page_title
stringlengths 1
91
| page_text
stringlengths 0
34.2k
|
|---|---|
Sitagliptin/simvastatin | Sitagliptin/simvastatin, sold under the brand name Juvisync, is a fixed-dose combination anti-diabetic medication used to treat type 2 diabetes and hypercholesterolemia. It contains sitagliptin and simvastatin. Sitagliptin is a dipeptidyl peptidase-4 inhibitor and simvastatin is an HMG-CoA reductase inhibitor. These two disorders commonly occur in people at the same time, and have been typically treated with administration of these medications separately. The combination was approved in 2011, and sold under the brand name Juvisync by Merck. Juvisync was later removed from the market in 2013, due to business reasons.
History
In 1991, Merck & Cos simvastatin was approved as an HMG-COA inhibitor to lower the levels of LDL cholesterol. In 2006, Merck & Cos sitagliptin was approved by the FDA for treatment of diabetes mellitus type 2.
Regulation
Juvisync was the first product to combine a cholesterol lowering drug with a type 2 diabetes drug in the same tablet.
Nonclinical toxicology
Sitagliptin: Using male and female rats, a two-year carcinogenicity study was carried out with doses of 50, 150, and 500 mg/kg/day. The 500 mg/kg dose has exposure limits of 60 times what would be seen in the highest dose in humans. At this dose, liver adenoma/carcinoma was seen. Tumors were not seen from the smaller doses. Nomutagenic or clastogenic effects were seen from tests using several assays (CHO, rat, etc.). Fertility studies in rats showed no teratogenic effects.Simvastatin: No tumorigenic effect was seen in a 72-week carcinogenicity study using mice at the low dose levels. However, at the higher dose levels (eight and 16 times the human dose equivalent), liver carcinomas and adenomas, lung adenomas, and adenomas of the Harderian gland occurred. No mutagenic effects were seen in assays. Testicular atrophy was noted in dogs and rats at four and eight times the human exposure, respectively.
Limitations of use
It should not be used in patients with type 1 diabetes, diabetic ketoacidosis, pancreatitis, Fredrickson types I and V dyslipidemias, and severe renal impairment.
Drug interactions
Juvisync should not be used with: strong CYP3A4 inhibitors, cyclosporine, danazol, gemfibrozil, and other fibrates. Caution should be used and the patient should be monitored if they are taking the following: amiodarone, dronedarone, ranolazine, calcium channel blockers, niacin, digoxin, coumarin anticoagulants, and colchicine.
References
External links
"Juvisync". Drug Information Portal. U.S. National Library of Medicine. |
Plasminogen (medication) | Plasminogen, sold under the brand name Ryplazim, is a biologic medication for the treatment of hypoplasminogenemia (plasminogen deficiency type 1). It is purified from human plasma and is administered intravenously.The most common side effects include abdominal pain, bloating, nausea, bleeding, limb pain, fatigue, constipation, dry mouth, headache, dizziness, joint pain, and back pain.Individuals with hypoplasminogenemia lack a protein called plasminogen, which is responsible for the ability of the body to break down fibrin clots. Plasminogen deficiency leads to an accumulation of fibrin, causing the development of growths (lesions) that can impair normal tissue and organ function and may lead to blindness when these lesions affect the eyes.Plasminogen, human-tvmh was approved for medical use in the United States in June 2021. It is the first therapy for hypoplasminogenemia approved by the U.S. Food and Drug Administration (FDA).
Medical uses
Plasminogen, human-tvmh is indicated for the treatment of people with plasminogen deficiency type 1, also referred to as hypoplasminogenemia, a disorder that can impair normal tissue and organ function and may lead to blindness.
History
The effectiveness and safety of plasminogen is primarily based on one single-arm, open-label (unblinded) clinical trial enrolling 15 adult and pediatric participants with plasminogen deficiency type 1. All participants received plasminogen administered every two to four days for 48 weeks. The effectiveness of plasminogen was demonstrated by at least 50% improvement of their lesions in all 11 participants who had lesions at baseline, and absence of recurrent or new lesions in any of the 15 participants through the 48 weeks of treatment.The U.S. Food and Drug Administration (FDA) granted the application for plasminogen orphan drug designation, fast track designation, priority review, and a rare pediatric disease priority review voucher. The FDA granted approval of Ryplazim to ProMetic Biotherapeutics Inc.
References
This article incorporates public domain material from the United States Department of Health and Human Services.
External links
"Plasminogen". Drug Information Portal. U.S. National Library of Medicine. |
Butorphanol | Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.
It was patented in 1971 and approved for medical use in 1979.
Medical uses
The most common indication for butorphanol is management of migraine using the intranasal spray formulation. It may also be used parenterally for management of moderate-to-severe pain, as a supplement for balanced general anesthesia, and management of pain during labor. Butorphanol is also quite effective at reducing post-operative shivering (owing to its Kappa agonist activity). Butorphanol is more effective in reducing pain in women than in men.
Pharmacology
Butorphanol exhibits partial agonist and antagonist activity at the μ-opioid receptor, as well as partial agonist activity at the κ-opioid receptor (Ki = 2.5 nM; EC50 = 57 nM; Emax = 57%). Stimulation of these receptors on central nervous system neurons causes an intracellular inhibition of adenylate cyclase, closing of influx membrane calcium channels, and opening of membrane potassium channels. This leads to hyperpolarization of the cell membrane potential and suppression of action potential transmission of ascending pain pathways.
Because of its κ-agonist activity, at analgesic doses butorphanol increases pulmonary arterial pressure and cardiac work. Additionally, κ-agonism can cause dysphoria at therapeutic or supertherapeutic doses; this gives butorphanol a lower potential for abuse than other opioid drugs.
Side effects
As with other opioid analgesics, central nervous system effects (such as sedation, confusion, and dizziness) are considerations with butorphanol. Nausea and vomiting are common. Less common are the gastrointestinal effects of other opioids (mostly constipation). Another side effect experienced by people taking the medication is increased perspiration.
Name
Within the INN, USAN, BAN, and AAN naming systems this drug is known as butorphanol, while within JAN it is named torbugesic. As the tartrate salt, butorphanol is known as butorphanol tartrate (USAN, BAN).Its tradename Stadol was recently discontinued by the manufacturer. It is now only available in its generic formulations manufactured by Apotex, Mylan, Novex and Ben Venue Laboratories.
Availability
Butorphanol is available in the U.S. as a generic drug; it is available in various nations under one of any number of trade names, including Moradol and Beforal (Brand name Stadol no longer available in the US); veterinary trade names include Butorphic, Dolorex, Morphasol, Torbugesic, and Torbutrol.
Legality
Butorphanol is listed under the Single Convention on Narcotic Drugs 1961 and in the United States is a Schedule IV Narcotic controlled substance with a DEA ACSCN of 9720; being in Schedule IV it is not subject to annual aggregate manufacturing quotas. The free base conversion ratio of the hydrochloride is 0.69. Butorphanol was originally in Schedule II and at one point it was decontrolled.
Veterinary use
In veterinary anesthesia, butorphanol (trade name: Torbugesic) is widely used as a sedative and analgesic in dogs, cats and horses. For sedation, it may be combined with tranquilizers such as alpha-2 agonists (medetomidine), benzodiazepines, or acepromazine in dogs, cats and exotic animals. It is frequently combined with xylazine or detomidine in horses.Butorphanol is frequently used for post-operative and accident-related pain in small mammals such as dogs, cats, ferrets, coatis, raccoons, mongooses, various marsupials, some rodents and perhaps some larger birds, both in the operating suite and as a regular prescription medication for home use, for management of moderate to severe pain.
Although butorphanol is commonly used for pain relief in reptiles, no studies (as of 2014) have conclusively shown that it is an effective analgesic in reptiles.
Use in horses
Butorphanol is a commonly used narcotic for pain relief in horses. It is administered either IM or IV, with its analgesic properties beginning to take effect about 15 minutes after injection and lasting 4 hours. It is also commonly paired with sedatives, such as xylazine and detomidine, to make the horse easier to handle during veterinary procedures.
Side effects specific to horses include sedation, CNS excitement (displayed by head pressing or tossing). Overdosing may result in seizures, falling, salivation, constipation, and muscle twitching. If an overdose occurs, a narcotic antagonist, such as naloxone, may be given. Caution should be used if butorphanol is administered in addition to other narcotics, sedatives, depressants, or antihistamines as it will cause an additive effect.
Butorphanol can cross the placenta, and it will be present in the milk of lactating mares who are given the drug.
The drug is also prohibited for use in competition by most equestrian organizations, including the FEI, which considers it a class A drug.
See also
Levallorphan
Nalbuphine
Nalfurafine
Nalorphine
Xorphanol
Notes
== References == |
Desloratadine/pseudoephedrine | Desloratadine/pseudoephedrine, sold under the brand name Clarinex-D among others, is a medication used for the treatment of seasonal allergic rhinitis.Desloratadine/pseudoephedrine was approved for use in the United States in 2005 and in the European Union in July 2007.
Medical uses
Desloratadine/pseudoephedrine is indicated for the symptomatic treatment of seasonal allergic rhinitis when accompanied by nasal congestion.
References
Further reading
Anolik R (June 2009). "Desloratadine and pseudoephedrine combination therapy as a comprehensive treatment for allergic rhinitis and nasal congestion". Expert Opin Drug Metab Toxicol. 5 (6): 683–94. doi:10.1517/17425250902980187. PMID 19473112. S2CID 22633518.
External links
"Desloratadine mixture with pseudoephedrine". Drug Information Portal. U.S. National Library of Medicine. |
Digoxin immune fab | Digoxin immune fab or digoxin-specific antibody is an antidote for overdose of digoxin. It is made from immunoglobulin fragments from sheep that have already been immunized with a digoxin derivative, digoxindicarboxymethoxylamine (DDMA). Its brand names include Digibind (GlaxoSmithKline) and DigiFab (BTG plc).
Medical uses
It is used for digoxin toxicity. Digoxin toxicity can emerge during long-term therapy as well as after an overdose. It can occur even when the serum digoxin concentration is within the therapeutic range when one of the following is present:
Hemodynamically unstable arrhythmia
End organ damage
digoxin level > 4 ng/ml if chronic ingestion
digoxin level > 10 ng/ml if acute ingestion
potassium > 5 mEq/L and symptomaticSide effects of digoxin immune fab may occur:
hives
difficult breathing
swelling of the lips, tongue, face, or throat
itching
skin redness
wheezing
cough
lightheadedness
Contraindications
Avoid use in hypokalemia as this drug, while reversing the effects of digitalis, will further reduce serum potassium levels and could precipitate dangerous and even fatal cardiac arrhythmias.
The patient must be closely monitored for anaphylactic shock, and anyone allergic to sheep protein, papain, bromelain, or papaya extracts (papain is used to cleave the antibody into Fab and Fc fragments) should not use ovine digoxin immune fab. Because it is relatively new, no drug interaction studies have been performed yet.
Pharmacology
It works by binding to the digoxin, rendering it unable to bind to its action sites on target cells. The complexes accumulate in the blood and are expelled by the kidney.
Regulatory information and clinical studies
Case series have reported benefits from anti‐digoxin Fab, but data regarding the response in acute or chronic poisoning are conflicting. Recent observational data support an effect in acute poisoning, but efficacy in chronic poisoning be minimally effective in alleviating cardiac toxicities in chronic digoxin poisoning.
Data also support outcomes of acute digoxin poisoning without use of anti‐digoxin Fab. A case series of 147 patients showed that not all cases of acute digoxin overdose require anti‐digoxin Fab, nor should anti‐digoxin Fab dose be calculated based on ingested dose. In contrast, a higher mortality (7.6%) was noted in a case series of acute and chronic digoxin and digitoxin poisoning despite Fab being used first line. Further, a retrospective case‐controlled study of chronic digoxin poisoning did not observe a beneficial effect of anti‐digoxin Fab on mortality.
An RCT (n = 66) in yellow oleander poisoning showed an early improvement in cardiac rhythm and hyperkalaemia from anti‐digoxin Fab, prompting early termination of the trial. It was not powered to detect a change in mortality and no deaths were noted.
As with all foreign proteins, anaphylaxis, serum sickness or febrile reactions are a source of concern, especially with repeated administration. These reactions appear uncommon for example, in a study of 717 adults where only six patients (0.8%) exhibited any evidence of allergic response.
Nevertheless, theoretically, patients previously dependent upon the inotropic effects of digoxin could develop heart failure and hypokalaemia could result within 1–5 hours, owing to intracellular shifts of potassium, as the effects of digoxin are reversed. Patients who require redigitalization must wait for the complexes to be eliminated from the body by the kidneys, this taking 2–3 days with normal renal function. Unfortunately, fab fragments interfere with both fluorescence excitation transfer immunoassays and radioimmunoassays for digoxin. This means that serum drug levels cannot be monitored until the drug-antibody complexes are cleared from the circulation.
Intellectual property
DigiFab is used as an antidote to treat a life-threatening overdose of digoxin or digitoxin. DigiFab is manufactured and distributed by BTG international Inc. under U.S. License No. 186. DigiFab is a sterile, lyophilized preparation of digoxin-immune ovine Fab (monovalent) immunoglobulin fragments. It is prepared by isolating the immunoglobulin fraction of the ovine serum, digesting it with papain and isolating the digoxin-specific Fab fragments by affinity chromatography. These antibody fragments have a molecular weight of approximately 46,000 Da. Each vial of DigiFab, which will bind approximately 0.5 mg digoxin, contains 40 mg of digoxin immune Fab, 75 mg (approx) of mannitol USP, and 2 mg (approx) sodium acetate USP as a buffering agent. The product contains no preservatives and is intended for intravenous administration.
Digibind is manufactured by GlaxoSmithkline, SpA, Parma Italy under US License No. 129. It’s distributed by GSK, Research Triangle park, NC 27709.
A patent to use digoxin immunoglobulins C07k16/44 as a regulator of the preeclamptic/eclamptic patients sodium/potassium ATPase activity was approved in 2003 to Charles David Adair under application number WO2004011028A1.
Commercial aspects
Price increase was reported to range from US $380 to US $750 during 2013 for digoxin-Fab. However, these price increases are not reflective of the United States average AWP for digoxin-Fab as it represents Australian costs converted to US. Prior to 2011, Digibind and DigiFab pricing was US $797 per 38 mg vial and US $786 per 40 mg vial respectively. After GSK discontinued Digibind sale in USA in 2011, the AWP of DigiFab increases by 15% to US $903 per 40 mg vial. AWP of DigiFab has continued to increase as much as 54% occurring in March 2014 to US $2,370 per 40 mg vial. However, the cost may vary depending on wholesaler contractor manufacturer rebates.
References
External links
Drug information online
Digibind description |
Zinc sulfate | Zinc sulfate is an inorganic compound. It is used as a dietary supplement to treat zinc deficiency and to prevent the condition in those at high risk. Side effects of excess supplementation may include abdominal pain, vomiting, headache, and tiredness.The most common form includes water of crystallization as the heptahydrate, with the formula ZnSO4·7H2O. It was historically known as "white vitriol". Zinc sulfate and its hydrates are colourless solids.
Uses
Medicine
In medicine it is used together with oral rehydration therapy (ORT) and an astringent.
Manufacturing
The hydrates, especially the heptahydrate, are the primary forms used commercially. The main application is as a coagulant in the production of rayon. It is also a precursor to the pigment lithopone.
It is also used as an electrolyte for zinc electroplating, as a mordant in dyeing, and as a preservative for skins and leather.
Other
Zinc sulfate is used to supply zinc in animal feeds, fertilizers, toothpaste, and agricultural sprays. Zinc sulfate, like many zinc compounds, can be used to control moss growth on roofs.Zinc sulfate can be used to supplement zinc in the brewing process. Zinc is a necessary nutrient for optimal yeast health and performance, although it is not a necessary supplement for low-gravity beers, as the grains commonly used in brewing already provide adequate zinc. It is a more common practice when pushing yeast to their limit by increasing alcohol content beyond their comfort zone. Before modern stainless steel, brew Kettles, fermenting vessels and after wood, zinc was slowly leached by the use of copper kettles. A modern copper immersion chiller is speculated to provide trace elements of zinc; thus care must be taken when adding supplemental zinc so as not to cause excess. Side effects include "...increased acetaldehyde and fusel alcohol production due to high yeast growth when zinc concentrations exceed 5 ppm. Excess zinc can also cause soapy or goaty flavors."
Zinc sulfate is a potent inhibitor of sweetness perception for most sweet-tasting substances.
Toxicity
Zinc sulfate powder is an eye irritant. Ingestion of trace amounts is considered safe, and zinc sulfate is added to animal feed as a source of essential zinc, at rates of up to several hundred milligrams per kilogram of feed. Excess ingestion results in acute stomach distress, with nausea and vomiting appearing at 2–8 mg/kg of body weight.
Production and reactivity
Zinc sulfate is produced by treating virtually any zinc-containing material (metal, minerals, oxides) with sulfuric acid.Specific reactions include the reaction of the metal with aqueous sulfuric acid:
Zn + H2SO4 + 7 H2O → ZnSO4·7H2O + H2Pharmaceutical-grade zinc sulfate is produced by treating high-purity zinc oxide with sulfuric acid:
ZnO + H2SO4 + 6 H2O → ZnSO4·7H2OIn aqueous solution, all forms of zinc sulfate behave identically. These aqueous solutions consist of the metal aquo complex [Zn(H2O)6]2+ and SO2−4 ions. Barium sulfate forms when these solutions are treated with solutions of barium ions:
ZnSO4 + BaCl2 → BaSO4 + ZnCl2With a reduction potential of −0.76 V, zinc(II) reduces only with difficulty.
When heated above 680 °C, zinc sulfate decomposes into sulfur dioxide gas and zinc oxide fume, both of which are hazardous.
Minerals
As a mineral, ZnSO4•7H2O is known as goslarite. Zinc sulfate occurs as several other minor minerals, such as zincmelanterite, (Zn,Cu,Fe)SO4·7H2O (structurally different from goslarite). Lower hydrates of zinc sulfate are rarely found in nature: (Zn,Fe)SO4·6H2O (bianchite), (Zn,Mg)SO4·4H2O (boyleite), and (Zn,Mn)SO4·H2O (gunningite).
== References == |
Pegvaliase | Pegvaliase, sold under the brand name Palynziq, is a medication for the treatment of the genetic disease phenylketonuria. Chemically, it is a pegylated derivative of the enzyme phenylalanine ammonia-lyase that metabolizes phenylalanine to reduce its blood levels.It was approved by the Food and Drug Administration for use in the United States in 2018. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
References
External links
"Pegvaliase". Drug Information Portal. U.S. National Library of Medicine. |
Tramadol | Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).
As is typical of opioids, common side effects include constipation, itchiness, and nausea. Serious side effects may include hallucinations, seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. A change in dosage may be recommended in those with kidney or liver problems. It is not recommended in those who are at risk of suicide or in those who are pregnant. While not recommended in women who are breastfeeding, those who take a single dose should not generally stop breastfeeding. Tramadol is converted in the liver to O-desmethyltramadol (desmetramadol), an opioid with a stronger affinity to the μ-opioid receptor. Tramadol is also a serotonin–norepinephrine reuptake inhibitor (SNRI).Tramadol was patented in 1963 and launched under the name "Tramal" in 1977 by the West German pharmaceutical company Grünenthal GmbH. In the mid-1990s, it was approved in the United Kingdom and the United States. It is available as a generic medication and marketed under many brand names worldwide. In 2020, it was the 35th most commonly prescribed medication in the United States, with more than 17 million prescriptions.
Medical uses
Tramadol (a schedule IV drug in the US) is used primarily to treat mild to severe pain, both acute and chronic. There is moderate evidence for use as a second-line treatment for fibromyalgia but it is not FDA approved for this use; however, its use is approved for treatment of fibromyalgia as a secondary painkiller by the NHS.Its analgesic effects take about one hour to come into effect and 2 to 4 h to peak after oral administration with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth the potency of morphine (thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with pethidine and codeine. For pain moderate in severity, its effectiveness is equivalent to that of codeine at low doses, and hydrocodone at very high doses; for severe pain it is less effective than morphine.These painkilling effects last about 6 h. The potency of analgesia varies considerably as it depends on an individuals genetics. People with specific variants of CYP2D6 enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control.Sleep medicine physicians sometimes prescribe tramadol (or other opiate medications) for refractory restless legs syndrome (RLS); that is, RLS that does not respond adequately to treatment with first-line medications such as dopamine agonists (like pramipexole) or alpha-2-delta (α2δ) ligands (gabapentinoids), often due to augmentation.
Contraindications
Tramadol may not provide adequate pain control for individuals with certain genetic variants of CYP2D6 enzymes as they metabolize tramadol to the inactive molecule. These genetic polymorphisms are not currently routinely tested for in clinical practice.
Pregnancy and lactation
Tramadols use in pregnancy is generally avoided, as it may cause some reversible withdrawal effects in the newborn. A small prospective study in France found, while an increased risk of miscarriages existed, no major malformations were reported in the newborn. Its use during lactation is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. No evidence of this dose harming the newborn was seen.
Labor and delivery
Its use as an analgesic during labor is not advised due to its long onset of action (1 hour). The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labor pains has been estimated to be 1:94.
Children
Its use in children is generally advised against, although it may be done under the supervision of a specialist. On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing. The FDA lists age under 12 years old as a contraindication.
Elderly
The risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation is increased. Tramadol may interact with other medications and increase the risk for adverse events.
Liver and kidney failure
The drug should be used with caution in those with liver or kidney failure, due to metabolism in the liver (to the active molecule desmetramadol) and elimination by the kidneys.
Side effects
The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness, and headache. Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression.
Dependence and withdrawal
Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome. These include both symptoms typical of opioid withdrawal and those associated with serotonin–norepinephrine reuptake inhibitor (SNRI) withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus. Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogues.
Overdose
Recognised risk factors for tramadol overdose include respiratory depression, addiction, and seizures. Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.Deaths with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol. There were 254 tramadol-related deaths in England and Wales in 2013, and 379 in Florida in 2011. In 2011, 21,649 emergency room visits in the United States were related to tramadol.
Interactions
Tramadol can interact with other medications with similar mechanisms of action.
Tramadol acts as a serotonin-norephinephrine reuptake inhibitor and thus can interact with other serotonergic medications (selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, triptans, cough and cold medications containing dextromethorphan, herbal products containing St. John’s wort, and medications that inhibit the metabolism of serotonin, such as monoamine oxidase inhibitors) and, in combination, may lead to serotonin syndrome. It may also make some serotonergic antagonist anti-emetic medications (ondansetron) less effective.Tramadol also acts as an opioid agonist and thus can increase the risk for side effects when used with other opioid analgesics (such as morphine, pethidine, tapentadol, oxycodone, and fentanyl).Tramadol is metabolized by CYP2D6 enzymes which contribute to the metabolism of approximately 25% of all medications. Any medications with the ability to inhibit or induce these enzymes may interact with tramadol.Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold (such as antipsychotic medications or amphetamines), further increases this risk.
Pharmacology
Mechanism of action
Tramadol induces analgesic effects through a variety of different targets on the noradrenergic system, serotoninergic system and opioid receptors system. Tramadol exists as a racemic mixture, the positive enantiomer inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters. Tramadol has also been shown to act as a serotonin releasing agent. Both enantiomers of tramadol are agonists of the μ-opioid receptor and its M1 metabolite, O-desmetramadol, is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself. All these effects work synergistically to induce analgesia.
Tramadol has been found to possess these actions:
Agonist of the μ-opioid receptor (MOR) and to a far lesser extent of the δ-opioid receptor (DOR) and κ-opioid receptor (KOR)
Serotonin reuptake inhibitor (SRI) and norepinephrine reuptake inhibitor; hence, an SNRI
Serotonin 5-HT2C receptor antagonist
M1 and M3 muscarinic acetylcholine receptor antagonist
α7 nicotinic acetylcholine receptor antagonist
NMDA receptor antagonist (very weak)
TRPA1 inhibitorTramadol acts on the opioid receptors through its major active metabolite desmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol. Moreover, tramadol itself has been found to possess no efficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that of morphine). As such, desmetramadol is exclusively responsible for the opioid effects of tramadol. Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.Tramadol is well-established as an SRI. In addition, a few studies have found that it also acts as a serotonin releasing agent (1–10 μM), similar in effect to fenfluramine. The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents such as fenfluramine and MDMA. However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 μM. In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor. It is not a norepinephrine releasing agent. Tramadol does not inhibit the reuptake or induce the release of dopamine.A positron emission tomography imaging study found that single oral 50-mg and 100-mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the serotonin transporter (SERT) in the thalamus. The estimated median effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/ml (1,300 nM). The estimated maximum daily dosage of tramadol of 400 mg (100 mg q.i.d.) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/ml or 4,632 nM). This is close to that of SSRIs, which occupy the SERT by 80% or more.Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/ml (266–2,250 nM) for tramadol and 55 to 143 ng/ml (221–573 nM) for desmetramadol. The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100-mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day). Some accumulation of tramadol occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100 mg q.i.d.) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100-mg dose. Positron emission tomography imaging studies have reportedly found that tramadol levels are at least four-fold higher in the brain than in plasma. Conversely, brain levels of desmetramadol "only slowly approach those in plasma". The plasma protein binding of tramadol is only 4 to 20%; hence, almost all tramadol in circulation is free, thus bioactive.
Correspondence to effects
Co-administration of quinidine, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers. However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers, hence indicating that its opioid action is unlikely the sole factor; tramadols analgesic effects are also partially reversed by α2-adrenergic receptor antagonists such as yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719. Pharmacologically, tramadol is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadols reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadols putative inhibition of GABAA receptors at high doses (significant inhibition at 100 μM). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadols ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.Nausea and vomiting caused by tramadol are thought to be due to activation of the 5-HT3 receptor via increased serotonin levels. In accordance, the 5-HT3 receptor antagonist ondansetron can be used to treat tramadol-associated nausea and vomiting. Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.
Pharmacokinetics
Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.Its volume of distribution is around 306 L after oral administration and 203 L after parenteral administration.
Chemistry
Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers, because the two isomers complement each others analgesic activities. The (+)-isomer is predominantly active as an opiate with a higher affinity for the µ-opiate receptor (20 times higher affinity than the (-)-isomer).
Synthesis and stereoisomerism
The chemical synthesis of tramadol is described in the literature. Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:
(1R,2R)-isomer
(1S,2S)-isomer
(1R,2S)-isomer
(1S,2R)-isomerThe synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides.
The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(−)-enantiomers.
The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(−)-isomer] was described employing (R)-(−)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.
Detection in biological fluids
Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantitate these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% those of the parent drug.
Society and culture
Formulations
Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets and powders for mixing with water, capsules, tablets including extended-release formulations, suppositories, compounding powder, and injections.
Patent history
The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005. ER Tramadol was protected by US patents nos. 6,254,887 and 7,074,430. The FDA listed the patents expiration as 10 May 2014. However, in August 2009, US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted prior to the expiration of the patents.
Legal status
Effective 18 August 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States. Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws.Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a Schedule 8 Controlled Drug (Possession without authority illegal) like most other opioids.Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as codeine and dextropropoxyphene, but allows a normal prescription to be used.The UK classified tramadol as a Class C, Schedule 3 controlled drug on 10 June 2014, but exempted it from the safe custody requirement.
Misuse
Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization. When used at higher doses, the drug "can produce similar effects to heroin." Said one former member, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it." Tramadol is also used as a coping mechanism in the Gaza Strip. It is also abused in the United Kingdom, inspiring the title of the TV show Frankie Boyles Tramadol Nights (2010).From March 2019, the Union Cycliste Internationale (UCI) banned the drug, after riders were using the painkiller to improve their performance.
Research
Investigational uses
Diabetic neuropathy
Antidepressant
Postherpetic neuralgia
Premature ejaculation
Adjunct to local anaesthesia
False findings about sources in nature
In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia). In 2014, however, it was reported that the presence of tramadol in the tree roots was the result of tramadol having been administered to cattle by farmers in the region: tramadol and its metabolites were present in the animals excreta, which contaminated the soil around the trees. Therefore, tramadol and its mammalian metabolites were found in tree roots in the far north of Cameroon, but not in the south where it is not administered to farm animals.A 2014 editorial in Lab Times online contested the notion that tramadol in tree roots was the result of anthropogenic contamination, stating that samples were taken from trees that grew in national parks, where livestock were forbidden; it also quoted researcher Michel de Waard, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating there" would be required to produce the concentrations discovered.In 2015, radiocarbon analysis confirmed that the tramadol found in N.latifolia roots could not be plant-derived and was of synthetic origin.
Veterinary medicine
Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.
See also
Tramadol/paracetamol
References
Further reading
Dean L (2015). "Tramadol Therapy and CYP2D6 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520365. Bookshelf ID: NBK315950.
