination medication used for the treatment of hypertension (high blood pressure). It contains enalapril, an angiotensin converting enzyme inhibitor, and hydrochlorothiazide a diuretic. It is taken by mouth.The most frequent side effects include dizziness, headache, fatigue, and cough. History Enalapril/hydrochlorothiazide was approved for medical use in the United States in October 1986. References Further reading Frishman WH, Goldberger J, Sherman D (December 1987). "Enalapril, hydrochlorothiazide, and combination therapy in patients with moderate hypertension". J Clin Hypertens. 3 (4): 520–7. PMID 2839628. External links "Enalapril". Drug Information Portal. U.S. National Library of Medicine. "Hydrochlorothiazide". Drug Information Portal. U.S. National Library of Medicine.
Midol	Midol is a brand of over-the-counter analgesic drugs marketed for menstrual cramping and other effects related to premenstrual syndrome and menstruation. Various subbrands are formulated using different active ingredients. Midol is distributed by Bayer. Midol was originally sold in 1911 as a headache and toothache remedy that was considered safer because it did not use the narcotics typically used at the time. It was then promoted as a cure for hiccups claiming it controlled spasms, and finally as a remedy for menstrual cramps and bloating. A formulation sold in the 1980s was made with the sympathomimetic cinnamedrine. It had been reported to have abuse potential as an appetite suppressant and sympathomimetic agent. The "Midol Complete" formulation consists of: Acetaminophen 500 mg (pain reliever) Caffeine 60 mg (stimulant) Pyrilamine maleate 15 mg (antihistamine)The "Extended Relief" formulation consists of: Naproxen sodium 220 mg (NSAID, pain reliever/fever reducer)The "Teen" formulation consists of: Acetaminophen 500 mg (pain reliever) Pamabrom 25 mg (diuretic)The "Liquid Gels" formulation consists of: Ibuprofen 200 mg (NSAID, pain reliever)The "PM" formulation consists of: Acetaminophen 500 mg (pain reliever) Diphenhydramine citrate 38 mg (sedative antihistamine)There are concerns drugs like Midol, which is an NSAID, increases risk of bleeding, kidney damage and has other negative effects on cardiovascular system. References External links Official website
Lusutrombopag	Lusutrombopag, sold under the brand name Mulpleta among others, is a medication that has been developed for certain conditions that lead to thrombocytopenia (abnormally low platelet counts) such as thrombocytopenia associated with chronic liver disease in patients prior to elective invasive procedures. It is being manufactured and marketed in Japan by Shionogi. It was approved by the U.S. Food and Drug Administration (FDA) in July 2018, and NICE in January 2020.It was approved for medical use in the European Union in February 2019. References External links "Lusutrombopag". Drug Information Portal. U.S. National Library of Medicine.
Valganciclovir	Valganciclovir, sold under the brand name Valcyte among others, is an antiviral medication used to treat cytomegalovirus (CMV) infection in those with HIV/AIDS or following organ transplant. It is often used long term as it only suppresses rather than cures the infection. Valganciclovir is taken by mouth.Common side effects include abdominal pain, headaches, trouble sleeping, nausea, fever, and low blood cell counts. Other side effects may include infertility and kidney problems. When used during pregnancy, it causes birth defects in some animals. Valganciclovir is the L-valyl ester of ganciclovir and works when broken down into ganciclovir by the intestine and liver.Valganciclovir was approved for medical use in 2001. It is on the World Health Organizations List of Essential Medicines. In 2017, a generic version was approved. Medical uses Adults Valganciclovir is commonly used for treatment of cytomegalovirus (CMV) retinitis (eye infection may cause blindness) in people who have acquired immunodeficiency syndrome (AIDS). Valganciclovir is also used to prevent cytomegalovirus disease in people who have received a heart, kidney, or kidney-pancreas transplant and who have a chance of getting CMV disease. Overall, valganciclovir works by preventing the spread of CMV disease or slowing the growth of CMV. Children Valganciclovir is used for the prevention of CMV disease in people following kidney transplant (4 months to 16 years of age) and heart transplant (1 month to 16 years of age) at high risk. Side effects Valganciclovir is commonly associated with vomiting, abdominal pain, diarrhea, and headache. Other side effects include fever, trouble sleeping, peripheral neuropathy, and retinal detachment.Of note, the FDA issued several black box warnings concerning potential severe toxicities. These include: Blood toxicities: neutropenia, anemia, thrombocytopenia Impairment of fertility (based on animal studies only) Fetal toxicities (based on animal studies only) Mutagenesis and carcinogenesis (based on animal studies only) Drug interactions While not studied in people, it can be assumed that interactions will be similar as those with ganciclovir, since valganciclovir is converted into ganciclovir in the body. Zidovudine may decrease the concentration of ganciclovir, and together the drugs can cause anemia and neutropenia. Probenecid can increase the concentration of ganciclovir, which could increase the chances of ganciclovir toxicity. People with kidney problems could have an increase in both mycophenolate mofetil and ganciclovir concentrations when both drugs are taken together. Ganciclovir can also increase the concentration of didanosine. Mechanism of action Valganciclovir is a prodrug for ganciclovir, which is a synthetic analog of 2′-deoxy-guanosine. Its structure is the same as ganciclovir, except for the addition of a L-valyl ester at the 5 end of the incomplete deoxyribose ring. The valine increases both the absorption of the drug in the intestines, as well as the bioavailability of the drug once it is absorbed. The L-valyl ester is cleaved by esterases in the intestines and the liver, leaving ganciclovir to be absorbed by the virus-infected cells.Ganciclovir is first phosphorylated to ganciclovir monophosphate by a viral thymidine kinase encoded by the cytomegalovirus (CMV) upon infection. Human cellular kinases further phosphorylate the molecule to create ganciclovir diphosphate, then ganciclovir triphosphate. These kinases are present in 10-fold greater concentrations in CMV or herpes simplex virus (HSV)-infected cells compared to uninfected human cells, allowing ganciclovir triphosphate to concentrate in infected cells.Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate (dGTP). It is incorporated into viral DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases. Ganciclovir triphosphate serves as a poor substrate for chain elongation. Once incorporated into viral DNA due to its structure similarity to dGTP, chain termination occurs once a single nucleotide is added to the distal hydroxyl group of the incomplete deoxyribose ring of ganciclovir. Pharmacokinetics Oral bioavailability is approximately 60%. Fatty foods significantly increase the bioavailability and the peak level in the serum. It takes about 2 hours to reach maximum concentrations in the serum. Valganciclovir is eliminated as ganciclovir in the urine, with a half-life of about 4 hours in people with normal kidney function. The mechanism of this drug is activation via a viral protein kinase HCMV UL97 and subsequent phosphorylation by cellular kinases. The phosphotransferase enzyme can likewise activate valganciclovir. Chemistry The synthesis of valganciclovir has been reviewed. Many routes use ganciclovir as a starting material. Society and culture Price and patent status Roches Valcyte is protected by patent. However a generic version manufactured by Japanese-owned Indian company Daiichi-Ranbaxy was found by the District Court of New Jersey, USA not to infringe Roches patent. In November 2014, FDA approved generics by two manufacturers.The price of a four-month course of valganciclovir from Roche is about US$8,500 in high-income countries, $6,000 in India. However, the valganciclovir patent was rejected by the Indian Patent Office in 2010, although Roche may appeal the rejection. Names Also known as Cymeval, Valcyt, Valixa, Darilin, Rovalcyte, Patheon, and Syntex. References External links "Valganciclovir". Drug Information Portal. U.S. National Library of Medicine.
Dobutamine	Dobutamine is a medication used in the treatment of cardiogenic shock (as a result of inadequate tissue perfusion) and severe heart failure. It may also be used in certain types of cardiac stress tests. It is given by IV only, as an injection into a vein or intraosseous as a continuous infusion. The amount of medication needs to be adjusted to the desired effect. Onset of effects is generally seen within 2 minutes. It has a half-life of two minutes. This drug is generally only administered short term, although it may be used for longer periods to relieve symptoms of heart failure in patients awaiting heart transplantation.Common side effects include a fast heart rate, an irregular heart beat, and inflammation at the site of injection. Use is not recommended in those with idiopathic hypertrophic subaortic stenosis. It primarily works by direct stimulation of β1 receptors, which increases the strength of the hearts contractions, leading to a positive ionotrophic effect. Generally it has little effect on a persons heart rate.Dobutamine was approved for medical use in the United States in 1978. It is available as a generic medication. It was initially made from isoproterenol. Medical uses Dobutamine is used to treat acute but potentially reversible heart failure, such as which occurs during cardiac surgery or in cases of septic or cardiogenic shock, on the basis of its positive inotropic action.Dobutamine can be used in cases of congestive heart failure to increase cardiac output. It is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of patients with cardiac decompensation due to depressed contractility, which could be the result of either organic heart disease or cardiac surgical procedures. Higher doses are not useful with history of recent ischemic heart disease because it increases heart rate and thus increases myocardial oxygen demand.The drug is also commonly used in the hospital setting as a pharmacologic stress testing agent to identify coronary artery disease. Adverse effects Primary side effects include those commonly seen for β1 active sympathomimetics, such as hypertension, angina, arrhythmia, and tachycardia. Used with caution in atrial fibrillation as it has the effect of increasing the atrioventricular (AV) conduction.The most dangerous side effect of dobutamine is increased risk of arrhythmia, including fatal arrhythmias. Overall, dobutamine tends to produce less tachycardia and peripheral vascular effects than agents such as epinephrine and isoproterenol. Pharmacology Dobutamine is a direct-acting agent whose primary activity results from stimulation of the β1-adrenoceptors of the heart, increasing contractility and cardiac output. Since it does not act on dopamine receptors to inhibit the release of norepinephrine (another α1 agonist), dobutamine is less prone to induce hypertension than is dopamine. Dobutamine is predominantly a β1-adrenergic agonist, with weak β2 activity, and α1 selective activity, although it is used clinically in cases of cardiogenic shock for its β1 inotropic effect in increasing heart contractility and cardiac output. Dobutamine is administered as a racemic mixture consisting of both (+) and (−) isomers; the (+) isomer is a potent β1 agonist and α1 antagonist, while the (−) isomer is an α1 agonist. The administration of the racemate results in the overall β1 agonism responsible for its activity. (+)-Dobutamine also has mild β2 agonist activity, which makes it useful as a vasodilator. History It was developed in the 1970s by Drs. Ronald Tuttle and Jack Mills at Eli Lilly and Company, as a structural analogue of isoprenaline. References External links "Dobutamine". Drug Information Portal. U.S. National Library of Medicine.
Econazole	Econazole is an antifungal medication of the imidazole class.It was patented in 1968, and approved for medical use in 1974. Medical uses Econazole is used as a cream to treat skin infections such as athletes foot, tinea, pityriasis versicolor, ringworm, and jock itch. It is also sold in Canada under the brand name Ecostatin as vaginal ovules to treat vaginal thrush. Econazole nitrate exhibits strong anti-feeding properties against the keratin-digesting common clothes moth Tineola bisselliella. Adverse effects About 3% of patients treated with econazole nitrate cream reported side effects. The most common symptoms were burning, itching, redness (erythema), and one outbreak of a pruritic rash. Synthesis Imidazoles devoid of the nitro group no longer have any antiprotozoal activity, however, such drugs are effective antifungal agents. Alkylation of imidazole (2) with bromoketone (1) prepared from o,p-dichloroacetophenone affords the displacement product (3). Reduction of the ketone with sodium borohydride gives the corresponding alcohol (4). Alkylation of the alkoxide from that alcohol with p-chlorobenzyl chloride leads to econazole (5); alkylation with o,p-dichlorobenzyl chloride gives miconazole. Society and culture Brand names It is sold under the brand names Spectrazole (United States) and Ecostatin (Canada), among others. It is a component of Pevisone, Ecoderm-TA and ECOSONE (econazole/triamcinolone). References External links "Econazole". Drug Information Portal. U.S. National Library of Medicine.
Adrenocorticotropic hormone (medication)	Adrenocorticotropic hormone is used as a medication and as diagnostic agent in the ACTH stimulation test.: 316, 1165 : 84, 271 The form that is purified from pig pituitary glands is known as corticotropin: 316 is a medication and naturally occurring polypeptide tropic hormone produced and secreted by the anterior pituitary gland.: 84 The form that is made synthetically is tetracosactide, also known as synacthen, tetracosactrin and cosyntropin.: 1165 : 271 It consists of the first 24 (of a total of 39) amino acids of ACTH and retains full function of the parent peptide.: 1165 Tetracosactide stimulates the release of corticosteroids such as cortisol from the adrenal glands, and is used for the ACTH stimulation test to assess adrenal gland function.: 271 Medical uses Both corticotropin and tetracosactide have been used for diagnostic purposes to determine adrenocortical insufficiency, particularly in Addisons disease, via the ACTH stimulation test. However, as of 2015 the US label for corticotropin does not include diagnostic use.Both corticotropin and tetracosactide have been used for therapeutic purposes. In the US the tetracosactide label is limited to diagnosis but the UK label provides for therapeutic uses.In the US corticotropin is used to treat epileptic spasms in infants, acute exacerbations of multiple sclerosis in adults; acute episodes of psoriatic arthritis and rheumatoid arthritis and ankylosing spondylitis; in acute exacerbations or as maintenance therapy for collagen disorders like systemic lupus erythematosus and systemic dermatomyositis; for skin conditions like severe erythema multiforme and Stevens–Johnson syndrome; for serum sickness; for severe acute and chronic allergic and inflammatory processes involving the eye such as keratitis, iritis and iridocyclitis, diffuse posterior uveitis, choroiditis, optic neuritis, chorioretinitis, and anterior segment inflammation; sarcoidosis in the lungs; and to treat edema in certain nephrotic syndromes.In the UK tetracosactide is used for short-term therapy in conditions for which glucocorticoids are usually used but for some reason should not be; some uses include use for people who dont respond to glucocorticoids or cannot tolerate them who have ulcerative colitis, Crohns disease, juvenile rheumatoid arthritis, rheumatoid arthritis, or osteoarthrosis. Contraindications In the US the only contraindication for tetracosactide for diagnostic use is hypersensitivity to ACTH but in the UK, regulators placed contraindications for hypersensitivity to ACTH and additionally, for people with allergic disorders including asthma, acute psychosis, infectious diseases, peptic ulcer, refractory heart failure, Cushings syndrome, treatment of primary adrenocortical insufficiency and adrenocongenital syndrome.The same contraindications that were applied in the UK for diagnostic use of tetracosactide, apply for therapeutic use of both tetracosactide and corticotropin in the US and UK.In addition, the US label for corticotropin for therapeutic uses includes contraindications for people who have recently had surgery, and people with scleroderma, osteoporosis, uncontrolled hypertension, or sensitivity to proteins of porcine origin; in addition the infection diseases systemic fungal infection, ocular herpes simplex, and infants who have congenital infections are specified. The label also notes that people taking corticotropin for immunosuppression should not be given live vaccines. Adverse effects People taking corticotropin or tetracosactide are more likely to get infections, and are at risk of hypothalamic-pituitary-axis (HPA) suppression and Cushings syndrome. Pharmacology In the normal situation, ACTH is released from the pituitary gland at the base of the brain. It acts on the adrenal glands to stimulate the production of steroid hormones (glucocorticoids). If the adrenal glands are healthy, a single injection of tetracosactide results in a rise in blood cortisol concentrations in 30 minutes. If the adrenal glands appear not to be working then tetracosactide injection can be given to check whether the problem is due to diseased or damaged adrenals or due to lack of pituitary ACTH. Tetracosactide stimulates the release of corticosteroids such as cortisol from the adrenal glands, and is used for the ACTH stimulation test to assess adrenal gland function.: 271 Chemistry The synthetic form consists of the first 24 (of a total of 39) amino acids of ACTH and retains full function of the parent peptide.: 1165 Manufacturing History Society and culture Approved forms In the US, available forms of animal-derived corticotrophin have included: Cortiocotrophin derived from pituitary glands from pigs, in a gel formulation as well as in a zinc hydrochloride formulation, each first approved in the US in 1955 and subsequently discontinued. In September 2015 ANI Pharmaceuticals and Merck & Co. agreed that ANI would purchase NDA 009854 and NDA 008975 and related trademarks and other assets related to these two versions of corticotrophin from Merck for $75M and ongoing royalties; the transaction closed in January 2016. As of November 2016 ANI was preparing its supplemental NDA to get approval to re-introduce this formulation; in 2015 ANI estimated that the US market for these products was about $1 billion per year, based on sales of Acthar gel. Corticotrophin, first approved in 1952 and subsequently discontinued; as of January 2017 this NDA was under control of Parkedale, a subsidiary of King Pharmaceuticals which is in turn a subsidiary of Pfizer. Corticotrophin branded as "Acthar", was first approved in 1950 and was subsequently discontinued; as of January 2017 this NDA was under control of Sanofi. A corticotrophin was approved in 1957 under NDA 010831, was subsequently discontinued, and as of January 2017 was under control of Organics/Lagrange, a subsidiary of Abbvie via Abbotts acquisition of Solvays drug business. A generic version under this NDA was approved under ANDA 088772 and was subsequently discontinued, and as of January 2017 was under the control of Actavis. A corticotrophin called H.P. Acthar Gel was approved in 1952 and as of January 2017 was under the control of Mallinckrodt. A repository version of H.P. Acthar gel was approved in 2010 and as of January 2017 was also under the control of Mallinkrodt.Synthetic forms were created as a replacement for the animal-derived products.In the US, available forms of tetracosactide/cosyntropin, the synthetic form of corticotrophin, have been approved only for diagnostic uses, and have included: A branded version called Cortrosyn, which was created and developed by Organon and was approved by the FDA in 1970, and as of January 2017 was under the control of Amphastar Pharmaceuticals, and there were three generic versions under ANDAs, one for Mylan approved in 2009, one for Sandoz/Novartis, approved in 2012, and another for Amphastar under ANDA 016750. This version is a powder that is reconstituted before use. A version of cosyntropin in solution (as opposed to powder) was developed by Sandoz/Novartis and was approved under the 505b(2) pathway in 2008; as of January 2017 it had been discontinued.In the UK, available forms of tetracosactide/cosyntropin, the synthetic form of corticotrophin, have been approved for both therapeutic and diagnostic uses, and have included: A version branded Synacthen and provided in solution 250 mcg ampoules, for diagnostic uses, approved in 2008 and as of January 2017 controlled by Mallinckrodt. A version branded Synacthen, absorbed on to zinc phosphate, provided in milky white suspension, approved in 2008 and as of January 2017 controlled by Mallinckrodt. Doping As of 2007, it was widely reported that tetracosactide had been used as an illegal performance-enhancing drug by professional cyclists. It is known to be used as a doping agent to increase the secretion of glucocorticoids by adrenal glands. Pricing Mallinckrodt acquired the US rights to the animal-derived form via its acquisition of Questcor Pharmaceuticals in 2014. When Questcor acquired the drug in 2001 it sold for $40 a vial; within a year of the acquisition Questcor raised the price of the drug to $1,500 per vial and to $28,000 by 2013. In 2013, Questcor acquired the US rights to a competing product, Synacthen Depot, from Novartis. In 2014 Mallinckrodt raised the price of Acthar further to $34,000. The Federal Trade Commission and attorneys general from five states sued Mallinckrodt for anti-competitive behavior with regard to the acquisition of Synacthen Depot and the monopolistic pricing of Acthar, and in January 2017 the company settled, agreeing to pay $100 million and to license Synacthen Depot to a competitor. According to Kaiser Health News, Mallinckrodt responded by increasing its Congressional lobbying to $610,000, and its contributions to Congress members to $44,000, in the first quarter of 2017.In Canada, Synacthen Depots pricing increased by 2000% in 2015, causing some provincial single payer authorities to delist the drug from funded medications. The increase in the drugs price came after Mallinckrodt acquired Questcor and its drug portfolio, which included the worldwide rights to Synacthen Depot. Prior to the price increase, Mallinckrodt claims that the drug was manufactured at a loss. Some have claimed that the price increase is abusive. The drug had been priced at $33 but rose to $680 per vial. As an off-patent pharmaceutical, a similar drug, differing in formulation, available in Europe, made by a different manufacturer, sells for $8 per vial. Research Acthar gel has been proposed as a therapy to treat refractory autoimmune diseases and refractory nephrotic syndrome due to a variety of glomerular diseases. Veterinary medicine Both versions of the hormone are also used to perform the ACTH stimulation test to diagnose hypoadrenocorticism in dogs and sometimes cats. References External links Adrenocorticotropic+Hormone at the US National Library of Medicine Medical Subject Headings (MeSH) Cosyntropin at the US National Library of Medicine Medical Subject Headings (MeSH)
Fluorometholone	Fluorometholone (INN, BAN, JAN) (brand names Efflumidex, Flucon, FML Forte, FML, others), also known as 6α-methyl-9α-fluoro-11β,17α-dihydroxypregna-1,4-diene-3,20-dione, is a synthetic glucocorticoid which is used in the treatment of inflammatory eye diseases. The C17α acetate ester, fluorometholone acetate (brand name Flarex), is also a glucocorticoid and is used for similar indications.Most common indication for this drug is seasonal allergic conjunctivitis and other allergies of the eye. See also 9α-Bromo-11-ketoprogesterone Flugestone Medrysone References External links Drugs.com flarex Alcon official page Fluorometholone all you should know.
Hydrocortisone sodium succinate	Hydrocortisone sodium succinate is a synthetic glucocorticoid corticosteroid and a corticosteroid ester. == References ==
Levomefolic acid	Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood–brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon unit for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by dihydrofolate reductase (DHFR) to become biologically active.It is synthesized in the absorptive cells of the small intestine from polyglutamylated dietary folate. It is a methylated derivative of tetrahydrofolate. Levomefolic acid is generated by methylenetetrahydrofolate reductase (MTHFR) from 5,10-methylenetetrahydrofolate (MTHF) and used to recycle homocysteine back to methionine by methionine synthase (MS).L-Methylfolate is water-soluble and primarily excreted via the kidneys. In a study of 21 subjects with coronary artery disease, peak plasma levels were reached in one to three hours following oral or parenteral administration. Peak concentrations were found to be more than seven times higher than folic acid (129 ng/ml vs. 14.1 ng/ml). Metabolism Medical uses Major depressive disorder Research suggests that levomefolic acid (L-methylfolate) taken with a first-line antidepressant provides a modest adjunctive antidepressant effect for individuals who do not respond or have only a partial therapeutic response to SSRI or SNRI medication, and might be a more cost-effective adjunctive agent than second-generation antipsychotics. Cardiovascular disease and cancer Levomefolic acid (and folic acid in turn) has been proposed for treatment of cardiovascular disease and advanced cancers such as breast and colorectal cancers. It bypasses several metabolic steps in the body and better binds thymidylate synthase with FdUMP, a metabolite of the drug fluorouracil. Patent issues In March 2012, Merck & Cie of Switzerland, Pamlab LLC (maker of Metanx and Cerefolin, Neevo DHA, and Deplin), and South Alabama Medical Science Foundation (SAMSF) (the plaintiffs) filed a complaint in the United States District Court for the Eastern District of Texas against four defendants: Macoven Pharmaceuticals (owned by Pernix Therapeutics), Gnosis SpA of Italy, Gnosis U.S.A and Gnosis Bioresearch Switzerland. The plaintiffs alleged that the defendants infringed on several of the plaintiffs patents. The Macoven products named in the suit are: "Vitaciric-B", "ALZ-NAC", "PNV DHA", and l-methylfolate calcium (levomefolate calcium).In September 2012, the same three plaintiffs filed a complaint requesting that the International Trade Commission begin an 19 U.S.C. § 1337 investigation of the same four defendants. The complaint states that Gnosis "Extrafolic-S" and products which are made from it, infringe upon three of their patents: US 5997915 , US 6673381 , and US 7172778 . Formulations Levomefolate calcium, a calcium salt of levomefolic acid is sold under the brand name Metafolin and incorporated in Deplin. Levomefolate magnesium is a magnesium salt of levomefolic acid, sold under the brand name Enlyte or Enlyte D. See also 5,10-Methylenetetrahydrofolate S-Adenosylmethionine (SAMe) References External links CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca) Brockton NT (October 2006). "Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate?". Cancer Causes & Control. 17 (8): 1005–16. doi:10.1007/s10552-006-0051-5. PMID 16933051. S2CID 20394873. Stahl SM (October 2007). "Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent". CNS Spectrums. 12 (10): 739–44. doi:10.1017/S1092852900015418. PMID 17934378. S2CID 27000937.