External links
"Tramadol". Drug Information Portal. U.S. National Library of Medicine.
"Tramadol hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Lidocaine/prilocaine | Lidocaine/prilocaine is a eutectic mixture of equal quantities (by weight) of lidocaine and prilocaine. A 5% emulsion preparation, containing 2.5% each of lidocaine/prilocaine, is marketed by APP Pharmaceuticals under the trade name EMLA (an abbreviation for Eutectic Mixture of Local Anesthetics). As a spray, it is marketed under the name Tempe (topical eutectic-like mixture for premature ejaculation) (PSD502) that can be used by men to help with premature ejaculation. The spray is manufactured by Plethora Solutions and branded as Fortacin in the UK and Recordati in the EU.
Eutectic mixture
Separately, lidocaine and prilocaine are solid bases. When mixed in equal quantities by weight, however, they form a eutectic mixture – that is the melting point of the mixture is lower than the melting points of the individual components. The lidocaine/prilocaine eutectic mixture is an oil with a melting point of 18 °C, and can be formulated into preparations without the use of a non-aqueous solvent. This allows higher concentrations of anaesthetic to be formulated into the preparation and maintained during application.
Clinical use
Indications
The lidocaine/prilocaine combination is indicated for dermal anaesthesia. Specifically it is applied to prevent pain associated with intravenous catheter insertion, blood sampling, superficial surgical procedures, and topical anaesthesia of leg ulcers for cleansing or debridement. Also, it can be used to numb the skin before tattooing as well as electrolysis and laser hair removal. It is also sometimes used in advance of injected local anaesthetics for minor surgery and biopsies.
A topical spray consisting of an aerosol formulation of lidocaine and prilocaine was evaluated under the name PSD502 for use in treating premature ejaculation. The spray is applied on the penile skin prior to intercourse. While this formulation was not approved by the FDA, a similar product, Promescent, is available over-the-counter in the U.S.
Dosage forms
Lidocaine/prilocaine eutectic mixture is marketed as a 5% oil-in-water emulsion incorporated in a cream base (EMLA cream) or a cellulose disk (EMLA patch). The cream is applied under an occlusive dressing, while the patch incorporates an occlusive dressing to facilitate absorption of lidocaine and prilocaine into the area where anaesthesia is required. Local dermal anaesthesia is achieved after approximately 60 minutes, whereupon the occlusive dressing (or patch) is removed. The duration of anaesthesia is approximately two hours following removal of the occlusive dressing.
E. Fougera & Co., makers of the generic cream widely used in the United States as Lidocaine and Prilocaine Cream, 2.5%/2.5%, recommends different timing for application of the cream as well as length of anesthesia. They state the cream must be applied at least one hour before the start of a routine procedure and for two hours before the start of a painful procedure. Additionally, they state that the duration of effective skin anesthesia will be at least one hour after removal of the occlusive dressing.
Circumcision
Lidocaine/prilocaine eutectic mixture has been used during circumcision in newborn boys and has been considered efficacious and safe to lessen pain from circumcision.The European Medicines Agency concludes in its latest (2014) statement on Emla:
"Safety and efficacy for the use of EMLA on genital skin and genital mucosa have not been established in children younger than 12 years. Available paediatric data do not demonstrate adequate efficacy for circumcision."The Patient Information Leaflet of EMLA in the UK states: "EMLA Cream should not be applied to the genital skin (e.g. penis) and genital mucosa (e.g. in the vagina) of children (below 12 years of age) owing to insufficient data on absorption of active
substances."
Tempe
The spray is a combination of local anaesthetics lidocaine and prilocaine in a metered-dose aerosol that is sprayed directly on the penis to numb sensations. It was developed by the same group that invented the erectile dysfunction drug sildenafil. The drug was approved in Europe and was released in the UK market in November 2016 and within the EU will be marketed by, early in 2017 In the United States, the Food and Drug Administration (FDA) is expected to approve the drug in 2018.
Compendial status
United States Pharmacopeia 31
See also
Dosage form
Eutectic point
Lidocaine
Prilocaine
References
External links
"Lidocaine mixture with Prilocaine". Drug Information Portal. U.S. National Library of Medicine. |
Ebanga | Ebanga is an Angolan commune. It belongs to the municipality of Ganda, in the province of Benguela.
== References == |
Dimenhydrinate | Dimenhydrinate, sold under the brand name Dramamine, among others, is an over-the-counter drug used to treat motion sickness and nausea. Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chlorotheophylline, a chlorinated theophylline derivative, in a 1∶1 ratio.
Medical uses
Nausea
Dimenhydrinate is an over-the-counter (OTC) antihistamine indicated for the prevention and relief of nausea and vomiting from a number of causes. It is an H1 receptor antagonist that demonstrates anticholinergic activity.
Medicinal chemistry
Diphenhydramine is the primary constituent of dimenhydrinate and dictates the primary effect. The main difference relative to pure diphenhydramine is a lower potency due to being combined with 8-chlorotheophylline. By weight, dimenhydrinate is between 53% to 55.5% diphenhydramine.
Side effects
Common side effects may include:
Drowsiness
Dry mouth, nose, or throat
Constipation
Blurred vision
Feeling restless or excited (especially in children)
Recreational use
Dimenhydrinate is recreationally used as a deliriant. Slang terms for Dramamine used this way include "drama", "dime", "dime tabs", "D-Q", "substance D", "d-house", and "drams". Abusing Dramamine is sometimes referred to as Dramatizing or "going a dime a dozen", a reference to the amount of Dramamine tablets generally necessary for a trip.Many users report a side-effect profile consistent with tropane alkaloid (e.g. atropine) poisoning as both show antagonism of muscarinic acetylcholine receptors in both the central and autonomic nervous system, which inhibits various signal transduction pathways.Other CNS effects occur within the limbic system and hippocampus, causing confusion and temporary amnesia due to decreased acetylcholine signaling. Toxicology also manifests in the autonomic nervous system, primarily at the neuromuscular junction, resulting in ataxia and extrapyramidal side effects and the feeling of heaviness in the legs, and at sympathetic post-ganglionic junctions, causing urinary retention, pupil dilation, tachycardia, irregular urination, and dry red skin caused by decreased exocrine gland secretions, and mucous membranes. Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular arrhythmias, coma, and death. Such a side effect profile is thought to give ethanolamine-class antihistamines a relatively low abuse liability. An antidote that can be used for dimenhydrinate poisoning is physostigmine.
Brand names
Dimenhydrinate is marketed under many brand names: in the US, Mexico, Turkey and Serbia as Dramamine; in Ukraine as Driminate; in Canada, Costa Rica, and India as Gravol; in Iceland as Gravamin; in Russia and Croatia as Dramina; in South Africa and Germany as Vomex; in Australia and Austria as Vertirosan; in Brazil as Dramin; in Colombia as Mareol; in Ecuador as Anautin; in Hungary as Daedalon; in Indonesia as Antimo; in Italy as Xamamina or Valontan; in Peru as Gravicoll; in Poland and Slovakia as Aviomarin; in Portugal as Viabom, Vomidrine, and Enjomin; in Spain as Biodramina; in Thailand as Daimenin; in Israel as Travamin; in Pakistan as Gravinate; and in Ethiopia as dimenhydrinate.
Popular culture
Modest Mouse produced a song titled "Dramamine" on their 1996 debut album This Is a Long Drive for Someone with Nothing to Think About. The song uses side effects of the drug as a metaphor for the deteriorating state of a personal relationship.
References
External links
Media related to Dimenhydrinate at Wikimedia Commons
"Diphenhydramine". Drug Information Portal. U.S. National Library of Medicine.
"8-Chlorotheophylline". Drug Information Portal. U.S. National Library of Medicine. |
Cenegermin | Cenegermin, sold under the brand name Oxervate, also known as recombinant human nerve growth factor (rhNGF), is a recombinant form of human nerve growth factor (NGF). In July 2017, it was approved in the European Union as an eye drop formulation for the treatment of moderate or severe neurotrophic keratitis in adults.As a recombinant form of NGF, cenegermin is a peripherally selective agonist of the TrkA and LNGFR (p75NTR) which must be administered parenterally.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
History
It was developed by Anabasis Pharma, Dompé Farmaceutici, and Ospedale San Raffaele.
Research
In addition to neurotrophic keratitis, cenegermin is also under development for the treatment of dry eyes, retinitis pigmentosa, and glaucoma.
References
Further reading
Sheha H, Tighe S, Hashem O, Hayashida Y (October 2019). "Update On Cenegermin Eye Drops In The Treatment Of Neurotrophic Keratitis". Clin Ophthalmol. 13: 1973–1980. doi:10.2147/OPTH.S185184. PMC 6789413. PMID 31631965.
External links
"Cenegermin". Drug Information Portal. U.S. National Library of Medicine. |
Rho(D) immune globulin | Rho(D) immune globulin (RhIG) is a medication used to prevent RhD isoimmunization in mothers who are RhD negative and to treat idiopathic thrombocytopenic purpura (ITP) in people who are Rh positive. It is often given both during and following pregnancy. It may also be used when RhD-negative people are given RhD-positive blood. It is given by injection into muscle or a vein. A single dose lasts 12 weeks.Common side effects include fever, headache, pain at the site of injection, and red blood cell breakdown. Other side effects include allergic reactions, kidney problems, and a very small risk of viral infections. In those with ITP, the amount of red blood cell breakdown may be significant. Use is safe with breastfeeding. Rho(D) immune globulin is made up of antibodies to the antigen Rho(D) present on some red blood cells. It is believed to work by blocking a persons immune system from recognizing this antigen.Rho(D) immune globulin came into medical use in the 1960s. It is on the World Health Organizations List of Essential Medicines. It is made from human blood plasma.
Medical uses
In a pregnancy where the mother is RhD negative and the father is RhD positive, the probability of the fetus having RhD positive blood is dependent on whether the father is homozygous for RhD (i.e., both RhD alleles are present) or heterozygous (i.e., only one RhD allele is present). If the father is homozygous, the fetus will necessarily be RhD positive, as the father will necessarily pass on a Rh D positive allele. If the father is heterozygous, there is a 50% chance that the fetus will be RhD positive, as he will randomly pass on either the RhD positive allele or not.If a fetus is RhD positive and the mother is RhD negative, the mother is at risk of RhD alloimmunization, where the mother mounts an immune response (develops antibodies) to fetal red blood cells. This usually has minimal effect on the first such pregnancy; but, in a second such pregnancy, pre-existing maternal antibodies to RhD antigens on fetal red blood cells often leads to erythroblastosis fetalis, a condition which can be fatal to the fetus. In countries without Rh immune globulin (RhIG) protocols, as many as 14% of affected fetuses are stillborn and 50% of live births result in neonatal death or brain injury.Because of this severe complication, the American College of Obstetricians and Gynecologists (ACOG) recommends that all RhD negative mothers, regardless of fetal blood type, receive RhIG at about 28 weeks gestation, and again shortly after delivery in the case of an RhD positive or RhD unknown baby. It should be given within 3 days of a potential exposure to Rh positive blood from the baby such as may occur during second or third trimester miscarriage, amniocentesis, cordocentesis, chorionic villus sampling, external cephalic version, trauma, or delivery. It should be considered after first trimester miscarriage. The 28 weeks recommendation comes from the fact that 92% of women who develop an anti-D during pregnancy do so at or after 28 weeks gestation. It is given by intramuscular injection as part of modern routine antenatal care. Despite excellent results, the medication retains an FDA Pregnancy Category C.RhIG is recommended in the UK after antenatal pathological events that are likely to cause a feto–maternal hemorrhage. Applicable pathologic events include accidents which may induce fetomaternal hemorrhage (motor vehicle accidents, falls, abdominal trauma), following obstetric/gynecologic procedures during pregnancy, and at the time of threatened- or spontaneous-/elective abortions, regardless of gestational age.
There is insufficient evidence that the use of Rho(D) immune globulin after a spontaneous miscarriage is needed and a Cochrane review recommends that local practices be followed.In an RhD negative mother, RhIG can prevent temporary sensitization of the maternal immune system to RhD antigens, which can cause rhesus disease in the current or in subsequent pregnancies. With the widespread use of RhIG, Rh disease of the fetus and newborn has almost disappeared in the developed world. The risk that an RhD negative mother can be alloimmunized by a RhD positive fetus can be reduced from approximately 16% to less than 0.1% by the appropriate administration of RhIG.Rh immune globulin is composed of IgG antibodies and therefore is able to cross the placenta. In rare cases this can cause a baby to have a weakly positive direct antiglobulin test (DAT) due to sensitization of fetal cells from mothers who have received multiple doses of RhIG. However, no treatment is necessary as the clinical course is benign.
Following delivery
A D-negative mother who is not alloimmunized to D should also receive an appropriate dose of RhIG after delivery of a D-positive infant. After delivery, a cord blood sample from infants born to D-negative mothers should be tested for the D antigen. If the neonate is D-negative, no further RhIG is needed. However, if the infant is D-positive, the mother should have a postpartum blood sample screened for fetomaternal hemorrhage in order to determine the appropriate dosage of RhIG to be administered. (The presence of residual anti-D from antepartum RhIG administration does not indicate ongoing protection from alloimmunization- repeat administration of RhIG is necessary.)The rosette test is a sensitive method to detect fetomaternal hemorrhage of 10 cc or more. This qualitative (not quantitative) test will be positive if fetal D-positive cells are present in the maternal sample, indicating a significantly large fetomaternal hemorrhage has occurred. A rosette test may be falsely positive if the mother is positive for the weak D phenotype and falsely negative if the neonate is weak D. If the mother is positive for the weak D phenotype, the rosette test should not be used; instead, a quantitative test such as the Kleihauer–Betke test or flow cytometry should be utilized. If the rosette test is negative, then a dose of 300 micrograms of RhIG is given (sufficient to prevent alloimmunization after delivery in 99% of cases). The RhIG dose suppresses the immune response to up to 30 cc of whole fetal blood (15 cc of red blood cells). If a fetomaternal hemorrhage in excess of 30 cc has occurred, additional testing is mandatory in order to determine the appropriate dosage of RhIG to prevent alloimmunization. A positive rosette test should be followed by a quantitative test such as the Kleihauer–Betke test or an alternative approach such as flow cytometry. See the article on Kleihauer–Betke test for details on how the volume of fetomaternal hemorrhage is calculated. The dosage of RhIG is calculated from the volume of fetal hemorrhage (in mL). Ex: 50 mL fetal hemorrhage / 30 mL = 1.667 (round up to 2) then add 1 = 3 vials of RhIG.Postpartum RhIG should be administered within 72 hours of delivery. If prophylaxis is delayed, the likelihood that alloimmunization will be prevented is decreased. However, ACOG still recommends that RhIG be administered because partial protection still occurs. If the D-type of a newborn or stillborn is unknown or cannot be determined, RhIG should be administered.
Immune thrombocytopenia
Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia, defined as a peripheral blood platelet count less than 100 x 109/L, and the absence of any obvious initiating and/or underlying cause of the thrombocytopenia. Symptoms of ITP include abnormal bleeding and bruising due to the reduction in platelet count. Rho(D) Immune Globulin Intravenous [Human; Anti-D] is indicated for use in non-splenectomized, Rho(D)-positive children with chronic or acute ITP, adults with chronic ITP, and children and adults with ITP secondary to HIV infection. Anti-D must be administered via the intravenous route when used in clinical situations requiring an increase in platelet count. The mechanism of action of anti-D is not fully understood; however, after administration the anti-D coated red blood cell complexes saturate Fcγ receptors sites on macrophages, resulting in preferential destruction of red blood cells (RBCs), therefore sparing antibody-coated platelets. Anti-D is recommended as a first-line therapy for ITP, along with corticosteroids and intravenous immune globulin (IVIG). WinRho SDF is an anti-D manufactured, distributed and marketed by Cangene in the US. There is a black box warning on WinRho SDF due to the risk of potentially fatal intravascular hemolysis when used in the treatment of ITP. Life-threatening anemia, kidney failure, and disseminated intravascular coagulation (DIC) have occurred in people treated with WinRho SDF for ITP.
Contraindications
The following females are not candidates for RhIG:
D-negative females whose fetus is known to be D-negative
D-negative females who have been previously alloimmunized to D (they have already formed an anti-D alloantibody)
Any D-positive females
Women who test positive for one of the weak D mutations by molecular testing should be considered RhD positive and not receive RhIG
Women who test positive for one of the partial D mutations (by molecular testing) should be treated as RhD negative and receive RhIG as clinically indicated
History
The first Rho(D) immune globulin treatment "skymed" was introduced by Ortho Clinical Diagnostics, a subsidiary holding of Jskymed, and was first administered on May 29, 1968, to Marianne Cummins in Teaneck, New Jersey.In 1996, ZLB Bioplasma (part of CSL Behring) was given approval to sell Rhophylac in Europe. Effectiveness was demonstrated in a clinical trial in 2003 and in 2004 Rhophylac was approved in the United States.
Society and culture
Manufacturing and safety
Rho(D) immune globulin is a derivative of human plasma. The most common way anti-D products are manufactured is by a form of the Cohn cold ethanol fractionation process developed in the 1950s. Variations of the Cohn method developed in the 1950s may not completely clear aggregates of immunoglobulins, which can cause problems for patients if administered intravenously, and is a primary reason why most anti-Ds are for intramuscular use only. A non-Cohn manufacturing variation is ChromaPlus process approved by the U.S. Food and Drug Administration (FDA) that is used to make Rhophylac. Rho(D) immune globulin may trigger an allergic reaction. Steps are taken in the plasma-donor screening process and the manufacturing process to eliminate bacterial and viral contamination, although a small, residual risk may remain for contamination with small viruses. There is also a theoretical possibility of transmission of the prion responsible for Creutzfeldt–Jakob disease, or of other, unknown infectious agents.
Routes of administration
RhIG can be administered by either intramuscular (IM) or intravenous (IV) injection, depending on the preparation. The IM-only preparation should never be administered IV due to the risk of complement system activation. Multiple IM doses should be given at different sites or at different times within the 72-hour window. Or, multiple IV doses can be administered according to the instructions in the package insert.
Names
Rho(D) immune globulin is also spelled Rh0(D) immune globulin (letter o and digit zero are both widely attested; more at Rh blood group system - Rh nomenclature).
Rhophylac is manufactured by CSL Limited. RhoGAM and MICRhoGam are brand names of Kedrion Biopharma. Other brand names are BayRHo-D, Gamulin Rh, HypRho-D Mini-Dose, Mini-Gamulin Rh, Partobulin SDF (Baxter), Rhesonativ (Octapharma), and RhesuGam (NBI). KamRho-D I.M. is a brand name of Kamada Ltd.
The United States distribution rights for WinRho SDF (another brand name) were transferred from Baxter to the manufacturer, Cangene, in 2010; they had been held by Baxter since 2005. Sales of WinRho fell every year under the agreement with Baxter, the supposition being that Baxter was favoring the sale of its own product over WinRho; according to one analyst, "WinRho was always an afterthought for a big company like Baxter."
See also
Rhesus blood group system
Blood types
Immunology
Rh disease
James Harrison (blood donor)
References
External links
Rho(D)+Immune+Globulin at the US National Library of Medicine Medical Subject Headings (MeSH)
"Rho(D) Immune Globulin". Drug Information Portal. U.S. National Library of Medicine. |
Chlormethine | Chlormethine (INN, BAN), also known as mechlorethamine (USAN, USP), mustine, HN2, and (in post-Soviet states) embikhin (эмбихин), is a nitrogen mustard sold under the brand name Mustargen among others. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention where it is classified as a Schedule 1 substance.
Mechlorethamine belongs to the group of nitrogen mustard alkylating agents.
Uses
It has been derivatized into the estrogen analogue estramustine phosphate, used to treat prostate cancer. It can also be used in chemical warfare where it has the code-name HN2. This chemical is a form of nitrogen mustard gas and a powerful vesicant. Historically, some uses of mechlorethamine have included lymphoid malignancies such as Hodgkins disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, and bronchogenic carcinoma Mechlorethamine is often administered intravenously, but when compounded into a topical formulation it can also be used to treat skin diseases. There have been studies demonstrating that topical administration of mechlorethamine has efficacy in mycosis fungoides-type cutaneous T cell lymphoma.Another important use of chlormethine is in the synthesis of pethidine (meperidine).
Side effects and toxicity
Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age. At high enough levels, exposure can be fatal.The adverse effects of mechlorethamine depend on the formulation. When used in chemical warfare, it can cause immunosuppression and damage to mucous membranes of the eyes, skin, and respiratory tract. Mucous membranes and damp or damaged skin are more affected by exposure to HN-2. Though symptoms of exposure are generally delayed, the DNA damage it causes occurs very quickly. More serious exposures cause symptoms to develop sooner. Eye symptoms develop first, in the first 1–2 hours (severe exposure) or 3–12 hours (mild to moderate exposure) followed by airway (2-6/12–24 hours) and skin symptoms (6–48 hours). Hot, humid weather shortens the latent (symptom-free) period.Symptoms of toxic exposure to HN-2 vary based on the route of exposure. Eye exposure causes lacrimation (tear production), burning, irritation, itching, a feeling of grittiness or dryness, blepharospasm (spasms of the eyelid), and miosis (pinpoint pupils). More severe cases cause edema (swelling from fluid accumulation) in the eyelids, photophobia (extreme sensitivity to light), severe pain, corneal ulceration, and blindness.Inhalation of chlormethine damages the upper and lower airways sequentially, with more severe exposures causing faster damage that afflicts lower parts of the respiratory tract. Early symptoms include rhinorrhea (runny nose), epistaxis (nosebleed), toneless voice, sneezing, barking cough, and dyspnea (in smokers and asthmatics). Later symptoms include pain in the nose/sinuses and inflammation of the airway. In severe cases, there may be epithelial necrosis throughout the respiratory tract, causing pseudomembrane formation, which can obstruct the airway. Pneumonia may develop and prove fatal.Skin exposure mainly causes erythema (redness) and vesication (blistering) at first, but absorption through the skin causes systemic toxicity. In cases where more than 25% of the skin is affected, fatal exposure is likely to have occurred.Though ingestion is uncommon, if mechlorethamine is swallowed it causes severe chemical burns to the gastrointestinal tract and concomitant nausea, vomiting, diarrhea, abdominal pain, and hemorrhage.Long-term effects of acute or chronic chlormethine exposure are caused by damage to the immune system. White blood cell counts drop, increasing the risk of infection, and red blood cell and platelet counts may also drop due to bone marrow damage. Chronic eye infections may result from exposure, but blindness is temporary. Long-term effects on the respiratory system include anosmia (inability to smell), ageusia (inability to taste), inflammation, chronic infections, fibrosis, and cancer. Skin that has been damaged by HN2 can change pigmentation or become scarred, and may eventually develop cancer.
History
The effect of vesicant (blister) agents in the form of mustard gas (sulfur mustard, Bis(2-chloroethyl) sulfide) on bone marrow and white blood cells had been known since the First World War. In 1935 several lines of chemical and biological research yielded results that would be explored after the start of the Second World War. The vesicant action of a family of chemicals related to the sulfur mustards, but with nitrogen substituting for sulfur was discovered—the "nitrogen mustards" were born. The particular nitrogen mustard chlormethine (mechlorethamine) was first synthesized. And the action of sulfur mustard on tumors in laboratory animals was investigated for the first time.After the U.S. entry into the Second World War the nitrogen mustards were candidate chemical warfare agents and research on them was initiated by the Office of Scientific Research and Development (OSRD). The OSRD let contracts to study them to two universities—Yale University and the University of Chicago. Inspired perhaps by the preliminary research in 1935, independently both groups thought to test whether a medically useful differential toxicity between animals and animal tumors existed. The Yale pharmacologists Louis Goodman and Alfred Gilman were the first to conduct a clinical trial, on 27 August 1942, using the agent HN3 (tris(2-chloroethyl)amine) on a patient known as J.D.The next year the Chicago group, led by Leon O. Jacobson, conducted trials with HN2 (chlormethine) which was the only agent in this group to see eventual clinical use. Wartime secrecy prevented any of this ground-breaking work on chemotherapy from being published, but papers were released once wartime secrecy ended, in 1946.Further clinical trials after the war, led by Cornelius P. Rhoads at Memorial Sloan-Kettering, helped establish the medical utility of the drug for Hodgkins disease and several other lymphomas and leukemia.
Chemistry
Chlormethine is combustible and becomes explosive under extreme conditions. It can react with metals to form gaseous hydrogen.
See also
Nitrogen mustards
HN1
HN3
References
External links
British Columbia Cancer Agency profile
"Chlormethine". Drug Information Portal. U.S. National Library of Medicine. |
Risperidone | Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions are long-acting and last for 2–4 weeks.Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of death. It is unknown if it is safe for use in pregnancy. Its mechanism of action is not entirely clear, but is believed to be related to its action as a dopamine and serotonin antagonist.Study of risperidone began in the late 1980s and it was approved for sale in the United States in 1993. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 149th most commonly prescribed medication in the United States, with more than 4 million prescriptions.
Medical uses
Risperidone is mainly used for the treatment of schizophrenia, bipolar disorder, and irritability associated with autism.
Schizophrenia
Risperidone is effective in treating psychogenic polydipsia and the acute exacerbations of schizophrenia.Studies evaluating the utility of risperidone by mouth for maintenance therapy have reached varying conclusions. A 2012 systematic review concluded that evidence is strong that risperidone is more effective than all first-generation antipsychotics other than haloperidol, but that evidence directly supporting its superiority to placebo is equivocal. A 2011 review concluded that risperidone is more effective in relapse prevention than other first- and second-generation antipsychotics with the exception of olanzapine and clozapine. A 2016 Cochrane review suggests that risperidone reduces the overall symptoms of schizophrenia, but firm conclusions are difficult to make due to very low-quality evidence. Data and information are scarce, poorly reported, and probably biased in favour of risperidone, with about half of the included trials developed by drug companies. The article raises concerns regarding the serious side effects of risperidone, such as parkinsonism. A 2011 Cochrane review compared risperidone with other atypical antipsychotics such as olanzapine for schizophrenia:
Long-acting injectable formulations of antipsychotic drugs provide improved compliance with therapy and reduce relapse rates relative to oral formulations. The efficacy of risperidone long-acting injection appears to be similar to that of long acting injectable forms of first generation antipsychotics.
Bipolar disorder
Second-generation antipsychotics, including risperidone, are effective in the treatment of manic symptoms in acute manic or mixed exacerbations of bipolar disorder. In children and adolescents, risperidone may be more effective than lithium or divalproex, but has more metabolic side effects. As maintenance therapy, long-acting injectable risperidone is effective for the prevention of manic episodes but not depressive episodes. The long-acting injectable form of risperidone may be advantageous over long acting first generation antipsychotics, as it is better tolerated (fewer extrapyramidal effects) and because long acting injectable formulations of first generation antipsychotics may increase the risk of depression.
Autism
Compared to placebo, risperidone treatment reduces certain problematic behaviors in autistic children, including aggression toward others, self-injury, challenging behaviour, and rapid mood changes. The evidence for its efficacy appears to be greater than that for alternative pharmacological treatments. Weight gain is an important adverse effect. Some authors recommend limiting the use of risperidone and aripiprazole to those with the most challenging behavioral disturbances in order to minimize the risk of drug-induced adverse effects. Evidence for the efficacy of risperidone in autistic adolescents and young adults is less persuasive.
Dementia
While antipsychotic medications such as risperidone have a slight benefit in people with dementia, they have been linked to higher incidence of death and stroke. Because of this increased risk of death, treatment of dementia-related psychosis with risperidone is not FDA approved and carries a black box warning. However many other jurisdictions regularly use it to control severe aggression and psychosis in those with dementia when other non-pharmacological interventions have failed and their pharmaceutical regulators have approved its use in this population.
Other uses
Risperidone has shown promise in treating therapy-resistant obsessive-compulsive disorder, when serotonin reuptake inhibitors alone are not sufficient.Risperidone has proven to be effective in treatment with Attention deficit hyperactivity disorder especially in cases of aggression or with another mental condition.Risperidone has not demonstrated a benefit in the treatment of eating disorders or personality disorders, except for limited evidence in schizotypal personality disorder.
Forms
Available forms of risperidone include tablet, oral dissolving tablet, oral solution, and powder and solvent for suspension for injection.
Adverse effects
Common side effects include movement problems, sleepiness, dizziness, trouble seeing, constipation, and increased weight. About 9 to 20% of people gained more than 7% of the baseline weight depending on the dose. Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, and high blood sugar levels. In older people with psychosis as a result of dementia, it may increase the risk of death.While atypical antipsychotics appear to have a lower rate of movement problems as compared to typical antipsychotics, risperidone has a high risk of movement problems among the atypicals. Atypical antipsychotics, however, are associated with a greater amount of weight gain and other metabolic side effects.
Drug interactions
Carbamazepine and other enzyme inducers may reduce plasma levels of risperidone. If a person is taking both carbamazepine and risperidone, the dose of risperidone will likely need to be increased. The new dose should not be more than twice the patients original dose.
CYP2D6 inhibitors, such as SSRI medications, may increase plasma levels of risperidone and those medications.
Since risperidone can cause hypotension, its use should be monitored closely when a patient is also taking antihypertensive medicines to avoid severe low blood pressure.
Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St Johns wort
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. Some have argued the additional somatic and psychiatric symptoms associated with dopaminergic super-sensitivity, including dyskinesia and acute psychosis, are common features of withdrawal in individuals treated with neuroleptics. This has led some to suggest the withdrawal process might itself be schizomimetic, producing schizophrenia-like symptoms even in previously healthy patients, indicating a possible pharmacological origin of mental illness in a yet unknown percentage of patients currently and previously treated with antipsychotics. This question is unresolved, and remains a highly controversial issue among professionals in the medical and mental health communities, as well as the public.
Dementia
Older people with dementia-related psychosis are at a higher risk of death.
Pharmacology
Pharmacodynamics
Risperidone has been classified as a "qualitatively atypical" antipsychotic agent with a relatively low incidence of extrapyramidal side effects (when given at low doses) that has more pronounced serotonin antagonism than dopamine antagonism. Risperidone contains the functional groups of benzisoxazole and piperidine as part of its molecular structure. Although not a butyrophenone, it was developed with the structures of benperidol and ketanserin as a basis. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT2C, linked to weight gain, 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the typical neuroleptics.It has been found that D-amino acid oxidase, the enzyme that catalyses the breakdown of D-amino acids (e.g. D-alanine and D-serine — the neurotransmitters) is inhibited by risperidone.Risperidone acts on the following receptors:
Dopamine receptors: This drug is an antagonist of the D1 (D1, and D5) as well as the D2 family (D2, D3 and D4) receptors, with 70-fold selectivity for the D2 family. It has "tight binding" properties, which means it has a long half-life. Like other antipsychotics, risperidone blocks the mesolimbic pathway, the prefrontal cortex limbic pathway, and the tuberoinfundibular pathway in the central nervous system. Risperidone may induce extrapyramidal side effects, akathisia and tremors, associated with diminished dopaminergic activity in the striatum. It can also cause sexual side effects, galactorrhoea, infertility, gynecomastia and, with chronic use reduced bone mineral density leading to breaks, all of which are associated with increased prolactin secretion.Serotonin receptors: Its action at these receptors results in a relatively lesser tendency to cause extrapyramidal side effects, like the reference substance clozapine.Alpha α1 adrenergic receptors: This action accounts for the orthostatic hypotensive effects and perhaps some of the sedating effects of risperidone.Alpha α2 adrenergic receptors: Risperidones action at these receptors may cause greater positive, negative, affective, and cognitive symptom control.Histamine H1 receptors: effects on these receptors account for its sedation and reduction in vigilance. This may also lead to drowsiness and weight gain.Voltage-gated sodium channels: Because it accumulates in synaptic vesicles, Risperidone inhibits voltage-gated sodium channels at clinically used concentrations.
Pharmacokinetics
Risperidone undergoes hepatic metabolism and renal excretion. Lower doses are recommended for patients with severe liver and kidney disease. The active metabolite of risperidone, paliperidone, is also used as an antipsychotic.
Society and culture
Legal status
Risperidone was approved by the United States Food and Drug Administration (FDA) in 1993 for the treatment of schizophrenia. In 2003, the FDA approved risperidone for the short-term treatment of the mixed and manic states associated with bipolar disorder. In 2006, the FDA approved risperidone for the treatment of irritability in autistic children and adolescents. The FDAs decision was based in part on a study of autistic people with severe and enduring problems of violent meltdowns, aggression, and self-injury; risperidone is not recommended for autistic people with mild aggression and explosive behavior without an enduring pattern. On 22 August 2007, risperidone was approved as the only drug agent available for treatment of schizophrenia in youths, ages 13–17; it was also approved that same day for treatment of bipolar disorder in youths and children, ages 10–17, joining lithium.
On 16 December 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 Okedi, intended for the treatment of schizophrenia in adults for whom tolerability and effectiveness has been established with oral risperidone. The applicant for this medicinal product is Laboratorios Farmacéuticos Rovi, S.A. Risperidone was approved for medical use in the European Union in February 2022.
Availability
Janssens patent on risperidone expired on 29 December 2003, opening the market for cheaper generic versions from other companies, and Janssens exclusive marketing rights expired on 29 June 2004 (the result of a pediatric extension). It is available under many brand names worldwide.Risperidone is available as a tablet, an oral solution, and an ampule, which is a depot injection.
Lawsuits
On 11 April 2012, Johnson & Johnson (J&J) and its subsidiary Janssen Pharmaceuticals Inc. were fined $1.2 billion by Judge Timothy Davis Fox of the Sixth Division of the Sixth Judicial Circuit of the U.S. state of Arkansas. The jury found the companies had downplayed multiple risks associated with risperidone. The verdict was later reversed by the Arkansas state supreme court.In August 2012, Johnson & Johnson agreed to pay $181 million to 36 U.S. states in order to settle claims that it had promoted risperidone and paliperidone for off-label uses including for dementia, anger management, and anxiety.In November 2013, J&J was fined $2.2 billion for illegally marketing risperidone for use in people with dementia.In 2015, Steven Brill posted a 15-part investigative journalism piece on J&J in The Huffington Post, called "Americas most admired lawbreaker", which was focused on J&Js marketing of risperidone.J&J has faced numerous civil lawsuits on behalf of children who were prescribed risperidone who grew breasts (a condition called gynecomastia); as of July 2016 there were about 1,500 cases in Pennsylvania state court in Philadelphia, and there had been a February 2015 verdict against J&J with $2.5 million awarded to a man from Alabama, a $1.75 million verdict against J&J that November, and in 2016 a $70 million verdict against J&J. In October 2019, a jury awarded a Pennsylvania man $8 billion in a verdict against J&J.
Names
Brand names include Risperdal, Risperdal Consta, Risperdal M-Tab, Risperdal Quicklets, Risperlet, Okedi, and Perseris.
References
Further reading
Dean L (2017). "Risperidone Therapy and CYP2D6 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520384. Bookshelf ID: NBK425795.
External links
"Risperidone". Drug Information Portal. U.S. National Library of Medicine. |
Hydrocortisone | Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD. It is the treatment of choice for adrenocortical insufficiency. It can be given by mouth, topically, or by injection. Stopping treatment after long-term use should be done slowly.Side effects may include mood changes, increased risk of infection, and edema (swelling). With long-term use common side effects include osteoporosis, upset stomach, physical weakness, easy bruising, and candidiasis (yeast infections). While used, it is unclear if it is safe during pregnancy. Hydrocortisone is a glucocorticoid and works as an anti-inflammatory and by immune suppression.Hydrocortisone was patented in 1936 and approved for medical use in 1941. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 147th most commonly prescribed medication in the United States, with more than 4 million prescriptions.
Medical uses
Hydrocortisone is the pharmaceutical term for cortisol used in oral administration, intravenous injection, or topical application. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients needing steroid treatment but unable to take oral medication, and perioperatively in patients on long-term steroid treatment to prevent an adrenal crisis. It may also be injected into inflamed joints resulting from diseases such as gout.
It may be used topically for allergic rashes, eczema, psoriasis, itching and other inflammatory skin conditions. Topical hydrocortisone creams and ointments are available in most countries without prescription in strengths ranging from 0.05% to 2.5% (depending on local regulations) with stronger forms available by prescription only. Covering the skin after application increases the absorption and effect. Such enhancement is sometimes prescribed, but otherwise should be avoided to prevent overdose and systemic impact.
Pharmacology
Pharmacodynamics
Hydrocortisone is a corticosteroid, acting specifically as both a glucocorticoid and as a mineralocorticoid. That is, it is an agonist of the glucocorticoid and mineralocorticoid receptors.
Hydrocortisone has low potency relative to synthetic corticosteroids. Compared to hydrocortisone, prednisolone is about 4 times as potent and dexamethasone about 40 times as potent in terms of anti-inflammatory effect. Prednisolone can also be used as cortisol replacement, and at replacement dose levels (rather than anti-inflammatory levels), prednisolone is about eight times more potent than cortisol.
Pharmacokinetics
Most cortisol in the blood (all but about 4%) is bound to proteins, including corticosteroid binding globulin (CBG) and serum albumin. Free cortisol passes easily through cellular membranes, explaining its 100% bioavailability after oral administration. Inside cells it interacts with corticosteroid receptors.
Chemistry
Hydrocortisone, also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione, is a naturally occurring pregnane steroid. A variety of hydrocortisone esters exist and have been marketed for medical use.
Society and culture
Legal status
On 25 March 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 Efmody, intended for the treatment of congenital adrenal hyperplasia (CAH) in people aged twelve years and older. The applicant for this medicinal product is Diurnal Europe BV. Hydrocortisone (Efmody) was approved for medical use in the European Union, in May 2021, for the treatment of congenital adrenal hyperplasia (CAH) in people aged twelve years and older.
Research
COVID-19
In September 2020, a meta-analysis study published by the World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group found hydrocortisone to be effective in reducing mortality rate of critically ill COVID-19 patients when compared to other usual care or a placebo.
References
External links
"Hydrocortisone". Drug Information Portal. U.S. National Library of Medicine. |
Minocycline | Minocycline, sold under the brand name Minocin among others, is a tetracycline antibiotic medication used to treat a number of bacterial infections such as pneumonia. It is generally less preferred than the tetracycline doxycycline. It is also used for the treatment of acne and rheumatoid arthritis. It is taken by mouth or applied to the skin.Common side effects include nausea, diarrhea, dizziness, allergic reactions, and kidney problems. Serious side effects may include anaphylaxis, a lupus-like syndrome, and easy sunburning. Use in the later part of pregnancy may harm the baby and safety during breastfeeding is unclear. It works by decreasing a bacteriums ability to make protein thus stopping its growth.Minocycline was patented in 1961 and came into commercial use in 1971. It is available as a generic medication. In 2017, it was the 237th most commonly prescribed medication in the United States, with more than two million prescriptions.
Medical uses
Acne
Minocycline and doxycycline are frequently used for the treatment of acne vulgaris. Both of these closely related antibiotics have similar levels of efficacy, although doxycycline has a slightly lower risk of adverse side effects. Historically, minocycline has been an effective treatment for acne vulgaris. However, acne that is caused by antibiotic-resistant bacteria is a growing problem in many countries. In Europe and North America, a number of people with acne no longer respond well to treatment with tetracycline family antibiotics because their acne symptoms are caused by bacteria (primarily Cutibacterium acnes) that are resistant to these antibiotics. In order to reduce resistance rates as well as increase the effectiveness of treatment, oral antibiotics should be generally combined with topical acne creams such as benzoyl peroxide or a retinoid (tretinoin, adapalene, etc.). Minocycline itself is used both orally and topically in the treatment of acne.
Infections
Minocycline is also used for other skin infections such as methicillin-resistant Staphylococcus aureus.Although minocyclines broader spectrum of activity, compared with other members of the group, includes activity against Neisseria meningitidis, its use for prophylaxis is no longer recommended because of side effects (dizziness and vertigo).
It may be used to treat certain strains of methicillin-resistant S. aureus infection and a disease caused by drug-resistant Acinetobacter spp.A list of uses includes:
Amoebic dysentery
Anthrax
Bubonic plague
Cholera
Ehrlichiosis
Gonorrhea (when penicillin cannot be given)
Gougerot-Carteaud syndrome (confluent and reticulated papillomatosis)
Hidradenitis suppurativa
For use as an adjuvant to HAART
Leprosy
Periodontal disease
Perioral dermatitis
Respiratory infections such as pneumonia
Rocky Mountain spotted fever
Rosacea
Syphilis (when penicillin cannot be given)
Urinary tract infections, rectal infections, and infections of the cervix caused by certain microbes
Other
Both minocycline and doxycycline have shown effectiveness in asthma due to immune-suppressing effects. Minocycline and doxycycline have modest effectiveness in treating rheumatoid arthritis. However, the 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis does not include minocycline.
Recent research indicate that centrally infused minocycline attenuates brain microglial activation, neuroinflammation and sympathetic activation during pulmonary hypertension
Contraindications
The drug is contraindicated in people with known hypersensitivity to tetracycline antibiotics, as there is complete cross sensitivity in this group. It is also contraindicated in people with severe liver impairment and after the 16th week of pregnancy.
Side effects
Minocycline may cause upset stomach, diarrhea, dizziness, unsteadiness, drowsiness, mouth sores, headache, and vomiting. It increases sensitivity to sunlight, and may affect the quality of sleep and rarely causes sleep disorders. It has also been linked to cases of lupus. Prolonged use of minocycline can lead to blue-gray staining of skin, fingernails, and scar tissue. This staining is not permanent, but can take a very long time for the skin color to return to normal; however, a muddy brown skin color in sun-exposed areas is usually permanent. Permanent blue discoloration of gums or teeth discoloration may also occur. Rare but serious side effects include fever, yellowing of the eyes or skin, stomach pain, sore throat, vision changes, and mental changes, including depersonalization.Occasionally, minocycline therapy may result in autoimmune disorders such as drug-related lupus and autoimmune hepatitis, which usually occurs in men who also developed minocycline-induced lupus; however, women are more likely to develop minocycline-induced lupus. Significant or complete recovery occurs in most people who develop minocycline-induced autoimmune problems within a period of a few weeks to a year of cessation of minocycline therapy. Autoimmune problems emerge during chronic therapy, but can sometimes occur after only short courses of a couple of weeks of therapy. Drug reaction with eosinophilia and systemic symptoms syndrome can occur during the first few weeks of therapy with minocycline.Minocycline, but not other tetracyclines, can cause vestibular disturbances with dizziness, ataxia, vertigo, and tinnitus. These effects are thought to be related to minocyclines greater penetration into the central nervous system. Vestibular side effects are much more common in women than in men, occurring in 50 to 70% of women receiving minocycline. As a result of the frequency of this bothersome side effect, minocycline is rarely used in female patients.Symptoms of an allergic reaction include rash, itching, swelling, severe dizziness, and trouble breathing. Minocycline has also been reported to very rarely cause idiopathic intracranial hypertension (pseudotumor cerebri), a side effect also more common in female patients, potentially leading to permanent vision damage if not recognized early and treated.
Contrary to most other tetracycline antibiotics (doxycycline excluded), minocycline may be used in those with kidney disease, but may aggravate systemic lupus erythematosus. It may also trigger or unmask autoimmune hepatitis.Minocycline can cause the rare condition of secondary intracranial hypertension, which has initial symptoms of headache, visual disturbances, dizziness, vomiting, and confusion. Brain swelling and rheumatoid arthritis are rare side effects of minocycline in some people.Minocycline, like most tetracyclines, becomes dangerous past its expiration date. While most prescription drugs lose potency after their expiration dates, tetracyclines are known to become toxic over time. Expired tetracyclines can cause serious damage to the kidney due to the formation of a degradation product, anhydro-4-epitetracycline.
Minocyclines absorption is impaired if taken at the same time of day as calcium or iron supplements. Unlike some of the other tetracycline group antibiotics, it can be taken with calcium-rich foods such as milk, although this does reduce the absorption slightly.Minocycline, like other tetracyclines, is associated with esophageal irritation and ulceration if insufficient fluids are taken with the drug before sleep.A 2007 study suggested that minocycline harms amyotrophic lateral sclerosis patients. Patients on minocycline declined more rapidly than those on placebo. The mechanism of this side effect is unknown, although a hypothesis is that the drug exacerbated an autoimmune component of the primary disease. The effect does not seem to be dose-dependent because the patients on high doses did not do worse than those on the low doses.The use of minocycline in acne vulgaris has been associated with skin and gut dysbiosis (see antibiotic misuse).
Interactions
The combination of minocycline with dairy, antacids, calcium and magnesium supplements, iron products, laxatives containing magnesium, or bile acid sequestrants may decrease minocyclines effectiveness by forming chelates. Combining it with isotretinoin, acitretin or other retinoids can increase the risk for intracranial hypertension. Minocycline significantly reduces concentrations of the anti-HIV drug atazanavir in the body.
Pharmacology
Mechanism of action
Pharmacokinetics
Minocycline is quickly and nearly completely absorbed from the upper part of the small intestine. Taking it together with food, including milk, has no relevant influence on resorption. It reaches highest blood plasma concentrations after one to two hours and has a plasma protein binding of 70–75%. The substance penetrates into almost all tissues; very high concentrations are found in the gallbladder and liver. It crosses the blood–brain barrier better than doxycycline and other tetracyclines, reaching therapeutically relevant concentrations in the cerebrospinal fluid and also in inflamed meninges.Minocycline is inactivated by metabolization in the liver to about 50%. The rest is predominantly excreted into the gut (in part via the gallbladder, in part directly from blood vessels) and eliminated via the feces. About 10–15% are eliminated via the kidneys. The biological half-life is 14–22 (11–26) hours in healthy people, up to 30 hours in those with kidney failure, and significantly longer in those with liver disease.
Chemistry
The drug is used in form of minocycline hydrochloride dihydrate, which is sparingly soluble in water and slightly soluble in ethanol. Minocycline reacts acidic in aqueous solution.
History
Minocycline was patented in 1961 and came into commercial use in 1971. A topical foam for treatment of acne was approved in 2019.
Society and culture
Trade names
Many forms of minocycline are no longer covered by patent, so it is marketed under a variety of trade names:
Minomycin
Minostad (in Europe, for the treatment of acne)
Akamin
Minocin
Minoderm
Cyclimycin
Arestin (1-mg doses administered locally into periodontal pockets, after scaling and root planing, for treatment of periodontal disease.)
Aknemin
Solodyn (extended-release, for the treatment of acne)
Dynacin
Sebomin
Mino-Tabs
Acnamino
Minopen (in Japan)
Maracyn 2 (for treatment of bacterial infections in aquarium fish and amphibians)
Quatrocin (in Syria)
Minox (in Ireland)
Minoz (in India and Romania)
Divaine (in India)
Vinocyclin 100 (100-mg dose approved for treatment of acne in Vietnam)
Dentomycin (2% minocylcine gel for use in periodontal pockets)
Amzeeq (4% foam, approved for treatment of acne United States)
Zilxi (1.5% foam, approved for treatment of rosacea in the United States)StoneBridge Pharma also markets Minocycline as Cleeravue-M in combination with SteriLid eyelid cleanser in the treatment of rosacea blepharitis.
Society and culture
It is available as a generic medication.
Research
Early research has found a tentative benefit from minocycline in schizophrenia, with several trials underway. A 2014 meta-analysis found minocycline may reduce negative and total symptom scores and was well tolerated.Current research is examining the possible neuroprotective and anti-inflammatory effects of minocycline against the progression of a group of neurodegenerative disorders including multiple sclerosis, rheumatoid arthritis, Huntingtons disease, and Parkinsons disease. As mentioned above, minocycline harms ALS patients.
Minocycline is also known to indirectly inhibit inducible nitric oxide synthase.A trial found no difference between minocycline and placebo in people with Alzheimers disease. Minocycline also has been used as a "last-ditch" treatment for toxoplasmosis in AIDS patients. Minocycline is somewhat neuroprotective in mouse models of Huntingtons disease.A 2007 study reported the impact of the antibiotic minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in 40 MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in the patient group prior to treatment (1.3/year pre-enrollment; 1.2/year during a three-month baseline period), no relapses occurred between months 6 and 24 on minocycline. Also, despite significant MRI disease-activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of interleukin-12 (IL-12), which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1 (VCAM-1). The activity of matrix metalloproteinase-9 was decreased by treatment. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.The overall antidepressant effect size of minocycline compared to placebo in a meta-analysis was -0.78, indicative of a potential antidepressant effect.In ongoing research and trial minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients.
Data from cellular and animal models
PARP1 inhibition Ki = 13.8 nM
Neuroprotection IC50 = 10 nM
Microglia full inhibition = 20 nM
Suppression of the mouses locomotor activity = 0.5 mg/kg
References
External links
"Minocycline". Drug Information Portal. U.S. National Library of Medicine. |
Bupivacaine/meloxicam | Bupivacaine/meloxicam, sold under the brand name Zynrelef, is a fixed-dose combination medication used to treat pain in small to medium-sized wounds after surgery. It contains bupivacaine and meloxicam.The most common side effects of bupivacaine/meloxicam are dizziness, constipation, vomiting, and headache.It was approved for medical use in the European Union in September 2020, and in the United States in May 2021.
Medical uses
In the European Union, the combination bupivacaine/meloxicam is indicated for treatment of somatic postoperative pain from small- to medium-sized surgical wounds in adults.In the United States it is indicated for soft tissue or periarticular instillation to produce postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy, and total knee arthroplasty in adults.
References
External links
"Bupivacaine mixture with meloxicam". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03295721 for "Bunionectomy Study for Postoperative Analgesia (EPOCH 1)" at ClinicalTrials.gov
Clinical trial number NCT03237481 for "Phase 3 Herniorrhaphy Study for Postoperative Analgesia (EPOCH 2)" at ClinicalTrials.gov
Clinical trial number NCT03015532 for "Total Knee Arthroplasty Infiltration Study for Postoperative Analgesia" at ClinicalTrials.gov |
Rasburicase | Rasburicase (trade names Elitek in the US and Fasturtec in the EU) is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.Rasburicase (Q00511) is a tetrameric protein with identical subunits. Each subunit is made up of a single 301 amino acid polypeptide chain with a molecular mass of about 34 kDa. The drug product is a sterile, white to off-white, lyophilized powder intended for intravenous administration following reconstitution with a diluent. Elitek (rasburicase) is supplied in 3 mL and 10 mL colorless, glass vials containing rasburicase at a concentration of 1.5 mg/mL after reconstitution.It is on the World Health Organizations List of Essential Medicines.
Medical uses
Rasburicase is approved for use by the U.S. Food and Drug Administration (and European counterparts) for the prevention and treatment of tumor lysis syndrome (TLS) in people receiving chemotherapy for hematologic cancers such as leukemias and lymphomas. However, it is not clear if it results in important benefits such as decreased kidney problems or decreased risk of death as of 2017.It is being investigated for treating severely high blood levels of uric acid from other sources. For example, it has been used for hyperuricemia in gout, in other rheumatologic conditions, and in rhabdomyolysis with kidney failure.
Contraindication
Rasburicase use is contraindicated in patients with a G6PDH deficiency.
Side effects
Rasburicase administration can cause anaphylaxis (incidence unknown); methemoglobinemia may occur in susceptible individuals such as those with G6PDH deficiency due to the production of hydrogen peroxide in the urate oxidase reaction. Testing patients for G6PDH deficiency prior to starting a course of rasburicase has been recommended.
Pharmacology
Mechanism of Action
In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite allantoin with carbon dioxide and hydrogen peroxide as byproducts in the chemical reaction.
Pharmacodynamics
The measurement of plasma uric acid was used to evaluate the effectiveness of rasburicase in clinical studies. Following administration of either 0.15 or 0.20 mg/kg rasburicase daily for up to 5 days, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least 7 days. There was no evidence of a dose response effect on uric acid control for doses between 0.15 and 0.20 mg/kg rasburicase.
Pharmacokinetics
The pharmacokinetics of rasburicase were evaluated in both pediatric and adult patients with leukemia, lymphoma or other hematological malignancies. Rasburicase exposure, as measured by AUC0-24 hr and Cmax, tended to increase with a dose range from 0.15 to 0.2 mg/kg. The mean terminal half-life was similar between pediatric and adult patients and ranged from 15.7 to 22.5 hours. The mean volume of distribution of rasburicase ranged from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients, respectively. Minimal accumulation of rasburicase ( < 1.3 fold) was observed between days 1 and 5 of dosing. In adults, age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=22).
Society and culture
Economics
Rasburicase is much more expensive than the conventional uric acid lowering treatment for tophaceous gout.
References
External links
"Rasburicase". Drug Information Portal. U.S. National Library of Medicine. |
Benzphetamine | Benzphetamine (brand name Didrex) is a substituted amphetamine used short-term along with a doctor-approved, reduced-calorie diet, exercise, and behavioral program for weight loss. It is prescribed for obesity to people who have been unable to lose weight through exercise and dieting alone. It is a prodrug to dextroamphetamine and dextromethamphetamine.Benzphetamine is an anorectic, primarily promoting weight loss through reduced appetite. It also slightly increases metabolism.
Pharmacology
Benzphetamine is a sympathomimetic amine and is classified as an anorectic. The drugs main function is to reduce appetite, which in turn reduces caloric intake.Although the mechanism of action of the sympathomimetic appetite suppressants in the treatment of obesity is not fully known, these medications have pharmacological effects similar to those of amphetamines. Amphetamine and related sympathomimetic medications (such as benzphetamine) are thought to stimulate the release of norepinephrine and/or dopamine from storage sites in nerve terminals of the lateral hypothalamic feeding center, thereby producing a decrease in appetite. This release is mediated through the binding of benzphetamine to VMAT2 and inhibiting its function, causing a release of these neurotransmitters into the synaptic cleft through their reuptake transporters. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class.Benzphetamine has a half-life of 4–6 hours.
Contraindications
Benzphetamine is contraindicated in patients with advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyper-thyroidism, known hypersensitivity or idiosyncrasy to sympathomimetic amines, and glaucoma, or who have recently used a MAOI. Benzphetamine should not be given to patients who are in an agitated state or who have a history of drug abuse.
Controlled substance classification
Benzphetamine is unique in its classification as a Schedule III drug in the United States. (Most members of the amphetamine family are classified in the more highly regulated Schedule II.) Benzphetamine is metabolized by the human body into amphetamine and methamphetamine, making it one of a number of drugs to undergo in vivo conversion to a substance of higher addiction and abuse potential.
References
External links
"Benzphetamine". Drug Information Portal. U.S. National Library of Medicine.
"Benzphetamine hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Ritonavir | Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor and is used with other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C. It is taken by mouth. Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.Common side effects include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet. Serious side effects include liver problems, pancreatitis, allergic reactions, and arrythmias. Serious interactions may occur with a number of other medications including amiodarone and simvastatin. At low doses it is considered to be acceptable for use during pregnancy. Ritonavir is of the protease inhibitor class. Typically, however, it is used to inhibit the enzyme that metabolizes other protease inhibitors. This inhibition allows lower doses of these latter medications to be used.Ritonavir was patented in 1989 and came into medical use in 1996. It is on the World Health Organizations List of Essential Medicines. Ritonavir capsules were approved as a generic medication in the United States in 2020.
Medical uses
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients.In December 2021, the combination of nirmatrelvir and ritonavir was granted emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease COVID-19. The co-packaged medications are sold under the brand name Paxlovid. Paxlovid is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19. On 31 December 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved the same combination "for people with mild to moderate COVID-19 who are at high risk of developing severe COVID-19".
Side effects
When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below.
Adverse drug reactions
Ritonavir exhibits hepatic activity.
Ritonavir induces CYP1A2 and inhibits the major P450 isoforms 3A4 and 2D6. Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.Due to it being a strong inhibitor (that causes at least a five-fold increase in the plasma AUC values, or more than 80% decrease in clearance) of both Cytochrome P450 enzymes CYP2D6 and CYP3A4, ritonavir can severely potentiate and prolong the serious and life-threatening side-effects of the opioid painkiller Oxycodone.
Mechanism of action
Ritonavir was originally developed as an inhibitor of HIV protease, one of a family of pseudo-C2-symmetric small molecule inhibitors.Ritonavir is rarely used for its own antiviral activity but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular enzyme, in intestines, liver, and elsewhere, that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4). The drug binds to and inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART. However, because of the general role of CYP3A4 in xenobiotic metabolism, dosing with ritonavir also affects the efficacy of numerous other medications, adding to the challenge of prescribing drugs concurrently.
Pharmacodynamics and pharmacokinetics
The capsules of the medication do not have the same bioavailability as the tablets.Ritonavir was demonstrated to have an in vitro potency of EC50=0.02µM and highly sustained concentration in plasma after oral administration in several species.
Chemistry
Ritonavir was initially derived from a moderately potent and orally bioavailable small molecule, A-80987. The P3 and P2′ heterocyclic groups of A-80987 were redesigned to create an analogue, now known as ritonavir, with improved pharmacokinetic properties to the original.Full details of the synthesis of ritonavir were first published by scientists from Abbott Laboratories.