Guaifenesin/phenylephrine	Guaifenesin/phenylephrine is a combination of the drugs guaifenesin and phenylephrine and is a preparation against the symptoms of cold, flu and allergy. Guaifenesine is an expectorant, phenylephrine is a decongestant. The drug is sold under the brand name Entex and as generic brands. Entex La is 400 mg guaifenesin and 30 mg phenylephrine hydrochloride. Entex Pse is 600 mg guaifenesin and 120 mg phenylephrine hydrochloride. Both are extended release products, meaning that the non-active ingredients are chosen to dissolve slowly to provide a prolonged therapeutic effect. Guaifenesin Guaifenesin is an oral medication used to try to help cough out phlegm from the airways. It is often used in combination with other medications. It is believed to work by making airway secretions more liquid. Side effects may include dizziness, sleepiness, skin rash, and nausea. Guaifenesin has been used medically since at least 1933. It is available as a generic medication and an over-the-counter drug. Phenylephrine Phenylephrine is an oral medication primarily used as a decongestant. It is a selective α1-adrenergic receptor activator which results in the constriction of both arteries and veins. Common side effects include nausea, headache, and anxiety. Phenylephrine was patented in 1927 and came into medical use in 1938. It is available as a generic medication. == References ==
Crotamiton	Crotamiton is a drug that is used both as a scabicidal (for treating scabies) and as a general antipruritic (anti-itching drug). It is a prescription, lotion-based medicine that is applied to the whole body to get rid of the scabies parasite that burrows under the skin and causes itching. Use For treating scabies, crotamiton should be applied to the whole body rather than a localized area. It is applied two or three times, with a 24-hour delay between applications, and the patient is asked to take a shower no sooner than after 48 hours. For children under 3 years, it is applied once daily. It can also be used to treat itching stemming from other causes, e.g. insect bites, in which case it is applied to the itching areas only, and repeated if necessary after 4 to 8 hours. Use near the eyes, or breaks in the skin, should be avoided. Pharmacology Crotamiton is toxic to the scabies mite. It probably acts as a general antipruritic by inhibition of TRPV4, a sensory ion channel that is expressed in the skin and primary sensory neurons. Pharmacokinetics After topical application, crotamiton is absorbed systemically. It has an elimination half-life of 30.9 hours and 4.8-8.8% is excreted in the urine. Side effects The most common side effect of crotamiton is skin irritation. Trade name Crotamiton is marketed under the trade names Eurax, which is manufactured by Ranbaxy Laboratories in the United States, and GlaxoSmithKline in the United Kingdom, and Euracin, which is manufactured by Green Cross in South Korea. In Germany, it is marketed under the brand name Crotamitex. In India, it is sold as Eurax by Ranbaxy Laboratories. == References ==
Fluocinonide	Fluocinonide (sold under various trade names) is a potent glucocorticoid used topically as an anti-inflammatory agent for the treatment of skin disorders such as eczema and seborrhoeic dermatitis. It relieves itching, redness, dryness, crusting, scaling, inflammation, and discomfort. The usual prescription concentration is 0.05% as a topical cream, ointment, solution, or gel. The application area should normally not be covered after application. In certain cases, the physician may recommend the use of an occlusive dressing after application to increase the rate and depth of absorption. The frequency of application depends on the condition being treated and the area affected, but most often it should be applied 2 to 4 times a day.Fluocinonide ranks as a "high-potency" (second-highest rank) topical corticosteroid. Minimal amounts should be used for a minimal length of time to avoid the occurrence of adverse effects.Fluocinonide should not be used if infection is present. It should not be applied to the eyes or to sensitive areas such as the genitals or anus.A common potential adverse effect is skin atrophy (thinning of the skin). Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal axis (HPA) suppression, manifestations of Cushings syndrome, hyperglycemia, and glucosuria in some patients. Fluocinonide should be used with caution when treating children, pregnant women, nursing mothers, and anyone using the medication for longer than two weeks. Fluocinonide is used in veterinary medicine. It is a treatment for allergies in dogs. Natural systemic cortisol concentrations can be suppressed for weeks after one week of topical exposure. See also Topical steroid relative strength groupings list == References ==
Sodium zirconium cyclosilicate	Sodium zirconium cyclosilicate (ZS-9), sold under the brand name Lokelma, is a medication used to treat high blood potassium. Onset of effects occurs in one to six hours. It is taken by mouth.Common side effects include swelling and low blood potassium. Use is likely safe in pregnancy and breastfeeding. It works by binding potassium ions in the gastrointestinal tract which is then lost in the stool.Sodium zirconium cyclosilicate was approved for medical use in the European Union and in the United States in 2018. It was developed by AstraZeneca. Medical use Sodium zirconium cyclosilicate is used to treat high blood potassium. Onset of effects occurs in one to six hours.One review found a decrease in potassium of 0.17 mEq/L at one hour and 0.67 mEq/L at 48 hours.It appears effective in people with chronic kidney disease, diabetes, and heart failure. Use has been studied for up to a year. Mechanism of action ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety. 11 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions, presumably by mimicking the actions of physiologic potassium channels. ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized. Background Hyperkalemia is rare among those who are otherwise healthy. Among those who are in hospital, rates are between 1% and 2.5%. Common causes include kidney failure, hypoaldosteronism, and rhabdomyolysis. A number of medications can also cause high blood potassium including spironolactone, NSAIDs, and angiotensin converting enzyme inhibitors.There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe. However, if hyperkalemia causes any ECG change it is considered a medical emergency due to a risk of potentially fatal abnormal heart rhythms and is treated urgently. Potassium levels greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively. Several approaches are used to treat hyperkalemia. Other approved potassium binders in the United States include patiromer and sodium polystyrene sulfonate.Hyperkalemia, particularly if severe, is a marker for an increased risk of death. However, there is disagreement regarding whether a modestly elevated levels directly causes problems. One viewpoint is that mild to moderate hyperkalemia is a secondary effect that denotes underlying medical problems. Accordingly, these problems are both proximate and ultimate causes of death, History Regulatory In the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration (FDA) in May 2016, due to issues associated with manufacturing. On May 18, 2018, the FDA approved sodium zirconium cyclosilicate for treatment of adults with hyperkalemia.It was first practically synthesized by UOP in the late 1990s. (reference -zirconium silicate and zirconium germate molecular sieves and the process of using the same, US Patent 5,888,472) the recognition of the unique ion exchange properties and the potential use to remove toxins from the body were identified shortly thereafter ("process for removing toxins from bodily fluids using zirconium or titanium microporous compositions, US Patent 6,332,985). References Further reading CADTH review External links "Sodium zirconium cyclosilicate". Drug Information Portal. U.S. National Library of Medicine.
Adrenaline	Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). Adrenaline is normally produced by the adrenal glands and by a small number of neurons in the medulla oblongata. It plays an essential role in the fight-or-flight response by increasing blood flow to muscles, heart output by acting on the SA node, pupil dilation response, and blood sugar level. It does this by binding to alpha and beta receptors. It is found in many animals, including humans, and some single-celled organisms. In 1901, Japanese chemist Jōkichi Takamine developed a purified extract from the adrenal glands, which Parke, Davis & Co trademarked in the US. The British Approved Name and European Pharmacopoeia term for this drug is hence adrenaline. Medical uses As a medication, it is used to treat several conditions, including allergic reaction anaphylaxis, cardiac arrest, and superficial bleeding. Inhaled adrenaline may be used to improve the symptoms of croup. It may also be used for asthma when other treatments are not effective. It is given intravenously, by injection into a muscle, by inhalation, or by injection just under the skin. Common side effects include shakiness, anxiety, and sweating. A fast heart rate and high blood pressure may occur. Occasionally it may result in an abnormal heart rhythm. While the safety of its use during pregnancy and breastfeeding is unclear, the benefits to the mother must be taken into account.A case has been made for the use of adrenaline infusion in place of the widely accepted treatment of inotropes for preterm infants with clinical cardiovascular compromise. Although sufficient data strongly recommends adrenaline infusions as a viable treatment, more trials are needed to conclusively determine that these infusions will successfully reduce morbidity and mortality rates among preterm, cardiovascularly compromised infants. Physiological effects The adrenal medulla is a Major contributor to total circulating catecholamines (L-DOPA is at a higher concentration in the plasma), though it contributes over 90% of circulating adrenaline. Little adrenaline is found in other tissues, mostly in scattered chromaffin cells and in a small number of neurons that use adrenaline as a neurotransmitter. Following adrenalectomy, adrenaline disappears below the detection limit in the bloodstream.Pharmacological doses of adrenaline stimulate α1, α2, β1, β2, and β3 adrenoceptors of the sympathetic nervous system. Sympathetic nerve receptors are classified as adrenergic, based on their responsiveness to adrenaline. The term "adrenergic" is often misinterpreted in that the main sympathetic neurotransmitter is noradrenaline, rather than adrenaline, as discovered by Ulf von Euler in 1946. Adrenaline has a β2 adrenoceptor-mediated effect on metabolism and the airway, with no direct neural connection from the sympathetic ganglia to the airway.Walter Bradford Cannon originally proposed the concept of the adrenal medulla and the sympathetic nervous system being involved in the flight, fight, and fright response. But the adrenal medulla, in contrast to the adrenal cortex, is not required for survival. In adrenalectomized patients, hemodynamic and metabolic responses to stimuli such as hypoglycemia and exercise remain normal. Exercise One physiological stimulus to adrenaline secretion is exercise. This was first demonstrated by measuring the dilation of a (denervated) pupil of a cat on a treadmill, later confirmed using a biological assay of urine samples. Biochemical methods for measuring catecholamines in plasma were published from 1950 onwards. Although much valuable work has been published using fluorimetric assays to measure total catecholamine concentrations, the method is too non-specific and insensitive to accurately determine the very small quantities of adrenaline in plasma. The development of extraction methods and enzyme–isotope derivate radio-enzymatic assays (REA) transformed the analysis down to a sensitivity of 1 pg for adrenaline. Early REA plasma assays indicated that adrenaline and total catecholamines rise late in exercise, mostly when anaerobic metabolism commences.During exercise, the adrenaline blood concentration rises partially from the increased secretion of the adrenal medulla and partly from the decreased metabolism of adrenaline due to reduced blood flow to the liver. Infusion of adrenaline to reproduce exercise circulating concentrations of adrenaline in subjects at rest has little hemodynamic effect other than a slight β2-mediated fall in diastolic blood pressure. Infusion of adrenaline well within the physiological range suppresses human airway hyper-reactivity sufficiently to antagonize the constrictor effects of inhaled histamine.A link between the sympathetic nervous system and the lungs was shown in 1887 when Grossman showed that stimulation of cardiac accelerator nerves reversed muscarine-induced airway constriction. In experiments in the dog, where the sympathetic chain was cut at the level of the diaphragm, Jackson showed that there was no direct sympathetic innervation to the lung, but bronchoconstriction was reversed by the release of adrenaline from the adrenal medulla. An increased incidence of asthma has not been reported for adrenalectomized patients; those with a predisposition to asthma will have some protection from airway hyper-reactivity from their corticosteroid replacement therapy. Exercise induces progressive airway dilation in normal subjects that correlates with workload and is not prevented by beta-blockade. The progressive airway dilation with increasing exercise is mediated by a progressive reduction in resting vagal tone. Beta blockade with propranolol causes a rebound in airway resistance after exercise in normal subjects over the same time course as the bronchoconstriction seen with exercise-induced asthma. The reduction in airway resistance during exercise reduces the work of breathing. Emotional responses Every emotional response has a behavioral component, an autonomic component, and a hormonal component. The hormonal component includes the release of adrenaline, an adrenomedullary response that occurs in response to stress and that is controlled by the sympathetic nervous system. The major emotion studied in relation to adrenaline is fear. In an experiment, subjects who were injected with adrenaline expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects. The findings from this study demonstrate that there are learned associations between negative feelings and levels of adrenaline. Overall, the greater amount of adrenaline is positively correlated with an aroused state of negative emotions. These findings can be an effect in part that adrenaline elicits physiological sympathetic responses, including an increased heart rate and knee shaking, which can be attributed to the feeling of fear regardless of the actual level of fear elicited from the video. Although studies have found a definite relation between adrenaline and fear, other emotions have not had such results. In the same study, subjects did not express a greater amusement to an amusement film nor greater anger to an anger film. Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce adrenaline. Findings support the idea that adrenaline has a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear. Memory It has been found that adrenergic hormones, such as adrenaline, can produce retrograde enhancement of long-term memory in humans. The release of adrenaline due to emotionally stressful events, which is endogenous adrenaline, can modulate memory consolidation of the events, ensuring memory strength that is proportional to memory importance. Post-learning adrenaline activity also interacts with the degree of arousal associated with the initial coding. There is evidence that suggests adrenaline does have a role in long-term stress adaptation and emotional memory encoding specifically. Adrenaline may also play a role in elevating arousal and fear memory under particular pathological conditions, including post-traumatic stress disorder. Overall, "Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects." Studies have also found that recognition memory involving adrenaline depends on a mechanism that depends on β adrenoceptors. Adrenaline does not readily cross the blood-brain barrier, so its effects on memory consolidation are at least partly initiated by β adrenoceptors in the periphery. Studies have found that sotalol, a β adrenoceptor antagonist that also does not readily enter the brain, blocks the enhancing effects of peripherally administered adrenaline on memory. These findings suggest that β adrenoceptors are necessary for adrenaline to have an impact on memory consolidation. Pathology Increased adrenaline secretion is observed in pheochromocytoma, hypoglycemia, myocardial infarction, and to a lesser degree, in essential tremor (also known as benign, familial, or idiopathic tremor). A general increase in sympathetic neural activity is usually accompanied by increased adrenaline secretion, but there is selectivity during hypoxia and hypoglycemia, when the ratio of adrenaline to noradrenaline is considerably increased. Therefore, there must be some autonomy of the adrenal medulla from the rest of the sympathetic system. Myocardial infarction is associated with high levels of circulating adrenaline and noradrenaline, particularly in cardiogenic shock.Benign familial tremor (BFT) is responsive to peripheral β adrenergic blockers, and β2-stimulation is known to cause tremor. Patients with BFT were found to have increased plasma adrenaline but not noradrenaline.Low or absent concentrations of adrenaline can be seen in autonomic neuropathy or following adrenalectomy. Failure of the adrenal cortex, as with Addisons disease, can suppress adrenaline secretion as the activity of the synthesizing enzyme, phenylethanolamine-N-methyltransferase, depends on the high concentration of cortisol that drains from the cortex to the medulla. Terminology In 1901, Jōkichi Takamine patented a purified extract from the adrenal glands, which was trademarked by Parke, Davis & Co in the US. The British Approved Name and European Pharmacopoeia term for this drug is hence adrenaline.However, the pharmacologist John Abel had already prepared an extract from adrenal glands as early as 1897, and he coined the name epinephrine to describe it (from Ancient Greek ἐπῐ́ (epí), "upon", and νεφρός (nephrós), "kidney"). In the belief that Abels extract was the same as Takamines (a belief since disputed), epinephrine became the generic name in the US and remains the pharmaceuticals United States Adopted Name and International Nonproprietary Name (though the name adrenaline is frequently used). The terminology is now one of the few differences between the INN and BAN systems of names. Although European health professionals and scientists preferentially use the term adrenaline, the converse is true among American health professionals and scientists. Nevertheless, even among the latter, receptors for this substance are called adrenergic receptors or adrenoceptors, and pharmaceuticals that mimic its effects are often called adrenergics. The history of adrenaline and epinephrine is reviewed by Rao. Mechanism of Action As a hormone, adrenaline acts on nearly all body tissues by binding to adrenergic receptors. Its effects on various tissues depend on the type of tissue and expression of specific forms of adrenergic receptors. For example, high levels of adrenaline cause smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles. Adrenaline is a nonselective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3. Adrenalines binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the liver and muscle, and stimulates glycolysis and inhibits insulin-mediated glycogenesis in muscle. β adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue. Together, these effects increase blood glucose and fatty acids, providing substrates for energy production within cells throughout the body.Adrenaline causes liver cells to release glucose into the blood, acting through both alpha and beta-adrenergic receptors to stimulate glycogenolysis. Adrenaline binds to β2 receptors on liver cells, which changes conformation and helps Gs, a heterotrimeric G protein, exchange GDP to GTP. This trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits. Gs alpha stimulates adenylyl cyclase, thus converting adenosine triphosphate into cyclic adenosine monophosphate (AMP). Cyclic AMP activates protein kinase A. Protein kinase A phosphorylates and partially activates phosphorylase kinase. Adrenaline also binds to α1 adrenergic receptors, causing an increase in inositol trisphosphate, inducing calcium ions to enter the cytoplasm. Calcium ions bind to calmodulin, which leads to further activation of phosphorylase kinase. Phosphorylase kinase phosphorylates glycogen phosphorylase, which then breaks down glycogen leading to the production of glucose.Adrenaline also has significant effects on the cardiovascular system. It increases peripheral resistance via α1 receptor-dependent vasoconstriction and increases cardiac output by binding to β1 receptors. The goal of reducing peripheral circulation is to increase coronary and cerebral perfusion pressures and therefore increase oxygen exchange at the cellular level. While adrenaline does increase aortic, cerebral, and carotid circulation pressure, it lowers carotid blood flow and end-tidal CO2 or ETCO2 levels. It appears that adrenaline improve macrocirculation at the expense of the capillary beds where perfusion takes place. Measurement in biological fluids Adrenaline may be quantified in blood, plasma, or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma adrenaline concentrations in resting adults usually are less than 10 ng/L, but they may increase by 10-fold during exercise and by 50-fold or more during times of stress. Pheochromocytoma patients often have plasma adrenaline levels of 1000–10,000 ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L. Biosynthesis In chemical terms, adrenaline is one of a group of monoamines called the catecholamines. Adrenaline is synthesized in the chromaffin cells of the adrenal glands adrenal medulla and a small number of neurons in the medulla oblongata in the brain through a metabolic pathway that converts the amino acids phenylalanine and tyrosine into a series of metabolic intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA by tyrosine hydroxylase; this is the rate-limiting step. Then it is subsequently decarboxylated to give dopamine by DOPA decarboxylase (aromatic L-amino acid decarboxylase). Dopamine is then converted to noradrenaline by dopamine beta-hydroxylase, which utilizes ascorbic acid (vitamin C) and copper. The final step in adrenaline biosynthesis is the methylation of the primary amine of noradrenaline. This reaction is catalyzed by the enzyme phenylethanolamine N-methyltransferase (PNMT), which utilizes S-adenosyl methionine (SAMe) as the methyl donor. While PNMT is found primarily in the cytosol of the endocrine cells of the adrenal medulla (also known as chromaffin cells), it has been detected at low levels in both the heart and brain. Regulation The major physiologic triggers of adrenaline release center upon stresses, such as physical threat, excitement, noise, bright lights, and high or low ambient temperature. All of these stimuli are processed in the central nervous system.Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of tyrosine hydroxylase and dopamine β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the adrenal cortex to release cortisol, which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of adrenaline. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream. For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out of granules of the chromaffin cells. This may occur via the catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.Unlike many other hormones, adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis. Abnormally adrenaline levels can occur in various conditions, such as surreptitious adrenaline administration, pheochromocytoma, and other tumors of the sympathetic ganglia. Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by monoamine oxidase and catechol-O-methyl transferase. History Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna ("adrenalin"), contained adrenaline and other catecholamines. American ophthalmologist William H. Bates discovered adrenalines usage for eye surgeries prior to 20 April 1896. In 1897, John Jacob Abel (1857–1938), the father of modern pharmacology, found a natural substance produced by the adrenal glands that he named epinephrine. The first hormone to be identified, it remains a crucial, first-line treatment for cardiac arrests, severe allergic reactions, and other conditions. Japanese chemist Jōkichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900. In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen. Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.Although secretin is mentioned as the first hormone, adrenaline is the first hormone since the discovery of the activity of adrenal extract on blood pressure was observed in 1895 before that of secretin in 1902. In 1895, George Oliver (1841–1915), a general practitioner in North Yorkshire, and Edward Albert Schäfer (1850–1935), a physiologist at University College of London published a paper about the active component of adrenal gland extract causing the increase in blood pressure and heart rate was from the medulla, but not the cortex of the adrenal gland. In 1897, John Jacob Abel (1857–1938) of Johns Hopkins University, the first chairman of the first US department of pharmacology, found a compound called epinephrine with the molecular formula of C17H15NO4. Abel claimed his principle from adrenal gland extract was active. In 1900, Jōkichi Takamine (1854–1922), a Japanese chemist, worked with his assistant, Keizo Uenaka (1876–1960), to purify a 2000 times more active principle than epinephrine from the adrenal gland, named adrenaline with the molecular formula C10H15NO3. Additionally, in 1900 Thomas Aldrich of Parke-Davis Scientific Laboratory also purified adrenaline independently. Takamine and Parke-Davis later in 1901 both got the patent for adrenaline. The fight for terminology between adrenaline and epinephrine was not ended until the first adrenaline structural discovery by Hermann Pauly (1870-1950) in 1903 and the first adrenaline synthesis by Friedrich Stolz (1860–1936), a German chemist in 1904. They both believed that Takamines compound was the active principle while Abels compound was the inactive one. Society and culture Adrenaline junkie An adrenaline junkie is someone who engages in sensation-seeking behavior through "the pursuit of novel and intense experiences without regard for physical, social, legal or financial risk". Such activities include extreme and risky sports, substance abuse, unsafe sex, and crime. The term relates to the increase in circulating levels of adrenaline during physiological stress. Such an increase in the circulating concentration of adrenaline is secondary to the activation of the sympathetic nerves innervating the adrenal medulla, as it is rapid and not present in animals where the adrenal gland has been removed. Although such stress triggers adrenaline release, it also activates many other responses within the central nervous system reward system, which drives behavioral responses; while the circulating adrenaline concentration is present, it may not drive behavior. Nevertheless, adrenaline infusion alone does increase alertness and has roles in the brain, including the augmentation of memory consolidation. Strength Adrenaline has been implicated in feats of great strength, often occurring in times of crisis. For example, there are stories of a parent lifting part of a car when their child is trapped underneath. See also Noradrenaline Catecholamines Adrenal gland References External links "U.S. National Library of Medicine: Drug Information Portal – Epinephrine". Archived from the original on 14 December 2019.