In the first step shown, an aldehyde derived from phenylalanine is treated with zinc dust in the presence of vanadium(III) chloride. This results in a pinacol coupling reaction which dimerizes the material to provide an intermediate which is converted to its epoxide and then reduced to (2S,3S,5S)-2,5-diamino-1,6-diphenylhexan-3-ol. Importantly, this retains the absolute stereochemistry of the amino acid precursor. The diamine is then treated sequentially with two thiazole derivatives, each linked by an amide bond, to provide ritonavir.
History
Ritonavir is sold as Norvir by AbbVie, Inc.. The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996, As a result of the introduction of "highly active antiretroviral thearap[ies]" the annual U.S. HIV-associated death rate fell from over 50,000 to about 18,000 over a period of two years.In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4.In 2021, a combination of ritonavir with nirmatrelvir, an orally active 3C-like protease inhibitor, was developed for the treatment of COVID-19. Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug. In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset.
Polymorphism and temporary market withdrawal
Ritonavir was originally dispensed as a capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I. However, like many drugs, crystalline ritonavir can exhibit polymorphism, i.e., the same molecule can crystallize into more than one crystal type, or polymorph, each of which contains the same repeating molecule but in different crystal packings/arrangements. The solubility and hence the bioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy, more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market. As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II, the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir; and indeed, form II was found in production lines, effectively halting ritonavir production. Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension. It has been estimated that Abbott lost more than $250 million USD as a result, and the incident is often cited as a high-profile example of disappearing polymorphs.The companys research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap. In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration. Ritonavir produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010.
Society and culture
Economics
In 2003, Abbott (AbbVie, Inc.) raised the price of a Norvir course from US$1.71 per day to US$8.57 per day, leading to claims of price gouging by patients groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004, that it lacked the legal right to allow generic production of Norvir.
Research
In 2020, the fixed-dose combination of lopinavir/ritonavir was found not to work in severe COVID-19. In the trial the medication was started around thirteen days after the start of symptoms. Virtual screening of the 1930 FDA-approved drugs followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS-CoV-2 spike (S) protein to the human angiotensin-converting enzyme-2 (hACE2) receptor, which is critical for the virus entry into human cells.
References
Further reading
Chemburkar SR, Bauer J, Deming K, Spiwek H, Patel K, Morris J, et al. (2000). "Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development". Organic Process Research & Development. 4 (5): 413–417. doi:10.1021/op000023y.
External links
"Ritonavir". Drug Information Portal. U.S. National Library of Medicine. |
Atoltivimab/maftivimab/odesivimab | Atoltivimab/maftivimab/odesivimab, sold under the brand name Inmazeb, is a fixed-dose combination of three monoclonal antibodies for the treatment of Zaire ebolavirus (Ebola virus). It contains atoltivimab, maftivimab, and odesivimab-ebgn and was developed by Regeneron Pharmaceuticals.The most common side effects include fever, chills, tachycardia (fast heart rate), tachypnea (fast breathing), and vomiting; however, these are also common symptoms of Ebola virus infection.Atoltivimab/maftivimab/odesivimab is the first FDA-approved treatment for Zaire ebolavirus. Atoltivimab/maftivimab/odesivimab was approved for medical use in the United States in October 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Atoltivimab/maftivimab/odesivimab is indicated for the treatment of infection caused by Zaire ebolavirus.
Contraindications
People who receive atoltivimab/maftivimab/odesivimab should avoid the concurrent administration of a live vaccine due to the treatments potential to inhibit replication of a live vaccine virus indicated for prevention of Ebola virus infection and possibly reduce the vaccines efficacy.
Pharmacology
Mechanism of action
Atoltivimab/maftivimab/odesivimab is a combination of Zaire ebolavirus glycoprotein-directed human monoclonal antibodies. The three antibodies target the glycoprotein that is on the surface of the Ebola virus. This glycoprotein normally attaches to the cell via a receptor and fuses the viral and host cell membranes allowing the virus to enter the cell. The antibodies can bind to it simultaneously at three different locations and block attachment and entry of the virus.This combination drug targets the Zaire species of Ebola virus. The Sudan and Bundibugyo strains have also caused outbreaks, and it is unlikely that it would be effective against these strains.
History
Early development
The 2014 Ebola outbreak killed more than 11,300 people. Regeneron used its VelociGene, VelocImmune and VelociMab antibody discovery and production technologies and coordinated with the U.S. governments Biomedical Advanced Research and Development Authority (BARDA). The therapy was developed in six months and a Phase 1 trial in healthy humans was completed in 2015.
PALM trial
During the 2018 Équateur province Ebola outbreak, a similar monoclonal antibody treatment, mAb114, was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. mAb114 was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. mAb114 was sent along with other therapeutic agents to the outbreak sites. However, the outbreak came to a conclusion before any therapeutic agents were given to patients.Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, mAb114 received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols. In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing mAb114, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725.
This is the second largest outbreak with (as of January 2020) over 3,400 confirmed or probable cases, including more than 2,200 who have died.An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that mAb114 and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and Remdesivir groups were 49% and 53% compared to 34% and 29% for mAb114 and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for mAB114 and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and mAb114, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either mAb114 or REGN-EB3.In August 2019, Congolese health officials announced it was more effective compared to two other treatments being used at the time.Among patients treated with it, 34% died; the mortality rate improved if the drug was administered soon after infection, in a timely diagnosis – critical for those infected with diseases like Ebola that can cause sepsis and, eventually, multiple organ dysfunction syndrome, more quickly than other diseases. The survival rate if the drug was administered shortly after the infection was 89%.
Atoltivimab/maftivimab/odesivimab was evaluated in 382 adult and pediatric participants with confirmed Zaire ebolavirus infection in one clinical trial (the PALM trial) and as part of an expanded access program conducted in the Democratic Republic of the Congo (DRC) during an Ebola virus outbreak in 2018/2019. In the PALM trial, the safety and efficacy of atoltivimab/maftivimab/odesivimab was evaluated in a multi-center, open-label, randomized controlled trial, in which 154 participants received atoltivimab/maftivimab/odesivimab (50 mg of each monoclonal antibody) intravenously as a single infusion, and 168 participants received an investigational control. The trial enrolled pediatric and adult participants (including pregnant women) with Zaire ebolavirus infection. All participants received standard, supportive care for the disease. The participants and the health care providers knew which treatment was being given. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all participants who were randomized and concurrently eligible to receive either atoltivimab/maftivimab/odesivimab or the investigational control during the same time period of the trial. Of the 154 participants who received atoltivimab/maftivimab/odesivimab, 33.8% died after 28 days, compared to 51% of the 153 participants who received a control. In the expanded access program, an additional 228 participants received atoltivimab/maftivimab/odesivimab.
Regulatory status
The FDA granted the application of atoltivimab/maftivimab/odesivimab-ebgn orphan drug and breakthrough therapy designations. The FDA granted the approval of Inmazeb to Regeneron Pharmaceuticals with an indication for the treatment of infection caused by Zaire ebolavirus in October 2020.The drug has also received orphan drug designation from the European Medicines Agency.
References
Further reading
External links
"Atoltivimab". Drug Information Portal. U.S. National Library of Medicine.
"Maftivimab". Drug Information Portal. U.S. National Library of Medicine.
"Odesivimab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03719586 for "Investigational Therapeutics for the Treatment of People With Ebola Virus Disease" at ClinicalTrials.gov
"Making a Drug You Hope No One Will Ever Need". Regeneron Pharmaceuticals. |
Benzamycin | Benzamycin is a topical gel containing of 5% benzoyl peroxide and 3% erythromycin. Its main usage is to fight acne. Benzamycin is a prescription medication.Side effects include dry skin, stinging, redness, and itchy rash (urticaria), with recommended usage is 2 times per day, once in the morning and once in the evening, or as prescribed by a doctor. The affected area should be washed with soap and warm water, rinsed, and gently dried before applying the gel. Using an oil-free face moisturizer in conjunction with Benzamycin is recommended.
On March 30, 2004, a generic form of Benzamycin was released by pharmaceutical company Atrix Laboratories.
References
External links
"Atrix Laboratories, Inc. (ATRX) Receives FDA Approval For Erythromycin/Benzoyl Peroxide", Biospace.com, 10/19/2005 |
Tropicamide/hydroxyamfetamine | Tropicamide/hydroxyamfetamine (trade name Paremyd) is a combination drug used as an ophthalmic solution to induce mydriasis. It consists of:
Tropicamide (0.25%), an anticholinergic drug
Hydroxyamfetamine (norpholedrine, 1%), a sympathomimetic drug
== References == |
Muses | In ancient Greek religion and mythology, the Muses (Ancient Greek: Μοῦσαι, romanized: Moûsai, Greek: Μούσες, romanized: Múses) are the inspirational goddesses of literature, science, and the arts. They were considered the source of the knowledge embodied in the poetry, lyric songs, and myths that were related orally for centuries in ancient Greek culture.
Melete, Aoede, and Mneme are the original Boeotian Muses, and Calliope, Clio, Erato, Euterpe, Melpomene, Polyhymnia, Terpsichore, Thalia, and Urania are the nine Olympian Muses.
In modern figurative usage, a Muse may be a source of artistic inspiration.
Etymology
The word Muses (Ancient Greek: Μοῦσαι, romanized: Moûsai) perhaps came from the o-grade of the Proto-Indo-European root *men- (the basic meaning of which is put in mind in verb formations with transitive function and have in mind in those with intransitive function), or from root *men- (to tower, mountain) since all the most important cult-centres of the Muses were on mountains or hills. R. S. P. Beekes rejects the latter etymology and suggests that a Pre-Greek origin is also possible.
Number and names
The earliest known records of the Muses come from Boeotia (Boeotian muses). Some ancient authorities regarded the Muses as of Thracian origin. In Thrace, a tradition of three original Muses persisted.In the first century BC, Diodorus Siculus cited Homer and Hesiod to the contrary, observing:
Writers similarly disagree also concerning the number of the Muses; for some say that there are three, and others that there are nine, but the number nine has prevailed since it rests upon the authority of the most distinguished men, such as Homer and Hesiod and others like them.
Diodorus states (Book I.18) that Osiris first recruited the nine Muses, along with the satyrs, while passing through Aethiopia, before embarking on a tour of all Asia and Europe, teaching the arts of cultivation wherever he went.
According to Hesiods account (c. 600 BC), generally followed by the writers of antiquity, the Nine Muses were the nine daughters of Zeus and Mnemosyne (i.e., "Memory" personified), figuring as personifications of knowledge and the arts, especially poetry, literature, dance and music.
The Roman scholar Varro (116–27 BC) relates that there are only three Muses: one born from the movement of water, another who makes sound by striking the air, and a third who is embodied only in the human voice. They were called Melete or "Practice", Mneme or "Memory" and Aoide or "Song". The Quaestiones Convivales of Plutarch (46–120 AD) also report three ancient Muses (9.I4.2–4).However, the classical understanding of the Muses tripled their triad and established a set of nine goddesses, who embody the arts and inspire creation with their graces through remembered and improvised song and mime, writing, traditional music, and dance. It was not until Hellenistic times that the following systematic set of functions became associated with them, and even then some variation persisted both in their names and in their attributes:
According to Pausanias, who wrote in the later second century AD, there were originally three Muses, worshipped on Mount Helicon in Boeotia: Aoide (song or tune), Melete (practice or occasion), and Mneme (memory). Together, these three form the complete picture of the preconditions of poetic art in cult practice.
In Delphi too three Muses were worshiped, but with other names: Nete, Mese, and Hypate, which are assigned as the names of the three chords of the ancient musical instrument, the lyre.Alternatively, later they were called Cephisso, Apollonis, and Borysthenis - names which characterize them as daughters of Apollo.A later tradition recognized a set of four Muses: Thelxinoë, Aoide, Archē, and Melete, said to be daughters of Zeus and Plusia or of Ouranos.
One of the people frequently associated with the Muses was Pierus. By some he was called the father (by a Pimpleian nymph, called Antiope by Cicero) of a total of seven Muses, called Neilṓ (Νειλώ), Tritṓnē (Τριτώνη), Asōpṓ (Ἀσωπώ), Heptápora (Ἑπτάπορα), Achelōís, Tipoplṓ (Τιποπλώ), and Rhodía (Ῥοδία).
Mythology
According to Hesiods Theogony (seventh century BC), they were daughters of Zeus, king of the gods, and Mnemosyne, Titan goddess of memory. Hesiod in Theogony narrates that the Muses brought to people forgetfulness, that is, the forgetfulness of pain and the cessation of obligations.For Alcman and Mimnermus, they were even more primordial, springing from the early deities Ouranos and Gaia. Gaia is Mother Earth, an early mother goddess who was worshipped at Delphi from prehistoric times, long before the site was rededicated to Apollo, possibly indicating a transfer to association with him after that time.
Sometimes the Muses are referred to as water nymphs, associated with the springs of Helicon and with Pieris. It was said that the winged horse Pegasus touched his hooves to the ground on Helicon, causing four sacred springs to burst forth, from which the Muses, also known as pegasides, were born. Athena later tamed the horse and presented him to the Muses (compare the Roman inspiring nymphs of springs, the Camenae, the Völva of Norse Mythology and also the apsaras in the mythology of classical India).
Classical writers set Apollo as their leader, Apollon Mousēgetēs (Apollo Muse-leader). In one myth, the Muses judged a contest between Apollo and Marsyas. They also gathered the pieces of the dead body of Orpheus, son of Calliope, and buried them in Leivithra. In a later myth, Thamyris challenged them to a singing contest. They won and punished Thamyris by blinding him and robbing him of his singing ability.
According to a myth from Ovids Metamorphoses—alluding to the connection of Pieria with the Muses—Pierus, king of Macedon, had nine daughters he named after the nine Muses, believing that their skills were a great match to the Muses. He thus challenged the Muses to a match, resulting in his daughters, the Pierides, being turned into chattering jays (with κίσσα often erroneously translated as magpies) for their presumption.Pausanias records a tradition of two generations of Muses; the first are the daughters of Ouranos and Gaia, the second of Zeus and Mnemosyne. Another, rarer genealogy is that they are daughters of Harmonia (the daughter of Aphrodite and Ares), which contradicts the myth in which they were dancing at the wedding of Harmonia and Cadmus.
Children
Calliope had two sons, Ialemus and Orpheus, with Apollo. In another version of the story, the father of Orpheus was Oeagrus, but Apollo adopted him and taught him the skill of lyre while Calliope trained him in singing.
Linus was said to have been the son of Apollo and one of the Muses, either Calliope or Terpsichore or Urania. Rhesus was the son of Strymon and Calliope or Euterpe.
The sirens were the children of Achelous and Melpomene or Terpsichore. Kleopheme was the daughter of Erato and Malos. Hyacinth was the son of Clio, according to an unpopular account.
Hymenaeus was assigned as Apollos son by one of the muses, either Calliope, or Clio, or Terpsichore, or Urania. Corybantes were the children of Thalia and Apollo.
Cult
The Muses had several temples and shrines in ancient Greece, their two main cult centres being Mount Helikon in Boiotia and Pieria in Makedonia.
Strabo wrote:
"Helikon, not far distant from Parnassos, rivals it both in height and in circuit; for both are rocky and covered with snow, and their circuit comprises no large extent of territory. Here are the temple of the Mousai and Hippukrene and the cave of the Nymphai called the Leibethrides; and from this fact one might infer that those who consecrated Helikon to the Mousai were Thrakians, the same who dedicated Pieris and Leibethron and Pimpleia [in Pieria] to the same goddesses. The Thrakians used to be called Pieres, but, now that they have disappeared, the Makedonians hold these places."The cult of the Muses was also commonly connected to that of Apollo.
Emblems
Some Greek writers give the names of the nine Muses as Kallichore, Helike, Eunike, Thelxinoë, Terpsichore, Euterpe, Eukelade, Dia, and Enope.In Renaissance and Neoclassical art, the dissemination of emblem books such as Cesare Ripas Iconologia (1593 and many further editions) helped standardize the depiction of the Muses in sculpture and painting, so they could be distinguished by certain props. These props, or emblems, became readily identifiable by the viewer, enabling one immediately to recognize the Muse and the art with which she had become associated. Here again, Calliope (epic poetry) carries a writing tablet; Clio (history) carries a scroll and books; Euterpe (song and elegiac poetry) carries a flute, the aulos; Erato (lyric poetry) is often seen with a lyre and a crown of roses; Melpomene (tragedy) is often seen with a tragic mask; Polyhymnia (sacred poetry) is often seen with a pensive expression; Terpsichore (choral dance and song) is often seen dancing and carrying a lyre; Thalia (comedy) is often seen with a comic mask; and Urania (astronomy) carries a pair of compasses and the celestial globe.
Functions
In society
The Greek word mousa is a common noun as well as a type of goddess: it literally means art or poetry. According to Pindar, to "carry a mousa" is to excel in the arts. The word derives from the Indo-European root *men-, which is also the source of Greek Mnemosyne and mania, English mind, mental and monitor, Sanskrit mantra and Avestan Mazda.
The Muses, therefore, were both the embodiments and sponsors of performed metrical speech: mousike (whence the English term music) was just "one of the arts of the Muses". Others included science, geography, mathematics, philosophy, and especially art, drama, and inspiration. In the archaic period, before the widespread availability of books (scrolls), this included nearly all of learning. The first Greek book on astronomy, by Thales, took the form of dactylic hexameters, as did many works of pre-Socratic philosophy. Both Plato and the Pythagoreans explicitly included philosophy as a sub-species of mousike. The Histories of Herodotus, whose primary medium of delivery was public recitation, were divided by Alexandrian editors into nine books, named after the nine Muses.
For poet and "law-giver" Solon, the Muses were "the key to the good life"; since they brought both prosperity and friendship. Solon sought to perpetuate his political reforms by establishing recitations of his poetry—complete with invocations to his practical-minded Muses—by Athenian boys at festivals each year. He believed that the Muses would help inspire people to do their best.
In literature
Ancient authors and their imitators invoke Muses when writing poetry, hymns or epic history. The invocation occurs near the beginning of their work. It asks for help or inspiration from the Muses, or simply invites the Muse to sing directly through the author.
Originally, the invocation of the Muse was an indication that the speaker was working inside the poetic tradition, according to the established formulas. For example:
These things declare to me from the beginning,
ye Muses who dwell in the house of Olympus,
and tell me which of them first came to be.
— Hesiod (c. 700 BCE), Theogony (Hugh G. Evelyn-White translation, 2015)
Sing to me of the man, Muse, the man of twists and turns
driven time and again off course, once he had plundered
the hallowed heights of Troy.
—Homer (c. 700 - 600 BCE), in Book I of The Odyssey (Robert Fagles translation, 1996)
O Muse! the causes and the crimes relate;
What goddess was provokd, and whence her hate;
For what offence the Queen of Heavn began
To persecute so brave, so just a man; [...]
—Virgil (c. 29 - 19 BCE), in Book I of the Aeneid (John Dryden translation, 1697)
Besides Homer and Virgil, other famous works that included an invocation of the Muse are the first of the carmina by Catullus, Ovids Metamorphoses and Amores, Dantes Inferno (Canto II), Chaucers Troilus and Criseyde (Book II), Shakespeares Henry V (Act 1, Prologue), his 38th sonnet, and Miltons Paradise Lost (openings of Books 1 and 7).
In cults and modern museums
When Pythagoras arrived at Croton, his first advice to the Crotoniates was to build a shrine to the Muses at the center of the city, to promote civic harmony and learning. Local cults of the Muses often became associated with springs or with fountains. The Muses themselves were sometimes called Aganippids because of their association with a fountain called Aganippe. Other fountains, Hippocrene and Pirene, were also important locations associated with the Muses. Some sources occasionally referred to the Muses as "Corycides" (or "Corycian nymphs") after a cave on Mount Parnassos, called the Corycian Cave. Pausanias referred to the Muses by the surnames "Ardalides" or "Ardaliotides", because of a sanctuary to them at Troezen said to have been built by the mythical Ardalus.
The Muses were venerated especially in Boeotia, in the Valley of the Muses near Helicon, and in Delphi and the Parnassus, where Apollo became known as Mousēgetēs (Muse-leader) after the sites were rededicated to his cult.
Often Muse-worship was associated with the hero-cults of poets: the tombs of Archilochus on Thasos and of Hesiod and Thamyris in Boeotia all played host to festivals in which poetic recitations accompanied sacrifices to the Muses. The Library of Alexandria and its circle of scholars formed around a mousaion (i.e., museum or shrine of the Muses) close to the tomb of Alexander the Great. Many Enlightenment figures sought to re-establish a "Cult of the Muses" in the 18th century. A famous Masonic lodge in pre-Revolutionary Paris was called Les Neuf Soeurs (The Nine Sisters, that is, the Nine Muses); Voltaire, Benjamin Franklin, Danton, and other influential Enlightenment figures attended it. As a side-effect of this movement the word museum (originally, cult place of the Muses) came to refer to a place for the public display of knowledge.
Museia (Μούσεια) was a festival dedicated to Muses which was held every fifth year on the lower slopes of Mount Helicon in Boeotia. There was also another festival which was called Museia, which was celebrated in schools.
Places named after the Muses
In New Orleans, Louisiana, there are streets named for all nine. It is commonly held that the local pronunciation of the names has been colorfully anglicized in an unusual manner by the "Yat" dialect. The pronunciations are actually in line with the French, Spanish and Creole roots of the city.
Modern use in the arts
The Muses are explicitly used in modern English to refer to an artistic inspiration, as when one cites ones own artistic muse, and also implicit in words and phrases such as amuse, museum (Latinised from mouseion—a place where the Muses were worshipped), music, and musing upon. In current literature, the influential role that the Muse plays has been extended to the political sphere.
Gallery
Genealogy
See also
Apsara
Artistic inspiration
Divine inspiration
Leibethra
Pimpleia
Saraswati
Muses in popular culture
Notes
References
West, Martin L. (2007). Indo-European Poetry and Myth. Oxford University Press. ISBN 978-0-19-928075-9.
Chisholm, Hugh, ed. (1911). "Muses, The" . Encyclopædia Britannica. Vol. 19 (11th ed.). Cambridge University Press. pp. 59–60.
External links
Muses in ancient art; ancientrome.ru
Warburg Institute Iconographic Database (c. 1,000 images of the Muses) |
Reslizumab | Reslizumab is a humanized monoclonal antibody against human interleukin-5 (IL-5). Reslizumab binds specifically to IL-5, a key cytokine responsible for the differentiation, maturation, recruitment and activation of human eosinophils. By binding to human IL-5, it blocks its biological function; consequently survival and activity of eosinophils are reduced. The benefits with reslizumab are its ability to reduce the exacerbation rate and improve lung function and asthma-related quality of life in patients with severe eosinophilic asthma (with blood eosinophil count ≥ 400 cells/μL) and with at least one previous asthma exacerbation in the preceding year. The most common side effects are increased blood creatine phosphokinase, myalgia and anaphylactic reactions.The FDA approved reslizumab (US trade name Cinqair) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on 23 March 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.The European Medicines Agency recommended the granting of a marketing authorisation for reslizumab (EU trade name Cinqaero) intended as add-on treatment in adult patients with severe eosinophilic asthma on 23 June 2016.Reslizumab is supplied as a refrigerated, sterile, single-use, preservative-free solution for intravenous infusion. The reslizumab solution is a slightly hazy/opalescent, slightly yellow liquid and is supplied as 100 mg in a 10 mL glass vial. Each single-use vial of reslizumab is formulated as 10 mg/mL reslizumab in an aqueous solution containing 2.45 mg/mL sodium acetate trihydrate, 0.12 mg/mL glacial acetic acid, and 70 mg/mL sucrose, with a pH of 5.5.
Medical uses
Eosinophilic asthma
Reslizumab was first used for eosinophilic asthma in 2008. In a 106-patient, phase II clinical trial, the researchers showed reslizumab was effective in reducing sputum eosinophils. Furthermore, the patients receiving reslizumab showed improvements in airway function, and a general trend toward greater asthma control than those receiving placebo was observed. A large, 981-patient, phase III clinical trial showed that reslizumab was effective at improving lung function, asthma control, and quality of life in comparison to placebo. These results led to the FDA approval for the maintenance treatment of severe asthma in patients aged 18 years and older, with an eosinophilic phenotype on March 23, 2016.
Adverse effects
Common adverse effects include:
oropharyngeal painLess common adverse effects include:
musculoskeletal pain
neck pain
muscle spasms
extremity pain
muscle fatigue
anaphylaxis
malignancyThe most common adverse effect of reslizumab was oropharyngeal (mouth and throat) pain. According to the phase III clinical trials data, oropharyngeal pain occurred in ≥2% of individuals along with elevated baseline creatine phosphokinase (CPK), which was more common in patients treated with reslizumab versus placebo. Myalgia was also reported more in patients in the reslizumab 3 mg/kg group versus the placebo group as well as some musculoskeletal adverse reactions. Lastly, some serious adverse reactions that occurred in subjects treated with reslizumab but not in those treated with placebo included anaphylaxis and malignancy.
Pharmacology
Mechanism of action
Reslizumab is an interleukin-5 antagonist monoclonal antibody. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Eosinophils play a role in the mediation of inflammation in the airways. Eosinophilic asthma is a phenotype of asthma that is characterized by the higher than normal presence of eosinophils in the lung and sputum. It has been shown that the numbers of eosinophils in the blood and bronchial fluid can correlate with asthma severity. Reslizumab binds to IL-5 with a dissociation constant of 81 pM and inhibiting IL-5 signaling, which reduces the production and survival of eosinophils. However, the mechanism of reslizumab action in asthma has not been definitively established.
Pharmacodynamics
Reductions in blood eosinophil counts were observed following the first dose of reslizumab and maintained through 52 weeks of treatment. In phase III clinical trials, mean eosinophil counts were 696 cells/µL (n=245) and 624 cells/µL (n=244) at baseline. Following 52 weeks of reslizumab treatment, eosinophil cells were counted and were reported to be 55 cells/µL (92% reduction, n=212) and 496 cells/µL (21% reduction, n=212) for the reslizumab and placebo treatment groups, respectively. Furthermore, eosinophil count returned towards baseline in those reslizumab-treated patients who completed a follow-up assessment (n=35, 480 cells/µL), approximately 120 days after the last dose of reslizumab. Therefore, reductions of blood eosinophils were related to reslizumab serum levels.
Pharmacokinetics
The pharmacokinetic characteristics of reslizumab are similar across the children and adults. Peak serum concentrations are observed at the end of infusion and declines in a biphasic manner. The mean observed accumulation ratio of reslizumab following multiple doses of administration ranged from 1.5 to 1.9-fold. Reslizumab has a volume of distribution of approximately 5 L, clearance of approximately 7 mL/hour, and a half-life of about 24 days. Reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids, as are other monoclonal antibodies.
History
Reslizumab was initially developed by Chuan-Chu Chou at Schering-Plough and was previously known as SCH-55700. In 1993, Chou and his group at Schering-Plough were granted the patent for the design, cloning and expression of the reslizumab drug. Ception Therapeutics acquired the drug and continued its development under the name CTx55700. In 2010, Ception Therapeutics was acquired by Cephalon for $250 million and the drug continued under development under the codename CEP-38072. In 2011, Teva Pharmaceuticals acquired Cephalon for $6.8 billion and continued the development of reslizumab.
References
External links
"Reslizumab". Drug Information Portal. U.S. National Library of Medicine. |
Bismuth subsalicylate | Bismuth subsalicylate, sold generically as pink bismuth and under the brand names Pepto-Bismol and BisBacter, is an antacid elixir medication used to treat temporary discomforts of the stomach and gastrointestinal tract, such as nausea, heartburn, indigestion, upset stomach, and diarrhea.
Bismuth subsalicylate has the empirical chemical formula of C7H5BiO4, and it is a colloidal substance obtained by hydrolysis of bismuth salicylate (Bi(C6H4(OH)CO2)3).
Medical uses
As a derivative of salicylic acid, bismuth subsalicylate displays anti-inflammatory and bactericidal action. It also acts as an antacid.
Adverse effects
There are some adverse effects. It can cause a black tongue and black stools in some users of the drug when it combines with trace amounts of sulfur in saliva and the colon to form bismuth sulfide. Bismuth sulfide is a highly insoluble black salt, and the discoloration seen is temporary and harmless.
Long-term use (greater than six weeks) may lead to accumulation and toxicity. Some of the risks of salicylism can apply to the use of bismuth subsalicylate.Children should not take medication with bismuth subsalicylate while recovering from influenza or chicken pox, as epidemiologic evidence points to an association between the use of salicylate-containing medications during certain viral infections and the onset of Reye syndrome. For the same reason, it is typically recommended that nursing mothers not use medication containing bismuth subsalicylate because small amounts of the medication are excreted in human breast milk, and these pose a theoretical risk of Reyes syndrome to nursing children.Salicylates are very toxic to cats, and thus bismuth subsalicylate should not be administered to cats.The British National Formulary does not recommend bismuth-containing antacids (unless chelated), cautioning that absorbed bismuth can be neurotoxic, causing encephalopathy, and that such antacids tend to be constipating.
Drug interactions
There is an increased risk of bleeding when using bismuth subsalicylate and anticoagulation therapy, like Coumadin (Warfarin)
Mechanism of action
Bismuth subsalicylate is used as an antacid and antidiarrheal, and to treat some other gastrointestinal symptoms, such as nausea. The means by which this occurs is still not well documented. It is thought to be some combination of the following:
Stimulation of absorption of fluids and electrolytes by the intestinal wall (antisecretory action)
As a salicylate, reducing inflammation/irritation of stomach and intestinal lining through inhibition of prostaglandin G/H synthase 1/2
Reduction in hypermotility of the stomach
Inhibits adhesion and filmogenesis by Escherichia coli
Bactericidal action of a number of its subcomponents, including salicylic acid
Bactericidal action via a so-called oligodynamic effect in which small amounts of heavy metals such as bismuth damage many different bacteria species.
Weak antacid propertiesIn vitro and in vivo data have shown that bismuth subsalicylate hydrolyzes in the gut to bismuth oxychloride and salicylic acid and less commonly bismuth hydroxide. In the stomach, this is likely an acid-catalyzed hydrolysis. The salicylic acid is absorbed and therapeutical concentrations of salicylic acid can be found in blood after bismuth subsalicylate administration. Bismuth oxychloride and bismuth hydroxide are both believed to have bactericidal effects, as is salicylic acid for enterotoxigenic E. coli a common cause of "travelers diarrhea."Organobismuth compounds have historically been used in growth media for selective isolation of microorganisms. Such salts have been shown to inhibit proliferation of Helicobacter pylori, other enteric bacteria, and some fungi.
Structure
Despite its common usage and commercial significance, the exact structure of the pharmaceutical long remained undetermined, but was revealed, through the use of advanced electron crystallography techniques, to be a layered coordination polymer with the formula BiO(C7H5O3). In the structure, both the carboxylate and phenol groups of the salicylate coordinate towards the bismuth cations. The determination of bismuth subsalicylate had long been hindered due to the small particle size as well as defects within the structure, arising from variations in the stacking arrangement of the bismuth subsalicylate layers, which could be observed as part of the structural investigation.
History
While bismuth salts were in use in Europe by the late 1700s, the combination of bismuth subsalicylate and zinc salts for astringency with salol (phenyl salicylate) appears to have begun in the US in the early 1900s as a remedy for life-threatening diarrhea in infants with cholera. At first sold directly to physicians, it was first marketed as Bismosal in 1918.Pepto-Bismol began being sold in 1900 or 1901 by a doctor in New York. It was originally sold as a remedy for infant diarrhea by Norwich Pharmacal Company under the name "Bismosal: Mixture Cholera Infantum". It was renamed Pepto-Bismol in 1919. Norwich Eaton Pharmaceuticals was acquired by Procter and Gamble in 1982.As of 1946 and 1959, Canadian advertisements placed by Norwich show the product as Pepto-Besmal both in graphic and text.Pepto-Bismol is an over-the-counter drug currently produced by the Procter & Gamble company in the United States, Canada and the United Kingdom. Pepto-Bismol is made in chewable tablets and swallowable caplets, but it is best known for its original formula, which is a thick liquid. This original formula is a medium pink in color, with a teaberry (methyl salicylate) flavor.Generic bismuth subsalicylate, and other branded versions of the drug, are widely available in pill and liquid form.
References
External links
Andrews PC, Deacon GB, Forsyth CM, Junk PC, Kumar I, Maguire M (August 2006). "Towards a structural understanding of the anti-ulcer and anti-gastritis drug bismuth subsalicylate". Angewandte Chemie. 45 (34): 5638–42. doi:10.1002/anie.200600469. PMID 16865763. |
Bacitracin/polymyxin B | Bacitracin/polymyxin B (trade name Polysporin among others) is a topical antibiotic cream or ointment. The active ingredients are polymyxin B, bacitracin and occasionally garamycin or gramicidin. Though Polysporin is marketed in the United States, it holds a much smaller market share than in Canada and acts as a substitute to J&Js Neosporin for those allergic to the antibiotic neomycin; although allergy to Bacitracin/Polymyxin B has also been reported. There is also an ophthalmological ointment, eye and ear drops.
References
External links
Official Canadian Site
Official U.S. Site |
Prednisone | Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and adrenal insufficiency along with other steroids. It is taken by mouth.Common side effects with long-term use include cataracts, bone loss, easy bruising, muscle weakness, and thrush. Other side effects include weight gain, swelling, high blood sugar, increased risk of infection, and psychosis. It is generally considered safe in pregnancy and low doses appear to be safe when breastfeeding. After prolonged use, prednisone needs to be stopped gradually.Prednisone is a prodrug and must be converted to prednisolone by the liver before it becomes active. Prednisolone then binds to glucocorticoid receptors, activating them and triggering changes in gene expression.Prednisone was patented in 1954 and approved for medical use in the United States in 1955. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 30th most commonly prescribed medication in the United States, with more than 19 million prescriptions.
Medical uses
Prednisone is used for many different autoimmune diseases and inflammatory conditions, including asthma, gout, COPD, CIDP, rheumatic disorders, allergic disorders, ulcerative colitis and Crohns disease, granulomatosis with polyangiitis, adrenocortical insufficiency, hypercalcemia due to cancer, thyroiditis, laryngitis, severe tuberculosis, hives, lipid pneumonitis, pericarditis, multiple sclerosis, nephrotic syndrome, sarcoidosis, to relieve the effects of shingles, lupus, myasthenia gravis, poison oak exposure, Ménières disease, autoimmune hepatitis, giant-cell arteritis, the Herxheimer reaction that is common during the treatment of syphilis, Duchenne muscular dystrophy, uveitis, and as part of a drug regimen to prevent rejection after organ transplant.Prednisone has also been used in the treatment of migraine headaches and cluster headaches and for severe aphthous ulcer. Prednisone is used as an antitumor drug. It is important in the treatment of acute lymphoblastic leukemia, non-Hodgkin lymphomas, Hodgkins lymphoma, multiple myeloma, and other hormone-sensitive tumors, in combination with other anticancer drugs.
Prednisone is often also prescribed as a form of treatment for Sudden Sensorineural Hearing Loss (SSNHL).Prednisone can be used in the treatment of decompensated heart failure to increase renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics. In terms of the mechanism of action for this purpose: prednisone, a glucocorticoid, can improve renal responsiveness to atrial natriuretic peptide by increasing the density of natriuretic peptide receptor type A in the renal inner medullary collecting duct, thereby inducing a potent diuresis.At high doses it may be used to prevent rejection following organ transplant.
Side effects
Short-term side effects, as with all glucocorticoids, include high blood glucose levels (especially in patients with diabetes mellitus or on other medications that increase blood glucose, such as tacrolimus) and mineralocorticoid effects such as fluid retention. The mineralocorticoid effects of prednisone are minor, which is why it is not used in the management of adrenal insufficiency, unless a more potent mineralocorticoid is administered concomitantly.
It can also cause depression or depressive symptoms and anxiety in some individuals.Long-term side effects include Cushings syndrome, steroid dementia syndrome, truncal weight gain, glaucoma and cataracts, diabetes mellitus type 2, and depression upon dose reduction or cessation. Long-term steroids can also increase the risk of osteoporosis, but research has found that few of these people were taking medications to protect bones. Prednisone also results in leukocytosis.When used as treatment for sudden deafness or sudden sensorineural hearing loss, it can cause or exacerbate Tinnitus or a ringing in the ears.
Major
Source:
Minor
Source:
Dependency
Adrenal suppression will begin to occur if prednisone is taken for longer than seven days. Eventually, this may cause the body to temporarily lose the ability to manufacture natural corticosteroids (especially cortisol), which results in dependence on prednisone. For this reason, prednisone should not be abruptly stopped if taken for more than seven days; instead, the dosage should be gradually reduced. This weaning process may be over a few days if the course of prednisone was short, but may take weeks or months if the patient had been on long-term treatment. Abrupt withdrawal may lead to an Addisonian crisis. For those on chronic therapy, alternate-day dosing may preserve adrenal function and thereby reduce side effects.Glucocorticoids act to inhibit feedback of both the hypothalamus, decreasing corticotropin-releasing hormone (CRH), and corticotrophs in the anterior pituitary gland, decreasing the amount of adrenocorticotropic hormone (ACTH). For this reason, glucocorticoid analogue drugs such as prednisone down-regulate the natural synthesis of glucocorticoids. This mechanism leads to dependence in a short time and can be dangerous if medications are withdrawn too quickly. The body must have time to begin synthesis of CRH and ACTH and for the adrenal glands to begin functioning normally again.
Prednisone may start to result in the suppression of the hypothalamic-pituitary-adrenal (HPA) axis if used at doses 7–10 mg or higher for several weeks. This is approximately equal to the amount of endogenous cortisol produced by the body every day. As such, the HPA axis starts to become suppressed and atrophy. If this occurs the patient should be tapered off prednisone slowly to give the adrenal gland enough time to regain its function and endogenous production of steroids. Supplemental doses, or "stress doses" may be required in those with HPA axis suppression who are experiencing a higher degree of stress (e.g., illness, surgery, trauma, etc.). Failing to do so in such situations could be life-threatening.
Withdrawal
The magnitude and speed of dose reduction in corticosteroid withdrawal should be determined on a case-by-case basis, taking into consideration the underlying condition being treated, and individual patient factors such as the likelihood of relapse and the duration of corticosteroid treatment. Gradual withdrawal of systemic corticosteroids should be considered in those whose disease is unlikely to relapse and have:
received more than 40 mg prednisone (or equivalent) daily for more than 1 week
been given repeat doses in the evening
received more than 3 weeks of treatment
recently received repeated courses (particularly if taken for longer than 3 weeks)
taken a short course within 1 year of stopping long-term therapy
other possible causes of adrenal suppressionSystemic corticosteroids may be stopped abruptly in those whose disease is unlikely to relapse and who have received treatment for 3 weeks or less and who are not included in the patient groups described above.
During corticosteroid withdrawal, the dose may be reduced rapidly down to physiological doses (equivalent to prednisolone 7.5 mg daily) and then reduced more slowly. Assessment of the disease may be needed during withdrawal to ensure that relapse does not occur.
Pharmacology
Prednisone is a synthetic glucocorticoid used for its anti-inflammatory and immunosuppressive properties. Prednisone is a prodrug; it is metabolised in the liver by 11-β-HSD to prednisolone, the active drug. Prednisone has no substantial biological effects until converted via hepatic metabolism to prednisolone.
Pharmacokinetics
Prednisone is absorbed in the gastrointestinal tract and has a half life of 2–3 hours. it has a volume of distribution of 0.4–1 L/kg. The drug is cleared by hepatic metabolism using cytochrome P450 enzymes. Metabolites are excreted in the bile and urine.
Lodotra
"Lodotra" is the brand name of an oral formulation, which releases prednisone four hours after ingestion. It is indicated for rheumatoid arthritis with morning stiffness. Taken at 10 p.m., it releases the drug at around 2 a.m.. The plasmic peak level is reached at 4 a.m., which is considered to be the optimal time for relieving morning stiffness. The drug was approved in the European Union, in January 2009.
Industry
The pharmaceutical industry uses prednisone tablets for the calibration of dissolution testing equipment according to the United States Pharmacopeia (USP).
Chemistry
Prednisone is a synthetic pregnane corticosteroid and derivative of cortisone and is also known as δ1-cortisone or 1,2-dehydrocortisone or as 17α,21-dihydroxypregna-1,4-diene-3,11,20-trione.
History
The first isolation and structure identifications of prednisone and prednisolone were done in 1950 by Arthur Nobile. The first commercially feasible synthesis of prednisone was carried out in 1955 in the laboratories of Schering Corporation, which later became Schering-Plough Corporation, by Arthur Nobile and coworkers. They discovered that cortisone could be microbiologically oxidized to prednisone by the bacterium Corynebacterium simplex. The same process was used to prepare prednisolone from hydrocortisone.The enhanced adrenocorticoid activity of these compounds over cortisone and hydrocortisone was demonstrated in mice.Prednisone and prednisolone were introduced in 1955 by Schering and Upjohn, under the brand names Meticorten and Delta-Cortef, respectively. These prescription medicines are now available from a number of manufacturers as generic drugs.
References
External links
"Prednisone". Drug Information Portal. U.S. National Library of Medicine.
The National Center for Biotechnology Information: Prednisone
National Inventors Hall of Fame induction of Arthur Nobile |
Homatropine | Homatropine (Equipin, Isopto Homatropine) is an anticholinergic medication that is an antagonist at muscarinic acetylcholine receptors and thus the parasympathetic nervous system. It is used in eye drops as a cycloplegic (to temporarily paralyze accommodation), and as a mydriatic (to dilate the pupil).
The related chemical compound homatropine methylbromide (methylhomatropine) is a different medication. Homatropine is less potent than atropine and has a shorter duration of action. It is available as the hydrobromide salt. Homatropine is also given as an atropine substitute given to reverse the muscarinic and CNS effects associated with indirect cholinomimetic (anti-AChase) administration.
It is on the World Health Organizations List of Essential Medicines.
Side effects
Blurred vision
Sensitivity to light
Contraindications
Untreated glaucoma
Myasthenia gravis
Severe heart failure
Thyrotoxicosis
== References == |
Benzoyl peroxide | Benzoyl peroxide is a chemical compound (specifically, an organic peroxide) with structural formula (C6H5−C(=O)O−)2, often abbreviated as (BzO)2. In terms of its structure, the molecule can be described as two benzoyl (C6H5−C(=O)−, Bz) groups connected by a peroxide (−O−O−). It is a white granular solid with a faint odour of benzaldehyde, poorly soluble in water but soluble in acetone, ethanol, and many other organic solvents. Benzoyl peroxide is an oxidizer, which is principally used as in the production of polymers.As a bleach, it has been used as a medication and a water disinfectant. In specialized contexts, the name may be abbreviated as BPO.
As a medication, benzoyl peroxide is mostly used to treat acne, either alone or in combination with other treatments. Some versions are sold mixed with antibiotics such as clindamycin. It is on the WHO List of Essential Medicines, and, in the US, it is available as an over-the-counter and generic medication. It is also used in dentistry for teeth whitening.
Benzoyl peroxide is also used in the plastics industry and for bleaching flour, hair, and textiles. It is also used to remove stubborn stains from dolls and other plastic toys, although some users have claimed that the product has unwanted long-term effects of discolouring the item, particularly with the My Little Pony brand.
History
Benzoyl peroxide was first prepared and described by Liebig in 1858. It was the first organic peroxide prepared intentionally.In 1901, J. H. Kastle and his graduate student A. S. Loevenhart observed that the compound made the tincture of guaiacum tincture turn blue, a sign of oxygen being released. Around 1905, Loevenhart reported on the successful use of BPO to treat various skin conditions, including burns, chronic varicose leg tumors, and tinea sycosis. He also reported animal experiments that showed the relatively low toxicity of the compound.Treatment with benzoyl peroxide was proposed for wounds by Lyon and Reynolds in 1929, and for sycosis vulgaris and acne varioliformis by Peck and Chagrin in 1934. However, preparations were often of questionable quality. It was officially approved for the treatment of acne in the US in 1960.
Medical uses
Acne treatment
Benzoyl peroxide is effective for treating acne lesions. It does not induce antibiotic resistance. It may be combined with salicylic acid, sulfur, erythromycin or clindamycin (antibiotics), or adapalene (a synthetic retinoid). Two common combination drugs include benzoyl peroxide/clindamycin and adapalene/benzoyl peroxide, adapalene being a chemically stable retinoid that can be combined with benzoyl peroxide unlike tezarotene and tretinoin. Combination products such as benzoyl peroxide/clindamycin and benzoyl peroxide/salicylic acid appear to be slightly more effective than benzoyl peroxide alone for the treatment of acne lesions. The combination tretinoin/benzoyl peroxide was approved for medical use in the United States in 2021.
Benzoyl peroxide for acne treatment is typically applied to the affected areas in gel, cream, or liquid, in concentrations of 2.5% increasing through 5.0%, and up to 10%. No strong evidence supports the idea that higher concentrations of benzoyl peroxide are more effective than lower concentrations.
Mechanism of action
Classically, benzoyl peroxide is thought to have a three-fold activity in treating acne. It is sebostatic, comedolytic, and inhibits growth of Cutibacterium acnes, the main bacterium associated with acne. In general, acne vulgaris is a hormone-mediated inflammation of sebaceous glands and hair follicles. Hormone changes cause an increase in keratin and sebum production, leading to blocked drainage. C. acnes has many lytic enzymes that break down the proteins and lipids in the sebum, leading to an inflammatory response. The free-radical reaction of benzoyl peroxide can break down the keratin, therefore unblocking the drainage of sebum (comedolytic). It can cause nonspecific peroxidation of C. acnes, making it bactericidal, and it was thought to decrease sebum production, but disagreement exists within the literature on this.Some evidence suggests that benzoyl peroxide has an anti-inflammatory effect as well. In micromolar concentrations it prevents neutrophils from releasing reactive oxygen species, part of the inflammatory response in acne.
Side effects
Application of benzoyl peroxide to the skin may result in redness, burning, and irritation. This side effect is dose-dependent.Because of these possible side effects, it is recommended to start with a low concentration and build up as appropriate, as the skin gradually develops tolerance to the medication. Skin sensitivity typically resolves after a few weeks of continuous use. Irritation can also be reduced by avoiding harsh facial cleansers and wearing sunscreen prior to sun exposure.One in 500 people experience hypersensitivity to BPO and are liable to experience burning, itching, crusting, and possibly swelling. About one-third of people experience phototoxicity under exposure to ultraviolet (UVB) light.
Dosage
In the U.S., the typical concentration for benzoyl peroxide is 2.5% to 10% for both prescription and over-the-counter drug preparations that are used in treatment for acne.
Other medical uses
Benzoyl peroxide is used in dentistry as a tooth whitening product.
Non-medical uses
Bleaching
Like most peroxides, it is a powerful bleaching agent. It has been used for the bleaching of flour, fats, oils, waxes, and cheeses, as well as a stain remover.
Polymerization
Benzoyl peroxide is also used as a radical initiator to induce chain-growth polymerization reactions, such as for polyester and poly(methyl methacrylate) (PMMA) resins and dental cements and restoratives. It is the most important among the various organic peroxides used for this purpose, a relatively safe alternative to the much more hazardous methyl ethyl ketone peroxide. It is also used in rubber curing and as a finishing agent for some acetate yarns.
Safety
Explosion hazard
Concentrated benzoyl peroxide is potentially explosive like other organic peroxides, and can cause fires without external ignition. The hazard is acute for the pure material, so the compound is generally used as a solution or a paste. For example, cosmetics contain only a small percentage of benzoyl peroxide and pose no explosion risk.
Toxicity
Benzoyl peroxide breaks down in contact with skin, producing benzoic acid and oxygen, neither of which is very toxic.The carcinogenic potential of benzoyl peroxide has been investigated. A 1981 study published in the journal Science found that although benzoyl peroxide is not a carcinogen, it does promote cell growth when applied to an initiated tumor. The study concluded, "caution should be recommended in the use of this and other free radical-generating compounds".A 1999 IARC review of carcinogenicity studies found no convincing evidence linking BPO acne medication to skin cancers in humans. However, some animal studies found that the compound could act as a carcinogen and enhance the effect of known carcinogens.
Skin irritation
In a 1977 study using a human maximization test, 76% of subjects acquired a contact sensitization to benzoyl peroxide. Formulations of 5% and 10% were used.The U.S. National Institute for Occupational Safety and Health has developed criteria for a recommended standard for occupational exposure to benzoyl peroxide.
Cloth staining
Contact with fabrics or hair, such as from still-moist acne medication, can cause permanent color dampening almost immediately. Even secondary contact can cause bleaching, for example, contact with a towel that has been used to wash off benzoyl peroxide-containing hygiene products.
Reactivity
The original 1858 synthesis by Liebig reacted benzoyl chloride with barium peroxide, a reaction that probably follows this equation:
2 C6H5C(O)Cl + BaO2 → (C6H5CO)2O2 + BaCl2Benzoyl peroxide is usually prepared by treating hydrogen peroxide with benzoyl chloride under alkaline conditions.
2 C6H5COCl + H2O2 + 2 NaOH → (C6H5CO)2O2 + 2 NaCl + 2 H2OThe oxygen–oxygen bond in peroxides is weak. Thus, benzoyl peroxide readily undergoes homolysis (symmetrical fission), forming free radicals:
(C6H5CO)2O2 → 2 C6H5CO•2The symbol • indicates that the products are radicals; i.e., they contain at least one unpaired electron. Such species are highly reactive. The homolysis is usually induced by heating. The half-life of benzoyl peroxide is one hour at 92 °C. At 131 °C, the half-life is one minute.
References
External links
"Benzoyl peroxide". Drug Information Portal. U.S. National Library of Medicine.
International Chemical Safety Card 0225
NIOSH Pocket Guide to Chemical Hazards. "#0052". National Institute for Occupational Safety and Health (NIOSH).
SIDS Initial Assessment Report from the Organisation for Economic Co-operation and Development (OECD)
Organic Peroxide Producers Safety Division (OPPSD) |
Amiloride | Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.Common side effects include high blood potassium, vomiting, loss of appetite, rash, and headache. The risk of high blood potassium is greater in those with kidney problems, diabetes, and those who are older. Amiloride blocks the epithelial sodium channel (ENaC) in the late distal tubule, connecting tubule, and collecting duct of the nephron, which both reduces absorption of sodium ion from the lumen of the nephron and reduces excretion of potassium ion into the lumen.Amiloride was developed in 1967. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Amiloride may be used in combination with a thiazide diuretic for treatment of high blood pressure or (less commonly) in combination with a loop diuretic for treatment of heart failure. The potassium-sparing effects of amiloride offset the low blood potassium (hypokalemia) that is often induced by thiazides or loop diuretics, which is of particular importance in people for whom maintaining a normal level of potassium is critically important. For example, people that are taking Digitalis (i.e. digoxin) are at higher risk for changes in heart rhythm if their potassium levels get too high. The 2017 clinical practice guidelines of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines list amiloride as a "secondary" oral antihypertensive, with minimal efficacy. For people with resistant hypertension, already taking a thiazide diuretic, an angiotensin converting enzyme inhibitor (ACE-i) or an angiotensin II receptor blocker (ARB), and a calcium channel blocker, the addition of amiloride (or spironolactone) was better at reducing blood pressure than adding a beta-blocker (bisoprolol) or an alpha-1 blocker (doxazosin). When combined with hydrochlorothiazide, the addition of amiloride had positive effects on blood pressure and blood sugar tolerance. Amiloride may therefore be useful for preventing the metabolic side effects of thiazide diuretics, allowing for the use of higher thiazide doses (in line with how they were originally studied).Amiloride is the treatment of choice for Liddle phenotype, which is characterized by high blood pressure, low blood potassium, and metabolic alkalosis in conjunction with a low plasma renin activity and a low aldosterone. Some people with the Liddle phenotype have Liddle syndrome, which involves a genetic mutation resulting in upregulation of the epithelial sodium channel (ENaC), located in the apical membrane of polarized epithelial cells in the late distal tubule and collecting duct of the kidney. Because Liddle phenotype usually involves an upregulation of ENaC channels, leading to retention of sodium and water and to hypokalemia, amiloride is useful as an ENaC channel inhibitor due to its promotion of sodium excretion and its potassium-sparing effects, restoring potassium to normal levels.Amiloride can be used as a monotherapy (single-drug therapy) or an adjunctive therapy alongside other diuretics (e.g. hydrochlorothiazide, furosemide) for the treatment of ascites and edema (swelling) due to cirrhosis of the liver. The 2012 clinical practice guidelines by the American Association for the Study of Liver Diseases (AASLD) states that amiloride can be used to treat ascites in place of spironolactone if it isnt tolerated (e.g. due to the side effect of gynecomastia), though amiloride isnt a preferred drug due to cost and lack of efficacy.
Specific populations
Diabetics
People with diabetes are at higher risk for kidney problems, which increases their risk for hyperkalemia (high blood potassium). The use of amiloride in people with diabetes requires careful potassium and kidney function monitoring to prevent toxicity. Amiloride must be discontinued for at least 3 days prior to glucose tolerance testing, due to the risk for fatal hyperkalemia.
Poor kidney function
People with poor kidney function (e.g. blood urea nitrogen >30 mg/dL, or serum creatinine >1.5 mg/dL) are at high risk for hyperkalemia.
Lactation
There is no data on the use of amiloride in women that are breastfeeding. While diuretics can make lactation difficult, it is unlikely that amiloride would induce this effect in the absence of other diuretics.
Pregnancy
Data from the use of amiloride in animals suggests that it does not pose a risk to the developing fetus. However, when used in combination with the drug acetazolamide during the process of organ formation, amiloride increases the risk for kidney and ureter abnormalities. Limited human data from use during pregnancy suggests an association with a specific congenital penis abnormality if taken during the first trimester, as well as a risk for mild intrauterine growth restriction if taken throughout pregnancy.
Contraindications
Amiloride is contraindicated in people with kidney problems (e.g. anuria, acute or chronic kidney disease, or diabetic nephropathy), elevated blood potassium (≥5.5 mEq/L), or people that are hypersensitive to amiloride or any ingredients within the specific formulation. Use is also contraindicated in people that are already taking potassium-sparing drugs (e.g. spironolactone and triamterene) or whom are taking potassium supplements (e.g. potassium chloride) in most circumstances.
Adverse effects
Amiloride is generally well tolerated. Common adverse effects to the use of amiloride include elevated blood potassium, mild skin rashes, headaches, and gastrointestinal side effects (nausea, vomiting, diarrhea, decreased appetite, flatulence, and abdominal pain). Mild symptoms of high blood potassium concentrations include unusual skin sensations, muscle weakness, or fatigue, but more severe symptoms such as flaccid paralysis of the limbs, slow heart rate, and even shock can occur.
Overdose
There exists no overdose data on amiloride in humans, though it is expected than an overdose would produce effects consistent with its therapeutic effects; e.g. dehydration due to over-diuresis, and electrolyte disturbances related to hyperkalemia. It is unknown if amiloride can be dialyzed off, and no specific antidote against it exists. Treatment is generally supportive, though hyperkalemia can be treated.
Interactions
Amiloride may have important drug-drug interactions when combined with other medications that also increase potassium levels in the blood, leading to hyperkalemia. For example, the combination of amiloride with angiotensin-converting enzyme (ACE) inhibitors like lisinopril, or angiotensin II receptor type 1 (AT1) antagonists like losartan, may lead to high levels of potassium in the blood, requiring frequent monitoring.
Pharmacology
Mechanism of action
Diuresis
Amiloride works by directly blocking the epithelial sodium channel (ENaC) with an IC50 around 0.1 μM, indicating potent blockade. Antagonism of ENaC thereby inhibits sodium reabsorption in the late distal convoluted tubules, connecting tubules, and collecting ducts in the nephron. This promotes the loss of sodium and water from the body, and reduces potassium excretion. The drug is often used in conjunction with a thiazide diuretic to counteract with a potassium-losing effect. Due to its potassium-sparing capacities, hyperkalemia (elevated potassium concentration in the blood) can occur. The risk of developing hyperkalemia is increased in patients who are also taking ACE inhibitors, angiotensin II receptor antagonists, other potassium-sparing diuretics, or any potassium-containing supplements.
Miscellaneous
A fraction of the effects of amiloride is inhibition of cyclic GMP-gated cation channels in the inner medullary collecting duct.Amiloride has a second action on the heart, blocking Na+/H+ exchangers sodium–hydrogen antiporter 1 or NHE-1.
Amiloride also blocks the Na+/H+ antiporter on the apical surface of the proximal tubule cells in the nephron, abolishing more than 80% of the action of angiotensin II on the secretion of hydrogen ions in proximal tubule cells. Note that amiloride is not an angiotensin II receptor blocker (like losartan, for example). The Na-H transporter is also found in the Jejunum of the small intestine, as a result, amiloride also blocks the reabsorption of Na, and thereby water in the intestines.Amiloride is considered to be a reversible, pan-acid-sensing ion channel (ASIC) inhibitor that prevents the transient flow of ions but not the sustained flow of ions. ASICs are members of the ENaC family of protein channels, and are found in the nervous system, the cardiovascular system, the gastrointestinal system, and the skin. Broadly, ASICs are involved in harm detection, chemosensation (pH changes specifically), and touch.