Urea-containing cream	Urea, also known as carbamide-containing cream, is used as a medication and applied to the skin to treat dryness and itching such as may occur in psoriasis, dermatitis, or ichthyosis. It may also be used to soften nails.In adults side effects are generally few. It may occasionally cause skin irritation. Urea works in part by loosening dried skin. Preparations generally contain 5 to 50% urea.Urea containing creams have been used since the 1940s. It is on the World Health Organizations List of Essential Medicines. It is available over the counter. Medical uses Urea cream is indicated for debridement and promotion of normal healing of skin areas with hyperkeratosis, particularly where healing is inhibited by local skin infection, skin necrosis, fibrinous or itching debris or eschar. Specific condition with hyperkeratosis where urea cream is useful include: Dry skin and rough skin Dermatitis Psoriasis Ichthyosis Eczema Keratosis Keratoderma Corns Calluses Damaged, ingrown and devitalized nails Side effects Common side effects of urea cream are: Mild skin irritation Temporary burning sensation Stinging sensation ItchingIn severe cases, there can be an allergic reaction with symptoms such as skin rash, urticaria, difficulty breathing and swelling of the mouth, face, lips, or tongue. Mechanism of action Urea in low doses is a humectant while at high doses (above 20%) it causes breakdown of protein in the skin.Urea dissolves the intercellular matrix of the cells of the stratum corneum, promoting desquamation of scaly skin, eventually resulting in softening of hyperkeratotic areas. In nails, urea causes softening and eventually debridement of the nail plate. References External links "Urea". Drug Information Portal. U.S. National Library of Medicine.
Senna glycoside	Senna glycoside, also known as sennoside or senna, is a medication used to treat constipation and empty the large intestine before surgery. The medication is taken by mouth or via the rectum. It typically begins working in around 30 minutes when given by rectum and within twelve hours when given by mouth. It is a weaker laxative than bisacodyl or castor oil.Common side effects of senna glycoside include abdominal cramps. It is not recommended for long-term use, as it may result in poor bowel function or electrolyte problems. While no harm has been found to result from use while breastfeeding, such use is not typically recommended. It is not typically recommended in children. Senna may change urine to a somewhat reddish color. Senna derivatives are a type of stimulant laxative and are of the anthraquinone type. While its mechanism of action is not entirely clear, senna is thought to act by increasing fluid secretion within and contraction of the large intestine.It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Sennosides come from the group of plants Senna. In plant form, it has been used at least since the 700s CE. In 2019, it was the 344th most commonly prescribed medication in the United States, with fewer than one million prescriptions. It is sold under a number of brand names including Ex-Lax and Senokot. Medical uses Senna is used for episodic and chronic constipation though there is a lack of high-quality evidence to support its use for these purposes. It may also be used to aid in the evacuation of the bowel prior to surgery or invasive rectal or colonic examinations. Administration It should be taken once daily at bedtime. Oral senna products typically produce a bowel movement in 6 to 12 hours. Rectal suppositories can act within minutes or take up to two hours. Contraindications According to Commission E, senna is contraindicated in cases of intestinal obstruction, acute intestinal inflammation (e.g., Crohns disease), ulcerative colitis, appendicitis, and abdominal pain of unknown origin.Senna is considered contraindicated in people with a documented allergy to anthraquinones. Such allergies are rare and typically limited to dermatological reactions of redness and itching. Adverse effects Adverse effects are typically limited to gastrointestinal reactions and include abdominal pain or cramps, diarrhea, nausea, and vomiting. Regular use of senna products can lead to a characteristic brown pigmentation of the internal colonic wall seen on colonoscopy. This abnormal pigmentation is known as melanosis coli. Interactions Senna glycosides can increase digoxin toxicity in patients taking digoxin by reducing serum potassium levels, thereby enhancing the effects of digoxin. Mechanism of action The breakdown products of senna act directly as irritants on the colonic wall to induce fluid secretion and colonic motility. Pharmacology They are anthraquinone derivatives and dimeric glycosides. Society and culture Formulations Senna is an over-the-counter medication available in multiple formulations, including oral formations (liquid, tablet, granular) and rectal suppositories. Senna products are manufactured by multiple generic drug makers and sold under various brand names.Kayam churna is a traditional Indian laxative that contains senna leaves. Brand names Ex-Lax, Geri-kot, Perdiem Overnight Relief, Senexon, Pursennid, Senna Smooth, Senna-Gen, Senna-GRX, Senna-Lax, Senna-Tabs, Senna-Time, SennaCon, Senno, Senokot. References External links "Senna". Drug Information Portal. U.S. National Library of Medicine.
Estrogen patch	An estrogen patch (oestrogen patch) is a transdermal delivery system for estrogens such as estradiol and ethinylestradiol which can be used in menopausal hormone therapy, feminizing hormone therapy for transgender women, hormonal birth control, and other uses. Transdermal preparations of estrogen are metabolized differently than oral preparations. Transdermal estrogens avoid the first pass through the liver and thus potentially reduce the risk of blood clotting and stroke.An estrogen patch is applied directly to the skin, preferably near the lower abdomen, hips, or buttocks, and is usually changed once or twice per week. For women who have not undergone a hysterectomy, it is often suggested that they take progestogen in addition to an estrogen patch in order to protect the endometrium of the uterus. Transdermal estrogens are not recommended for all women; there are important precautions and side effects that should be considered before use. Medical uses Menopause An estrogen patch may be recommended for women experiencing moderate to severe symptoms of menopause, such as vasomotor symptoms and vaginal atrophy. During menopause, the ovaries stop producing estrogen which causes estrogen levels to fall. The sudden change in estrogen levels may cause vasomotor symptoms, such as hot flashes. Research suggests that the estrogen patch can relieve both the frequency and severity of vasomotor symptoms by increasing estrogen levels. An estrogen patch may also be used to treat vulvar and vaginal atrophy, another symptom of menopause associated with the sudden change in estrogen levels. Hypoestrogenism Hypoestrogenism, or estrogen deficiency, may suggest menopause is approaching for middle aged women. Other causes of hypoestrogenism are excessive exercise, restrictive diet, underactive pituitary gland, ovarian failure, Turner Syndrome, and kidney disease. Symptoms of hypoestrogenism may include pain during sex, irregular periods, mood swings, hot flashes, breast tenderness, headache, depression, fatigue, weak bones, and an increase risk of urinary tract infections. Estrogen therapies, including the use of an estrogen patch, can be used to alleviate these symptoms by increasing estrogen levels to a normal state. Premenopausal women may be recommended to take progestin with estrogen therapy. Prevention of osteoporosis Estrogen patches may be effective in preventing osteoporosis in postmenopausal women. Research suggests that estrogen patches can significantly increases bone mineral density and reduce risks of fractures in postmenopausal women by raising estrogen levels and avoiding first-pass metabolism.There is evidence that the combination of an estrogen patch with a progestin pill can improve bone mineral density in young, premenopausal amenorrheic athletes, and may be more effective than an oral estrogen with progestin. Hormonal birth control Contraceptive patches such as norelgestromin/ethinylestradiol are a form of estrogen patch which are used for hormonal birth control. Patches with progestogens Taking a progestogen in addition to an estrogen patch should be considered for women who have not undergone a hysterectomy to regulate the thickness of the endometrial lining and reduce the risk of endometrial cancer. Hysterectomized women rarely need a progestogen, however it may be considered if a history of endometriosis exists. There are different types of delivery systems of progestogens that can be used in addition to an estrogen patch, including pills, injections, and patches, among others.Research has suggested that estrogen plus progestogen therapy may increase the risk of heart attacks, stroke, breast cancer, blot clots, and dementia in postmenopausal women. Taking the lowest effective dose of both estrogen and a progestogen may reduce risks. Administration Depending on the brand, patches are applied to the skin once or twice weekly. Patches should be placed on clean skin where hair and moisture is not present. Preferred areas of application include lower abdomen, hip, and buttocks. Patches should never be applied to the breasts. To reduce the risk of the patch detaching from the skin and skin irritation, skin care products, sun exposure, damaged skin, and tight-fitting clothing should be avoided where the patch is placed. Side effects Headache, breast pain or tenderness, nausea, vomiting, hair loss, vaginal discharge or irritation, and mood changes are some of the common side effects that may occur while using an estrogen patch. More serious side effects may include fever, loss of appetite, joint pain, difficulty breathing or swallowing, and yellowing of the skin or eyes.Seeing a health professional regularly, taking progestin, having pelvic and breast exams, lowering blood pressure, and lowering cholesterol may reduce the likelihood of developing severe side effects while using an estrogen patch. Precautions Women who have experienced vaginal bleeding post menopause, certain cancers, stroke, heart attack, blood clotting, or uncontrollable bleeding, and women who are pregnant or allergic to ingredients in estrogen patches should not use an estrogen patch as serious adverse effects may occur. Society and culture Brand names Estrogen patches are available in multiple brand names in different countries. Some patches are available with a progestin such as levonorgestrel, norethisterone acetate, or norelgestromin. See also Pharmacokinetics of estradiol § Transdermal administration Hormone replacement therapy References External links "Estradiol". Drug Information Portal. U.S. National Library of Medicine. "Estradiol mixture with levonorgestrel". Drug Information Portal. U.S. National Library of Medicine. "Estradiol mixture with norethindrone acetate". Drug Information Portal. U.S. National Library of Medicine.
Butoconazole	Butoconazole (trade names Gynazole-1, Mycelex-3) is an imidazole antifungal used in gynecology. It is administered as a vaginal cream. Synthesis Reaction of epichlorohydrin with 4-Chlorobenzyl magnesium bromide leads to 1-chloro-4-(4-chlorophenyl)butan-2-ol (3). Displacement with sodium imidazole, conversion of the secondary alcohol to the chloride (SOCl2), and displacement with 2,6-dichlorobenzenethiol concludes the synthesis of the antifungal butoconazole. References External links "Butoconazole". Drug Information Portal. U.S. National Library of Medicine.
Nix	Nix or NIX may refer to: Places Nix, Alabama, an unincorporated community, United States Nix, Texas, a ghost town in southwestern Lampasas County, Texas, United States Nix (moon), a moon of Pluto People Nix (surname), listing people with the surname In science and technology Nix (gene), a pro-apoptotic gene Norwegian Internet Exchange (NIX), an Internet exchange point in Oslo Neutral Internet Exchange of the Czech Republic, the Internet exchange point in Prague Nix package manager, a "purely functional" package and configuration manager for computer systems Unix-like, abbreviated *nix or nix Codes Nioro Airport, Mali (IATA airport code: NIX) Hema language, (ISO 639-3 code: nix) Other uses Nix Federal Building, a historic building in Philadelphia, Pennsylvania Nix Professional Building, a hospital in San Antonio, Texas Permethrin, branded as Nix in North America, an anti-lice drug "Nix", a song by Golden Boy with Miss Kittin from Or The Nix, a 2017 novel by Nathan Hill Neck (water spirit) or nix, an aquatic being in Germanic folklore See also All pages with titles beginning with Nix Nyx (disambiguation) Nixe (disambiguation) Nick (disambiguation) NIC (disambiguation) New York Knicks, basketball team
Netarsudil/latanoprost	Netarsudil/latanoprost, sold under the brand name Rocklatan among others, is a fixed-dose combination medication use to treat elevated intraocular pressure (IOP) in people with open-angle glaucoma or ocular hypertension. It contains netarsudil mesylate and latanoprost. It is applied as eye drops to the eyes.The most common side effects include conjunctival hyperaemia (red eye), pain at the site where the medicine was applied, cornea verticillata (deposits in the cornea, the transparent layer in front of the eye that covers the pupil and iris), pruritus (itching of the eye), erythema (reddening) and discomfort in the eye, increased lacrimation (watery eyes), and conjunctival haemorrhage (bleeding in the surface layer of the eye).Netarsudil/latanoprost was approved for medical use in the United States in March 2019, and in the European Union in January 2021. Medical uses Netarsudil/latanoprost is indicated for the reduction of elevated intraocular pressure (IOP) in adults with primary open-angle glaucoma or ocular hypertension. References External links "Latanoprost mixture with netarsudil". Drug Information Portal. U.S. National Library of Medicine.
Glycerol phenylbutyrate	Glycerol phenylbutyrate (USAN), trade name Ravicti, is a medication used in the treatment of certain inborn urea cycle disorders. The medication works by preventing the harmful buildup of ammonia in the body. It is an FDA-approved prescription drug in the US. It is approved for anyone over 2 months of age. It was developed by Hyperion Therapeutics based on the existing drug Buphenyl, and received approval on February 1, 2013. Hyperion has been criticized for setting a high price for the drug. The price was set at US$250,000–290,000. In 2014, the drug generated $30.8 million in net sales, far behind the older and less expensive Buphenyl ($113.6 million in sales). In March 2015, Horizon Pharma acquired Hyperion Therapeutics and thus Raviciti. References External links "Glycerol phenylbutyrate". Drug Information Portal. U.S. National Library of Medicine.
Testosterone undecanoate	Testosterone undecanoate, sold under the brand names Andriol and Aveed among others, is an androgen and anabolic steroid (AAS) medication that is used mainly in the treatment of low testosterone levels in men, including hormone therapy for transgender men. It is taken by mouth or given by injection into muscle.Side effects of testosterone undecanoate include symptoms of masculinization like acne, increased hair growth, voice changes, hypertension, elevated liver enzymes, hypertriglyceridemia, and increased sexual desire. The drug is a prodrug of testosterone, the biological ligand of the androgen receptor (AR) and hence is an androgen and anabolic steroid. It has strong androgenic effects and moderate anabolic effects, which make it useful for producing masculinization and suitable for androgen replacement therapy. Testosterone undecanoate is a testosterone ester and a prodrug of testosterone in the body. Because of this, it is considered to be a natural and bioidentical form of testosterone.Testosterone undecanoate was introduced in China for use by injection and in the European Union for use by mouth in the 1970s. It became available for use by injection in the European Union in the early to mid 2000s and in the United States in 2014. Formulations for use by mouth are approved in the United States. Along with testosterone enanthate, testosterone cypionate, and testosterone propionate, testosterone undecanoate is one of the most widely used testosterone esters. However, it has advantages over other testosterone esters in that it can be taken by mouth and in that it has a far longer duration when given by injection. In addition to its medical use, testosterone undecanoate is used to improve physique and performance. The drug is a controlled substance in many countries and so non-medical use is generally illicit. Medical dosage Testosterone undecanoate is used in androgen replacement therapy. It is specifically approved only for the treatment of hypogonadism. As an intramuscular injection, it is administered at a dosage of 1,000 mg once every 12 weeks. Conversely, oral testosterone undecanoate must be taken two or three times a day with food. Side effects Side effects of testosterone undecanoate include virilization among others. Anaphylaxis The Reandron 1000 formulation (Nebido in the United States) contains 1,000 mg of testosterone undecanoate suspended in castor oil with benzyl benzoate for solubilization and as a preservative, and is administered by intramuscular injection. As an excipient in Reandron 1000, benzyl benzoate has been reported as a cause of anaphylaxis (a serious life-threatening allergic reaction) in a case in Australia. Bayer includes this report in information for health professionals and recommends that physicians "should be aware of the potential for serious allergic reactions" to preparations of this type. In Australia, reports to the Adverse Drug Reactions Advisory Committee (ADRAC), which evaluates reports of adverse drug reactions for the Therapeutic Goods Administration (TGA), show several reports of allergic reactions since the anaphylaxis case from 2011. Pharmacology Pharmacodynamics Testosterone undecanoate is a prodrug of testosterone and is an androgen and anabolic–androgenic steroid (AAS). That is, it is an agonist of the androgen receptor (AR). Pharmacokinetics Testosterone undecanoate has a very long elimination half-life and mean residence time when given as a depot intramuscular injection. Its elimination half-life is 20.9 days and its mean residence time is 34.9 days in tea seed oil, while its elimination half-life is 33.9 days and its mean residence time is 36.0 days in castor oil. These values are substantially longer than those of testosterone enanthate (which, in castor oil, has values of 4.5 days and 8.5 days, respectively). Testosterone undecanoate is administered via intramuscular injection once every three months or so. Chemistry Testosterone undecanoate, or testosterone 17β-undecanoate, is a synthetic androstane steroid and a derivative of testosterone. It is an androgen ester; specifically, it is the C17β undecylate (undecanoate) ester of testosterone. A related testosterone ester with a similarly very long duration is testosterone buciclate. History In the late 1970s, testosterone undecanoate was introduced for oral use in Europe, although intramuscular testosterone undecanoate had already been in use in China for several years. Intramuscular testosterone undecanoate was not introduced in Europe and the United States until much later, in the early to mid 2000s and 2014, respectively. Testosterone undecanoate was approved in the United States after three previous rejections due to safety concerns. Society and culture Generic names Testosterone undecanoate is the generic name of the drug and its USAN and BAN. It is also referred to as testosterone undecylate. Brand names Testosterone undecanoate is or has been marketed under a variety of brand names, including Andriol, Androxon, Aveed, Cernos Depot, Jatenzo, Nebido, Nebido-R, Panteston, Reandron 1000, Restandol, Undecanoate 250, and Undestor. Availability Intramuscular testosterone undecanoate is available in the United States, Canada, Europe, and elsewhere in the world. It is approved in over 100 countries worldwide. Oral testosterone undecanoate is available in Canada, Europe, Mexico, Asia, and in the United States. Intramuscular testosterone undecanoate is marketed most commonly as Nebido in Canada and Europe and as Aveed in the United States while oral testosterone undecanoate is marketed most commonly as Andriol. Legal status Testosterone undecanoate, along with other AAS, is a schedule III controlled substance in the United States under the Controlled Substances Act and a schedule IV controlled substance in Canada under the Controlled Drugs and Substances Act.In March 2019, the US Food and Drug Administration (FDA) approved testosterone undecanoate (Jatenzo), an oral testosterone capsule to treat men with certain forms of hypogonadism. These men have low testosterone levels due to specific medical conditions, such as genetic disorders like Klinefelter syndrome or tumors that have damaged the pituitary gland. The FDA granted the approval of Jatenzo to Clarus Therapeutics.In March 2022, testosterone undecanoate (Tlando) was approved for medical use in the United States. Research Non-alcoholic steatohepatitis In 2013, a phase II clinical trial testing intramuscular testosterone undecanoate for the treatment of non-alcoholic steatohepatitis (NASH) was initiated in the United Kingdom. In the United States in 2018, Lipocine Inc. began investigating the potential of using an oral testosterone undecanoate formulation, known as LPCN-1144, in patients with NASH. References External links "Testosterone undecanoate". Drug Information Portal. U.S. National Library of Medicine.
Triamterene	Triamterene (trade name Dyrenium among others) is a potassium-sparing diuretic often used in combination with thiazide diuretics for the treatment of high blood pressure or swelling. The combination with hydrochlorothiazide, is known as hydrochlorothiazide/triamterene. Side effects Common side effects may include a depletion of sodium, folic acid, and calcium, nausea, vomiting, diarrhea, headache, dizziness, fatigue, and dry mouth. Serious side effects may include heart palpitations, tingling/numbness, fever, chills, sore throat, rash, and back pain. Triamterene can also cause kidney stones through direct crystallization or by seeding calcium oxalate stones. Triamterene is best avoided in patients with chronic kidney disease due to the possibility of hyperkalemia. People using this drug should use salt substitute cautiously.Triamterene may impart a blue fluorescent color to the urine. Caution with certain disease states Diabetes: Use with caution in people with prediabetes or diabetes mellitus as there may be a change in glucose control. Liver impairment: Use with caution in people with severe liver dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Kidney failure: combined triamterene and indomethacin therapy caused reversible acute kidney injury in some people.Kidney stones: Use with caution in people with kidney stones. Use should be avoided if the creatinine clearance is less than 10 ml/minute. Mechanism of action Triamterene directly blocks the epithelial sodium channel (ENaC) on the lumen side of the kidney collecting tubule.: 127 Other diuretics cause a decrease in the sodium concentration of the forming urine due to the entry of sodium into the cell via the ENaC, and the concomitant exit of potassium from the principal cell into the forming urine. Blocking ENaC prevents this from happening. Amiloride works in the same way. Sodium channel blockers directly inhibit the entry of sodium into the sodium channels. With hydrochlorothiazide Triamterene is commonly prepared in combination with hydrochlorothiazide for treatment of hypertension (high blood pressure) and edema (water retention). This combination is in a class of medications called diuretics or water pills, and causes the kidneys to get rid of the bodys unneeded water and sodium through the urine. History The triamterene ring system is found in many naturally occurring compounds, such as folic acid and riboflavin. The observation that the naturally occurring compound xanthopterin had renal affects led scientists at Smith Kline and French Laboratories in Philadelphia to begin a medicinal chemistry campaign to discover potential drugs, as part of a program to discover potassium-sparing diuretics.: 125 The first clinical studies were published in 1961 and the first trials combining it with hydrochlorothiazide were published the next year.: 126 Smith Kline & French launched it as a single agent under the brand Dyrenium in 1964.: 83 The combination drug with hydrochlorothiazide, Dyazide, was first approved in the US in 1965 and the first generic, brought by Bolar Pharmaceutical Co., was approved in 1987. In 1986 Dyazide was the most prescribed drug in the US and had $325 million in sales, making it SmithKline Beckmans second-biggest seller behind Tagamet.The patents had expired on Dyazide in 1980, but complications arose with the introductions of generics, because the formulation of Dyazide resulted in variable batches that made it impossible for generic manufacturers to show that their versions were bioequivalent.Bolar Pharmaceutical was in the running to be the first to bring a generic, but its application was delayed by these concerns about whether its formulation provided the same amount of each drug; these were complicated by accusations that Bolar had fraudulently substituted Dyazide for its own version to conduct studies that were submitted to the FDA. Shortly after Bolars generic was approved, further concerns were raised with regard to Bolars applications to market generics more generally; these findings among others raised widespread concern among doctors and the public over whether generics were really the same as branded drugs. Bolar ended up recalling its generic form of Dyazide and withdrawing the product in 1990. In 1991 the US Justice Department on behalf of the FDA filed 20 criminal charges against Bolar for its fraud, and early the next year Bolar pled guilty and agreed to pay a $10M fine. Public concern over the safety of generic drugs was further exacerbated by a Congressional investigation into bribery at the FDA by generics companies that found pervasive corruption; the investigation had been spurred by the generics company Mylan, which had hired private investigators based on its beliefs that competitors were getting unfair advantages in getting their generics approved.Mylan itself developed a version of a triamterene/hydrochlorothiazide combination drug after the Dyazide patent expired, and used a different, more stable formulation as well as different dosages of each active ingredient (50 mg hydrochlorothiazide and 75 mg triamterene, compared with Dyazides 25 mg hydrochlorothiazide and 50 mg triamterene) so it had to get approval as a new drug, as opposed to a generic; their product was called Maxzide and was approved in 1984. The higher dose allowed once per day dosing, which Mylan and its marketing partner, Lederle, believed would help it compete against Dyazide, which had $210M in sales in 1983.Mylans patents on the drug were declared invalid in court, and its marketing exclusivity expired in 1987, prompting a rush of generic competition and litigation by two of them, American Therapeutics Inc. and Vitarine Pharmaceuticals, with the FDA. Vitarine, along with Par Pharmaceutical, were two of the companies that Mylan had targeted in its investigation into corruption and it turned out that Par and Vitarine had each used Mylans Maxzide to obtain its bioequivalence data, leading both companies to withdraw its generic competitor to Mylans product. Generics eventually entered the market. Research While there is a lack of randomized controlled trials evaluating the use of triamterene in the treatment of Ménières disease, the typical treatment is 37.5 mg of triamterene with 25 mg of hydrochlorothiazide 1–2 capsules daily. This recommendation was given a Strength of Recommendation Taxonomy (SORT) grade of C. References == External links ==
Nadolol	Nadolol, sold under the brand name Corgard among others, is a medication used to treat high blood pressure, heart pain, atrial fibrillation, and some inherited arrhythmic syndromes. It has also been used to prevent migraine headaches and complications of cirrhosis. It is taken orally.Common side effects include dizziness, feeling tired, a slow heart rate, and Raynaud syndrome. Serious side effects may include heart failure and bronchospasm. Its use in pregnancy and breastfeeding is of unclear safety. It is a non-selective beta blocker and works by blocking β1-adrenergic receptors in the heart and β2-adrenergic receptors in blood vessels.Nadolol was patented in 1970 and came into medical use in 1978. It is available as a generic medication. In 2016, it was the 283rd most commonly prescribed medication in the United States, with more than a million prescriptions. Medical uses Nadolol is used to treat hypertension and for long-term treatment of angina pectoris and is approved by the FDA for these purposes.It is regularly used off-label for control of heart rate in people with atrial fibrillation, prevention of migraine headaches; prevention of bleeding veins in people with portal hypertension caused by cirrhosis; and to treat people with high levels of thyroid hormone.Nadolol is the preferred beta-blockers in the management of patients with LQTS for prevention of ventricular arrhythmia. It is more efficacious than selective beta blockers or propranolol in the prevention of breakthrough cardiac events. Similarly, it is the preferred type of beta blocker for treatment of patients with CPVT, as it has been shown to be more efficacious than selective beta blockers, like atenolol or bisoprolol.Nadolol has the advantage of once daily dosing and thus improved patient compliance. For patients with decreased kidney function, nadolol may be dosed less often. It has also been found to be useful (off-label) for several neurological disorders such as the prevention of migraine attacks, attention deficit/hyperactivity disorder(ADHD) and its use has been explored as a treatment for essential tremor and Parkinsons disease but neither is well established. Side effects The most common side effects include dizziness and fatigue. Contraindications Nadolol and other beta blockers should be used with cautions in people with heart failure and its use should not be abruptly stopped. It is contraindicated for people with asthma, a slow heart rate and certain severe heart problems. Mechanism of action Nadolol is a non-selective beta blocker; that is, it non-selectively blocks both beta-1 and beta-2 receptors. It has a preference for beta-1 receptors, which are predominantly located in the heart, thereby inhibiting the effects of catecholamines and causing a decrease in heart rate and blood pressure. Its inhibition of beta-2 receptors, which are mainly located in the bronchial smooth muscle of the airways, leads to airway constriction similar to that seen in asthma. Inhibition of beta-1 receptors in the juxtaglomerular apparatus of the kidney inhibits the renin–angiotensin system, causing a decrease in vasoconstriction and a decrease in water retention. Nadolols inhibition of beta-1 receptors in the heart and kidney leads to its effects on lowering blood pressure. The drug impairs AV node conduction and decreases sinus rate. Nadolol may also increase plasma triglycerides and decrease HDL-cholesterol levels. Chemistry Nadolol is a mixture of stereoisomers. It is polar and hydrophilic, with low lipid solubility. References External links "Nadolol". Drug Information Portal. U.S. National Library of Medicine.