Pharmacokinetics
Absorption
Amiloride has an oral bioavailability of 50%, meaning that about 50% of an oral dose is absorbed into the blood stream. Coadministration with food reduces the amount of amiloride that is absorbed by the body by about 30%, though it does not affect the rate of absorption. However, taking amiloride with food helps to reduce the incidence of its gastrointestinal side effects. After being taken, amilorides diuretic effect occurs within 2 hours, with peak diuresis within 6–10 hours. The diuretic effects of amiloride persist for about 24 hours after administration.
Distribution
Amiloride cross the placenta and distributes into breast milk in vivo.
Metabolism
Amiloride is not metabolized by the liver. In comparison, the ENaC inhibitor triamterene is metabolized by the liver.
Excretion
About 50% of amiloride is excreted unchanged by the kidneys, while around 40% is excreted in the feces (likely drug that wasnt absorbed). The half-life of amiloride in humans is between 6 and 9 hours, which may be prolonged in people with poor kidney function.
Pharmacogenomics
A single nucleotide polymorphism (SNP) in the protein NEDD4L may impact how amiloride affects a persons blood pressure in people with high blood pressure.
Chemistry
Amiloride is a pyrazinoylguanidine, composed of a substituted pyrazine ring structure with a carbonylguanidinium substituent. Amilorides pKa is 8.67, which is due to the guanidinium group. In high pH (alkaline, low hydrogen concentration) environments, the guanidinium group is deprotonated and the compound is rendered neutral, depleting its activity on sodium channels. Amiloride, as a pure substance, is highly fluorescent, with excitation wavelengths at 215, 288, and 360 nm, emitting light at 420 nm.
History
Amiloride was first synthesized and discovered by the Merck Sharp and Dohme Research Laboratories in the late 1960s. The drug was discovered as part of a screening process of chemicals that reversed the effects of mineralocorticoids in vivo. Amiloride was the only drug in the screen that was capable of causing the excretion of sodium (natriuresis) without a concomitant urinary excretion of potassium (kaliuresis). Thousands of amiloride analogues have been studied since its initial discovery, which have been used to study the effects of sodium transporters.Amiloride was approved by the U.S. Food and Drug Administration (FDA) on October 5, 1981.
Society and culture
It is on the World Health Organizations List of Essential Medicines.Amiloride is on the World Anti-Doping Agencys list of banned substances, as it is considered a masking agent. Diuretics like amiloride act as masking agents by reducing the concentration of other doping agents due to promoting diuresis, increasing the total volume of the urine. The list includes other potassium-sparing diuretics, such as triamterene and spironolactone. In 2008, amiloride and the potassium-sparing diuretic triamterene were found in 3% of positive diuretic doping samples.
Formulations and trade names
Amiloride hydrochloride
Midamor (U.S.)
Co-amilozide (amiloride hydrochloride with hydrochlorothiazide)
Co-amilofruse (amiloride hydrochloride with furosemide)
Amiloride hydrochloride with cyclopenthiazide
Amiloride hydrochloride with bumetanide
Research
Amiloride is an inhibitor of NHE-1, which helps to maintain normal pH within cells. Cancer cells in leukemia, a type of blood cancer, have higher pH compared to normal cells. Amiloride affects the splicing and regulation of multiple genes involved in cancer, though they do not appear to be directly related to its effects on pH. Amiloride has been tested in vitro as an adjunct to the anticancer drug imatinib, which appeared to show a synergistic effect. Modified versions of amiloride, known as 5-(N,N-dimethyl)-amiloride (DMA), 5-N-ethyl-N-isopropyl amiloride (EIPA), and 5-(N,N-hexamethylene)-amiloride (HMA), are being studied for the treatment of leukemia.
Cystic fibrosis is a genetic disorder due to a mutation in the CFTR gene, which encodes for the CFTR chloride channel. There is evidence that suggests that the molecular target of amiloride, ENaC, is also implicated in cystic fibrosis due to its effects on mucus in the lungs. Aerosolized formulations of amiloride have been tested in clinical trials, though long-term clinical trials have failed to show much utility. Due to its short duration of action, it was thought that longer-acting ENaC inhibitors may prove more effective. However, longer-acting ENaC inhibitors (i.e. benzamil) have also failed clinical trials, despite an improvement in both the solubility and potency of the drugs. A third generation amiloride analogue (N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate, research name "552-02"), with better pharmacokinetic properties, is being studied.
Pain induced by exposure to acid is attenuated by amiloride in human trials, which may indicate a role for amiloride in the treatment of pain in the future.
References
External links
Media related to Amiloride at Wikimedia Commons
"Amiloride". Drug Information Portal. U.S. National Library of Medicine. |
Moxetumomab pasudotox | Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti-CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A.
Hairy cell leukemia (HCL) is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.
Medical uses
Moxetumomab pasudotox as monotherapy is indicated for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) after receiving at least two prior systemic therapies, including treatment with a purine nucleoside analogue (PNA).
Adverse effects
Common side effects include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.The prescribing information for moxetumomab pasudotox includes a boxed warning about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The boxed warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells.Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities.Women who are breastfeeding should not be given moxetumomab pasudotox.
Discovery and ownership background
On 1 November 2005, Cambridge Antibody Technology (CAT) announced it was acquiring two anti-CD22 immunotoxin products from Genencor, namely GCR-3888 and GCR-8015. Genencor is the biotechnology division of Danisco and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes.GCR-3888 and GCR-8015 were discovered and initially developed by the National Cancer Institute, which is part of the U.S. National Institutes of Health. Genencor licensed the candidates for hematological malignancies and entered into a Cooperative Research and Development Agreement (CRADA) with the NIH, which will now be continued by CAT. Under the original
license agreement with the NIH, CAT gained the rights to a portfolio of intellectual property associated with the programs and would pay future royalties to the NIH.
CAT intended to file an Investigational New Drug (IND) application for GCR-8015 in various CD22 positive B-cell malignancies, including Non-Hodgkin lymphoma and chronic lymphocytic leukemia, following a period of manufacturing development which is expected to be complete by the end of 2006 and to support the NCIs ongoing development of GCR-3888 in Hairy cell leukemia (HCL) and pediatric acute lymphoblastic leukemia (pALL).CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888 and CATs language such as "CAT will support the NCIs ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.CAT was acquired by AstraZeneca, who also acquired MedImmune, combining the two into a biologics division. MedImmune renamed CAT-8015 to moxetumomab pasudotox.On 16 May 2013, AstraZeneca announced that CAT-8015 had started Phase III clinical trials.
History
On 5 December 2008, orphan designation (EU/3/08/592) was granted by the European Commission to Medimmune Limited, United Kingdom, for murine anti-CD22 antibody variable region fused to truncated Pseudomonas exotoxin 38 for the treatment of hairy cell leukaemia. It was renamed to Moxetumomab pasudotox. The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.On 17 July 2013, orphan designation (EU/3/13/1150) was granted by the European Commission to MedImmune Ltd, United Kingdom, for moxetumomab pasudotox for the treatment of B-lymphoblastic leukaemia / lymphoma. The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.Moxetumomab pasudotox was approved for use in the United States in September 2018.The efficacy of moxetumomab pasudotox was studied in a single-arm, open-label clinical trial of 80 subjects who had received prior treatment for hairy cell leukemia with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of subjects in the trial achieved durable CR, and the overall response rate (number of subjects with partial or complete response to therapy) was 75 percent.The US Food and Drug Administration (FDA) granted the application for moxetumomab pasudotox fast track, priority review, and orphan drug designations. The FDA granted the approval of a Biologics License Application for Lumoxiti to AstraZeneca Pharmaceuticals. This was subsequently transferred to Innate Pharma in March 2020.On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Lumoxiti, intended for the treatment of relapsed or refractory hairy cell leukemia after two prior systemic therapies including a purine nucleoside analog. The orphan designation for Lumoxiti for treatment of hairy cell leukaemia was also maintained. The applicant for this medicinal product is AstraZeneca AB. Moxetumomab pasudotox was approved for medical use in the European Union in February 2021. The EU marketing authorization was withdrawn in July 2021.
References
External links
"Moxetumomab pasudotox". Drug Information Portal. U.S. National Library of Medicine.
"Moxetumomab Pasudotox-tdfk". National Cancer Institute. 24 October 2018.
"Moxetumomab Pasudotox-tdfk". NCI Drug Dictionary. National Cancer Institute. |
Tobi | Tobi may refer to:
Tobi (given name), a unisex name
Tobi (island), island in the Palauan state of Hatohobei
Tobian language, the language of Tobi
Hatohobei, an island and the southernmost of Palaus sixteen states
Tobi (month), in the Coptic calendar
Tobi!, a 2009 television series
Tobramycin, an antibiotic drug that is sold under the brand name "Tobi"
Tobi (Naruto), the alias of Obito Uchiha, one of the primary antagonists in the anime and manga series Naruto Shippuden
ToBI, a standard for transcribing English intonation
Tobi shokunin or tobi for short; construction workers in Japan
Tobi trousers, the typical piece of clothing of tobi shokunin
Texas Oilmans Bass Invitational (TOBI)
Tobi (1978 film)
See also
Tobias
Toby (disambiguation) |
Motofen | Motofen is the brand name for an antiperistaltic anti-diarrheal medication, containing 1.0 mg difenoxin HCl and 0.025 mg atropine (U.S. Food and Drug Administration: Schedule IV Combination). It was invented by Kendra Clark. Atropine is purposely added at 25 micrograms per tablet, or 1/24 to 1/40 of the usual therapeutic dose for atropine to minimize the potential of misuse by swallowing large numbers of tablets or preparing them for injection since difenoxin is chemically related to the pethidine-piritramide subgroup of the opioid family, and could theoretically be misused. Although unlikely, physical and mental withdrawal symptoms (from both anticholinergic rebound caused by atropine, and opiate withdrawal caused by the difenoxin) are possible if taken for long periods of time. However, both of these compounds are responsible for the medicinal effects of the medicine (both atropine and difenoxin slow gut movement).
This combination medication should not be confused with Lomotil (2.5 mg diphenoxylate and 0.025 mg atropine – a Schedule V combination), because the active ingredients in the two medications are different compounds, except for the inclusion of atropine. Motofen is approximately 2 to 4 times more effective in treating symptoms than Lomotil.
Indications and uses
Although Motofen is officially indicated by the U.S. Food and Drug Administration (FDA) for diarrhea, it has also been successfully used by physicians for irritable bowel syndrome (IBS), and hyperhidrosis (chronic, severe sweating).
Side effects, interactions, and misuse potential
Side effects include drowsiness, nausea, vomiting, burning eyes, blurred vision, dry eyes, dizziness, dry mouth, epigastric distress, and constipation. Side effects attributed to the atropine content (especially when taken in excess doses, or in children), include: flushing, dryness in many areas, urinary retention, insomnia, headache, anxiety, hyperthermia, and tachycardia. It is these side effects that make it undesirable for most patients to take higher amounts of the medicine.
Dosing and administration
The recommended initial dosing is two tablets, and one tablet to be taken after each loose stool thereafter. The therapeutic dosage for Motofen should not exceed 8 tablets (8 milligrams of Difenoxin). There are currently no instructions indicating usage for irritable bowel syndrome (IBS) and Hyperhidrosis, although as stated above, it has been used successfully in treating symptoms of both disorders (which can accompany each other). There was a "Motofen half-strength" tablet, containing only 0.5 milligram of difenoxin, but it has since been discontinued. Only standard 1.0 milligram strength tablets are available by prescription.
Availability, price, and supply
There is currently only one manufacturer of Motofen tablets: Valeant Pharmaceuticals. It acquired the drug from Amarin Pharmaceuticals in 2004. Valeants tablets are pentagonal shaped, impressed with a "V" on one side, and vertically scored on the other side. In addition, the number "0500" is impressed bisecting the score line perpendicularly. The aforementioned bisection renders "05" and "00" on the left and right side of the score, respectively. Amarins version were also pentagonal shaped, but impressed with an "A" on one side with "74" on the opposing.
Motofen is higher priced than both Imodium and Lomotil, does not have a generic equivalent, and is only available by prescription in the United States. Many United States insurance companies do not include Motofen as one of their formulary drugs, causing consumers to pay the highest copay, if it is covered by their health insurance at all. This is most likely due to the high cost of the medication itself, and the fact that similar lower-priced medicines can help ease symptoms of diarrhea. The United States is currently the only country where Motofen tablets are prescribed, approved by the government, and sold.
Miscellaneous information
Strangely, Motofen is only included in the Physicians Desk Reference (PDR) for the years 2005 and 2006 as a literal snippet entry. Nothing is said about the indications and usage, only the ingredients, current appearance (at the time of publishing), NDC#, and the quantities in which it is supplied. As of August 1, 2008, Motofen appears to have been discontinued by Valeant Pharmaceuticals. No reason has officially been released, and many severe irritable bowel syndrome (IBS) sufferers, for whom medications such as Imodium or Lomotil did not satisfactorily treat them, were left wondering why it was no longer available. The few pharmacists that were familiar with Motofen and their wholesalers were not given any notice either. In threads on medical sites, such as, WebMD, that had irritable bowel syndrome as the topic, those sufferers unable to find out any information on Motofens status indicated that many pharmacists were unaware of the medications existence or that it was even unavailable. Many Motofen users reported that they ended up contacting numerous pharmacies in their area to gather what remaining stocks of the little used niche drug. Some state that traveling distances of up to 200 miles, one way, to get the medication; almost exclusively found in smaller, more traditional pharmacies like The Medicine Shoppe or independent local ones, rather than major chains. It is because of the small numbers of those who cannot find relief from the above listed drugs that Motofen can run up to $200, out of pocket, for a monthly supply. As a result, there are virtually no health plans where Motofen is not an off-legend medication.
According to e-mails and calls to Valeants customer service department, there was apparent issue with a manufacturer of one of the chemicals used in the making of difenoxin. This chemicals name, nor the manufacturer, would not be released to the public at-large. It was said that the manufacturer was not in the United States. Valeant did set up a list of those calling in about the medication to inform interested parties and it is assumed that this reaction by those who do need this medication is what prompted the return of Motofen despite the numerous instances of pushing back of the return date by Valeant.
Motofen is now back on the market as of June 2011 and available only by prescription in the United States.
References
External links
A comprehensive article about the subgroup of anti-diarrhoeal drugs including Motofen can be found at the article Diphenoxylate. |
Tamsulosin | Tamsulosin, sold under the brand name Flomax among others, is a medication used to treat symptomatic benign prostatic hyperplasia (BPH) and chronic prostatitis and to help with the passage of kidney stones. The evidence for benefit with a kidney stone is better when the stone is larger. It is taken by mouth.Common side effects include dizziness, headache, sleeplessness, nausea, blurry vision, and sexual problems. Other side effects may include feeling lightheaded with standing and angioedema. Tamsulosin is an alpha blocker and works by relaxing muscles in the prostate. Specifically it is an α1 adrenergic receptor blocker.Tamsulosin was approved for medical use in the United States in 1997. It is available as a generic medication. In 2020, it was the 24th most commonly prescribed medication in the United States, with more than 24 million prescriptions.
Medical uses
Tamsulosin is primarily used for benign prostatic hyperplasia and to help with the passage of kidney stones. Tamsulosin, however, appears to be effective only for stones over 4 mm and less than 10 mm in size.Tamsulosin is also used as an add-on treatment for acute urinary retention. People may void more successfully after catheter removal if they are taking tamsulosin. People taking tamsulosin also are less likely to need re-catheterization.Tamsulosin does not decrease the overall size of the prostate in men with benign prostatic hyperplasia (BPH), and is not recommended for prevention of prostate cancer.
Combination therapy
The results of the CombAT (combination of dutasteride (Avodart) and tamsulosin, under the brand name Duodart) trial in 2008 demonstrated that treatment with the combination of dutasteride and tamsulosin provides greater symptom benefits compared to monotherapy with either agent alone for treatment of benign prostatic hyperplasia.
The CombAT trial became the medication Jalyn. It was approved by the FDA on 14 June 2010. This combination can be useful because it may take up to six months for symptomatic relief to be found when using 5-alpha-reductase inhibitors such as dutasteride compared to alpha-1 receptor blockers, which can provide relief in some cases within 48 hours.
Adverse effects
Eyes: People taking tamsulosin are prone to a complication known as floppy iris syndrome during cataract surgery. Adverse outcomes of the surgery are greatly reduced by the surgeons prior knowledge of the persons history with this drug, and thus having the option of alternative techniques.
Severe hypotension.
Persons with cardiac conditions including hypotension, mechanical heart failure (valvular, pulmonary embolism, pericarditis), and congestive heart failure should be monitored carefully while taking tamsulosin.
Alpha blockers, including prazosin, terazosin, doxazosin, or tamsulosin, do not appear to affect all-cause mortality in heart failure re-hospitalization in those also receiving β-blockers.
Tamsulosin can also cause retrograde ejaculation, which occurs when semen is redirected to the urinary bladder instead of being ejaculated normally. This is because tamsulosin relaxes the muscles of the urethral sphincters, which are normally closed during ejaculation. This side effect can be mitigated by regular pelvic floor (Kegel) exercise and contracting the pelvic floor during ejaculation.
Mechanism
Tamsulosin is a selective α1 receptor antagonist that has preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in the blood vessels.When alpha 1 receptors in the bladder neck, the prostate, the ureter, and the urethra are blocked, a relaxation in smooth muscle tissue results. This mechanism decreases resistance to urinary flow, reduces discomfort associated with BPH, and facilitates passage of kidney stones.Selective action of tamsulosin in alpha 1A/D receptors is controversial and over three quarters of tamsulosin registered human studies are unpublished.
Brand names
Tamsulosin was first marketed in 1996 under the trade name Flomax. The U.S. patent expired in October 2009. The U.S. Food and Drug Administration (FDA) approved generics in March 2010. In 2010, tamsulosin was available as OTC medication in UK.It is marketed by various companies under licence, including Boehringer Ingelheim and CSL. Tamsulosin hydrochloride extended-release capsules are marketed under the trade names Urimax 0.4(India), Flomax, Flomaxtra, Contiflo XL, bestflo, Mecir LP (France), Urimax, Pamsvax, and Pradif, although generic, non-modified-release capsules are still approved and marketed in many countries (such as Canada). Generic extended-release tablets are marketed in most countries of the EEA. In Mexico, it is marketed as Secotex and as Harnal D in Japan and Indonesia and as Harnal OCAS (oral controlled absorption system) in Thailand. In Egypt, Italy, Russia and Iceland, it is marketed under the trade name Omnic by Astellas Pharma Europe. The largest manufacturer of tamsulosin, drug substance, is Synthon BV (The Netherlands). Tamsulosin hydrochloride is marketed in Bangladesh under the trade names Uromax, Prostanil MR, Tamisol MR, Tamsin.
References
External links
"Tamsulosin". Drug Information Portal. U.S. National Library of Medicine.
"Tamsulosin hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Oxacillin | Oxacillin (trade name Bactocill) is a narrow-spectrum beta-lactam antibiotic of the penicillin class developed by Beecham.It was patented in 1960 and approved for medical use in 1962.
Medical uses
Oxacillin is a penicillinase-resistant β-lactam. It is similar to methicillin, and has replaced methicillin in clinical use. Other related compounds are nafcillin, cloxacillin, dicloxacillin, and flucloxacillin. Since it is resistant to penicillinase enzymes, such as that produced by Staphylococcus aureus, it is widely used clinically in the US to treat penicillin-resistant Staphylococcus aureus. However, with the introduction and widespread use of both oxacillin and methicillin, antibiotic-resistant strains called methicillin-resistant and oxacillin-resistant Staphylococcus aureus (MRSA/ORSA) have become increasingly prevalent worldwide. MRSA/ORSA can be treated with vancomycin or other new antibiotics.
Contraindications
The use of oxacillin is contraindicated in individuals that have experienced a hypersensitivity reaction to any medication in the penicillin family of antibiotics. Cross-allergenicity has been documented in individuals taking oxacillin that experienced a previous hypersensitivity reaction when given cephalosporins and cephamycins.
Adverse effects
Commonly reported adverse effects associated with the use of oxacillin include skin rash, diarrhea, nausea, vomiting, hematuria, agranulocytosis, eosinophilia, leukopenia, neutropenia, thrombocytopenia, hepatotoxicity, acute interstitial nephritis, and fever. High doses of oxacillin have been reported to cause renal, hepatic, and nervous system toxicity. Common to all members of the penicillin class of drugs, oxacillin may cause acute or delayed hypersensitivity reactions. As an injection, oxacillin may cause injection site reactions, which may be characterized by redness, swelling, and itching.
Pharmacology
Mechanism of Action
Oxacillin, through its β-lactam ring, covalently binds to penicillin-binding proteins, which are enzymes involved in the synthesis of the bacterial cell wall. This binding interaction interferes with the transpeptidation reaction and inhibits the synthesis of peptidoglycan, a prominent component of the cell wall. By decreasing the integrity of the bacterial cell wall, it is thought that oxacillin and other penicillins kill actively growing bacteria through cell autolysis.
Chemistry
As with other members of the penicillin family, the chemical structure of oxacillin features a 6-aminopenicillanic acid nucleus with a substituent attached to the amino group. The 6-aminopenicillanic acid nucleus consists of a thiazolidine ring attached to a β-lactam ring, which is the active moiety responsible for the antibacterial activity of the penicillin family. The substituent present on oxacillin is thought to impart resistance to degradation via bacterial β-lactamases.
History
Oxacillin, a derivative of methicillin, was first synthesized in the early 1960s as part of a research initiative led by Peter Doyle and John Naylor of Beecham, in consort with Bristol-Myers. Members of the isoxazolyl penicillin family, which includes cloxacillin, dicloxacillin, and oxacillin, were synthesized to counter the increasing prevalence of infections caused by penicillin-resistant Staphylococcus aureus. While methicillin could only be administered via injection, the isoxazolyl penicillins, including oxacillin, could be given orally or by injection. Following the synthesis of cloxacillin and oxacillin, Beecham retained the right to commercially develop cloxacillin in the United Kingdom while Bristol-Myers was given the marketing rights for oxacillin in the United States.
Society and Culture
FDA Approval History
April 8, 1971: Oxacillin Sodium Injectable
Applicant: Sandoz
July 27, 1973: Bactocill Capsule
Applicant: GlaxoSmithKline
March 10, 1980: Oxacillin Sodium Capsule
Applicant: Ani Pharms Inc
May 15, 1980: Oxacillin Sodium for Solution
Applicant: TEVA
June 2, 1981: Bactocill for Solution
Applicant: GlaxoSmithKline
December 23, 1986: Oxacillin Sodium Powder
Applicant: Sandoz
September 29, 1988: Oxacillin Sodium Injectable
Applicant: Watson Labs Inc
October 26, 1988: Oxacillin Sodium Injectable
Applicant: Watson Labs Inc
October 26, 1989: Bactocill in Plastic Container Injectable
Applicant: Baxter Healthcare
March 30, 2012: Oxacillin Sodium Injectable
Applicant: Sagent Pharms
January 18, 2013: Oxacillin Sodium Injectable
Applicant: Aurobindo Pharma LTD
August 25, 2014: Oxacillin Sodium Injectable
Applicant: Mylan Labs LTD
December 11, 2015: Oxacillin Sodium Injectable
Applicant: Hospira Inc
July 31, 2017: Oxacillin Sodium Injectable
Applicant: Wockhardt Bio/Ag
Pricing
The average wholesale price (AWP) for oxacillin products are provided as follows. The prices listed below are intended to serve as reference values and do not represent the pricing determined by any single manufacturer or entity.
Bactocill in Dextrose Intravenous
1 g/50 mL: $20.37
2 g/50 mL: $32.48
Oxacillin Sodium Injection
1 g: $17.52
2 g: $33.99
10 g: $138.77
References
ChemBank |
Zaleplon | Zaleplon, sold under the brand names Sonata among others, is a sedative-hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.It is manufactured by King Pharmaceuticals and Gedeon Richter Plc. It has been discontinued in Canada but can be manufactured if a prescription is brought to a compounding pharmacy. It was prescribed rarely in the United Kingdom, with zopiclone being the preferred Z-drug by the National Health Service (NHS) and is now unavailable.
Medical uses
Zaleplon is slightly effective in insomnia, primarily characterized by difficulty falling asleep. Zaleplon significantly reduces the time required to fall asleep by improving sleep latency and may therefore facilitate sleep induction rather than sleep maintenance. Due to its ultrashort elimination half-life, zaleplon may not be effective in reducing premature awakenings; however, it may be administered to alleviate middle-of-the-night awakenings. However, zaleplon has not been empirically shown to increase total sleep time.It may result in an impaired ability to drive the next day, though it has proven promising when compared to other sedative/hypnotics in terms of next-day residual sedation. It may have advantages over benzodiazepines with fewer adverse effects.Neither zaleplon, nor any nonbenzodiazepine hypnotic class medication should be combined with alcohol, as both modulate GABAA receptor sites, and in a synergistic manner increase the chances of fatal respiratory depression and asphyxiation from vomiting.
Special populations
Zaleplon is not recommended for chronic use in the elderly. The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention.When compared with benzodiazepines, nonbenzodiazepines (including zaleplon) offer few significant advantages in efficacy and tolerability among elderly individuals. Long-term use of sedative/hypnotics for insomnia has traditionally been discouraged for reasons that include concerns about addiction and rebound insomnia, as well to the risk of side effects associated to GABAA agonists, such as cognitive impairment, anterograde amnesia, daytime sedation, musculoskeletal impairment, and subsequently an increased risk of harm to oneself (e.g. falling) and to others (e.g. automotive accidents). Though, quite obviously as the body and brain age, these aforementioned phenomena are expected events, as they occur daily regardless of ingestion of a sedative/hypnotic. Thus, statistically significant and empirical evidence are arguably still absent as dramatic precautions and conclusions are drawn irrespective of the debilitating realities that accompany insomnia and the fact that these medicines do indeed provide assistance to millions of elderly individuals. It is important to distinguish between the extrapolation of potential side effects relative to the vast number of examples, wherein the sedative/hypnotic has proven therapeutically beneficial and appropriate.
In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but nothing concrete suggests long-term use poses any direct harm to a person. Still, as of today neither benzodiazepines nor nonbenzodiazepines are recommended for the long-term treatment of insomnia.
Adverse effects
The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation, and in two studies zaleplon use was found not to cause an increase in traffic accidents, as compared to other hypnotics currently on the market.Sleeping pills, including zaleplon, have been associated with an increased risk of death.Available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of zaleplon (typically 5–20 mg before bed). Other sedative/hypnotics have been associated with various signs and symptoms of a withdrawal syndrome, following abrupt discontinuation, ranging from mild dysphoria and insomnia to more serious cases that include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Following abrupt cessation, the seizure threshold is further lowered, wherein coma and death are possible outcomes if untreated.
Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs.
Interactions
Cimetidine, rifampicin, and thioridazine cause interactions with zaleplon.Cimetidine and grapefruit are known to increase blood plasma concentrations of benzodiazepines metabolized by the P450 CYP3A4 liver enzyme (e.g. alprazolam) by extending the time by which the drug leaves the body, effectively extending the half-life and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect and not just chemical structure, it is reasonable to take precautions (e.g. inquire at a pharmacy) before one consumes cimetidine (or grapefruit) while also taking zaleplon.
Pharmacology
Mechanism of action
Zaleplon is a high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills. Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the natural sleep architecture.A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.Zaleplon has a pharmacological profile similar to benzodiazepines, characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine α1 receptor located on the GABAA receptor complex in the body, with lower affinity for the α2 and α3 subsites. It selectively enhances the action of GABA similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar pharmacological profile nonetheless, known for inducing hypnotic effects by α1 subreceptor sites, anxiolytic and muscle relaxant effects via α2 and α3 subsites, with negligible anticonvulsant properties (via α5 subsite), as zaleplon action is modulated at benzodiazepine receptor sites. The elimination half-life of zaleplon is about 1–1.5 hours. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5–15 minutes following ingestion.
Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band
Pharmacokinetics
Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in about one hour. It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine.
Chemistry
Pure zaleplon in its solid state is a white to off-white powder with very low solubility in water, as well as low solubility in ethanol and propylene glycol. It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7.
It is classified as a pyrazolopyrimidine.
Synthesis
The synthesis starts with the condensation of 3-acetylacetanilide (1) with N,N-dimethylformamide dimethyl acetal (DMFDMA) to give the eneamide (2). The anilide nitrogen is then alkylated by means of sodium hydride and ethyl iodide to give 3. The first step in the condensation with 3-amino-4-cyanopyrazole can be visualized as involving an addition-elimination reaction sequence on the eneamide function to give a transient intermediate such as 5. Cyclization then leads to formation of the fused pyrimidine ring to afford zaleplon (6).