Saizen	Saizen is a commercial preparation of synthetic somatropin (growth hormone, a.k.a. GH). Manufactured by Merck Serono, Saizen is produced by recombinant DNA technology from a mammalian cell line (mouse C127) that was modified by the addition of the human GH gene, resulting in an identical 191-amino acid sequence and structure. Usage Saizen is injected. It is intended for long-term treatment of individuals who are growth hormone deficient. Saizen, like all synthetic somatropin, has special importance for children and adolescents whose growth failure is due to inadequate production of growth hormone. Studies have shown that somatropin usage fails to produce athletic performance enhancement despite claims to the contrary. More recently, Saizen has been used in IVF protocols by a few physicians for female patients undergoing infertility treatment in an attempt to increase the number and quality of oocytes retrieved. It affects: Tissue growth Skeletal growth Cell growth (especially muscle growth) Organ growthMetabolism Protein metabolism Carbohydrate metabolism Lipid metabolism Mineral metabolism Connective tissue and bone metabolismSaizen usage should be performed under the regular guidance of a physician who is experienced in the diagnosis and management of growth hormone deficiency. Individuals with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with growth hormone. Using Saizen may decrease glucose tolerance. Because human growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance. As with all human growth hormone supplementation, Saizen should be used with caution in patients with diabetes mellitus or a family history of diabetes mellitus. See also Growth hormone treatment External links "Somatropin". Drug Information Portal. U.S. National Library of Medicine.
Nusinersen	Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder. Since the condition it treats is so rare, Nusinersen has so-called "orphan drug" designation in the United States and the European Union. Medical uses The drug is used to treat spinal muscular atrophy associated with a mutation in the SMN1 gene. It is administered directly to the central nervous system (CNS) using intrathecal injection.In clinical trials, the drug halted the disease progression. In around 60% of infants affected by type 1 spinal muscular atrophy, it improves motor function. Side effects People treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, pulmonary aspiration, teething, and scoliosis. There is a risk that growth of infants and children might be stunted. In older clinical trial subjects, the most common adverse events were headache, back pain, and other adverse effects from the spinal injection, such as post-dural-puncture headache.Although not observed in the trial patients, a reduction in platelets as well as a risk of kidney damage are theoretical risks for antisense drugs and therefore platelets and kidney function should be monitored during treatment.In 2018, several cases of communicating hydrocephalus in children and adults treated with nusinersen emerged; it remains unclear whether this was drug related. Pharmacology Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene which codes for survival motor neuron (SMN) protein. People survive owing to low amounts of the SMN protein produced from the SMN2 gene. Nusinersen modulates alternative splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS.The drug distributes to CNS and peripheral tissues.The half-life is estimated to be 135 to 177 days in cerebrospinal fluid (CSF) and 63 to 87 days in blood plasma. The drug is metabolized via exonuclease (3′- and 5′)-mediated hydrolysis and does not interact with CYP450 enzymes. The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites. Chemistry Nusinersen is an antisense oligonucleotide in which the 2-hydroxy groups of the ribofuranosyl rings are replaced with 2-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages. History Nusinersen was developed in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals). Initial work of target discovery of nusinersen was done by Dr. Ravindra Singh and co-workers at the University of Massachusetts Medical School funded by Cure SMA.Starting in 2012, Ionis partnered with Biogen on development and, in 2015, Biogen acquired an exclusive license to the drug for a US$75 million license fee, milestone payments up to US$150 million, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license. The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.In November 2016, the new drug application was accepted under the FDAs priority review process on the strength of the Phase III trial and the unmet need, and was also accepted for review at the European Medicines Agency (EMA) at that time. It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat SMA. Subsequently, nusinersen was approved to treat SMA in Canada (July 2017), Japan (July 2017), Brasil (August 2017), Switzerland (September 2017), and China (February 2019). Society and culture Economics Nusinersen list price in the USA is US$125,000 per injection which puts the treatment cost at US$750,000 in the first year and US$375,000 annually after that. According to The New York Times, this places nusinersen "among the most expensive drugs in the world".In October 2017, the authorities in Denmark recommended nusinersen for use only in a small subset of people with SMA type 1 (young babies) and refused to offer it as a standard treatment for all other people with SMA quoting an "unreasonably high price" compared to the benefit.Norwegian authorities rejected the funding in October 2017 because the price of the medicine was "unethically high". In February 2018, the funding was approved for people under 18 years old.In August 2018, the National Institute for Health and Care Excellence (NICE), which weighs the cost-effectiveness of therapies for the NHS in England and Wales, recommended against offering nusinersen to people with SMA. Children with SMA type 1 were treated in the UK under a Biogen-funded expanded access programme; after enrolling 80 children, the scheme closed to new people in November 2018. In May 2019, however, NICE reversed its stance and announced its decision to recommend nusinersen for use across a wide spectrum of SMA for a 5-year period.The Irish Health Service Executive decided in February 2019 that nusinersen was too expensive to fund, saying the cost would be about €600,000 per patient in the first year and around €380,000 a year thereafter "with an estimated budget impact in excess of €20 million over a five-year period" for the 25 children with SMA living in Ireland. Both the manufacturer and patient groups disputed the numbers and pointed out that actual pricing arrangements for Ireland are in line with the negotiated price for the BeneluxA initiative which Ireland has been a member of since June 2018.As of May 2019, nusinersen was available in public healthcare in more than 40 countries.In December 2021, nusinersen was included in the extended insurance coverage of China, and the price was reduced from ¥697,000 per vial to around ¥33,000 (~US$5,100) per vial. References Further reading External links "Cut and Paste: Treating Spinal Muscular Atrophy with Nusinersen". Youreka Science. Retrieved 2019-05-28. "Spinraza access by country". TreatSMA. 18 October 2018. Retrieved 2019-05-28.
Afamelanotide	Afamelanotide, sold under the brand name Scenesse, is a synthetic peptide and analogue of α-melanocyte stimulating hormone. It has been used to prevent skin damage from the sun in people with erythropoietic protoporphyria in the European Union since January 2015 and the United States since October 2019. As a medication, it is administered in subcutaneous implant form. Each implant lasts two months.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical use Afamelanotide is used in the European Union to prevent phototoxicity in adults with erythropoietic protoporphyria (EPP). Adverse effects Very common (may affect more than 10% of people) adverse effects in people with EPP include headache and nausea. Common (between 1% and 10%) adverse effects include back pain, upper respiratory tract infections, decreased appetite, migraine, dizziness, weakness, fatigue, lethargy, sleepiness, feeling hot, stomach pain, diarrhea, vomiting, flushing and red skin, development of warts, spots and freckles, itchy skin, and reactions at the injection site. There are many uncommon (less than 1%) adverse effects. Pharmacology Afamelanotide is thought to cause skin to darken by binding to the melanocortin 1 receptor which in turn drives melanogenesis.Afamelanotide has a half-life of 30 minutes. After the implant is injected, most of the drug is released within the first two days, with 90% released by the fifth day. By the tenth day no drug is detectable in plasma.Its metabolites, distribution, metabolism and excretion were not understood as of 2017. Chemistry The amino acid sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2. It is additionally known as [Nle4,D-Phe7]-α-MSH, which is sometimes abbreviated as NDP-MSH or NDP-α-MSH. Afamelanotide is the International Nonproprietary Name. History After the isolation and primary structure determination of a-MSH in the 1950s, many investigators initiated studies into the synthesis of this peptide. The role of α-MSH in promoting melanin diffusion has been known since the 1960s. In the 1980s, teams at the University of Arizona started to synthesise more potent analogs of a-MSH, including afamelanotide, which they initially named melano-tan (or melanotan-I) due to its ability to tan skin with minimal sun exposure, and later synthesised melanotan-II.Following initial development at the University of Arizona as a sunless tanning agent; the Australian company Clinuvel conducted further clinical trials in that and other indications, and brought the drug to market in the European Union, the United States, and Australia. To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan, which changed its name to Clinuvel in 2006.Early clinical trials showed that the peptide had to be injected about ten times a day due to its short half-life, so the company collaborated with Southern Research in the US to develop a depot formulation that would be injected under the skin, and release the peptide slowly. This was done by 2004.As of 2010, afamelanotide was in Phase III trials for erythropoietic protoporphyria and polymorphous light eruption and was in Phase II trials for actinic keratosis and squamous cell carcinoma; as well, it had been trialled in phototoxicity associated with systemic photodynamic therapy and solar urticaria. Clinuvel had also obtained orphan drug status for afamelanotide in the US and the EU by that time.In May 2010, the Italian Medicines Agency (AIFA, or Agenzia Italiana del Farmaco) approved afamelanotide as a treatment for erythropoietic protoporphyria.In January 2015, afamelanotide was approved by the European Medicines Agency (EMA) in Europe for the treatment of phototoxicity in people with EPP.There were three trials that evaluated afamelanotide in those with erythropoietic protoporphyria (EPP).In Trial 1, subjects received afamelanotide or vehicle implant every two months and were followed for 180 days. Subjects recorded every day the number of hours spent in direct sunlight and whether they experienced any phototoxic pain that day. The trial measured the total number of hours over 180 days spent in direct sunlight between 10 am and 6 pm on days with no pain.In Trial 2, subjects received afamelanotide or vehicle implants every two months and were followed for 270 days. Subjects daily recorded the number of hours spent outdoors as well as whether "most of the day" was spent in direct sunlight, shade, or a combination of both, and whether they experienced any phototoxic pain that day. The trial measured the total number of hours over 270 days spent outdoors between 10 am and 3 pm on days with no pain for which "most of the day" was spent in direct sunlight.In Trial 3 subjects were randomized to receive a total of three afamelanotide or vehicle implants administered subcutaneously every two months and were followed for 180 days. Data from this trial were used primarily for assessment of side effects.The FDA approved afamelanotide based on evidence from three clinical trials (Trial 1/ NCT 01605136, Trial 2/ NCT00979745 and Trial 3/ NCT01097044) of 244 adults 18–74 years of age with EPP. The trials were conducted at 22 sites in the US and Europe.In October 2019, afamelanotide was approved by the US Food and Drug Administration (FDA) as a medicine to reduce pain caused by light exposure (particularly sunlight) as experienced by people with erythropoietic protoporphyria. Society and culture Usage in general public A number of products are sold online and in gyms and beauty salons as "melanotan" or "melanotan-1" which discuss afamelanotide in their marketing.Without a prescription, these drugs are not legally sold in many jurisdictions and are potentially dangerous.Starting in 2007, health agencies in various countries began issuing warnings against their use.Unlicensed and untested powders sold as "melanotan" are found on the Internet (marketed for tanning and other purposes). Multiple regulatory bodies have warned consumers that the peptides may be unsafe and ineffective. Research Ongoing research is underway for other skin disorders. Afamelanotide causes skin to turn darker by causing skin to produce more melanin. References External links "Afamelanotide". Drug Information Portal. U.S. National Library of Medicine. "Afamelanotide acetate". Drug Information Portal. U.S. National Library of Medicine.
Eluxadoline	Eluxadoline, sold under the brand names Viberzi and Truberzi, is a medication taken by mouth for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D). It was approved for use in the United States in 2015. The drug originated from Janssen Pharmaceutica and was developed by Actavis. Contraindications This drug is contraindicated in case of having: Blockage of the gallbladder or a sphincter of Oddi problem Problems with excessive alcohol use Pancreatitis Liver problems Chronic or severe constipation Adverse effects Common adverse effects are constipation and nausea, but rates of discontinuation due to constipation were low for both eluxadoline and placebo. Rare adverse effects: fatigue, bronchitis, viral gastroenteritis. Rare serious adverse effects include pancreatitis with a general incidence of 0.3% - higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%). The risk is even greater in those who do not have a gall bladder and the medication is not recommended in this group.In March 2017, the U.S. Food and Drug Administration issued a safety alert for eluxadoline concerning an increased risk of serious pancreatitis in patients without a gallbladder. An FDA review found that in such patients, spasm of the sphincter of Oddi may lead to severe pancreatitis. The FDA reported that in some cases symptoms have occurred with just one or two doses at the recommended dosage for patients without a gallbladder (75 mg). Of two deaths associated with eluxadoline reported up to February 2017, both occurred in patients without a gallbladder. Interactions Elevated concentrations of eluxadoline were observed with co-administration of inhibitors of the transporter protein OATP1B1, such as: Cyclosporine Gemfibrozil Certain antiretrovirals Rifampin EltrombopagAlso, concurrent use of other drugs that cause constipation is not preferred, such as: Opioids Alosetron Anticholinergics Bismuth subsalicylate, potentially dangerous synergism.Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates. Also, co-administration of eluxadoline with rosuvastatin may increase the risk of rhabdomyolysis. Pharmacology Mechanism of action Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system, possibly decreasing adverse effects on the central nervous system. Pharmacokinetics In the in vitro studies, eluxadoline was found to be transported by OAT3 (SLC22A8), OATP1B1 (SLCO1B1) and BSEP (ABCB11) at the highest concentrations tested (400 ng/ml which is 162-fold larger than the observed Cmax of the highest therapeutic dose of 100 mg). However, it was not to be transported by OCT1 POU2F1, OAT1 Organic anion transporter 1, OCT2, OATP1B3 (SLCO1B3), P-gp (P-glycoprotein), or BCRP (ABCG2). Multidrug resistance-associated protein 2 (MRP2)-vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2. Eluxadoline was not found to inhibit BCRP-, BSEP-, MRP2-, OCT1-, OCT2-, OAT1-, OAT3-, or OATP1B3-mediated transport of probe substrates but inhibited the transport of probe substrates of OATP1B1 and P-gp. Also in the in vitro studies, it was observed that eluxadoline is an in vivo substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of cytochrome P450 enzymes was observed.Following a 100 mg dose of eluxadoline, the Cmax was about 2 to 4 ng/ml and AUC was 12-22 ng.h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the Cmax by 50% and AUC by 60%. Chemistry Synthesis The synthesis of eluxadoline was extensively discussed in the patent No. WO2006099060 A2, with the title : "Process for the preparation of opioid modulators" which was published in Sept. 2006 See also Asimadoline Axelopran Difenoxin Diphenoxylate Loperamide == References ==
Iron(II) gluconate	Iron(II) gluconate, or ferrous gluconate, is a black compound often used as an iron supplement. It is the iron(II) salt of gluconic acid. It is marketed under brand names such as Fergon, Ferralet and Simron. Uses Medical Ferrous gluconate is effectively used in the treatment of hypochromic anemia. The use of this compound compared with other iron preparations results in satisfactory reticulocyte responses, a high percentage utilization of iron, and daily increase in hemoglobin that a normal level occurs in a reasonably short time. Food additive Ferrous gluconate is also used as a food additive when processing black olives. It is represented by the food labeling E number E579 in Europe. It imparts a uniform jet black color to the olives. Toxicity Ferrous gluconate may be toxic in case of overdose. Children may show signs of toxicity with ingestions of 10–20 mg/kg of elemental iron. Serious toxicity may result from ingestions of more than 60 mg/kg. Iron exerts both local and systemic effects: it is corrosive to the gastrointestinal mucosa, it can have a negative impact on the heart and blood (dehydration, low blood pressure, fast and weak pulse, shock), lungs, liver, gastrointestinal system (diarrhea, nausea, vomiting blood), nervous system (chills, dizziness, coma, convulsions, headache), and skin (flushing, loss of color, bluish-colored lips and fingernails). The symptoms may disappear in a few hours, but then emerge again after 1 or more days. See also Acceptable daily intake Iron poisoning == References ==
Paracetamol	Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior to ibuprofen in that respect, and the benefits of its use for fever are unclear. Paracetamol may relieve pain in acute mild migraine but only slightly in episodic tension headache. However, the aspirin/paracetamol/caffeine combination helps with both conditions where the pain is mild and is recommended as a first-line treatment for them. Paracetamol is effective for post-surgical pain, but it is inferior to ibuprofen. The paracetamol/ibuprofen combination provides further increase in potency and is superior to either drug alone. The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant. The evidence in its favor for the use in low back pain, cancer pain, and neuropathic pain is insufficient.In the short term, paracetamol is safe and effective when used as directed. Short term adverse effects are uncommon and similar to ibuprofen, but paracetamol is typically safer than NSAIDs for long term use. Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen. Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding, and abnormal liver function tests. Some epidemiological studies have linked paracetamol to cardiovascular, renal, and gastrointestinal diseases, but are largely due to confounding biases and is of insignificant relevance with short-term use of paracetamol. Paracetamol may slightly increase systolic blood pressure in hypertensive patients at a dose of 4 grams a day. Elevated frequency of asthma and developmental and reproductive disorders is observed in the offspring of women with prolonged use of paracetamol during pregnancy, although whether paracetamol is the true cause of this increase is unclear. Some studies suggest that there is evidence for the association between paracetamol during pregnancy and autism spectrum disorder and attention deficit hyperactivity disorder, while making clear further research is required to establish any causal link, which has prompted some calls to limit its use in pregnancy to the lowest effective dosage for the shortest possible time.The recommended maximum daily dose for an adult is three to four grams. Higher doses may lead to toxicity, including liver failure. Paracetamol poisoning is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.Paracetamol was first made in 1877 or possibly 1852. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the World Health Organizations List of Essential Medicines. Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others. In 2019, it was the 145th most commonly prescribed medication in the United States, with more than 4 million prescriptions. Medical uses Fever Paracetamol is a drug of choice for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly, in adults. The most recent review on paracetamol and management of fever in the general practice (2008) argued that its benefits are unclear. Additionally, when taken for the common cold paracetamol may relieve stuffed or runny nose but not other cold symptoms such as sore throat, malaise, sneezing and cough; this data, however, is of low quality.For patients in critical care, paracetamol decreased body temperature by only 0.2–0.3 °C more than control interventions; there was no difference in mortality. It did not change the outcome in febrile patients with stroke. The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported. Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of a potential liver damage. Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.The efficacy of paracetamol in children with fever is unclear. Paracetamol should not be used solely with the aim of reducing body temperature; however, it may be considered for children with fever who appear distressed. It does not prevent febrile seizures and should not be used for that purpose. It appears that 0.2 °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergency situations. Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7 °C. Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis), including children younger than 2 years old, with equivalent safety. Exacerbation of asthma occurs with similar frequency for both medications. Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended, however doses may be alternated if required. Pain Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and dysmenorrhea. It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient. Musculoskeletal pain The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.It appears to provide only small and not clinically important benefits in osteoarthritis. American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective. The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required. Essentially the same recommendation was issued by EULAR for hand osteoarthritis. Similarly, European algorithm ESCEO for the treatment of knee osteoarthritis recommends limiting the of use paracetamol to short-term rescue analgesia only.Paracetamol is ineffective for acute low back pain. No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking. Headaches Paracetamol is effective for acute migraine: 39% of people experience pain relief at one hour compared with 20% in the control group. The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine." The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend the combination as a "highlighted" one for self-medication of migraine, and paracetamol alone as a first choice.Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently. However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: 2 hours after administering the medication, 29% of those who took the combination were pain free as compared with 21% on paracetamol and 18% on placebo. The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice". Dental and other post-surgical pain Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain. For the relief of such pain, paracetamol is inferior to ibuprofen. Full therapeutic doses of non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen or diclofenac are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain. The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone. Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53% of the participants, while the placebo helped only 7%. Other pain Paracetamol fails to relieve procedural pain in newborn babies. For perineal pain postpartum paracetamol appears to be less effective than non-steroidal anti-inflammatory drugs (NSAIDs).The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking. There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department. The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain. Patent ductus arteriosus Paracetamol helps ductal closure in patent ductus arteriosus. It is as effective for this purpose as ibuprofen or indomethacin, but results in a less frequent gastrointestinal bleeding than ibuprofen. Adverse effects Gastrointestinal adverse effects such as nausea and abdominal pain are common, and their frequency is similar to that of ibuprofen. Increase in risk-taking behavior is possible. According to the US Food and Drug Administration, the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis, although an analysis of the French Pharmacovigilance Database indicated no obvious risk of these reactions.In clinical trials for osteoarthritis, the number of participants reporting adverse effects were similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain. After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20% of participants, this rate being similar to ibuprofen group.Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies. These indicate a consistent pattern of increased mortality as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol. Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer. Those who take it regularly at a higher dose (more than 2–3 g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events. Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23% and kidney cancer by 28%. Paracetamol is particularly dangerous to the liver in overdose, but even without overdose those who take this drug may develop acute liver failure requiring liver transplantation more frequently than the users of nonsteroidal anti-inflammatory drugs. Paracetamol slightly but significantly increases blood pressure and heart rate. The majority of observational studies suggests that, used chronically, it may increase the risk of developing hypertension, as confirmed in a prospective randomized confirmed trial. The risk is higher with the higher dose.The association between paracetamol use and asthma in children has been a matter of controversy. However, the most recent research suggests that there is no association, and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen. Use in pregnancy Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or birth defects. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma, but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult. Paracetamol, in a small scale meta analysis was also associated with 20–30% increase in autism spectrum disorder, attention deficit hyperactivity disorder, hyperactivity symptoms, and conduct disorder, with the association being lower in a meta analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings. There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders. In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mothers paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time. Overdose Overdoses of paracetamol, that is, taking more than the recommended maximum daily dose of paracetamol for healthy adults of three or four grams, can cause potentially fatal liver damage.Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance. According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths."Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol. The overdose risk may be heightened by frequent consumption of alcohol.Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts. People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.Treatment is aimed at removing the paracetamol from the body and replenishing glutathione. Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote, acetylcysteine (also called N-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; a liver transplant is often required if damage to the liver becomes severe. NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it. Kidney failure is also a possible side effect. Interactions Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and morphine lengthen tmax and decrease Cmax. The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed. Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital, primidone, isoniazid, and possibly St Johns wort. On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol.Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation. Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week. Pharmacology Pharmacodynamics Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase and actions of its metabolite AM404.Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors. Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight. The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding. The second mechanism centers on the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol. Apparently, it is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase. AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor. This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol. Pharmacokinetics After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same. In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate, but not high protein or high fat, food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.Paracetamols bioavailability is dose-dependent: it increases from 63% for 500 mg dose to 89% for 1000 mg dose. Its plasma terminal elimination half-life is 1.9–2.5 hours, and volume of distribution is roughly 50 L. Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%. The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L). After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L). Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5% of the drug are excreted unchanged in the urine. Glucuronidation by UGT1A1 and UGT1A6 accounts for 50–70% of the drug metabolism. Additional 25–35% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1.A minor metabolic pathway (5-15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as NAPQI (N-acetyl-p-benzoquinone imine). NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by the large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity.Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to form p-aminophenol. p-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol. Chemistry Synthesis Classical methods The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-aminophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol. Celanese synthesis An alternative industrial synthesis developed at Celanese involves direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride, conversion of the resulting ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement. Reactions 4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air. History Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886. But its unacceptable toxic effects—the most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives. Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative. Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.Von Merings claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin. In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia. In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor. They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol. This led to a "rediscovery" of paracetamol.Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine. Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected. The following year, 1952, paracetamol returned to the US market as a prescription drug. In the United Kingdom, marketing of paracetamol began in 1956 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers. In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.Concerns about paracetamols safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and
Paracetamol	hematological toxicity. Available in the US without a prescription since 1955 (1960, according to another source) paracetamol has become a common household drug. In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage. Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.In September 2013, "Use Only as Directed", an episode of the radio program This American Life highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson" and "McNeil, the maker of Tylenol,... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."During the COVID-19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID-19, but this was found to be unsubstantiated. Society and culture Naming Paracetamol is the Australian Approved Name and British Approved Name as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name and Japanese Accepted Name and also the name generally used in Canada, Venezuela, Colombia, and Iran. Both paracetamol and acetaminophen are contractions of para-acetylaminophenol, a chemical name for the compound. The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name [N-]acetyl-para-aminophenol. Available forms Paracetamol is available in oral, suppository, and intravenous forms. Intravenous paracetamol is sold under the brand name Ofirmev in the United States.In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the US, this combination is available only by prescription. As of 1 February 2018, medications containing codeine also became prescription-only in Australia. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (British Approved Name (BAN)), oxycodone or hydrocodone. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate. A combination of paracetamol, codeine, and the doxylamine succinate is also available.Paracetamol is sometimes combined with phenylephrine hydrochloride. Sometimes a third active ingredient, such as ascorbic acid, caffeine, chlorpheniramine maleate, or guaifenesin is added to this combination. Veterinary use Cats Paracetamol is extremely toxic to cats, which lack the necessary UGT1A6 enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobinemia and hemolytic anemia). Treatment with N-acetylcysteine is recommended. Dogs Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs. A paracetamol-codeine product (brand name Pardale-V) licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person. It should be administered to dogs only on veterinary advice and with extreme caution.The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported. N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion. Snakes Paracetamol is lethal to snakes, and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam. Doses of 80 mg are inserted into dead mice that are scattered by helicopter, as lethal bait to be consumed by the snakes. Footnotes References External links "Acetaminophen". Drug Information Portal. U.S. National Library of Medicine. "Acetaminophen: Avoiding Liver Injury". Food and Drug Administration (FDA). 24 June 2009. "Evidence for the efficacy of pain medications" (PDF). National Safety Council (NSC). 26 August 2020.
Avita	Avita may refer to: Australian Green Tree Frog Tretinoin
Ethanol	Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is a simple alcohol with the chemical formula C2H6O. Its formula can be also written as CH3−CH2−OH or C2H5OH (an ethyl group linked to a hydroxyl group). Ethanol is a volatile, flammable, colorless liquid with a characteristic wine-like odor and pungent taste. It is a psychoactive recreational drug, the active ingredient in alcoholic drinks. Ethanol is naturally produced by the fermentation process of sugars by yeasts or via petrochemical processes such as ethylene hydration. It has medical applications as an antiseptic and disinfectant. It is used as a chemical solvent and in the synthesis of organic compounds, and as a fuel source. Ethanol also can be dehydrated to make ethylene, an important chemical feedstock. Etymology Ethanol is the systematic name defined by the International Union of Pure and Applied Chemistry (IUPAC) for a compound consisting of an alkyl group with two carbon atoms (prefix "eth-"), having a single bond between them (infix "-an-") and an attached functional group −OH group (suffix "-ol").The "eth-" prefix and the qualifier "ethyl" in "ethyl alcohol" originally come from the name "ethyl" assigned in 1834 to the group C2H5− by Justus Liebig. He coined the word from the German name Aether of the compound C2H5−O−C2H5 (commonly called "ether" in English, more specifically called "diethyl ether"). According to the Oxford English Dictionary, Ethyl is a contraction of the Ancient Greek αἰθήρ (aithḗr, "upper air") and the Greek word ὕλη (hýlē, "substance").The name ethanol was coined as a result of a resolution that was adopted at the International Conference on Chemical Nomenclature that was held in April 1892 in Geneva, Switzerland.The term "alcohol" now refers to a wider class of substances in chemistry nomenclature, but in common parlance it remains the name of ethanol. It is a medieval loan from Arabic al-kuḥl, a powdered ore of antimony used since antiquity as a cosmetic, and retained that meaning in Middle Latin. The use of "alcohol" for ethanol (in full, "alcohol of wine") is modern and was first recorded in 1753. Before the late 18th century the term "alcohol" generally referred to any sublimated substance. Uses Medical Antiseptic Ethanol is used in medical wipes and most commonly in antibacterial hand sanitizer gels as an antiseptic for its bactericidal and anti-fungal effects. Ethanol kills microorganisms by dissolving their membrane lipid bilayer and denaturing their proteins, and is effective against most bacteria, fungi and viruses. However, it is ineffective against bacterial spores, but that can be alleviated by using hydrogen peroxide. A solution of 70% ethanol is more effective than pure ethanol because ethanol relies on water molecules for optimal antimicrobial activity. Absolute ethanol may inactivate microbes without destroying them because the alcohol is unable to fully permeate the microbes membrane. Ethanol can also be used as a disinfectant and antiseptic because it causes cell dehydration by disrupting the osmotic balance across the cell membrane, so water leaves the cell leading to cell death. Antidote Ethanol may be administered as an antidote to ethylene glycol poisoning and methanol poisoning. Ethanol serves this process by acting as a competitive inhibitor against methanol and ethylene glycol for alcohol dehydrogenase. Though it has more side effects, ethanol is less expensive and more readily available than fomepizole, which is also used as an antidote for methanol and ethylene glycol poisoning. Medicinal solvent Ethanol, often in high concentrations, is used to dissolve many water-insoluble medications and related compounds. Liquid preparations of pain medications, cough and cold medicines, and mouth washes, for example, may contain up to 25% ethanol and may need to be avoided in individuals with adverse reactions to ethanol such as alcohol-induced respiratory reactions. Ethanol is present mainly as an antimicrobial preservative in over 700 liquid preparations of medicine including acetaminophen, iron supplements, ranitidine, furosemide, mannitol, phenobarbital, trimethoprim/sulfamethoxazole and over-the-counter cough medicine. Pharmacology In mammals, ethanol is primarily metabolized in the liver and stomach by alcohol dehydrogenase (ADH) enzymes. These enzymes catalyze the oxidation of ethanol into acetaldehyde (ethanal): CH3CH2OH + NAD+ → CH3CHO + NADH + H+When present in significant concentrations, this metabolism of ethanol is additionally aided by the cytochrome P450 enzyme CYP2E1 in humans, while trace amounts are also metabolized by catalase.The resulting intermediate, acetaldehyde, is a known carcinogen, and poses significantly greater toxicity in humans than ethanol itself. Many of the symptoms typically associated with alcohol intoxication — as well as many of the health hazards typically associated with the long-term consumption of ethanol — can be attributed to acetaldehyde toxicity in humans.The subsequent oxidation of acetaldehyde into acetate is performed by aldehyde dehydrogenase (ALDH) enzymes. A mutation in the ALDH2 gene that encodes for an inactive or dysfunctional form of this enzyme affects roughly 50% of east Asian populations, contributing to the characteristic alcohol flush reaction that can cause temporary reddening of the skin as well as a number of related, and often unpleasant, symptoms of acetaldehyde toxicity. This mutation is typically accompanied by another mutation in the alcohol dehydrogenase enzyme ADH1B in roughly 80% of east Asians, which improves the catalytic efficiency of converting ethanol into acetaldehyde. Recreational As a central nervous system depressant, ethanol is one of the most commonly consumed psychoactive drugs.Despite alcohols psychoactive and carcinogenic properties, it is readily available and legal for sale in most countries. However, there are laws regulating the sale, exportation/importation, taxation, manufacturing, consumption, and possession of alcoholic beverages. The most common regulation is prohibition for minors. Fuel Engine fuel The largest single use of ethanol is as an engine fuel and fuel additive. Brazil in particular relies heavily upon the use of ethanol as an engine fuel, due in part to its role as one of the globes leading producers of ethanol. Gasoline sold in Brazil contains at least 25% anhydrous ethanol. Hydrous ethanol (about 95% ethanol and 5% water) can be used as fuel in more than 90% of new gasoline fueled cars sold in the country. Brazilian ethanol is produced from sugar cane, which has relatively high yields (830% more fuel than the fossil fuels used to produce it) compared to some other energy crops. The US and many other countries primarily use E10 (10% ethanol, sometimes known as gasohol) and E85 (85% ethanol) ethanol/gasoline mixtures. Australian law limits the use of pure ethanol from sugarcane waste to 10% in automobiles. Older cars (and vintage cars designed to use a slower burning fuel) should have the engine valves upgraded or replaced.According to an industry advocacy group, ethanol as a fuel reduces harmful tailpipe emissions of carbon monoxide, particulate matter, oxides of nitrogen, and other ozone-forming pollutants. Argonne National Laboratory analyzed greenhouse gas emissions of many different engine and fuel combinations, and found that biodiesel/petrodiesel blend (B20) showed a reduction of 8%, conventional E85 ethanol blend a reduction of 17% and cellulosic ethanol 64%, compared with pure gasoline. Ethanol has a much greater research octane number (RON) than gasoline, meaning it is less prone to pre-ignition, allowing for better ignition advance which means more torque, and efficiency in addition to the lower carbon emissions.Ethanol combustion in an internal combustion engine yields many of the products of incomplete combustion produced by gasoline and significantly larger amounts of formaldehyde and related species such as acetaldehyde. This leads to a significantly larger photochemical reactivity and more ground level ozone. This data has been assembled into The Clean Fuels Report comparison of fuel emissions and show that ethanol exhaust generates 2.14 times as much ozone as gasoline exhaust. When this is added into the custom Localized Pollution Index (LPI) of The Clean Fuels Report, the local pollution of ethanol (pollution that contributes to smog) is rated 1.7, where gasoline is 1.0 and higher numbers signify greater pollution. The California Air Resources Board formalized this issue in 2008 by recognizing control standards for formaldehydes as an emissions control group, much like the conventional NOx and Reactive Organic Gases (ROGs).World production of ethanol in 2006 was 51 gigalitres (1.3×1010 US gal), with 69% of the world supply coming from Brazil and the United States. More than 20% of Brazilian cars are able to use 100% ethanol as fuel, which includes ethanol-only engines and flex-fuel engines. Flex-fuel engines in Brazil are able to work with all ethanol, all gasoline or any mixture of both. In the US flex-fuel vehicles can run on 0% to 85% ethanol (15% gasoline) since higher ethanol blends are not yet allowed or efficient. Brazil supports this fleet of ethanol-burning automobiles with large national infrastructure that produces ethanol from domestically grown sugar cane. Sugar cane not only has a greater concentration of sucrose than corn (by about 30%), but is also much easier to extract. The bagasse generated by the process is not wasted, but is used in power plants to produce electricity.In the United States, the ethanol fuel industry is based largely on corn (also known as maize). According to the Renewable Fuels Association, as of 30 October 2007, 131 grain ethanol bio-refineries in the United States have the capacity to produce 7.0 billion US gallons (26,000,000 m3) of ethanol per year. An additional 72 construction projects underway (in the US) can add 6.4 billion US gallons (24,000,000 m3) of new capacity in the next 18 months. Over time, it is believed that a material portion of the ≈150-billion-US-gallon (570,000,000 m3) per year market for gasoline will begin to be replaced with fuel ethanol.Sweet sorghum is another potential source of ethanol, and is suitable for growing in dryland conditions. The International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) is investigating the possibility of growing sorghum as a source of fuel, food, and animal feed in arid parts of Asia and Africa. Sweet sorghum has one-third the water requirement of sugarcane over the same time period. It also requires about 22% less water than corn. The worlds first sweet sorghum ethanol distillery began commercial production in 2007 in Andhra Pradesh, India.Ethanols high miscibility with water makes it unsuitable for shipping through modern pipelines like liquid hydrocarbons. Mechanics have seen increased cases of damage to small engines (in particular, the carburetor) and attribute the damage to the increased water retention by ethanol in fuel. Rocket fuel Ethanol was commonly used as fuel in early bipropellant rocket (liquid-propelled) vehicles, in conjunction with an oxidizer such as liquid oxygen. The German A-4 ballistic rocket of World War II, better known by its propaganda name V-2, which is credited as having begun the space age, used ethanol as the main constituent of B-Stoff. Under such nomenclature, the ethanol was mixed with 25% water to reduce the combustion chamber temperature. The V-2s design team helped develop US rockets following World War II, including the ethanol-fueled Redstone rocket which launched the first US satellite. Alcohols fell into general disuse as more energy-dense rocket fuels were developed, although ethanol is currently used in lightweight rocket-powered racing aircraft. Fuel cells Commercial fuel cells operate on reformed natural gas, hydrogen or methanol. Ethanol is an attractive alternative due to its wide availability, low cost, high purity and low toxicity. There is a wide range of fuel cell concepts that have entered trials including direct-ethanol fuel cells, auto-thermal reforming systems and thermally integrated systems. The majority of work is being conducted at a research level although there are a number of organizations at the beginning of the commercialization of ethanol fuel cells. Household heating and cooking Ethanol fireplaces can be used for home heating or for decoration. Ethanol can also be used as stove fuel for cooking. Feedstock Ethanol is an important industrial ingredient. It has widespread use as a precursor for other organic compounds such as ethyl halides, ethyl esters, diethyl ether, acetic acid, and ethyl amines. Solvent Ethanol is considered a universal solvent, as its molecular structure allows for the dissolving of both polar, hydrophilic and nonpolar, hydrophobic compounds. As ethanol also has a low boiling point, it is easy to remove from a solution that has been used to dissolve other compounds, making it a popular extracting agent for botanical oils. Cannabis oil extraction methods often use ethanol as an extraction solvent, and also as a post-processing solvent to remove oils, waxes, and chlorophyll from solution in a process known as winterization. Ethanol is found in paints, tinctures, markers, and personal care products such as mouthwashes, perfumes and deodorants. However, polysaccharides precipitate from aqueous solution in the presence of alcohol, and ethanol precipitation is used for this reason in the purification of DNA and RNA. Low-temperature liquid Because of its low freezing point -173.20 °F (−114.14 °C) and low toxicity, ethanol is sometimes used in laboratories (with dry ice or other coolants) as a cooling bath to keep vessels at temperatures below the freezing point of water. For the same reason, it is also used as the active fluid in alcohol thermometers. Chemistry Chemical formula Ethanol is a 2-carbon alcohol. Its molecular formula is CH3CH2OH. An alternative notation is CH3−CH2−OH, which indicates that the carbon of a methyl group (CH3−) is attached to the carbon of a methylene group (−CH2–), which is attached to the oxygen of a hydroxyl group (−OH). It is a constitutional isomer of dimethyl ether. Ethanol is sometimes abbreviated as EtOH, using the common organic chemistry notation of representing the ethyl group (C2H5−) with Et. Physical properties Ethanol is a volatile, colorless liquid that has a slight odor. It burns with a smokeless blue flame that is not always visible in normal light. The physical properties of ethanol stem primarily from the presence of its hydroxyl group and the shortness of its carbon chain. Ethanols hydroxyl group is able to participate in hydrogen bonding, rendering it more viscous and less volatile than less polar organic compounds of similar molecular weight, such as propane. Ethanols adiabatic flame temperature for combustion in air is 2082 Celsius or 3779 Fahrenheit.Ethanol is slightly more refractive than water, having a refractive index of 1.36242 (at λ=589.3 nm and 18.35 °C or 65.03 °F). The triple point for ethanol is 150 K at a pressure of 4.3 × 10−4 Pa. Solvent properties Ethanol is a versatile solvent, miscible with water and with many organic solvents, including acetic acid, acetone, benzene, carbon tetrachloride, chloroform, diethyl ether, ethylene glycol, glycerol, nitromethane, pyridine, and toluene. Its main use as a solvent is in making tincture of iodine, cough syrups etc. It is also miscible with light aliphatic hydrocarbons, such as pentane and hexane, and with aliphatic chlorides such as trichloroethane and tetrachloroethylene.Ethanols miscibility with water contrasts with the immiscibility of longer-chain alcohols (five or more carbon atoms), whose water miscibility decreases sharply as the number of carbons increases. The miscibility of ethanol with alkanes is limited to alkanes up to undecane: mixtures with dodecane and higher alkanes show a miscibility gap below a certain temperature (about 13 °C for dodecane). The miscibility gap tends to get wider with higher alkanes, and the temperature for complete miscibility increases. Ethanol-water mixtures have less volume than the sum of their individual components at the given fractions. Mixing equal volumes of ethanol and water results in only 1.92 volumes of mixture. Mixing ethanol and water is exothermic, with up to 777 J/mol being released at 298 K. Mixtures of ethanol and water form an azeotrope at about 89 mole-% ethanol and 11 mole-% water or a mixture of 95.6 percent ethanol by mass (or about 97% alcohol by volume) at normal pressure, which boils at 351K (78 °C). This azeotropic composition is strongly temperature- and pressure-dependent and vanishes at temperatures below 303 K. Hydrogen bonding causes pure ethanol to be hygroscopic to the extent that it readily absorbs water from the air. The polar nature of the hydroxyl group causes ethanol to dissolve many ionic compounds, notably sodium and potassium hydroxides, magnesium chloride, calcium chloride, ammonium chloride, ammonium bromide, and sodium bromide. Sodium and potassium chlorides are slightly soluble in ethanol. Because the ethanol molecule also has a nonpolar end, it will also dissolve nonpolar substances, including most essential oils and numerous flavoring, coloring, and medicinal agents. The addition of even a few percent of ethanol to water sharply reduces the surface tension of water. This property partially explains the "tears of wine" phenomenon. When wine is swirled in a glass, ethanol evaporates quickly from the thin film of wine on the wall of the glass. As the wines ethanol content decreases, its surface tension increases and the thin film "beads up" and runs down the glass in channels rather than as a smooth sheet. Flammability An ethanol–water solution will catch fire if heated above a temperature called its flash point and an ignition source is then applied to it. For 20% alcohol by mass (about 25% by volume), this will occur at about 25 °C (77 °F). The flash point of pure ethanol is 13 °C (55 °F), but may be influenced very slightly by atmospheric composition such as pressure and humidity. Ethanol mixtures can ignite below average room temperature. Ethanol is considered a flammable liquid (Class 3 Hazardous Material) in concentrations above 2.35% by mass (3.0% by volume; 6 proof). Dishes using burning alcohol for culinary effects are called flambé. Natural occurrence Ethanol is a byproduct of the metabolic process of yeast. As such, ethanol will be present in any yeast habitat. Ethanol can commonly be found in overripe fruit. Ethanol produced by symbiotic yeast can be found in bertam palm blossoms. Although some animal species, such as the pentailed treeshrew, exhibit ethanol-seeking behaviors, most show no interest or avoidance of food sources containing ethanol. Ethanol is also produced during the germination of many plants as a result of natural anaerobiosis. Ethanol has been detected in outer space, forming an icy coating around dust grains in interstellar clouds. Minute quantity amounts (average 196 ppb) of endogenous ethanol and acetaldehyde were found in the exhaled breath of healthy volunteers. Auto-brewery syndrome, also known as gut fermentation syndrome, is a rare medical condition in which intoxicating quantities of ethanol are produced through endogenous fermentation within the digestive system. Production Ethanol is produced both as a petrochemical, through the hydration of ethylene and, via biological processes, by fermenting sugars with yeast. Which process is more economical depends on prevailing prices of petroleum and grain feed stocks. In the 1970s most industrial ethanol in the United States was made as a petrochemical, but in the 1980s the United States introduced subsidies for corn-based ethanol and today it is almost all made from that source. In India ethanol is made from sugarcane. Ethylene hydration Ethanol for use as an industrial feedstock or solvent (sometimes referred to as synthetic ethanol) is made from petrochemical feed stocks, primarily by the acid-catalyzed hydration of ethylene: C2H4 + H2O → CH3CH2OHThe catalyst is most commonly phosphoric acid, adsorbed onto a porous support such as silica gel or diatomaceous earth. This catalyst was first used for large-scale ethanol production by the Shell Oil Company in 1947. The reaction is carried out in the presence of high pressure steam at 300 °C (572 °F) where a 5:3 ethylene to steam ratio is maintained. This process was used on an industrial scale by Union Carbide Corporation and others in the US, but now only LyondellBasell uses it commercially. In an older process, first practiced on the industrial scale in 1930 by Union Carbide, but now almost entirely obsolete, ethylene was hydrated indirectly by reacting it with concentrated sulfuric