Society and culture
Recreational use
Zaleplon has the potential to be a drug of recreational use, and has been found to have an addictive potential similar to benzodiazepine and benzodiazepine-like hypnotics. The mind- and judgment-altering effects of zaleplon are similar to those of many benzodiazepines, but the fast-acting nature and short half-life of the chemical mean high doses set on much more quickly and last for short periods of time (usually from 45 to 60 minutes).
Some individuals use a different delivery method than prescribed, such as insufflation, to induce effects faster.
A common effect of recreational zaleplon use is the occurrence of (typically short-lived) hallucinations. Fewer visual and auditory hallucinations/disruptions occur with the use of zaleplon than with other Z-drugs, like zolpidem. Anterograde amnesia can occur and can cause one to lose track of the amount of zaleplon already ingested, prompting the ingesting of more than originally planned. However, continuous ingestion is extremely unlikely precisely because of zaleplons quick onset of action.The combination of alcohol and zaleplon can result in fatal respiratory depression and asphyxiation from vomiting.
Aviation use
The Federal Aviation Administration allows zaleplon with a 12-hour wait period and no more than twice a week, which makes it the sleep medication with the shortest allowed waiting period after use. The substances with the 2nd shortest period, which is of 24 hours, are zolpidem and ramelteon.
Military use
The United States Air Force uses zaleplon as one of the hypnotics approved as a "no-go pill" to help aviators and special-duty personnel sleep in support of mission readiness (with a four-hour restriction on subsequent flight operation). "Ground tests" are required prior to authorization being issued to use the medication in an operational situation. The other hypnotics used as "no-go pills" are temazepam and zolpidem, which both have longer mandatory recovery periods.
See also
== References == |
Protein-bound paclitaxel | Protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel or nab-paclitaxel, is an injectable formulation of paclitaxel used to treat breast cancer, lung cancer and pancreatic cancer, among others. Paclitaxel kills cancer cells by preventing the normal breakdown of microtubules during cell division. In this formulation, paclitaxel is bonded to albumin as a delivery vehicle. It is manufactured and sold in the United States by Celgene under the trade name Abraxane where it is designated as an orphan drug as first-line treatment, in combination with gemcitabine, for the orphan disease "metastatic adenocarcinoma of the pancreas".This treatment was approved in the United States in 2005, and the European Union in 2008, for breast cancer cases where cancer did not respond to other chemotherapy or has relapsed. In 2012, the FDA widened the approved uses to include treatment for NSCLC. In 2013, the FDA approved protein-bound paclitaxel for use in treating advanced pancreatic cancer as a less toxic (although less effective) alternative to FOLFIRINOX.
Society and culture
Abraxane is registered on the Australian Register of Therapeutic Goods for the treatment of metastatic carcinoma of the breast after failure of anthracycline therapy. Abraxane is also included on the Schedule of the Australian Pharmaceutical Benefits Scheme although the manufacturer was unable to convince the independent Pharmaceutical Benefits Advisory Committee that the drug warranted a higher price than existing comparator drugs.
Protein-bound paclitaxel was developed by VivoRx which became Abraxis BioScience as the first in its class of drugs to use the nanoparticle albumin bound (nab) technology platform.In 2010, Abraxis was acquired by Celgene, which now markets Abraxane. Total revenue from the sales of Abraxane for 2009 were $314.5 million. In 2013, Abraxane was FDA approved for the treatment of pancreatic cancer. In 2014, Abraxanes sales were $848 million, 31 percent year-over-year increase.The British National Institute for Health and Care Excellence (NICE) announced in 2015, that it would not support the routine use of protein-bound paclitaxel in advanced pancreatic cancer on the NHS.
References
Further reading
Miele E, Spinelli GP, Miele E, Tomao F, Tomao S (2009). "Albumin-bound formulation of paclitaxel (Abraxane ABI-007) in the treatment of breast cancer". International Journal of Nanomedicine. 4: 99–105. doi:10.2147/ijn.s3061. PMC 2720743. PMID 19516888.
Stinchcombe, Thomas E (2007). "Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL®-free formulation of paclitaxel". Nanomedicine. 2 (4): 415–423. doi:10.2217/17435889.2.4.415. ISSN 1743-5889. PMID 17716129.
Gradishar, William J (2006). "Albumin-bound paclitaxel: a next-generation taxane". Expert Opinion on Pharmacotherapy. 7 (8): 1041–1053. doi:10.1517/14656566.7.8.1041. ISSN 1465-6566. PMID 16722814. S2CID 12736839.
External links
"Human albumin". Drug Information Portal. U.S. National Library of Medicine.
"Paclitaxel". Drug Information Portal. U.S. National Library of Medicine. |
Allergen immunotherapy | Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies, such as insect bites, and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergen in an attempt to change the immune systems response.Meta-analyses have found that injections of allergens under the skin are effective in the treatment in allergic rhinitis in children and in asthma. The benefits may last for years after treatment is stopped. It is generally safe and effective for allergic rhinitis, allergic conjunctivitis, allergic forms of asthma, and stinging insects. The evidence also supports the use of sublingual immunotherapy against rhinitis and asthma, but it is less strong. In this form the allergen is given under the tongue and people often prefer it to injections. Immunotherapy is not recommended as a stand-alone treatment for asthma.Side effects during sublingual immunotherapy treatment are usually local and mild and can often be eliminated by adjusting the dosage. Anaphylaxis during sublingual immunotherapy treatment has occurred on rare occasions.Potential side effects related to subcutaneous immunotherapy treatment for asthma and allergic rhinoconjunctivitis include mild or moderate skin or respiratory reactions. Severe side effects such as anaphylaxis during subcutaneous immunotherapy treatment are relatively uncommon.Discovered by Leonard Noon and John Freeman in 1911, allergen immunotherapy is the only medicine known to tackle not only the symptoms but also the causes of respiratory allergies. A detailed diagnosis is necessary to identify the allergens involved.
Types
Subcutaneous
Subcutaneous immunotherapy (SCIT), also known as allergy shots, is the historical route of administration and consists of injections of allergen extract, which must be performed by a medical professional. Subcutaneous immunotherapy protocols generally involve weekly injections during a build-up phase, followed by monthly a maintenance phase that consists of injections for a period of 3–5 years. The build-up phase involves the patient being administered injections which contain increasing amounts of allergens about one to two times per week. The length of the build-up phase is dependent upon how often injections are administered, but normally ranges from three to six months. After the effective dose is reached, the maintenance phase is implemented, which varies depending upon an individuals response to the build-up phase.When accounting for a persons age, type of allergen, and severity of allergy, there is a high probability that subcutaneous allergen immunotherapy may provide greater clinical and immunological responses than sublingual allergen immunotherapy. Compared to sublingual allergen immunotherapy, there are no significant differences observed in quality of life.It is possible, but rare (1/2.5 million), that people undergoing subcutaneous allergen immunotherapy may experience a fatal anaphylactic event. Subcutaneous allergen immunotherapy adverse events vary significantly depending on different allergenic extracts and the application of different allergen immunotherapy schedules.Allergen immunotherapy schedules include the "cluster" approach, which involves administering several doses sequentially in a single day; a "conventional" approach, which involves incrementally increasing the dose over approximately 15 weeks; and the "rush" approach, which involves administering incremental doses at intervals of 15–60 minutes over 1–3 days).It is challenging to perform an adequate risk assessment on the use of subcutaneous allergen immunotherapy compared to other forms of allergen immunotherapy administration due to the variability of immunotherapy schedules and further research is required.
Sublingual
Sublingual immunotherapy involves putting drops or a tablet of allergen extracts under the tongue, which are then absorbed through the lining of the mouth. Sublingual immunotherapy has been demonstrated to be effective against rhinoconjuctivitis and asthma symptoms. This effectiveness, however, varies depending on the type of allergen. The strongest evidence for the efficacy of sublingual immunotherapy comes from studies that used grass allergens or mite allergens to alleviate allergic rhinitis symptoms; the evidence shows modest improvement.Sublingual immunotherapy is used to treat allergic rhinitis, often from seasonal allergies, and is typically given in several doses over a 12-week period. It works best when given 12 weeks before the start of the pollen season. The first dose is given by a physician to monitor for any rare reactions or anaphylaxis. Subsequent doses can be taken at home which makes this a convenient alternative to subcutaneous immunotherapy.
While a number of side effects have been associated with sublingual immunotherapy, serious adverse effects are very rare (about 1.4/100000 doses), and there has not been a reported fatality. There have been a small number of reports of anaphylaxis. The majority of side effects are local and usually resolve within a few days. They include swelling of the mouth, tongue or lip, throat irritation, nausea, abdominal pain, vomiting, diarrhea, heartburn, and uvular edema. It is not yet clear if there are any risk factors that might increase a persons susceptibility to these adverse effects. Sublingual immunotherapy appears to be better tolerated than subcutaneous immunotherapy and causes fewer side effects. The safety of sublingual immunotherapy has not been studied extensively in people with chronic immunodeficiency or autoimmune disorders.
Oral
Oral immunotherapy (OIT) involves feeding an allergic individual increasing amounts of a food allergen in order to raise the threshold which triggers a reaction. Long-term, many study participants still experienced mild allergic reactions or needed to regularly consume the allergen to maintain desensitivity. Additionally, oral immunotherapy is known to have an increased risk in the probability of needing epinephrine in patients who take it.
Transdermal
Transdermal immunotherapy (TDIT) involves skin-induced suppression via epicutaneous (EC) application of an antigen in order to raise the threshold which triggers a reaction.
Mechanism of action
In desensitization immunotherapy the aim is to induce or restore tolerance to the allergen by reducing its tendency to induce IgE production. People are desensitized through the administration of escalating doses of allergen that gradually decreases the IgE-dominated response. The objective of immunotherapy is to direct the immune response away from humoral immunity and toward cellular immunity, thereby encouraging the body to produce fewer IgE antibodies and more CD4+ T regulatory cells that secrete IL-10 and TGF-β, which skews the response away from IgE production.Oral immunotherapy also creates an increase in allergen-specific IgG4 antibodies and a decrease in allergen-specific IgE antibodies, as well as diminished mast cells and basophils, two cell types that are large contributors to allergic reaction.
Protocol
Reactivity is tested using oral food challenges or with skin prick tests. Phases 1 & 2 of sublingual immunotherapy are conducted in a supervised clinical setting. However, phase 3 can be done at home.
History
In the late 19th century and early 20th century, allergic conditions were increasingly attracting both medical attention (as an emerging public health problem) and scientific interest (aided by progress in biochemical techniques and the development of molecular and pathogenic theories). However, the many and varied treatment approaches were very unscientific.The British physicians Noon and Freeman were the first researchers to test pollen allergen immunotherapy in humans. Noon and Freeman, researchers at the Department of Therapeutic Inoculation at St. Marys Hospital in London, published their findings in The Lancet in 1911. Building on the observations of his predecessors Bostock, Blackley and Dunbar, Noon noted that people with hay fever "sometimes become cured" and that this was possibly because they "have had the good fortune to develop an active immunity against the toxin." He hypothesized that by injecting people with hay fever with small amounts of a pollen "toxin", a state of immunity could be achieved.Allergen immunotherapy was part of mainstream medical practice for hay fever treatment in the 1930s.
Society and culture
Sublingual immunotherapy drops are currently commercialized and used in most European and South American countries, and in Australia and Asian countries. In most European countries, national regulations allow marketing of allergen products as "named patient preparations" (NPPs). In the United States, drop formulations have not yet received FDA approval, though off-label prescription is becoming common. In 2014, the FDA approved a once-daily sublingual tablet containing allergen extracts for the treatment of "hay fever" (allergic rhinitis with or without conjunctivitis).
Recognition by international agencies
The use of subcutaneous immunotherapy for treatment of environmental-based allergies and asthma is well supported by the majority of national and international allergy groups such as the World Allergy Organization, Canadian Society of Allergy and Immunology, European Academy of Allergy and Clinical Immunology, and the American Academy of Allergy, Asthma and Immunology. The use of sublingual immunotherapy is supported by few allergy agencies in order to allow for more investigation to occur on its practical use. Oral immunotherapy is generally not recommended, however the EAACI recommends that this treatment only be administered at specialized centres with expert professionals.Subcutaneous immunotherapy is both approved and regulated by the American Food and Drug Administration (FDA) and the European Medicinal Agency (EMEA). The FDA currently allows individual allergists to create the formula for each dosage, whereas the EMEA requires treatment extracts to be prepared at manufacturing sites. The FDA has approved sublingual therapy through the use of tablets, but has not approved specific formulation. The EMEA has also approved sublingual therapy through both tablets and solution, and this administration now accounts for 45% of immunotherapy treatments.The FDA advisory board has supported the use of AR101, an oral immunotherapy, for patients with peanut allergies in 2019.
Science communication
Allergen immunotherapy is viewed as a beneficial way to curb allergies in the perspective of the media. It is seen where it can be covered by insurance and offer a more permanent solution than antihistamines or nasal steroids that treat symptoms, not the bodys reaction. Communication about allergen immunotherapy is not described very often in the news media; it is usually only communicated by the science community. The scientific community describes allergen immunotherapy as a scientific solution that helps not only patients with allergies but also positively impacts the quality of life of them and others around them. As temperatures increase due to changing climates, pollen levels also increase. Allergies are becoming a more common problem among the public, which is why the science community advocates for allergen immunotherapy. Subcutaneous allergen immunotherapy, according to the scientific community, is an effective solution to allergies due to numerous positive studies.
Research
Oral immunotherapy
As of 2015, oral immunotherapys balance of risk to benefit for food allergies was not well studied. As of 2011, OIT was under investigation as a treatment for a variety of common food allergies including peanuts, milk, and eggs. Studies involving OIT have shown desensitization towards the allergen. However, there are still questions about longevity of tolerance after the study has ended. However, almost every study has excluded people with severe allergen-induced anaphylaxis.One approach being studied is in altering the protein structure of the allergen to decrease immune response but still induce tolerance. Extensive heating of some foods can change the conformation of epitopes recognized by IgE antibodies. In fact, studies show that regular consumption of heated food allergens can speed up allergy resolution. In one study, subjects allergic to milk were 16x more likely to develop complete milk tolerance compared to complete milk avoidance. Another approach regarding changes in protein is to change specific amino acids in the protein to decrease recognition of the allergen by allergen-specific antibodies.Another approach to improving oral immunotherapy is to change the immune environment to prevent TH2 cells from responding to the allergens during treatment. For example, drugs that inhibit IgE-mediated signaling pathways can be used in addition to OIT to reduce immune response. In 1 trial, the monoclonal antibody omalizumab was combined with high-dose milk oral immunotherapy and saw positive results. Several other trials are also currently being done combining omalizumab with OIT for a variety of food allergens. FAHF-2, a Chinese herbal mixture, has shown positive effects on the immune system and has been shown to protect mice from peanut-induced anaphylaxis. FAHF-2 was also well tolerated in a phase I study. While it is possible that omalizumab, FAHF-2 or other immunomodulatory agents alone might be able to treat dangerous allergies, combining these with OIT may be more effective and synergistic, warranting further investigation.In addition, various adjuvants (nanoparticles) is a field of development that can be used for OIT. With the potential to modulate antigen release, it may one day be possible to take a pill containing nanoparticles that will modulate dosing, requiring fewer office visits.Studies have also been done to determine the efficacy of OIT for multiple allergens simultaneously. One study concluded that multi-OIT would be possible and relatively, though larger studies would be necessary.
References
External links
"American Academy of Allergy, Asthma, and Immunology" information and articles of interest.
"American College of Allergy, Asthma, and Immunology" information and articles of interest.
"American Board of Allergy and Immunology" American Board of Allergy and Immunology
"Allergy shots, allergy immunotherapy" FAQs on Allergy Immunotherapy. |
Creon | Creon may refer to:
Greek history
Creon, the first annual eponymous archon of Athens, 682–681 BC
Greek mythology
Creon (king of Thebes), mythological king of Thebes
Creon (king of Corinth), father of Creusa/Glauce in Euripides Medea
Creon, son of Heracles by a daughter of Thespius, king of Thespiae
Medicine
Creon, a brand name of a pancreatic enzymes medication
Places
Créon, a commune in the Gironde department in France
Créon-dArmagnac, a commune in the Landes department in France
Other
Creon a genus of butterfly, in the family Lycaenidae, containing the species Broadtail royal
USS Creon (ARL-11), a World War II U.S. Navy landing craft repair ship
See also
Kreon, a DC Comics character
Kreon, a minifigure (similar to Lego minifigure) from Kre-O construction toys manufactured by Oxford, a Korean company, and marketed by Hasbro |
Pentostatin | Pentostatin (or deoxycoformycin, trade name Nipent, manufactured by SuperGen) is an anticancer chemotherapeutic drug.
Mechanism
It is classified as a purine analog, which is a type of antimetabolite.
It mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, interfering with the cells ability to process DNA.Cancer cells generally divide more often than healthy cells; DNA is highly involved in cell division (mitosis) and drugs which target DNA-related processes are therefore more toxic to cancer cells than healthy cells.
Uses
Pentostatin is used to treat hairy cell leukemia. It is given by intravenous infusion once every two weeks for three to six months.
Additionally, pentostatin has been used to treat steroid-refractory acute and chronic graft-versus-host disease.Pentostatin is also used in chronic lymphocytic leukemia (CLL) patients who have relapsed.
== References == |
Naldemedine | Naldemedine (brand name Symproic in the US and Rizmoic in the European Union) is a medication that is used for the treatment of opioid-induced constipation in adults with chronic non-cancer pain. It is a peripherally acting μ-opioid receptor antagonist and was developed by Shionogi. Clinical studies have found it to possess statistically significant effectiveness for these indications and to be generally well tolerated, with predominantly mild to moderate gastrointestinal side effects. Effects indicative of central opioid withdrawal or impact on the analgesic or miotic effects of co-administered opioids have only been observed in a small number of patients.
Medical uses
In the US, naldemedine is approved for the treatment of opioid induced constipation in adults with chronic non-cancer pain, including those who have chronic pain related to prior cancer or its treatment and do not need frequent opioid dosage escalation.In the European Union, naldemedine is also approved for the treatment of opioid induced constipation in adults, but as a second-line therapy after treatment with a laxative.
Contraindications
The drug is contraindicated in patients with gastrointestinal obstruction or perforation, or those at risk for these problems.
Side effects
Side effects in studies were abdominal pain (8–11% of patients as compared to 2–5% under placebo, depending on the study), diarrhea (7% versus 2–3%), nausea (4–6% versus 2–5%), vomiting (3% versus 2%), gastroenteritis (2–3% versus 1%), and opioid withdrawal syndrome (1.5–3.2% versus 0.5–1.5%). The latter was severe but manageable in one patient, and otherwise mild to moderate. Hypersensitivity reactions were rare; they occurred in two patients.
Overdose
Single doses up to 500 times the recommended dose, as well as multiple doses up to 150 times the recommended dose for ten days, resulted in an increase of the mentioned side effects. Theses side effects were mild to moderate.
Interactions
As naldemedine is mainly metabolized by the liver enzyme CYP3A4, inhibitors of this enzyme can increase its concentrations in the body and thus its potential for side effects. Examples include itraconazole (which increased naldemedine exposure 2.9-fold in a study), ketoconazole, clarithromycin and grapefruit juice. Conversely, CYP3A4 inducers such as rifampicin and St Johns wort decrease naldemedine concentrations; with rifampicin, the reduction was 83% in a study.Strong inhibitors of the pump P-glycoprotein such as ciclosporin may increase naldemedine concentrations in the blood plasma.
Pharmacology
Mechanism of action
Naldemedine is a derivative of naltrexone and, like this substance, blocks opioid receptors of the types μ (mu), δ (delta) and κ (kappa). While naltrexone is able to cross the blood–brain barrier and can therefore be used to treat opioid dependence, the large hydrophilic side chain of naldemedine and its affinity to P-glycoprotein result in negligible concentrations in the central nervous system when recommended doses are applied. Instead, it acts mainly on μ-receptors in the gastrointestinal tract, where it counteracts the constipation inducing effects of opioid drugs.
Pharmacokinetics
After oral intake, naldemedine has an absolute bioavailability in the range of 20% to 56% and reaches highest blood plasma levels after 0.75 hours when taken without food and 2.5 hours when taken with a high-fat meal. As the area under the curve is not significantly different with or without a meal, the drug can be taken independently of food. Once in the bloodstream, 93 to 94% of the substance is bound to plasma proteins, mainly to albumin.Naldemedine is mainly metabolized by the enzyme CYP3A4 to nor-naldemedine (which makes up about 9–13% of the circulating substance), and to a much lesser extent by UGT1A3 to naldemedine 3-glucuronide. Minor metabolites are the 6-glucuronide, the 7-(R/S)-hydroxy-derivates, and two products formed by enterobacteria through cleaving the oxadiazole ring: naldemedine carboxylic acid and benzamidine. Nor-naldemedine, the glucuronides, and the carboxylic acid are opioid receptor antagonists, but less potent than the original substance.
Naldemedine and its metabolites are excreted via urine and faeces. The part of the molecule "left" of the cleavage line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and carboxylic acid) is found to 20.4% in the urine and to 64.3% in the faeces, while the part "right" to the line (the sum of original substance, nor-naldemedine, glucuronides, hydroxy-derivative, and benzamidine) is found to 57.3% in the urine and to 34.8% in the faeces. This indicates that benzamidine is predominantly excreted in the urine and the carboxylic acid is predominantly excreted in the faeces. The terminal half-life is about 11 hours.
Chemistry
Naldemedine is used in form of the tosylate, a white to light tan powder. It is not hygroscopic and has a high water solubility at a physiologic pH.
Society and culture
Commercialization
Naldemedine is manufactured by Shionogi Inc., a United States-based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a pharmaceutical company founded in 1878 based in Osaka, Japan. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States.
In the US market, Shionogi Inc. has partnered with Purdue Pharma in a joint venture for US commercialization of Symproic. Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders.Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on July 12, 2017. The Drug Enforcement Administration officially removed the Class II scheduling in September 2017.
Manufacturer finances
Since 2015, Shionogi & Co., Ltd. has produced increasing net income. At the end of fiscal year 2016, Shionogi & Co., Ltd. had a net income of $66,687,000. At the end of fiscal year 2017, they increased their net income to $83,879,000. How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on March 31 of each year. Considering the drug was only FDA approved on March 23 of 2017, the true valuation of the drug is yet to be seen. Purdue Pharma has begun advertising for the medication to be available by October 2017.
Intellectual property
There are currently three patents issued for naldemedine tosylate by the United States Patent and Trademark Office. All patents are owned by Shionogi Inc. and will expire from 2026 to 2031. Naldemedine tosylate has 46 other patents in 18 different countries.
Clinical trials
The approval of naldemedine came from the results of the COMPOSE program, a phase three clinical studies program conducted in adults 18–80 years of age with chronic non-cancer pain opioid induced constipation. COMPOSE-I and COMPOSE-II were 12-week double blind randomized controlled trials comparing the use of naldemedine to placebo in the patient population. COMPOSE-I began in August 2013 until January 2015 in 68 outpatient clinic in seven countries. COMPOSE-II began in November 2013 until June 2015 taking place in 69 outpatient clinics in six countries. In both trials, patients were randomly assigned to receive either naldemedine 0.2 mg or placebo once daily for 12 weeks. A responder had at least three spontaneous bowel movements per week with an increase of one spontaneous bowel movement for nine of the 12 weeks, including three of the final four weeks of the study. In COMPOSE-I and COMPOSE-II, the proportion of responders were significantly higher in the naldemedine group than the placebo group. Adverse events were similar in both trials, however, patients in the naldemedine group had slightly higher rates of adverse events.COMPOSE-III was a 52-week clinical trial examining the long term safety with naldemedine in patients with non cancer chronic pain. Results from this trial showed statistical significance for increased weekly bowel movements and no opioid withdrawal symptoms. The study also concluded adverse effects were more similar between two groups.All trials were conducted following Good Clinical Practice guidelines.
See also
Alvimopan
Bevenopran
Naloxegol
References
External links
"Naldemedine". Drug Information Portal. U.S. National Library of Medicine. |
Progesterone | Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.In addition to its role as a natural hormone, progesterone is also used as a medication, such as in combination with estrogen for contraception, to reduce the risk of uterine or cervical cancer, in hormone replacement therapy, and in feminizing hormone therapy. It was first prescribed in 1934.
Biological activity
Progesterone is the most important progestogen in the body. As a potent agonist of the nuclear progesterone receptor (nPR) (with an affinity of KD = 1 nM) the resulting effects on ribosomal transcription plays a major role in regulation of female reproduction. In addition, progesterone is an agonist of the more recently discovered membrane progesterone receptors (mPRs), of which the expression has regulation effects in reproduction function (oocyte maturation, labor, and sperm motility) and cancer although additional research is required to further define the roles. It also functions as a ligand of the PGRMC1 (progesterone receptor membrane component 1) which impacts tumor progression, metabolic regulation, and viability control of nerve cells. Moreover, progesterone is also known to be an antagonist of the sigma σ1 receptor, a negative allosteric modulator of nicotinic acetylcholine receptors, and a potent antagonist of the mineralocorticoid receptor (MR). Progesterone prevents MR activation by binding to this receptor with an affinity exceeding even those of aldosterone and glucocorticoids such as cortisol and corticosterone, and produces antimineralocorticoid effects, such as natriuresis, at physiological concentrations. In addition, progesterone binds to and behaves as a partial agonist of the glucocorticoid receptor (GR), albeit with very low potency (EC50 >100-fold less relative to cortisol).Progesterone, through its neurosteroid active metabolites such as 5α-dihydroprogesterone and allopregnanolone, acts indirectly as a positive allosteric modulator of the GABAA receptor.Progesterone and some of its metabolites, such as 5β-dihydroprogesterone, are agonists of the pregnane X receptor (PXR), albeit weakly so (EC50 >10 μM). In accordance, progesterone induces several hepatic cytochrome P450 enzymes, such as CYP3A4, especially during pregnancy when concentrations are much higher than usual. Perimenopausal women have been found to have greater CYP3A4 activity relative to men and postmenopausal women, and it has been inferred that this may be due to the higher progesterone levels present in perimenopausal women.Progesterone modulates the activity of CatSper (cation channels of sperm) voltage-gated Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis). As a result, it has been suggested that substances that block the progesterone binding site on CatSper channels could potentially be used in male contraception.
Biological function
Hormonal interactions
Progesterone has a number of physiological effects that are amplified in the presence of estrogens. Estrogens through estrogen receptors (ERs) induce or upregulate the expression of the PR. One example of this is in breast tissue, where estrogens allow progesterone to mediate lobuloalveolar development.Elevated levels of progesterone potently reduce the sodium-retaining activity of aldosterone, resulting in natriuresis and a reduction in extracellular fluid volume. Progesterone withdrawal, on the other hand, is associated with a temporary increase in sodium retention (reduced natriuresis, with an increase in extracellular fluid volume) due to the compensatory increase in aldosterone production, which combats the blockade of the mineralocorticoid receptor by the previously elevated level of progesterone.
Reproductive system
Progesterone has key effects via non-genomic signalling on human sperm as they migrate through the female tract before fertilization occurs, though the receptor(s) as yet remain unidentified. Detailed characterisation of the events occurring in sperm in response to progesterone has elucidated certain events including intracellular calcium transients and maintained changes, slow calcium oscillations, now thought to possibly regulate motility. It is produced by the ovaries. Progesterone has also been shown to demonstrate effects on octopus spermatozoa.Progesterone is sometimes called the "hormone of pregnancy", and it has many roles relating to the development of the fetus:
Progesterone converts the endometrium to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making it thick and impenetrable to sperm. Progesterone is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen. If pregnancy does not occur, progesterone levels will decrease, leading, in the woman, to menstruate. Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation does not occur and the corpus luteum does not develop, levels of progesterone may be low, leading to anovulatory dysfunctional uterine bleeding.
During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.
Progesterone decreases contractility of the uterine smooth muscle. This effect contributes to prevention of preterm labor.
A drop in progesterone levels is possibly one step that facilitates the onset of labor.
In addition, progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.The fetus metabolizes placental progesterone in the production of adrenal steroids.
Breasts
Lobuloalveolar development
Progesterone plays an important role in breast development in women. In conjunction with prolactin, it mediates lobuloalveolar maturation of the mammary glands during pregnancy to allow for milk production and thus lactation and breastfeeding of offspring following parturition (childbirth). Estrogen induces expression of the PR in breast tissue and hence progesterone is dependent on estrogen to mediate lobuloalveolar development. It has been found that RANKL is a critical downstream mediator of progesterone-induced lobuloalveolar maturation. RANKL knockout mice show an almost identical mammary phenotype to PR knockout mice, including normal mammary ductal development but complete failure of the development of lobuloalveolar structures.