acid to produce ethyl sulfate, which was hydrolyzed to yield ethanol and regenerate the sulfuric acid: C2H4 + H2SO4 → CH3CH2SO4H CH3CH2SO4H + H2O → CH3CH2OH + H2SO4 From CO2 Ethanol has been produced in the laboratory by converting carbon dioxide via biological and electrochemical reactions. CO2 + H2O → CH3CH2OH + side products Fermentation Ethanol in alcoholic beverages and fuel is produced by fermentation. Certain species of yeast (e.g., Saccharomyces cerevisiae) metabolize sugar, producing ethanol and carbon dioxide. The chemical equations below summarize the conversion: C6H12O6 → 2 CH3CH2OH + 2 CO2 C12H22O11 + H2O → 4 CH3CH2OH + 4 CO2Fermentation is the process of culturing yeast under favorable thermal conditions to produce alcohol. This process is carried out at around 35–40 °C (95–104 °F). Toxicity of ethanol to yeast limits the ethanol concentration obtainable by brewing; higher concentrations, therefore, are obtained by fortification or distillation. The most ethanol-tolerant yeast strains can survive up to approximately 18% ethanol by volume. To produce ethanol from starchy materials such as cereals, the starch must first be converted into sugars. In brewing beer, this has traditionally been accomplished by allowing the grain to germinate, or malt, which produces the enzyme amylase. When the malted grain is mashed, the amylase converts the remaining starches into sugars. Cellulose Sugars for ethanol fermentation can be obtained from cellulose. Deployment of this technology could turn a number of cellulose-containing agricultural by-products, such as corncobs, straw, and sawdust, into renewable energy resources. Other agricultural residues such as sugar cane bagasse and energy crops such as switchgrass may also be fermentable sugar sources. Testing Breweries and biofuel plants employ two methods for measuring ethanol concentration. Infrared ethanol sensors measure the vibrational frequency of dissolved ethanol using the C−H band at 2900 cm−1. This method uses a relatively inexpensive solid-state sensor that compares the C−H band with a reference band to calculate the ethanol content. The calculation makes use of the Beer–Lambert law. Alternatively, by measuring the density of the starting material and the density of the product, using a hydrometer, the change in specific gravity during fermentation indicates the alcohol content. This inexpensive and indirect method has a long history in the beer brewing industry. Purification Distillation Ethylene hydration or brewing produces an ethanol–water mixture. For most industrial and fuel uses, the ethanol must be purified. Fractional distillation at atmospheric pressure can concentrate ethanol to 95.6% by weight (89.5 mole%). This mixture is an azeotrope with a boiling point of 78.1 °C (172.6 °F), and cannot be further purified by distillation. Addition of an entraining agent, such as benzene, cyclohexane, or heptane, allows a new ternary azeotrope comprising the ethanol, water, and the entraining agent to be formed. This lower-boiling ternary azeotrope is removed preferentially, leading to water-free ethanol. Molecular sieves and desiccants Apart from distillation, ethanol may be dried by addition of a desiccant, such as molecular sieves, cellulose, or cornmeal. The desiccants can be dried and reused. Molecular sieves can be used to selectively absorb the water from the 95.6% ethanol solution. Molecular sieves of pore-size 3 Ångstrom, a type of zeolite, effectively sequester water molecules while excluding ethanol molecules. Heating the wet sieves drives out the water, allowing regeneration of their dessicant capability. Membranes and reverse osmosis Membranes can also be used to separate ethanol and water. Membrane-based separations are not subject to the limitations of the water-ethanol azeotrope because the separations are not based on vapor-liquid equilibria. Membranes are often used in the so-called hybrid membrane distillation process. This process uses a pre-concentration distillation column as the first separating step. The further separation is then accomplished with a membrane operated either in vapor permeation or pervaporation mode. Vapor permeation uses a vapor membrane feed and pervaporation uses a liquid membrane feed. Other techniques A variety of other techniques have been discussed, including the following: Salting using potassium carbonate to exploit its insolubility will cause a phase separation with ethanol and water. This offers a very small potassium carbonate impurity to the alcohol that can be removed by distillation. This method is very useful in purification of ethanol by distillation, as ethanol forms an azeotrope with water. Direct electrochemical reduction of carbon dioxide to ethanol under ambient conditions using copper nanoparticles on a carbon nanospike film as the catalyst; Extraction of ethanol from grain mash by supercritical carbon dioxide; Pervaporation; Fractional freezing is also used to concentrate fermented alcoholic solutions, such as traditionally made Applejack (beverage); Pressure swing adsorption. Grades of ethanol Denatured alcohol Pure ethanol and alcoholic beverages are heavily taxed as psychoactive drugs, but ethanol has many uses that do not involve its consumption. To relieve the tax burden on these uses, most jurisdictions waive the tax when an agent has been added to the ethanol to render it unfit to drink. These include bittering agents such as denatonium benzoate and toxins such as methanol, naphtha, and pyridine. Products of this kind are called denatured alcohol. Absolute alcohol Absolute or anhydrous alcohol refers to ethanol with a low water content. There are various grades with maximum water contents ranging from 1% to a few parts per million (ppm). If azeotropic distillation is used to remove water, it will contain trace amounts of the material separation agent (e.g. benzene). Absolute alcohol is not intended for human consumption. Absolute ethanol is used as a solvent for laboratory and industrial applications, where water will react with other chemicals, and as fuel alcohol. Spectroscopic ethanol is an absolute ethanol with a low absorbance in ultraviolet and visible light, fit for use as a solvent in ultraviolet-visible spectroscopy.Pure ethanol is classed as 200 proof in the US, equivalent to 175
Ethanol	degrees proof in the UK system. Rectified spirits Rectified spirit, an azeotropic composition of 96% ethanol containing 4% water, is used instead of anhydrous ethanol for various purposes. Spirits of wine are about 94% ethanol (188 proof). The impurities are different from those in 95% (190 proof) laboratory ethanol. Reactions Ethanol is classified as a primary alcohol, meaning that the carbon that its hydroxyl group attaches to has at least two hydrogen atoms attached to it as well. Many ethanol reactions occur at its hydroxyl group. Ester formation In the presence of acid catalysts, ethanol reacts with carboxylic acids to produce ethyl esters and water: RCOOH + HOCH2CH3 → RCOOCH2CH3 + H2OThis reaction, which is conducted on large scale industrially, requires the removal of the water from the reaction mixture as it is formed. Esters react in the presence of an acid or base to give back the alcohol and a salt. This reaction is known as saponification because it is used in the preparation of soap. Ethanol can also form esters with inorganic acids. Diethyl sulfate and triethyl phosphate are prepared by treating ethanol with sulfur trioxide and phosphorus pentoxide respectively. Diethyl sulfate is a useful ethylating agent in organic synthesis. Ethyl nitrite, prepared from the reaction of ethanol with sodium nitrite and sulfuric acid, was formerly used as a diuretic. Dehydration In the presence of acid catalysts, alcohols can be converted to alkenes such as ethanol to ethylene. Typically solid acids such as alumina are used. CH3CH2OH → H2C=CH2 + H2OSince water is removed from the same molecule, the reaction is known as intramolecular dehydration. Intramolecular dehydration of an alcohol requires a high temperature and the presence of an acid catalyst such as sulphuric acid.Ethylene produced from sugar-derived ethanol (primarily in Brazil) competes with ethylene produced from petrochemical feedstocks such as naphtha and ethane. At a lower temperature than that of intramolecular dehydration, intermolecular alcohol dehydration may occur producing a symmetrical ether. This is a condensation reaction. In the following example, diethyl ether is produced from ethanol: 2 CH3CH2OH → CH3CH2OCH2CH3 + H2O Combustion Complete combustion of ethanol forms carbon dioxide and water: C2H5OH (l) + 3 O2 (g) → 2 CO2 (g) + 3 H2O (l); −ΔHc = 1371 kJ/mol = 29.8 kJ/g = 327 kcal/mol = 7.1 kcal/gC2H5OH (l) + 3 O2 (g) → 2 CO2 (g) + 3 H2O (g); −ΔHc = 1236 kJ/mol = 26.8 kJ/g = 295.4 kcal/mol = 6.41 kcal/gSpecific heat = 2.44 kJ/(kg·K) Acid-base chemistry Ethanol is a neutral molecule and the pH of a solution of ethanol in water is nearly 7.00. Ethanol can be quantitatively converted to its conjugate base, the ethoxide ion (CH3CH2O−), by reaction with an alkali metal such as sodium: 2 CH3CH2OH + 2 Na → 2 CH3CH2ONa + H2or a very strong base such as sodium hydride: CH3CH2OH + NaH → CH3CH2ONa + H2The acidities of water and ethanol are nearly the same, as indicated by their pKa of 15.7 and 16 respectively. Thus, sodium ethoxide and sodium hydroxide exist in an equilibrium that is closely balanced: CH3CH2OH + NaOH ⇌ CH3CH2ONa + H2O Halogenation Ethanol is not used industrially as a precursor to ethyl halides, but the reactions are illustrative. Ethanol reacts with hydrogen halides to produce ethyl halides such as ethyl chloride and ethyl bromide via an SN2 reaction: CH3CH2OH + HCl → CH3CH2Cl + H2OThese reactions require a catalyst such as zinc chloride. HBr requires refluxing with a sulfuric acid catalyst. Ethyl halides can, in principle, also be produced by treating ethanol with more specialized halogenating agents, such as thionyl chloride or phosphorus tribromide. CH3CH2OH + SOCl2 → CH3CH2Cl + SO2 + HClUpon treatment with halogens in the presence of base, ethanol gives the corresponding haloform (CHX3, where X = Cl, Br, I). This conversion is called the haloform reaction. " An intermediate in the reaction with chlorine is the aldehyde called chloral, which forms chloral hydrate upon reaction with water: 4 Cl2 + CH3CH2OH → CCl3CHO + 5 HCl CCl3CHO + H2O → CCl3C(OH)2H Oxidation Ethanol can be oxidized to acetaldehyde and further oxidized to acetic acid, depending on the reagents and conditions. This oxidation is of no importance industrially, but in the human body, these oxidation reactions are catalyzed by the enzyme liver alcohol dehydrogenase. The oxidation product of ethanol, acetic acid, is a nutrient for humans, being a precursor to acetyl CoA, where the acetyl group can be spent as energy or used for biosynthesis. Metabolism Ethanol is similar to macronutrients such as proteins, fats, and carbohydrates in that it provides calories. When consumed and metabolized, it contributes 7 calories per gram via ethanol metabolism. Safety Pure ethanol will irritate the skin and eyes. Nausea, vomiting, and intoxication are symptoms of ingestion. Long-term use by ingestion can result in serious liver damage. Atmospheric concentrations above one part per thousand are above the European Union occupational exposure limits. History The fermentation of sugar into ethanol is one of the earliest biotechnologies employed by humans. Ethanol has historically been identified variously as spirit of wine or ardent spirits, and as aqua vitae or aqua vita. The intoxicating effects of its consumption have been known since ancient times. Ethanol has been used by humans since prehistory as the intoxicating ingredient of alcoholic beverages. Dried residue on 9,000-year-old pottery found in China suggests that Neolithic people consumed alcoholic beverages.The inflammable nature of the exhalations of wine was already known to ancient natural philosophers such as Aristotle (384–322 BCE), Theophrastus (c. 371–287 BCE), and Pliny the Elder (23/24–79 CE). However, this did not immediately lead to the isolation of ethanol, even despite the development of more advanced distillation techniques in second- and third-century Roman Egypt. An important recognition, first found in one of the writings attributed to Jābir ibn Ḥayyān (ninth century CE), was that by adding salt to boiling wine, which increases the wines relative volatility, the flammability of the resulting vapors may be enhanced. The distillation of wine is attested in Arabic works attributed to al-Kindī (c. 801–873 CE) and to al-Fārābī (c. 872–950), and in the 28th book of al-Zahrāwīs (Latin: Abulcasis, 936–1013) Kitāb al-Taṣrīf (later translated into Latin as Liber servatoris). In the twelfth century, recipes for the production of aqua ardens ("burning water", i.e., ethanol) by distilling wine with salt started to appear in a number of Latin works, and by the end of the thirteenth century it had become a widely known substance among Western European chemists.The works of Taddeo Alderotti (1223–1296) describe a method for concentrating ethanol involving repeated fractional distillation through a water-cooled still, by which an ethanol purity of 90% could be obtained. The medicinal properties of ethanol were studied by Arnald of Villanova (1240–1311 CE) and John of Rupescissa (c. 1310–1366), the latter of whom regarded it as a life-preserving substance able to prevent all diseases (the aqua vitae or "water of life", also called by John the quintessence of wine).In China, archaeological evidence indicates that the true distillation of alcohol began during the Jin (1115–1234) or Southern Song (1127–1279) dynasties. A still has been found at an archaeological site in Qinglong, Hebei, dating to the 12th century. In India, the true distillation of alcohol was introduced from the Middle East, and was in wide use in the Delhi Sultanate by the 14th century.In 1796, German-Russian chemist Johann Tobias Lowitz obtained pure ethanol by mixing partially purified ethanol (the alcohol-water azeotrope) with an excess of anhydrous alkali and then distilling the mixture over low heat. French chemist Antoine Lavoisier described ethanol as a compound of carbon, hydrogen, and oxygen, and in 1807 Nicolas-Théodore de Saussure determined ethanols chemical formula. Fifty years later, Archibald Scott Couper published the structural formula of ethanol. It was one of the first structural formulas determined.Ethanol was first prepared synthetically in 1825 by Michael Faraday. He found that sulfuric acid could absorb large volumes of coal gas. He gave the resulting solution to Henry Hennell, a British chemist, who found in 1826 that it contained "sulphovinic acid" (ethyl hydrogen sulfate). In 1828, Hennell and the French chemist Georges-Simon Serullas independently discovered that sulphovinic acid could be decomposed into ethanol. Thus, in 1825 Faraday had unwittingly discovered that ethanol could be produced from ethylene (a component of coal gas) by acid-catalyzed hydration, a process similar to current industrial ethanol synthesis.Ethanol was used as lamp fuel in the United States as early as 1840, but a tax levied on industrial alcohol during the Civil War made this use uneconomical. The tax was repealed in 1906. Use as an automotive fuel dates back to 1908, with the Ford Model T able to run on petrol (gasoline) or ethanol. It fuels some spirit lamps. Ethanol intended for industrial use is often produced from ethylene. Ethanol has widespread use as a solvent of substances intended for human contact or consumption, including scents, flavorings, colorings, and medicines. In chemistry, it is both a solvent and a feedstock for the synthesis of other products. It has a long history as a fuel for heat and light, and more recently as a fuel for internal combustion engines. See also References Further reading External links Alcohol (Ethanol) at The Periodic Table of Videos (University of Nottingham) International Labour Organization ethanol safety information National Pollutant Inventory – Ethanol Fact Sheet CDC – NIOSH Pocket Guide to Chemical Hazards – Ethyl Alcohol National Institute of Standards and Technology chemical data on ethanol Chicago Board of Trade news and market data on ethanol futures Calculation of vapor pressure, liquid density, dynamic liquid viscosity, surface tension of ethanol Ethanol History A look into the history of ethanol ChemSub Online: Ethyl alcohol Industrial ethanol production process flow diagram using ethylene and sulphuric acid
Methylprednisolone acetate	Methylprednisolone acetate, sold under the brand names Depo-Medrol among others, is a synthetic glucocorticoid corticosteroid and a corticosteroid ester—specifically the C21 acetate ester of methylprednisolone—which is used in clinical and veterinary medicine. It has been formulated as an aqueous suspension for intramuscular, intra-articular, soft tissue, and intralesional injection alone and in combination with lidocaine, a local anesthetic. Methylprednisolone acetate was previously suspended with polyethylene glycol but is no longer formulated with this excipient due to concerns about possible toxicity. Depo methylprednisolone acetate is a depot injection and is absorbed slowly with a duration of weeks to months with a single intramuscular injection. See also List of corticosteroid esters § Methylprednisolone esters == References ==
Herbal distillate	Herbal distillates, also known as floral waters, hydrosols, hydrolates, herbal waters, and essential waters, are aqueous products of hydrodistillation. They are colloidal suspensions of essential oils as well as water-soluble components obtained by steam distillation or hydrodistillation (a variant of steam distillation) from plants and herbs. These herbal distillates have uses as flavorings and cosmetics. Common herbal distillates for skincare include rose water, orange flower water, and witch hazel. Rosemary, oregano, and thyme are hydrosols that may be used in food manufacturing. Production Herbal distillates are produced in the same or similar manner as essential oils. However, essential oils will float to the top of the distillate where it is removed, leaving behind the watery distillate. For this reason the term essential water is an apt description. In the past, these essential waters were often considered a byproduct of distillation, but are now considered an important co-product. The produced herbal waters are essentially diluted essential oils at less than 1% concentration (typically 0.02% to 0.05%). Several factors, such as temperature and an herbs growth cycle, impact the characteristics of a distillate, and therefore influence the timing of the distillation. Rosemary, for example, should be distilled in the peak of summer before it flowers. Usage Distillates are used as flavorings, cosmetics and as herbal treatments. Herbal distillates are less concentrated than essential oils, possibly making them more suitable for some topical uses. Science The science of distillation is based on the fact that different substances vaporise at different temperatures. Unlike other extraction techniques based on solubility of a compound in either water or oil, distillation will separate components regardless of their solubility. The distillate will contain compounds that vaporize at or below the temperature of distillation. The actual chemical components of these orange herbal distillates have not yet been fully identified, but plant distillates will usually contain essential oil compounds as well as organic acids and other water-soluble plant components. Compounds with a higher vaporization point will remain behind and will include many of the water-soluble plant pigments and flavonoids.Because hydrosols are produced at high temperatures and are somewhat acidic, they tend to inhibit bacterial growth but not fungal growth. They are not sterile, and should be kept refrigerated to preserve freshness. Herbal distillates degrade over time and will degrade faster than essential oils, which are more stable and will degrade slower. Small-scale producers of hydrosols must be particularly aware of the risk of bacterial contamination and take steps to prevent it. Despite concerns that there may be significant amounts of heavy metals in popular herbal distillates, this has not shown to be the case. See also Orange flower water Rose water Witch hazel (astringent) References Books Firth, Grace. Secrets of the Still. Epm Pubns Inc; First edition (June 1983) Price, Len and Price, Shirley. Understanding Hydrolats: The Specific Hydrosols for Aromatherapy: A Guide for Health Professional. Churchill Livingstone 2004 Rose, Jeanne. 375 Essential Oils & Hydrosols. Frog, Ltd, Berkeley, CA, 1999. ISBN 1-883319-89-7 Rose, Jeanne. Hydrosols & Aromatic Waters. Institute of Aromatic & Herbal Study, 2007.
Nedocromil	Nedocromil sodium is a medication considered as mast cell stabilizer which acts to prevent wheezing, shortness of breath, and other breathing problems caused by asthma. It is administered by an inhaler under the brand name Tilade, and as an eye drop under the brand name Alocril. The effects of nedocromil versus asthma are gradual rather than fast-acting and it is not indicated for acute respiratory distress compared to fast acting bronchodilators like albuterol or other well-known inhaler medications. Liquid preparations of nedocromil are available in the UK under the name Rapitil for use for allergic eye reactions. Nedocromil sodium has been shown to be effective in alleviating symptoms of allergic conjunctivitis.Nedocromil is classified as a benzopyrone. Nedocromil acts as a mast cell stabilizer, inhibits the degranulation of mast cells, prevents release of histamine and tryptase, so preventing the synthesis of prostaglandins and leukotrienes. US Production of inhaled nedocromil ceased in April 2008 because it used CFCs as propellant. References Media related to Nedocromil at Wikimedia Commons
Bevacizumab	Bevacizumab, sold under the brand name Avastin among others, is a medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).Common side effects when used for cancer include nose bleeds, headache, high blood pressure, and rash. Other severe side effects include gastrointestinal perforation, bleeding, allergic reactions, blood clots, and an increased risk of infection. When used for eye disease side effects can include vision loss and retinal detachment. Bevacizumab is a monoclonal antibody that functions as an angiogenesis inhibitor. It works by slowing the growth of new blood vessels by inhibiting vascular endothelial growth factor A (VEGF-A), in other words anti–VEGF therapy.Bevacizumab was approved for medical use in the United States in 2004. It is on the World Health Organizations List of Essential Medicines. It is listed for its use in treating eye disease. Medical uses Colorectal cancer Bevacizumab was approved in the United States in February 2004, for use in metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment). In June 2006, it was approved with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer.It was approved by the European Medicines Agency (EMA) in January 2005, for use in colorectal cancer.Bevacizumab has also been examined as an add on to other chemotherapy drugs in people with non-metastatic colon cancer. The data from two large randomized studies showed no benefit in preventing the cancer from returning and a potential to cause harm in this setting.In the EU, bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adults with metastatic carcinoma of the colon or rectum. Lung cancer In 2006, the U.S. Food and Drug Administration (FDA) approved bevacizumab for use in first-line advanced nonsquamous non-small cell lung cancer in combination with carboplatin/paclitaxel chemotherapy. The approval was based on the pivotal study E4599 (conducted by the Eastern Cooperative Oncology Group), which demonstrated a two-month improvement in overall survival in patients treated with bevacizumab (Sandler, et al. NEJM 2004). A preplanned analysis of histology in E4599 demonstrated a four-month median survival benefit with bevacizumab for people with adenocarcinoma (Sandler, et al. JTO 2010); adenocarcinoma represents approximately 85% of all non-squamous cell carcinomas of the lung. A subsequent European clinical trial, AVAiL, was first reported in 2009 and confirmed the significant improvement in progression-free survival shown in E4599 (Reck, et al. Ann. Oncol. 2010). An overall survival benefit was not demonstrated in patients treated with bevacizumab; however, this may be due to the more limited use of bevacizumab as maintenance treatment in AVAiL versus E4599 (this differential effect is also apparent in the European vs US trials of bevacizumab in colorectal cancer: Tyagi and Grothey, Clin Colorectal Cancer, 2006). As an anti-angiogenic agent, there is no mechanistic rationale for stopping bevacizumab before disease progression. Stated another way, the survival benefits achieved with bevacizumab can only be expected when used in accordance with the clinical evidence: continued until disease progression or treatment-limiting side effects. Another large European-based clinical trial with bevacizumab in lung cancer, AVAPERL, was reported in October 2011 (Barlesi, et al. ECCM 2011). First-line patients were treated with bevacizumab plus cisplatin/pemetrexed for four cycles, and then randomized to receive maintenance treatment with either bevacizumab/pemetrexed or bevacizumab alone until disease progression. Maintenance treatment with bevacizumab/pemetrexed demonstrated a 50% reduction in risk of progression vs bevacizumab alone (median PFS: 10.2 vs 6.6 months). Maintenance treatment with bevacizumab/pemetrexed did not confer a significant increase in overall survival vs bevacizumab alone on follow up analysis.The National Comprehensive Cancer Network recommends bevacizumab as standard first-line treatment in combination with any platinum-based chemotherapy, followed by maintenance bevacizumab until disease progression. Higher doses are usually given with carboplatin-based chemotherapy, whereas the lower dose is usually given with cisplatin-based chemotherapy.In the EU, bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adults with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adults with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations. Breast cancer In December 2010, the U.S. Food and Drug Administration (FDA) notified its intention to remove the breast cancer indication from bevacizumab, saying that it had not been shown to be safe and effective in breast cancer patients. The combined data from four different clinical trials showed that bevacizumab neither prolonged overall survival nor slowed disease progression sufficiently to outweigh the risk it presents to patients. This only prevented Genentech from marketing bevacizumab for breast cancer. Doctors are free to prescribe bevacizumab off label, although insurance companies are less likely to approve off-label treatments. In June 2011, an FDA panel unanimously rejected an appeal by Roche. A panel of cancer experts ruled for a second time that Avastin should no longer be used in breast cancer patients, clearing the way for the U.S. government to remove its endorsement from the drug. The June 2011 meeting of the FDAs oncologic drug advisory committee was the last step in an appeal by the drugs maker. The committee concluded that breast cancer clinical studies of patients taking Avastin have shown no advantage in survival rates, no improvement in quality of life, and significant side effects.On 11 October 2011, the U.S. Food and Drug Administration (FDA) announced that the agency was revoking the agencys approval of the breast cancer indication for bevacizumab after concluding that the drug had not been shown to be safe and effective for that use.In the EU, bevacizumab in combination with paclitaxel is indicated for first-line treatment of adults with metastatic breast cancer. Bevacizumab in combination with capecitabine is indicated for first-line treatment of adults with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Renal cancers In certain renal (kidney) cancers, bevacizumab improves the progression free survival time but not survival time. In 2009, the FDA approved bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer). following earlier reports of activity EU approval was granted in 2007.In the EU, bevacizumab in combination with interferon alfa-2a is indicated for first-line treatment of adults with advanced and/or metastatic renal cell cancer. Brain cancers Bevacizumab slows tumor growth but does not affect overall survival in people with glioblastoma multiforme. The FDA granted accelerated approval for the treatment of recurrent glioblastoma multiforme in May 2009. A 2018 Cochrane review deemed there to not be good evidence for its use in recurrences either. Eye disease Many diseases of the eye, such as age-related macular degeneration (AMD) and diabetic retinopathy, damage the retina and cause blindness when blood vessels around the retina grow abnormally and leak fluid, causing the layers of the retina to separate. This abnormal growth is caused by VEGF, so bevacizumab has been successfully used to inhibit VEGF and slow this growth.Bevacizumab has been used by ophthalmologists in an off-label use as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. The injection of 1.25–2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity. Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity and macular edema secondary to retinal vein occlusions.Several reviews concluded that similar results concerning effects and safety were obtained using either bevacizumab or ranibizumab. Ovarian cancer In 2018, the U.S. Food and Drug Administration (FDA) approved bevacizumab in combination with chemotherapy for stage III or IV of ovarian cancer after initial surgical operation, followed by single-agent bevacizumab. The approval was based on a study of the addition of bevacizumab to carboplatin and paclitaxel. Progression-free survival was increased to 18 months from 13 months.In the EU, bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adults with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adults with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.In May 2020, the Food and Drug Administration expanded the indication of olaparib to include its combination with bevacizumab for first-line maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. Cervical cancer In the EU, bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in people who cannot receive platinum therapy, is indicated for the treatment of adults with persistent, recurrent, or metastatic carcinoma of the cervix. Administration Bevacizumab is usually given intravenously every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan. For treatment of eye diseases it is injected intravitreously. Off-label use for age-related macular degeneration (AMD) Dr Philip Rosenfeld developed off-label use of bevacizumab for age-related macular degeneration.[1] Adverse effects Bevacizumab inhibits the growth of blood vessels, which is part of the bodys normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported. Fatigue and infection are also common. In advanced lung cancer, less than half of patients qualify for treatment. Nasal septum perforation and renal thrombotic microangiopathy have been reported. In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines. In 2013, Hoffmann-La Roche announced that the drug was associated with 52 cases of necrotizing fasciitis from 1997 to 2012, of which 17 patients died. About 2/3 of cases involved patients with colorectal cancer, or patients with gastrointestinal perforations or fistulas. These effects are largely avoided in ophthalmological use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.Neurological adverse events include reversible posterior encephalopathy syndrome. Ischemic and hemorrhagic strokes are also possible.Protein in the urine occurs in approximately 20% of people. This does not require permanent discontinuation of the drug. Nonetheless, the presence of nephrotic syndrome necessitates permanent discontinuation of bevacizumab. Mechanism of action Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A). VEGF-A is a growth factor protein that stimulates angiogenesis in a variety of diseases, especially in cancer. Bevacizumab is the first available angiogenesis inhibitor in the United States. Chemistry Bevacizumab was originally derived from a mouse monoclonal antibody generated from mice immunized with the 165-residue form of recombinant human vascular endothelial growth factor. It was humanized by retaining the binding region and replacing the rest with a human full light chain and a human truncated IgG1 heavy chain, with some other substitutions. The resulting plasmid was transfected into Chinese hamster ovary cells which are grown in industrial fermentation systems.: 4 History Bevacizumab is a recombinant humanized monoclonal antibody and in 2004, it became the first clinically used angiogenesis inhibitor. Its development was based on the discovery of human vascular endothelial growth factor (VEGF), a protein that stimulated blood vessel growth, in the laboratory of Genentech scientist Napoleone Ferrara. Ferrara later demonstrated that antibodies against VEGF inhibit tumor growth in mice. His work validated the hypothesis of Judah Folkman, proposed in 1971, that stopping angiogenesis might be useful in controlling cancer growth. Approval It received its first approval in the United States in 2004, for combination use with standard chemotherapy for metastatic colon cancer. It has since been approved for use in certain lung cancers, renal cancers, ovarian cancers, and glioblastoma multiforme of the brain.In 2008, bevacizumab was approved for breast cancer by the FDA, but the approval was revoked on 18 November 2011 because, although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging.In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDAs advisory panel had recommended against approval. In July 2010, after new studies failed to show a significant benefit, the FDAs advisory panel recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA ruled to withdraw the breast cancer indication in November 2011. FDA approval is required for Genentech to market a drug for that indication. Doctors may sometimes prescribe it for that indication, although insurance companies are less likely to pay for it.The drug remains approved for breast cancer use in other countries, including Australia. It has been funded by the English NHS Cancer Drugs Fund, but in January 2015 it was proposed to remove it from the approved list. Society and culture Use for macular degeneration In 2015, there was a fierce debate in the UK and other European countries concerning the choice of prescribing bevacizumab or ranibizumab (Lucentis) for wet AMD. In the UK, part of the tension was between on the one hand, both the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency which had approved Lucentis but not Avastin for wet AMD, and their interest in ensuring that doctors to do not use medicines off-label when there are other, approved medications for the same indication, and on the other hand, NICE in the UK, which sets treatment guidelines, and has been unable so far to appraise Avastin as a first-line treatment, in order to save money for the National Health Service. Novartis and Roche (which respectively have marketing rights and ownership rights for Avastin) had not conducted clinical trials to get approval for Avastin for wet AMD and had no intention of doing so. Further, both companies lobbied against treatment guidelines that would make Avastin a first-line treatment, and when government-funded studies comparing the two drugs were published, they published papers emphasizing the risks of using Avastin for wet AMD. Breast cancer approval On 28 March 2007, the European Commission approved bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer.In 2008, the FDA approved bevacizumab for use in breast cancer. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the clinical trial did not show any increase in quality of life or prolonging of life for patients—two important benchmarks for late-stage cancer treatments. The clinical trial did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time. It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. This decision was lauded by patient advocacy groups and some oncologists. Other oncologists felt that granting approval for late-stage cancer therapies that did not prolong or increase the quality of life for patients would give license to pharmaceutical companies to ignore these important benchmarks when developing new late-stage cancer therapies.In 2010, before the FDA announcement, The National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines for Oncology (NCCN Guidelines) for Breast Cancer to affirm the recommendation regarding the use of bevacizumab in the treatment of metastatic breast cancer.In 2011, the US Food and Drug Administration removed bevacizumab indication for metastatic breast cancer after concluding that the drug has not been shown to be safe and effective. The specific indication that was withdrawn was for the use of bevacizumab in metastatic breast cancer, with paclitaxel for the treatment of people who have not received chemotherapy for metastatic HER2-negative breast cancer. Counterfeit On Tuesday, 14 February 2012, Roche and its U.S. biotech unit Genentech announced that counterfeit Avastin had been distributed in the United States. The investigation is ongoing, but differences in the outer packaging make identification of the bogus drugs simple for medical providers. Roche analyzed three bogus vials of Avastin and found they contained salt, starch, citrate, isopropanol, propanediol, t-butanol, benzoic acid, di-fluorinated benzene ring, acetone and phthalate moiety, but no active ingredients of the cancer drug. According to Roche, the levels of the chemicals were not consistent; whether the chemicals were at harmful concentrations could not therefore be determined. The counterfeit Avastin has been traced back to Egypt, and it entered legitimate supply chains via Europe to the United States. Biosimilars In July 2014, two pharming companies, PlantForm and PharmaPraxis, announced plans to commercialize a biosimilar version of bevacizumab made using a tobacco expression system in collaboration with the Fraunhofer Center for Molecular Biology.In September 2017, the US FDA approved Amgens biosimilar (generic name bevacizumab-awwb, product name Mvasi) for six cancer indications.In January 2018, Mvasi was approved for use in the European Union.In February 2019, Zirabev was approved for use in the European Union. Zirabev was approved for medical use in the United States in June 2019, and in Australia in November 2019.In June 2020, Mvasi was approved for medical use in Australia.In August 2020, Aybintio was approved for use in the European Union.In September 2020, Equidacent was approved for use in the European Union.On 28 January 2021, 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 Alymsys, intended for the treatment of carcinoma of the colon or rectum, breast cancer, non-small cell lung cancer, renal cell cancer, epithelial ovarian, fallopian tube or primary peritoneal cancer, and carcinoma of the cervix. Alymsys was approved for medical use in the European Union in March 2021.In January 2021, Onbevzi was approved for medical use in the European Union.In June 2019, and June 2021, Zirabev was approved for medical use in Canada.Abevmy was approved for medical use in the European Union in April 2021, and in Australia in September 2021.In September 2021, Bambevi was approved for medical use in Canada.Bevacip and Bevaciptin were approved for medical use in Australia in November 2021.In November 2021, Abevmy and Aybintio were approved for medical use in Canada.In April 2022, Alymsys was approved for medical use in the United States.In September 2022, Vegzelma was approved for medical use in the United States. Research A study released in April 2009, found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery.Bevacizumab has been tested in ovarian cancer where it has shown improvement in progression-free survival but not in overall survival. and glioblastoma multiforme where it failed to improve overall survival.Bevacizumab has been investigated as a possible treatment of pancreatic cancer, as an addition to chemotherapy, but studies have shown no improvement in survival. It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.The drug has also undergone trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma, and other sarcomas, such as leiomyosarcoma.Bevacizumab has been studied as a treatment for cancers that grow from the nerve connecting the ear and the brain. References Further reading Berenson A (15 February 2006). "A Cancer Drug Shows Promise, at a Price That Many Cant Pay". The New York Times. Sachdev JC, Jahanzeb M (October 2008). "Evolution of bevacizumab-based therapy in the management of breast cancer". Clinical Breast Cancer. 8 (5): 402–10. doi:10.3816/CBC.2008.n.048. PMID 18952553. External links "Bevacizumab". Drug Information Portal. U.S. National Library of Medicine. "Bevacizumab". National Cancer Institute. 5 October 2006. "Bevacizumab". NCI Drug Dictionary.
Estradiol cypionate	Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in cis women, in hormone therapy for trans women, and in hormonal birth control for cis women. It is given by injection into muscle once every 1 to 4 weeks.Side effects of estradiol cypionate include breast tenderness, breast enlargement, nausea, headache, and fluid retention. Estradiol cypionate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. Estradiol cypionate is an estrogen ester and a long-lasting prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.Estradiol cypionate was first described as well as introduced for medical use in 1952. Along with estradiol valerate, it is one of the most commonly used esters of estradiol. Estradiol cypionate has mostly been used in the United States, but is also marketed in a few other countries. The medication is not available in Europe. It is not currently available as a generic medication in the United States. Medical uses The medical uses of estradiol cypionate are the same as those of estradiol and other estrogens. Examples of indications for the drug include hormone therapy and hormonal contraception. In regard to the latter, estradiol cypionate has been used in combination with medroxyprogesterone acetate as a combined injectable contraceptive. Along with estradiol valerate, estradiol undecylate, and estradiol benzoate, estradiol cypionate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women. The medication has been used to induce puberty in girls with delayed puberty due to hypogonadism.Estradiol cypionate is usually used at a dosage of 1 to 5 mg by intramuscular injection every 3 to 4 weeks in the treatment of menopausal symptoms such as hot flashes and vaginal atrophy, at a dosage of 1.5 to 2 mg by intramuscular injection once a month in the treatment of female hypoestrogenism due to hypogonadism, and at a dosage of 2 to 10 mg by intramuscular injection once every 1 or 2 weeks for hormone therapy in transgender women. The doses used to induce puberty in girls are 0.2 to 2.5 mg per month, gradually increased over a period of 4 years. Available forms Estradiol cypionate is and has been available as an oil solution for intramuscular injection provided in vials and ampoules at concentrations of 1, 3, and 5 mg/mL (and containing 5, 10, 15, 25, or 50 mg estradiol cypionate total). The 1 and 3 mg/mL concentrations (containing 5 and 15 mg estradiol cypionate total) have been discontinued in the United States, but the 5 mg/mL concentration (containing 25 mg estradiol cypionate total) remains available. Aside from estradiol cypionate, the only other injectable estrogen formulations that remain available in the United States are estradiol valerate (10 mg/mL, 20 mg/mL, and 40 mg/mL in oil) and conjugated estrogens (25 mg/vial in solution).In addition to single-drug formulations, estradiol cypionate has been marketed in combination with medroxyprogesterone acetate as a microcrystalline aqueous suspension (brand name Lunelle) and in combination with testosterone cypionate as an oil solution (brand name Depo-Testadiol). Contraindications Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others. Side effects The side effects of estradiol cypionate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, vomiting, bloating, edema, headache, migraine, and melasma. High-dose estrogen therapy with estradiol cypionate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin. Overdose Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage. Interactions Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels. Pharmacology Pharmacodynamics Estradiol cypionate is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. The affinity of estradiol valerate for the estrogen receptor has been reported to be 50 times less than that of estradiol, and estradiol valerate and estradiol cypionate have been found to possess similar affinity for the estrogen receptor. Both estradiol cypionate and estradiol valerate are rapidly cleaved into estradiol in the body, and estradiol valerate has been found to be unable to reach target tissues in any concentration of significance. As such, estradiol valerate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol, and estradiol cypionate is described as a prodrug of estradiol similarly. Estradiol cypionate is of about 46% higher molecular weight than estradiol due to the presence of its C17β cypionate ester, and contains about 69% of the amount of estradiol by weight. Because estradiol cypionate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen. Effects on liver protein synthesis A study compared the combination of 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate as a combined injectable contraceptive (which has been associated with peak estradiol levels of around 300 pg/mL) with an ethinylestradiol-containing combined birth control pill and found that whereas the birth control pill produced significant changes in coagulation parameters, there were no significant prothrombotic effects of the combined injectable contraceptive on levels of fibrinogen, factors VII and X, plasminogen, or the activated prothrombin time. As such, it appears that similarly to depot medroxyprogesterone acetate, combined injectable contraceptives with 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate have less or no procoagulant effect relative to combined birth control pills. Pharmacokinetics Intramuscular injection In contrast to oral administration, which is associated with very low bioavailability (<10%), the bioavailability of both estradiol and estradiol esters like estradiol valerate is complete (i.e., 100%) via intramuscular injection. In addition, estradiol esters like estradiol cypionate and estradiol valerate when given as an injection of oil solution or microcrystalline aqueous suspension have a relatively long duration due to the formation of an intramuscular depot from which they are slowly released and absorbed. Upon intramuscular injection of estradiol cypionate in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection. In addition, a secondary depot may be formed in adipose tissue. The slow release of estradiol cypionate from the tissue depot is caused by the high lipophilicity of the estradiol ester, which in turn is due to its long fatty acid cypionic acid ester moiety. Estradiol cypionate is formulated for use alone and in combination with testosterone cypionate as an oil solution, and for use in combination with medroxyprogesterone acetate as a microcrystalline aqueous suspension. Aqueous suspensions of steroid esters generally have longer durations by intramuscular injection than oil solutions.A single intramuscular injection of 5 mg estradiol cypionate has been found to result in peak circulating concentrations of 338 pg/mL estradiol and 145 pg/mL estrone, which occurred at about 4 and 5 days post-injection, respectively (see right table). Compared to two other commonly used estradiol esters (which were also assessed in the study), estradiol cypionate had the longest duration, at approximately 11 days, whereas estradiol benzoate and estradiol valerate were found to last for 4 to 5 days and 7 to 8 days, respectively. This is because estradiol cypionate has a more extensive fatty acid chain and in relation to this is comparatively more lipophilic. For a given estradiol ester, the longer or more extensive the fatty acid chain is, the more lipophilic, longer-lasting, and more uniform/plateau-like the resultant levels of estradiol are as well as the lower the peak/maximal levels are (and hence less spike-like).Estradiol cypionate/medroxyprogesterone acetate (brand names Lunelle, Cyclofem) is a combined injectable contraceptive containing 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate in microcrystalline aqueous suspension for once-monthly intramuscular administration. With this formulations, estradiol levels peak 2 to 3 days post-injection with average maximal circulating levels of about 250 pg/mL. The elimination half-life of estradiol with these formulations is 8.4 to 10.1 days, and circulating estradiol levels return to a baseline of about 50 pg/mL approximately 14 to 24 days post-injection. Subcutaneous injection Estradiol cypionate in a microcrystalline aqueous suspension has been found to have equivalent effectiveness and virtually identical pharmacokinetics when administered by subcutaneous injection versus intramuscular injection. However, subcutaneous injection is considered to be easier and less painful relative to intramuscular injection, and for these reasons, may result in comparatively greater satisfaction and compliance. Chemistry Estradiol cypionate is a synthetic estrane steroid and the C17β cyclopentylpropionate (cypionate) fatty acid ester of estradiol. It is also known as estra-1,3,5(10)-triene-3,17β-diol 17β-cyclopentylpropionate. Other common esters of estradiol in use include estradiol valerate, estradiol enantate, and estradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol cypionate and the latter of which is the C3 acetate ester of estradiol. The experimental octanol/water partition coefficient (logP) of estradiol cypionate is 6.9. History Estradiol cypionate was patented by Upjohn in 1952, with a priority date of 1951. It was first introduced for medical use by Upjohn in 1952 under the brand name Depo-Estradiol in the United States. Subsequently, it was also marketed in other countries such as European countries and Japan. The first clinical reports of estradiol cypionate were published in 1952 and thereafter. It was initially known as estradiol cyclopentylpropionate (ECP), and did not become known as estradiol cypionate until over a decade later in the mid-to-late 1960s. Along with estradiol valerate (1954) and estradiol benzoate (1933), estradiol cypionate has become one of the most commonly used esters of estradiol.When estradiol cypionate was to be combined with medroxyprogesterone acetate as a once-a-month injectable contraceptive, there was a problem in that estradiol cypionate was prepared as an oil solution while medroxyprogesterone acetate was used as a microcrystalline aqueous suspension. This issue was resolved by switching to a microcrystalline aqueous suspension in the case of estradiol cypionate, allowing it to be combined with medroxyprogesterone acetate in a single suspension. As a result, single-drug preparations of estradiol cypionate are oil solutions, while the combination of estradiol cypionate and medroxyprogesterone acetate are microcrystalline aqueous suspensions. Society and culture Generic names Estradiol cypionate is the generic name of the drug and its INN and USAN. It is also known as estradiol cyclopentylpropionate (ECP). Brand names Estradiol cypionate has been marketed under the brand names Cicloestradiolo, D-Est, depGynogen, Depo-Estradiol, Depoestra, Depofemin, Depogen, Dura-Estrin, E-Cypionate, E-Ionate, Estradep, Estro-Cyp, Estrofem, Estroject, Estromed-PA, Estronol, Femovirin, Neoginon Depositum, Oestradiol-Retard, Pertradiol, Spendepiol, and T-E Cypionate, among others. Availability Estradiol cypionate is available in the United States. It was previously marketed in Spain and Italy, but was discontinued in these countries and is no longer available in Europe. Estradiol cypionate has mostly been used in the United States, similarly to testosterone cypionate, with both of these medications having been developed by Upjohn, an American pharmaceutical company. Besides the United States, estradiol cypionate has been marketed in France, Germany, Italy, Spain, and Japan, among other countries. Estradiol cypionate is not available in Canada, although it is marketed in several veterinary formulations in this country.Estradiol cypionate is available in Taiwan in combination with testosterone cypionate. It is also available as a combined injectable contraceptive in combination with medroxyprogesterone acetate in at least 18 countries, mostly in Latin America and Southeast Asia. Estradiol cypionate/testosterone cypionate and estradiol cypionate/medroxyprogesterone acetate were both formerly marketed in the United States, but have been discontinued in this country. See also Estradiol cypionate/medroxyprogesterone acetate Estradiol cypionate/testosterone cypionate == References ==
Mepron	Mepron may refer to: Mepron, a brand name of the medication atovaquone Mepron (rumen-protected methionine), a trademarked source of methionine used in dairy cattle
Pegcetacoplan	Pegcetacoplan, sold under the brand name Empaveli among others, is a medication used to treat paroxysmal nocturnal hemoglobinuria (PNH).The most common side effects include injection-site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells).Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to and inhibits complement protein C3. Pegcetacoplan was approved for medical use in the United States in May 2021. Pegcetacoplan binds to complement protein C3 and its activation fragment C3b with high affinity, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. Medical uses Pegcetacoplan is indicated to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is only available for patients who are under the special REMS program. Two weeks before receiving pegcetacoplan, patients must receive vaccinations for pneumonia, meningitis, or influenza type B. Patients who have been vaccinated in the past may still need to get vaccinated two weeks before initiation of the medication. Pharmacology Patients with PNH have greater and uninhibited complement activity, which may leads to intravascular (inside blood vessels) or extravascular (within the liver or spleen) hemolysis. Adverse effects Meningococcal (a type of bacteria) infections can occur in people taking pegcetacoplan and can become life-threatening or fatal if not treated early. Pegcetacoplan may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria. These infections include but are not limited to Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Patients should contact their healthcare team right if way if they experience muscle pain with flu-like symptoms, fever, rash, headache, clammy skin, extreme pain, fast heartbeats, and eye sensitivity to light. Common adverse effects associated with the medication include nausea, diarrhea, cold sores, common-cold like symptoms, tiredness as well as any itching, redness, or sensitivity at the injection site. Pegcetacoplan may cause fetal harm so it should be avoided in pregnant patients. Pegcetacoplan may also interfere with silica reagents in coagulation panels, that can result in patients demonstrating a falsely prolonged activated partial thromboplastin time (aPTT). History The effectiveness of pegcetacoplan was evaluated in a study enrolling 80 participants with paroxysmal nocturnal hemoglobinuria and anemia who had been taking eculizumab, a treatment previously approved for paroxysmal nocturnal hemoglobinuria. Society and culture Legal status On 14 October 2021, 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 Aspaveli, intended for the treatment of adults with paroxysmal nocturnal hemoglobinuria. The applicant for this medicinal product is Swedish Orphan Biovitrum AB (publ). Pegcetacoplan was approved for medical use in the European Union in December 2021. References This article incorporates public domain material from the United States Department of Health and Human Services. External links "Pegcetacoplan". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03500549 for "Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)" at ClinicalTrials.gov
Istradefylline	Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinsons disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patients medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.Relatively common side effects include involuntary muscle movements (dyskinesia), constipation, hallucinations, dizziness and, much like its parent molecule caffeine, nausea and sleeplessness.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Mechanism of action Istradefylline is a selective antagonist at the adenosine A2A receptor (A2AR), but the precise mechanism by which it exerts its therapeutic effect in Parkinsons disease is unknown. However, it is known that dimers of these receptors form heterotetramers with the dimers of dopamine D2 receptors (D2R) within striatum. Adenosine acts as an endogenous A2AR agonist, but also as a negative allosteric modulator (NAM) within these tetramers towards D2Rs, thus inhibiting the D2R mediated effects of dopamine, an endogenous D2R agonist. Istradefylline is believed to bind an A2AR within an A2AR-D2R-tetramer and function as a NAM towards the other A2AR (instead of D2R), thus inhibiting the effects of adenosine and enhancing the movement (locomotion) promoting effects exerted by dopamine via D2R. However, at high istradefylline concentration, it causes locomotion depression akin to caffeine (which is a broad-spectrum adenosine receptor antagonist), and might do so by displacing adenosine, and working as a NAM towards D2R (instead of A2AR). History It was first approved in Japan in 2013.The effectiveness of Nourianz in treating "off" episodes in patients with Parkinsons disease who are already being treated with levodopa/carbidopa was shown in four 12-week placebo-controlled clinical studies that included a total of 1,143 participants. In all four studies, people treated with Nourianz experienced a statistically significant decrease from baseline in daily "off" time compared to patients receiving a placebo.It was approved for medical use in the United States in 2019. and approval was granted to Kyowa Kirin, Inc. References External links "Istradefylline". Drug Information Portal. U.S. National Library of Medicine.
Meloxicam	Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory medication (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is used by mouth or by injection into a vein. It is recommended that it be used for as short a period as possible and at a low dose.Common side effects include abdominal pain, dizziness, swelling, headache, and a rash. Serious side effects may include heart disease, stroke, kidney problems, and stomach ulcers. Use is not recommended in the third trimester of pregnancy. It blocks cyclooxygenase-2 (COX-2) more than it blocks cyclooxygenase-1 (COX-1). It is in the oxicam family of chemicals and is closely related to piroxicam.Meloxicam was patented in 1977 and approved for medical use in the United States in 2000. It was developed by Boehringer Ingelheim; however, it is also available as a generic medication. In 2020, it was the 28th most commonly prescribed medication in the United States, with more than 19 million prescriptions. An intravenous version of meloxicam (Anjeso) was approved for medical use in the United States in February 2020. Adverse effects Meloxicam use can result in gastrointestinal toxicity and bleeding, headaches, rash, and very dark or black stool (a sign of intestinal bleeding). Like other NSAIDs, its use is associated with an increased risk of cardiovascular events such as heart attack and stroke. It has fewer gastrointestinal side effects than diclofenac, piroxicam, naproxen, and perhaps all other NSAIDs which are not COX-2 selective. Although meloxicam inhibits formation of thromboxane A, it does not appear to do so at levels that would interfere with platelet function.A pooled analysis of randomized, controlled studies of meloxicam therapy of up to 60 days duration found that meloxicam was associated with a statistically significantly lower number of thromboembolic complications than the NSAID diclofenac (0.2% versus 0.8% respectively) but a similar incidence of thromboembolic events to naproxen and piroxicam.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 People with hypertension, high cholesterol, or diabetes are at risk for cardiovascular side effects. People with family history of heart disease, heart attack, or stroke should tell their treating physician as the potential for serious cardiovascular side effects is significant. Gastrointestinal NSAIDs cause and increase the risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events. Mouth It is recommended to withhold meloxicam use for at least four to six half-lives prior to surgical or dental procedures due to increased risk for taste perversion, ulcerative stomatitis and dry mouth. Mechanism of action Meloxicam blocks cyclooxygenase (COX), the enzyme responsible for converting arachidonic acid into prostaglandin H2—the first step in the synthesis of prostaglandins, which are mediators of inflammation. Meloxicam has been shown, especially at low therapeutic doses, to selectively inhibit COX-2 over COX-1.Meloxicam concentrations in synovial fluid range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown, but it may account for the fact that it performs exceptionally well in treatment of arthritis in animal models. Pharmacokinetics Absorption The bioavailability of meloxicam is decreased when administered orally compared to an equivalent IV bolus dose. Use of oral meloxicam following a high-fat breakfast increases the mean peak drug levels by about 22%; however, the manufacturer does not make any specific meal recommendations. In addition, the use of antacids does not show pharmacokinetic interactions. Distribution The mean volume of distribution of meloxicam is approximately 10L. It is highly protein-bound, mainly to albumin. Metabolism Meloxicam is extensively metabolized in the liver by the enzymes CYP2C9 and CYP3A4 (minor) into four inactive metabolites. Peroxidase activity is thought to be responsible for the other two remaining metabolites. Excretion Meloxicam is predominantly excreted in the form of metabolites and occurs to equal extents in the urine and feces. Traces of unchanged parent drug are found in urine and feces. The mean elimination half-life ranges from 15 to 20 hours. Specific populations Geriatrics Use of meloxicam is not recommended in people with peptic ulcer disease or increased gastrointestinal bleed risk, including those over 75 years of age or those taking medications associated with bleeding risk. Adverse events have been found to be dose-dependent and associated with length of treatment. Veterinary use Meloxicam is used in veterinary medicine to treat dogs, but also sees off-label use in other animals such as cattle and exotics.The most common side effects include gastrointestinal irritation (vomiting, diarrhea, and ulceration).In healthy dogs given meloxicam, no perioperative adverse effects on the cardiovascular system have been reported at recommended dosages. Perioperative administration of meloxicam to cats did not affect postoperative respiratory rate nor heart rate.A peer-reviewed journal article cites NSAIDs, including meloxicam, as causing gastrointestinal upset and, at high doses, acute kidney injury and CNS signs such as seizures and comas in cats. It adds that cats have a low tolerance for NSAIDs.No decline in renal excretory function was observed when meloxicam was administered to cats with chronic kidney disease. Cats that received meloxicam had greater proteinuria at 6 months than cats that received placebo. It was concluded that meloxicam should be used with caution in cats with chronic kidney disease.Meloxicam has been investigated as an alternative to diclofenac by the Royal Society for the Protection of Birds (RSPB) to prevent deaths of vultures. Pharmacokinetics In dogs, the absorption of meloxicam from the stomach is not affected by the presence of food, with the peak concentration (Cmax) of meloxicam occurring in the blood 7–8 hours after administration. The half-life of meloxicam is approximately 24 hours in dogs.In the koala (Phascolarctos cinereus), very little meloxicam is absorbed into the blood after oral administration (that is, it has poor bioavailability). Legal status United States In 2003, meloxicam was approved in the U.S. for use in dogs for the management of pain and inflammation associated with osteoarthritis, as an oral (liquid) formulation of meloxicam. In January 2005, the product insert added a warning in bold-face type: "Do not use in cats." An injectable formulation for use in dogs was approved by the U.S. Food and Drug Administration (FDA) in November 2003.In October 2004, a formulation for use in cats was approved for use prior to surgery only. This is an injectable meloxicam, indicated for as a single, one-time dose only, with specific and repeated warnings not to administer a second dose.In 2005, the FDA sent a Notice of Violation to the manufacturer for its promotional materials which included promotion of the drug for off-label use.In February 2020, meloxicam injection was approved for use in the United States. The FDA granted the approval of Anjeso to Baudax Bio. European Union In Europe the product is licensed for other anti-inflammatory benefits including relief from both acute and chronic pain in dogs. Meloxicam is also licensed for use in horses, to relieve the pain associated with musculoskeletal disorders.Meloxicam was authorised for use in cattle throughout the European Union in January 1998, via a centralised marketing authorisation. The first generic meloxicam product was approved in 2006. Other countries As of June 2008, meloxicam is registered for long-term use in cats in Australia, New Zealand, and Canada. See also Bupivacaine/meloxicam References External links "Meloxicam". Drug Information Portal. U.S. National Library of Medicine.
Doral	Doral may refer to: Places Doral, Florida, US, a suburb of Miami Brands and enterprises Doral (cigarette) Doral, a trade name for ergocalciferol, vitamin D2 Doral, a trade name for the sleep medicine quazepam Doral Financial Corporation, in Puerto Rico Doral Hotel, a hotel in nearby Miami Beach; now the Miami Beach Resort and Spa Trump National Doral Miami, a golf resort in Doral, Florida Other uses Cylon (Battlestar Galactica)#Number Five (Aaron Doral), a character in the re-imagined Battlestar Galactica TV series Doral Open, a golf tournament held in Doral, Florida Doral t Giuk Dorali aka The Doral is a character in Robert A. Heinleins Glory Road Ronald W Reagan/Doral High School, in Doral, Florida
Segesterone acetate/ethinylestradiol	Segesterone acetate/ethinylestradiol (EE/SGA), sold under the brand name Annovera, is a contraceptive vaginal ring and combined form of hormonal birth control which contains segesterone acetate, a progestin and ethinylestradiol, an estrogen. It contains 17.4 mg ethinylestradiol and 103 mg segesterone acetate, releases an average of 13 μg ethinylestradiol and 0.15 mg segesterone acetate per day.Annovera is inserted into the vagina and left for 21 days, then removed, washed and stored for seven days, during which the user experiences a period (withdrawal bleeding.) This can be repeated thirteen times, for one full year of use. Unlike NuvaRing, another vaginal ring contraceptive, Annovera does not need to be refrigerated before being dispensed and can be stored at temperatures up to 30 degrees Celsius.The medication was developed by the Population Council, an international non-profit organization, and licensed to TherapeuticsMD. It was approved for medical use in the United States in August 2018. See also Combined injectable birth control § Available forms List of combined sex-hormonal preparations References External links "Segesterone acetate". Drug Information Portal. U.S. National Library of Medicine. "Ethinylestradiol". Drug Information Portal. U.S. National Library of Medicine.
Nabilone	Nabilone, sold under the brand name Cesamet among others, is a synthetic cannabinoid with therapeutic use as an antiemetic and as an adjunct analgesic for neuropathic pain. It mimics tetrahydrocannabinol (THC), the primary psychoactive compound found naturally occurring in Cannabis.The Food and Drug Administration in the United States has indicated nabilone for chemotherapy-induced nausea/vomiting. In other countries, such as Canada, it is widely used as an adjunct therapy for chronic pain management. Numerous trials and case studies have demonstrated modest effectiveness for relieving fibromyalgia and multiple sclerosis. Medical uses Nabilone is used to treat nausea and vomiting in people under chemotherapy.Nabilone has shown modest effectiveness in relieving fibromyalgia. A 2011 systematic review of cannabinoids for chronic pain determined there was evidence of safety and modest efficacy for some conditions.The main settings that have seen published clinical trials of nabilone include movement disorders such as parkinsonism, chronic pain, dystonia and spasticity neurological disorders, multiple sclerosis, and the nausea of cancer chemotherapy. Nabilone is also effective in the treatment of inflammatory bowel disease, especially ulcerative colitis. In one study of current daily users of cannabis, oral nabilone at 4, 6, and 8 mg produced sustained and dose-dependent mood elevation and psychomotor slowing comparable to 10 or 20 mg oral dronabinol (THC). Nabilone had a slower onset of peak action and a greater dose-dependence of effects, which the investigators attributed to greater bioavailability. A study comparing nabilone with metoclopramide, conducted before the development of modern 5-HT3 antagonist anti-emetics such as ondansetron, revealed that patients taking cisplatin chemotherapy preferred metoclopramide, while patients taking carboplatin preferred nabilone to control nausea and vomiting.Nabilone is sometimes used for nightmares in post-traumatic stress disorder, but there have not been studies longer than nine weeks, so effects of longer-term use are not known. Nabilone has also been used for medication overuse headache. Side effects Nabilone can increase – rather than decrease – postoperative pain. In the treatment of fibromyalgia, adverse effects limit the useful dose. Adverse effects of nabilone include, but are not limited to: dizziness/vertigo, euphoria, drowsiness, dry mouth, ataxia, sleep disturbance, dysphoria, headache, nausea, disorientation, depersonalization, and asthenia. Pharmacology Pharmacokinetics Nabilone is given in 1 or 2 mg doses multiple times a day up to a total of 6 mg. It is completely absorbed from oral administration and highly plasma protein bound. Multiple cytochrome P450 enzymes extensively metabolize nabilone to various metabolites that have not been fully characterized. Chemistry Nabilone is a racemic mixture consisting of (S,S)-(+)- and (R,R)-(−)-isomers. History Nabilone was originally developed by Eli Lilly and Company; Lilly received FDA approval in 1985 to market it, but withdrew that approval in 1989 for commercial reasons. Valeant Pharmaceuticals acquired the rights from Lilly in 2004. Valeant tried and failed to get the medication approved in 2005 and then succeeded in 2006.In 2007, Valeant acquired the United Kingdom and European Union rights to market nabilone from Cambridge Laboratories.Nabilone was approved in Austria to treat chemotherapy-induced nausea in 2013; it was already approved in Spain for the same indication and was legal in Belgium to treat glaucoma, spasticity in multiple sclerosis, wasting due to AIDS, and chronic pain. See also List of investigational analgesics == References ==
Interferon beta-1a	Interferon beta-1a (also interferon beta 1-alpha) is a cytokine in the interferon family used to treat multiple sclerosis (MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified E. coli. Some research indicates that interferon injections may result in an 18–38% reduction in the rate of MS relapses.Interferon beta has not been shown to slow the advance of disability. Interferons are not a cure for MS (there is no known cure); the claim is that interferons may slow the progress of the disease if started early and continued for the duration of the disease. Medical uses Clinically isolated syndrome The earliest clinical presentation of relapsing-remitting multiple sclerosis is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of demyelination which should be included in the spectrum of MS phenotypes. Treatment with interferons after an initial attack decreases the risk of developing clinical definite MS. Relapsing-remitting MS Medications are modestly effective at decreasing the number of attacks in relapsing-remitting multiple sclerosis and in reducing the accumulation of brain lesions, which is measured using gadolinium-enhanced magnetic resonance imaging (MRI). Interferons reduce relapses by approximately 30% and their safe profile make them the first-line treatments. Nevertheless, not all the patients are responsive to these therapies. It is known that 30% of MS patients are non-responsive to Beta interferon. They can be classified in genetic, pharmacological and pathogenetic non-responders. One of the factors related to non-respondance is the presence of high levels of interferon beta neutralizing antibodies. Interferon therapy, and specially interferon beta 1b, induces the production of neutralizing antibodies, usually in the second 6 months of treatment, in 5 to 30% of treated patients. Moreover, a subset of RRMS patients with specially active MS, sometimes called "rapidly worsening MS" are normally non-responders to interferon beta 1a.While more studies of the long-term effects of the drugs are needed, existing data on the effects of interferons indicate that early-initiated long-term therapy is safe and it is related to better outcomes. Side effects Interferon beta-1a is available only in injectable forms, and can cause skin reactions at the injection site that may include cutaneous necrosis. Skin reactions with interferon beta are more common with subcutaneous administration and vary greatly in their clinical presentation. They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of treatment. Skin reactions are more prevalent in women. Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy. Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop, however, this rarely occurs with interferon treatment.Interferons, a subclass of cytokines, are produced in the body during illnesses such as influenza in order to help fight the infection. They are responsible for many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches. Many patients report influenza-like symptoms hours after taking interferon beta that usually improve within 24 hours, being such symptoms related to the temporary increase of cytokines. This reaction tends to disappear after 3 months of treatment and its symptoms can be treated with over-the-counter nonsteroidal anti-inflammatory drugs, such as ibuprofen, that reduce fever and pain. Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease. Such deterioration is similar to the one produced in MS patients due to heat, fever or stress (Uhthoffs phenomenon), usually appears within 24 hours of treatment, is more common in the initial months of treatment, and may last several days. A symptom specially sensitive to worsening is spasticity. Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function. In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment. Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.To help prevent injection-site reactions, patients are advised to rotate injection sites and use an aseptic injection technique. Injection devices are available to optimize the injection process. Side effects are often onerous enough that many patients ultimately discontinue taking interferons (or glatiramer acetate, a comparable disease-modifying therapy requiring regular injections). Mechanism of action Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood brain barrier. Overall, therapy with interferon beta leads to a reduction of neuron inflammation. Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival. In vitro, interferon beta reduces production of Th17 cells which are a subset of T lymphocytes believed to have a role in the pathophysiology of MS. Society and culture Brand names Avonex Avonex was approved in the US in 1996, and in the European Union in 1997, and is registered in more than 80 countries worldwide. It is the leading MS therapy in the US, with around 40% of the overall market, and in the European Union, with around 30% of the overall market. It is produced by the Biogen biotechnology company, originally under competition protection in the US under the Orphan Drug Act. Avonex is sold in three formulations, a lyophilized powder requiring reconstitution, a pre-mixed liquid syringe kit, and a pen; it is administered via intramuscular injection. Rebif Rebif is a disease-modifying drug (DMD) used to treat multiple sclerosis in cases of clinically isolated syndromes as well as relapsing forms of multiple sclerosis and is similar to the interferon beta protein produced by the human body. It is co-marketed by Merck Serono and Pfizer in the US under an exception to the Orphan Drug Act. It was approved in the European Union in 1998, and in the US in 2002; it has since been approved in more than 90 countries worldwide including Canada and Australia. EMD Serono has had sole rights to Rebif in the US since January 2016. Rebif is administered via subcutaneous injection. Cinnovex Cinnovex is the brand name of recombinant Interferon beta-1a, which is manufactured as biosimilar/biogeneric in Iran. It is produced in a lyophilized form and sold with distilled water for injection. Cinnovex was developed at the Fraunhofer Society in collaboration with CinnaGen, and is the first therapeutic protein from a Fraunhofer laboratory to be approved as biogeneric / biosimilar medicine. There are several clinical studies to prove the similarity of CinnoVex and Avonex. A more water-soluble variant is currently being investigated by the Vakzine Projekt Management (VPM) GmbH in Braunschweig, Germany. Plegridy Plegridy is a brand name of a pegylated form of Interferon beta-1a. Plegridys advantage is it only needs injecting once every two weeks. Betaferon (interferon beta-1b) Closely related to interferon beta-1a is interferon beta-1b, which is also indicated for MS, but is formulated with a different dose and administered with a different frequency. Each drug has a different safety/efficacy profile. Interferon beta-1b is marketed only by Bayer in the US as Betaseron, and outside the US as Betaferon. Economics In the United States, as of 2015, the cost is between US$1,284 and US$1,386 per 30 mcg vial. As of 2020, the National Average Drug Acquisition Cost (NADAC) in the United States for Avonex was $6,872.94 for a 30 mcg kit.Avonex and Rebif are on the top ten best-selling multiple sclerosis drugs of 2013:It is an example of a specialty drug that would only be available through a specialty pharmacy. This is because it requires a refrigerated chain of distribution and costs $17,000-a-year. Research COVID-19 Interferon beta-1a administered subcutaneously or intravenously was investigated since March 2020 as a potential treatment in patients hospitalized with COVID-19 in a multinational Solidarity trial (initially in combination with lopinavir) but it did not reduce in-hospital mortality compared to local standard of care.SNG001, an inhalation formulation of interferon beta-1a, is being developed as a treatment for COVID-19 by Synairgen. A pilot trial in hospitalized patients showed higher odds of clinical improvement with SNG001 compared to placebo and in January 2021 a phase 3 trial in this population started. References External links "Interferon beta-1a". Drug Information Portal. U.S. National Library of Medicine. "Interferon Beta-1a Intramuscular Injection". MedlinePlus.
Ketotifen	Ketotifen, sold under the brand name Zaditor among others, is a second-generation noncompetitive H1-antihistamine and mast cell stabilizer. It is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms. In its ophthalmic form, it is used to treat allergic conjunctivitis. In its oral form, it is used to prevent asthma attacks or anaphylaxis, as well as various mast cell, allergic-type disorders.It was patented in 1970 and came into medical use in 1976. Medical uses Ketotifen relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies. It starts working within minutes after administering the drops. The drug has not been studied in children under three. The mean elimination half life is 12 hours. Besides its anti-histaminic activity, it is also a functional leukotriene antagonist and a phosphodiesterase inhibitor."[O]ral ketotifen has been used in patients with asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, chronic urticaria, cold-induced urticaria, cholinergic urticaria, exercise-induced urticaria, [systemic mast cell disease including mastocytosis, Mast Cell Activation Syndrome (MCAS), allergic and nonallergic anaphylaxis, angioedema], and food allergy in Canada, Europe, and Mexico." Now available via prescription at US compounding pharmacies: "For adults and older children with asthma or allergic disease, the recommended dose of ketotifen is 1 mg twice daily." "FDA staff did recommend more extensive evaluations for management of urticaria."The drug may also help relieve irritable bowel syndrome. Side effects Side effects of systemic (oral) use include drowsiness, weight gain (11-12lbs), dry mouth, irritability, and increased nosebleeds. Pharmacology Ketotifen is a selective antihistamine – that is, an inverse agonist of the histamine H1 receptor (Ki = 0.166 nM) – and mast cell stabilizer. In addition, ketotifen has weak anticholinergic (Ki = 204 nM for mACh) and antiserotonergic (Ki = 38.9 nM for 5-HT2A) activity. However, at the dosages in which it is typically used clinically, both the anticholinergic and antiserotonergic activity of ketotifen are said not to be appreciable. Society and culture Brand names Ketotifen is marketed under many brand names worldwide. References External links "Ketotifen". Drug Information Portal. U.S. National Library of Medicine.
Propantheline bromide	Propantheline bromide (INN) is an antimuscarinic agent used for the treatment of excessive sweating (hyperhidrosis), cramps or spasms of the stomach, intestines (gut) or bladder, and involuntary urination (enuresis). It can also be used to control the symptoms of irritable bowel syndrome and similar conditions. This agent can also be used for patients who experience intense GI symptoms while tapering off of TCAs. Indications By relaxing the gut muscle, propantheline can relieve pain in conditions caused by spasm of the muscle in the gut. Relaxing the smooth muscle in the bladder prevents the involuntary spasms that can allow leakage of urine from the bladder in the condition known as enuresis (involuntary urination in adults). Propantheline can also be used to treat excessive sweating because acetylcholine block also reduces secretions such as sweat and tears. Adverse effects Side effects include tachycardia, constipation, hypersensitivity to light, dry mouth, and urinary retention. This can also be prescribed by dentists for certain patients who salivate excessively. By giving this medication it becomes easier to do "dry" dentistry. Mechanism of action Propantheline is one of a group of antispasmodic medications which work by blocking the action of the chemical messenger acetylcholine, which is produced by nerve cells, to muscarinic receptors present in various smooth muscular tissues, in places such as the gut, bladder and eye. Normally, the binding of acetylcholine induces involuntary smooth muscular contractions. == References ==

Subsets and Splits

No saved queries yet

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