Ductal development
Though to a far lesser extent than estrogen, which is the major mediator of mammary ductal development (via the ERα), progesterone may be involved in ductal development of the mammary glands to some extent as well. PR knockout mice or mice treated with the PR antagonist mifepristone show delayed although otherwise normal mammary ductal development at puberty. In addition, mice modified to have overexpression of PRA display ductal hyperplasia, and progesterone induces ductal growth in the mouse mammary gland. Progesterone mediates ductal development mainly via induction of the expression of amphiregulin, the same growth factor that estrogen primarily induces the expression of to mediate ductal development. These animal findings suggest that, while not essential for full mammary ductal development, progesterone seems to play a potentiating or accelerating role in estrogen-mediated mammary ductal development.
Breast cancer risk
Progesterone also appears to be involved in the pathophysiology of breast cancer, though its role, and whether it is a promoter or inhibitor of breast cancer risk, has not been fully elucidated. Most progestins, or synthetic progestogens, like medroxyprogesterone acetate, have been found to increase the risk of breast cancer in postmenopausal women in combination with estrogen as a component of menopausal hormone therapy. The combination of natural oral progesterone or the atypical progestin dydrogesterone with estrogen has been associated with less risk of breast cancer than progestins plus estrogen. However, this may simply be an artifact of the low progesterone levels produced with oral progesterone. More research is needed on the role of progesterone in breast cancer.
Skin health
The estrogen receptor, as well as the progesterone receptor, have been detected in the skin, including in keratinocytes and fibroblasts. At menopause and thereafter, decreased levels of female sex hormones result in atrophy, thinning, and increased wrinkling of the skin and a reduction in skin elasticity, firmness, and strength. These skin changes constitute an acceleration in skin aging and are the result of decreased collagen content, irregularities in the morphology of epidermal skin cells, decreased ground substance between skin fibers, and reduced capillaries and blood flow. The skin also becomes more dry during menopause, which is due to reduced skin hydration and surface lipids (sebum production). Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.Hormone replacement therapy, consisting of systemic treatment with estrogen alone or in combination with a progestogen, has well-documented and considerable beneficial effects on the skin of postmenopausal women. These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids. Topical estrogen has been found to have similar beneficial effects on the skin. In addition, a study has found that topical 2% progesterone cream significantly increases skin elasticity and firmness and observably decreases wrinkles in peri- and postmenopausal women. Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone. These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin, and may be independently protective against skin aging.
Sexuality
Libido
Progesterone and its neurosteroid active metabolite allopregnanolone appear to be importantly involved in libido in females.
Homosexuality
Dr. Diana Fleischman, of the University of Portsmouth, and colleagues looked for a relationship between progesterone and sexual attitudes in 92 women. Their research, published in the Archives of Sexual Behavior found that women who had higher levels of progesterone scored higher on a questionnaire measuring homoerotic motivation. They also found that men who had high levels of progesterone were more likely to have higher homoerotic motivation scores after affiliative priming compared to men with low levels of progesterone.
Nervous system
Progesterone, like pregnenolone and dehydroepiandrosterone (DHEA), belongs to an important group of endogenous steroids called neurosteroids. It can be metabolized within all parts of the central nervous system.Neurosteroids are neuromodulators, and are neuroprotective, neurogenic, and regulate neurotransmission and myelination. The effects of progesterone as a neurosteroid are mediated predominantly through its interactions with non-nuclear PRs, namely the mPRs and PGRMC1, as well as certain other receptors, such as the σ1 and nACh receptors.
Brain damage
Previous studies have shown that progesterone supports the normal development of neurons in the brain, and that the hormone has a protective effect on damaged brain tissue. It has been observed in animal models that females have reduced susceptibility to traumatic brain injury and this protective effect has been hypothesized to be caused by increased circulating levels of estrogen and progesterone in females.
Proposed mechanism
The mechanism of progesterone protective effects may be the reduction of inflammation that follows brain trauma and hemorrhage.Damage incurred by traumatic brain injury is believed to be caused in part by mass depolarization leading to excitotoxicity. One way in which progesterone helps to alleviate some of this excitotoxicity is by blocking the voltage-dependent calcium channels that trigger neurotransmitter release. It does so by manipulating the signaling pathways of transcription factors involved in this release. Another method for reducing the excitotoxicity is by up-regulating the GABAA, a widespread inhibitory neurotransmitter receptor.Progesterone has also been shown to prevent apoptosis in neurons, a common consequence of brain injury. It does so by inhibiting enzymes involved in the apoptosis pathway specifically concerning the mitochondria, such as activated caspase 3 and cytochrome c.
Not only does progesterone help prevent further damage, it has also been shown to aid in neuroregeneration. One of the serious effects of traumatic brain injury includes edema. Animal studies show that progesterone treatment leads to a decrease in edema levels by increasing the concentration of macrophages and microglia sent to the injured tissue. This was observed in the form of reduced leakage from the blood brain barrier in secondary recovery in progesterone treated rats. In addition, progesterone was observed to have antioxidant properties, reducing the concentration of oxygen free radicals faster than without. There is also evidence that the addition of progesterone can also help remyelinate damaged axons due to trauma, restoring some lost neural signal conduction. Another way progesterone aids in regeneration includes increasing the circulation of endothelial progenitor cells in the brain. This helps new vasculature to grow around scar tissue which helps repair the area of insult.
Addiction
Progesterone enhances the function of serotonin receptors in the brain, so an excess or deficit of progesterone has the potential to result in significant neurochemical issues. This provides an explanation for why some people resort to substances that enhance serotonin activity such as nicotine, alcohol, and cannabis when their progesterone levels fall below optimal levels.
Sex differences in hormone levels may induce women to respond differently than men to nicotine. When women undergo cyclic changes or different hormonal transition phases (menopause, pregnancy, adolescence), there are changes in their progesterone levels. Therefore, females have an increased biological vulnerability to nicotines reinforcing effects compared to males and progesterone may be used to counter this enhanced vulnerability. This information supports the idea that progesterone can affect behavior.
Similar to nicotine, cocaine also increases the release of dopamine in the brain. The neurotransmitter is involved in the reward center and is one of the main neurotransmitters involved with substance abuse and reliance. In a study of cocaine users, it was reported that progesterone reduced craving and the feeling of being stimulated by cocaine. Thus, progesterone was suggested as an agent that decreases cocaine craving by reducing the dopaminergic properties of the drug.
Societal
In a 2012 University of Amsterdam study of 120 women, womens luteal phase (higher levels of progesterone, and increasing levels of estrogen) was correlated with lower level of competitive behavior in gambling and math contest scenarios, while their premenstrual phase (sharply-decreasing levels of progesterone, and decreasing levels of estrogen) was correlated with a higher level of competitive behavior.
Other effects
Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually dimorphic proportions of those.
During pregnancy, progesterone is said to decrease uterine irritability.
During pregnancy, progesterone helps to suppress immune responses of the mother to fetal antigens, which prevents rejection of the fetus.
Progesterone raises epidermal growth factor-1 (EGF-1) levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.
Progesterone increases core temperature (thermogenic function) during ovulation.
Progesterone reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (PRs are widely present in submucosal tissue.)
Progesterone acts as an antiinflammatory agent and regulates the immune response.
Progesterone reduces gall-bladder activity.
Progesterone normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.
Progesterone may affect gum health, increasing risk of gingivitis (gum inflammation).
Progesterone appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.
Progesterone plays an important role in the signaling of insulin release and pancreatic function, and may affect the susceptibility to diabetes or gestational diabetes.
Biochemistry
Biosynthesis
In mammals, progesterone, like all other steroid hormones, is synthesized from pregnenolone, which itself is derived from cholesterol.
Cholesterol undergoes double oxidation to produce 22R-hydroxycholesterol and then 20α,22R-dihydroxycholesterol. This vicinal diol is then further oxidized with loss of the side chain starting at position C22 to produce pregnenolone. This reaction is catalyzed by cytochrome P450scc.
The conversion of pregnenolone to progesterone takes place in two steps. First, the 3β-hydroxyl group is oxidized to a keto group and second, the double bond is moved to C4, from C5 through a keto/enol tautomerization reaction. This reaction is catalyzed by 3β-hydroxysteroid dehydrogenase/δ5-4-isomerase.
Progesterone in turn is the precursor of the mineralocorticoid aldosterone, and after conversion to 17α-hydroxyprogesterone, of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone, and estradiol, highlighting the critical role of progesterone in testosterone synthesis.
Pregnenolone and progesterone can also be synthesized by yeast.Approximately 25 mg of progesterone is secreted from the ovaries per day in women, while the adrenal glands produce about 2 mg of progesterone per day.
Distribution
Progesterone binds extensively to plasma proteins, including albumin (50–54%) and transcortin (43–48%). It has similar affinity for albumin relative to the PR.
Metabolism
The metabolism of progesterone is rapid and extensive and occurs mainly in the liver, though enzymes that metabolize progesterone are also expressed widely in the brain, skin, and various other extrahepatic tissues. Progesterone has an elimination half-life of only approximately 5 minutes in circulation. The metabolism of progesterone is complex, and it may form as many as 35 different unconjugated metabolites when it is ingested orally. Progesterone is highly susceptible to enzymatic reduction via reductases and hydroxysteroid dehydrogenases due to its double bond (between the C4 and C5 positions) and its two ketones (at the C3 and C20 positions).The major metabolic pathway of progesterone is reduction by 5α-reductase and 5β-reductase into the dihydrogenated 5α-dihydroprogesterone and 5β-dihydroprogesterone, respectively. This is followed by the further reduction of these metabolites via 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase into the tetrahydrogenated allopregnanolone, pregnanolone, isopregnanolone, and epipregnanolone. Subsequently, 20α-hydroxysteroid dehydrogenase and 20β-hydroxysteroid dehydrogenase reduce these metabolites to form the corresponding hexahydrogenated pregnanediols (eight different isomers in total), which are then conjugated via glucuronidation and/or sulfation, released from the liver into circulation, and excreted by the kidneys into the urine. The major metabolite of progesterone in the urine is the 3α,5β,20α isomer of pregnanediol glucuronide, which has been found to constitute 15 to 30% of an injection of progesterone. Other metabolites of progesterone formed by the enzymes in this pathway include 3α-dihydroprogesterone, 3β-dihydroprogesterone, 20α-dihydroprogesterone, and 20β-dihydroprogesterone, as well as various combination products of the enzymes aside from those already mentioned. Progesterone can also first be hydroxylated (see below) and then reduced. Endogenous progesterone is metabolized approximately 50% into 5α-dihydroprogesterone in the corpus luteum, 35% into 3β-dihydroprogesterone in the liver, and 10% into 20α-dihydroprogesterone.Relatively small portions of progesterone are hydroxylated via 17α-hydroxylase (CYP17A1) and 21-hydroxylase (CYP21A2) into 17α-hydroxyprogesterone and 11-deoxycorticosterone (21-hydroxyprogesterone), respectively, and pregnanetriols are formed secondarily to 17α-hydroxylation. Even smaller amounts of progesterone may be also hydroxylated via 11β-hydroxylase (CYP11B1) and to a lesser extent via aldosterone synthase (CYP11B2) into 11β-hydroxyprogesterone. In addition, progesterone can be hydroxylated in the liver by other cytochrome P450 enzymes which are not steroid-specific. 6β-Hydroxylation, which is catalyzed mainly by CYP3A4, is the major transformation, and is responsible for approximately 70% of cytochrome P450-mediated progesterone metabolism. Other routes include 6α-, 16α-, and 16β-hydroxylation. However, treatment of women with ketoconazole, a strong CYP3A4 inhibitor, had minimal effects on progesterone levels, producing only a slight and non-significant increase, and this suggests that cytochrome P450 enzymes play only a small role in progesterone metabolism.
Levels
In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase, as shown in the diagram above. Progesterone levels tend to be less than 2 ng/mL prior to ovulation and greater than 5 ng/mL after ovulation. If pregnancy occurs, human chorionic gonadotropin is released, maintaining the corpus luteum and allowing it to maintain levels of progesterone. Between 7 and 9 weeks, the placenta begins to produce progesterone in place of the corpus luteum in a process called the luteal-placental shift.After the luteal-placental shift, progesterone levels start to rise further and may reach 100 to 200 ng/mL at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.
Progesterone levels are low in children and postmenopausal women. Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.
Ranges
Blood test results should always be interpreted using the reference ranges provided by the laboratory that performed the results. Example reference ranges are listed below.
Sources
Animal
Progesterone is produced in high amounts in the ovaries (by the corpus luteum) from the onset of puberty to menopause, and is also produced in smaller amounts by the adrenal glands after the onset of adrenarche in both males and females. To a lesser extent, progesterone is produced in nervous tissue, especially in the brain, and in adipose (fat) tissue, as well.
During human pregnancy, progesterone is produced in increasingly high amounts by the ovaries and placenta. At first, the source is the corpus luteum that has been "rescued" by the presence of human chorionic gonadotropin (hCG) from the conceptus. However, after the 8th week, production of progesterone shifts to the placenta. The placenta utilizes maternal cholesterol as the initial substrate, and most of the produced progesterone enters the maternal circulation, but some is picked up by the fetal circulation and used as substrate for fetal corticosteroids. At term the placenta produces about 250 mg progesterone per day.
An additional animal source of progesterone is milk products. After consumption of milk products the level of bioavailable progesterone goes up.
Plants
In at least one plant, Juglans regia, progesterone has been detected. In addition, progesterone-like steroids are found in Dioscorea mexicana. Dioscorea mexicana is a plant that is part of the yam family native to Mexico. It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone. Diosgenin and progesterone are also found in other Dioscorea species, as well as in other plants that are not closely related, such as fenugreek.
Another plant that contains substances readily convertible to progesterone is Dioscorea pseudojaponica native to Taiwan. Research has shown that the Taiwanese yam contains saponins — steroids that can be converted to diosgenin and thence to progesterone.Many other Dioscorea species of the yam family contain steroidal substances from which progesterone can be produced. Among the more notable of these are Dioscorea villosa and Dioscorea polygonoides. One study showed that the Dioscorea villosa contains 3.5% diosgenin. Dioscorea polygonoides has been found to contain 2.64% diosgenin as shown by gas chromatography-mass spectrometry. Many of the Dioscorea species that originate from the yam family grow in countries that have tropical and subtropical climates.
Medical use
Progesterone is used as a medication. It is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone has been shown to prevent miscarriage in women with 1) vaginal bleeding early in their current pregnancy and 2) a previous history of miscarriage. Progesterone can be taken by mouth, through the vagina, and by injection into muscle or fat, among other routes.
Chemistry
Progesterone is a naturally occurring pregnane steroid and is also known as pregn-4-ene-3,20-dione. It has a double bond (4-ene) between the C4 and C5 positions and two ketone groups (3,20-dione), one at the C3 position and the other at the C20 position.
Synthesis
Progesterone is commercially produced by semisynthesis. Two main routes are used: one from yam diosgenin first pioneered by Marker in 1940, and one based on soy phytosterols scaled up in the 1970s. Additional (not necessarily economical) semisyntheses of progesterone have also been reported starting from a variety of steroids. For the example, cortisone can be simultaneously deoxygenated at the C-17 and C-21 position by treatment with iodotrimethylsilane in chloroform to produce 11-keto-progesterone (ketogestin), which in turn can be reduced at position-11 to yield progesterone.
Marker semisynthesis
An economical semisynthesis of progesterone from the plant steroid diosgenin isolated from yams was developed by Russell Marker in 1940 for the Parke |
Progesterone | -Davis pharmaceutical company. This synthesis is known as the Marker degradation.
The 16-DPA intermediate is important to the synthesis of many other medically important steroids. A very similar approach can produce 16-DPA from solanine.
Soy semisynthesis
Progesterone can also be made from the stigmasterol found in soybean oil also. c.f. Percy Julian.
Total synthesis
A total synthesis of progesterone was reported in 1971 by W.S. Johnson. The synthesis begins with reacting the phosphonium salt 7 with phenyl lithium to produce the phosphonium ylide 8. The ylide 8 is reacted with an aldehyde to produce the alkene 9. The ketal protecting groups of 9 are hydrolyzed to produce the diketone 10, which in turn is cyclized to form the cyclopentenone 11. The ketone of 11 is reacted with methyl lithium to yield the tertiary alcohol 12, which in turn is treated with acid to produce the tertiary cation 13. The key step of the synthesis is the π-cation cyclization of 13 in which the B-, C-, and D-rings of the steroid are simultaneously formed to produce 14. This step resembles the cationic cyclization reaction used in the biosynthesis of steroids and hence is referred to as biomimetic. In the next step the enol orthoester is hydrolyzed to produce the ketone 15. The cyclopentene A-ring is then opened by oxidizing with ozone to produce 16. Finally, the diketone 17 undergoes an intramolecular aldol condensation by treating with aqueous potassium hydroxide to produce progesterone.
History
George W. Corner and Willard M. Allen discovered the hormonal action of progesterone in 1929. By 1931–1932, nearly pure crystalline material of high progestational activity had been isolated from the corpus luteum of animals, and by 1934, pure crystalline progesterone had been refined and obtained and the chemical structure of progesterone was determined. This was achieved by Adolf Butenandt at the Chemisches Institut of Technical University in Danzig, who extracted this new compound from several thousand liters of urine.Chemical synthesis of progesterone from stigmasterol and pregnanediol was accomplished later that year. Up to this point, progesterone, known generically as corpus luteum hormone, had been being referred to by several groups by different names, including corporin, lutein, luteosterone, and progestin. In 1935, at the time of the Second International Conference on the Standardization of Sex Hormones in London, England, a compromise was made between the groups and the name progesterone (progestational steroidal ketone) was created.
Veterinary use
The use of progesterone in tests dog breeding to pinpoint ovulation is becoming more widely used. There are several tests available but the most reliable test is a blood test with blood drawn by a veterinarian and sent to a lab for processing. Results can usually be obtained with 24 to 72 hours. The rationale for using progesterone tests is that increased numbers begin in close proximity to preovulatory surge in gonadotrophins and continue through ovulation and estrus. When progesterone levels reach certain levels they can signal the stage of estrus the female is. Prediction of birth date of the pending litter can be very accurate if ovulation date is known. Puppies deliver with a day or two of 9 weeks gestation in most cases. It is not possible to determine pregnancy using progesterone tests once a breeding has taken place, however. This is due to the fact that, in dogs, progesterone levels remain elevated throughout the estrus period.
References
External links
Progesterone MS Spectrum
Progesterone at the US National Library of Medicine Medical Subject Headings (MeSH)
Kimball JW (2007-05-27). "Progesterone". Kimballs Biology Pages. Archived from the original on 2008-06-18. Retrieved 2008-06-18. |
Diflorasone diacetate | Diflorasone diacetate is a topical steroid that comes in the form of a cream. It is manufactured by E. Fougera & Co. and is used as an anti-inflammatory and anti-itching agent, like other topical corticosteroids. It is prescribed for psoriasis and atopic dermatitis, among other conditions. With respect to potency, it is regarded as a Class I corticosteroid [of classes I – VII] in the United States.No long-term animal studies have been done to determine whether diflorasone diacetate could have carcinogenic properties.Little data is available regarding whether diflorasone diacetate would be present in great enough quantities to cause harm to an infant.
References
External links
"Diflorasone diacetate". Drug Information Portal. U.S. National Library of Medicine. |
Azelaic acid | Azelaic acid (AzA) is an organic compound with the formula HOOC(CH2)7COOH. This saturated dicarboxylic acid exists as a white powder. It is found in wheat, rye, and barley. It is a precursor to diverse industrial products including polymers and plasticizers, as well as being a component of a number of hair and skin conditioners. AzA inhibits tyrosinase.
Production
Azelaic acid is industrially produced by the ozonolysis of oleic acid. The side product is nonanoic acid. It is produced naturally by Malassezia furfur (also known as Pityrosporum ovale), a yeast that lives on normal skin. The bacterial degradation of nonanoic acid gives azelaic acid.
Biological function
In plants, azelaic acid serves as a "distress flare" involved in defense responses after infection. It serves as a signal that induces the accumulation of salicylic acid, an important component of a plants defensive response.
Applications
Polymers and related materials
Esters of this dicarboxylic acid find applications in lubrication and plasticizers. In lubricant industries it is used as a thickening agent in lithium complex grease. With hexamethylenediamine, azelaic acid forms Nylon-6,9, which finds specialized uses as a plastic.
Medical
Azelaic acid is used to treat mild to moderate acne, both comedonal acne and inflammatory acne. It belongs to a class of medication called dicarboxylic acids. It works by killing acne bacteria that infect skin pores. It also decreases the production of keratin, which is a natural substance that promotes the growth of acne bacteria. Azelaic acid is also used as a topical gel treatment for rosacea, due to its ability to reduce inflammation. It clears the bumps and swelling caused by rosacea. The mechanism of action is thought to be through the inhibition of hyperactive protease activity that converts cathelicidin into the antimicrobial skin peptide LL-37.In topical pharmaceutical preparations and scientific research AzA is typically used in concentrations between 15% and 20% but some research demonstrates that in certain vehicle formulations the pharmaceutical effects of 10% Azelaic acid has the potential to be fully comparable to that of some 20% creams.
Acne treatment
Azelaic acid is effective for mild to moderate acne when applied topically at a 15%-20% concentration. In patients with moderate acne, twice daily application over 3 months of 20% AzA significantly reduced the number of comedones, papules, and pustules; at this strength, it’s considered to be as effective as benzoyl peroxide 5%, tretinoin 0.05%, erythromycin 2%, and oral tetracycline at 500mg-1000mg. In a comparative review of effects of topical AzA, Salicylic acid, Nicotinamide, Sulfur, Zinc, and alpha-hydroxy acid, AzA had more high-quality evidence of effectiveness than the rest. Results can be expected after 4 weeks of twice-daily treatment. The effectiveness of long term use is unclear, but it’s been recommended that AzA be used for at least 6 months continuously for maintenance.
Whitening agent
Azelaic acid has been used for treatment of skin pigmentation, including melasma and postinflammatory hyperpigmentation, particularly in those with darker skin types. It has been recommended as an alternative to hydroquinone. As a tyrosinase inhibitor, azelaic acid reduces synthesis of melanin. According to one report in 1988, azelaic acid in combination with zinc sulfate in vitro was found to be a potent (90% inhibition) 5α-reductase inhibitor, similar to the hair loss drugs finasteride and dutasteride. In vitro research during mid-1980s evaluating azelaic acids depigmenting (whitening) capability concluded it is effective (cytotoxic to melanocytes) at only high concentrations.A 1996 review claimed 20% AzA is as potent as 4% hydroquinone after a period of application of three months without the latters adverse effects and even more effective if applied along with tretinoin for the same period of time.
Brand names
Brand names for azelaic acid include Dermaz 99, Crema Pella Perfetta (micronized azelaic acid, kojic dipalmitate, and liquorice extract), Azepur99, Azetec99, Azaclear (azelaic acid and niacinamide), AzClear Action, Azelex, White Action cream, Finacea, Finevin, Melazepam, Skinoren, Ezanic, Azelac, Azaderm, (Acnegen, Eziderm, Acnicam, Azelexin in Pakistan)
References
External links
DermNet treatments/azelaic-acid"Azelaic Acid Topical". MedlinePlus. |
Clobazam | Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.
Medical uses
Clobazam is used for its anxiolytic effect, and as an adjunctive therapy in epilepsy.
As an adjunctive therapy in epilepsy, it is used in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. In addition to epilepsy and severe anxiety, clobazam is also approved as a short-term (2–4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due to drug tolerance which may render long-term therapy less effective. Other antiepileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.
Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures, certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for the treatment of anxiety.
In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2–4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until October 25, 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.
Contraindications
Clobazam should be used with great care in patients with the following disorders:
Myasthenia gravis.
Sleep apnea.
Severe liver diseases such as cirrhosis and hepatitis.
Severe respiratory failure.Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals, and individuals with comorbid psychiatric disorders.
Side effects
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.
Common
Common side effects include fever, drooling, and constipation.
Post-marketing experience
Hives.
Rashes.
Warnings and precautions
In December 2013, the FDA added warnings to the label for clobazam, that it can cause serious skin reactions, Stevens–Johnson syndrome, and toxic epidermal necrolysis, especially in the first eight weeks of treatment.
Drug interactions
Alcohol increases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity.
Cimetidine increases the effects of clobazam.
Valproate.
Overdose
Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.
Abuse potential and addiction
Classic (non-anxioselective) benzodiazepines in animal studies have been shown to increase reward-seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation report.
Dependence and withdrawal
In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or overrapid withdrawal.Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen.
Pharmacology
Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additional activity at sodium channels and voltage-sensitive calcium channels.Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, or CP-1414S), the active metabolite N-desmethylclobazam has less affinity for the α1 subunit of the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for α2 containing receptors, where it has positive modulatory activity.In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg of clobazam was shown to be less sedative than either 0.5 mg or 1 mg of clonazepam.The α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al. in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1 receptors were insensitive to diazepam.In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride influx at GABAA receptors, creating a hyperpolarizing, inhibitory postsynaptic potential. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.
Metabolism
Clobazam has two major metabolites: N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.
Chemistry
Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4).It is not soluble in water and is available in oral form only.
History
Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969; Maestretti was acquired by Roussel Uclaf which became part of Sanofi.
See also
Benzodiazepine dependence
Effects of long-term benzodiazepine use
References
Further reading
Dean L (September 2019). "Clobazam Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 31550100.
External links
"Clobazam". Drug Information Portal. U.S. National Library of Medicine. |
Siltuximab | Siltuximab (INN, trade name Sylvant; also known as CNTO 328, anti-IL-6 chimeric monoclonal antibody or cCLB8) is a chimeric (made from human and mouse proteins) monoclonal antibody. It binds to interleukin-6. Siltuximab has been investigated for the treatment of neoplastic diseases: metastatic renal cell cancer, prostate cancer, other types of cancer, and for Castlemans disease.On April 23, 2014, siltuximab was FDA approved under the brand name of Sylvant for the treatment of patients with idiopathic multicentric Castleman’s disease (iMCD) who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8).
Medical uses
Used for the treatment of idiopathic multicentric Castleman disease (iMCD).
Clinical trials
Siltuximab has demonstrated significant efficacy and safety in patients with idiopathic multicentric Castleman disease. Treatment results with Siltuximab in B-cell non-Hodgkins lymphoma are inferior to those obtained in multicentric Castleman disease. Siltuximab has also been evaluated in the treatment ovarian cancer, however the efficacy for this cancer is debatable. In addition, siltuximab has been evaluated for multiple myeloma, but there was an insignificant increase in response rates.
Side effects
Siltuximab may lower resistance to infections and should not be administered to patients with severe infections. Siltuximab should be discontinued in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions or cytokine release syndromes. Live vaccines should not be administered to patients receiving siltuximab since IL-6 inhibition may interfere with normal immune response to new antigens.Common
The following has been shown to occur in treatment of Multicentric Castlemans disease with siltuximab during a clinical trial (>10% compared to placebo):
Peripheral edema
Abdominal Pain
Pruritus
Increased weight
Rash
Hyperuricemia
Upper respiratory tract infectionsLong term exposure
Upper respiratory tract infection
Pain in extremities
Arthralgia
Fatigue
Drug interactions
Siltuximab may increase CYP450 activity leading to increased metabolism of drugs that are CYP450 substrates. Co-administration of siltuximab and CYP450 substrates with narrow therapeutic index such as warfarin, ciclosporin or theophylline should be closely monitored.
Mechanism of action
Siltuximab is a chimeric monoclonal antibody that binds to interleukin-6 (IL-6), preventing binding to soluble and membrane bound interleukin-6 receptors. Siltuximab interferes with IL-6 mediated growth of B-lymphocytes and plasma cells, secretion of vascular endothelial growth factor (VEGF) and autoimmune phenomena.
== References == |
Aminocaproic acid | Aminocaproic acid (also known as ε-aminocaproic acid, ε-Ahx, or 6-aminohexanoic acid) is a derivative and analogue of the amino acid lysine, which makes it an effective inhibitor for enzymes that bind that particular residue. Such enzymes include proteolytic enzymes like plasmin, the enzyme responsible for fibrinolysis. For this reason it is effective in treatment of certain bleeding disorders, and it is sold under the brand name Amicar. Aminocaproic acid is also an intermediate in the polymerization of Nylon-6, where it is formed by ring-opening hydrolysis of caprolactam. The crystal structure determination showed that the 6-aminohexanoic acid is present as a salt, at least in the solid state.
Medical use
Aminocaproic acid (Amicar) is FDA-approved for use in the treatment of acute bleeding due to elevated fibrinolytic activity. It also carries an orphan drug designation from the FDA for the prevention of recurrent hemorrhage in patients with traumatic hyphema. In clinical practice, aminocaproic acid is frequently used off-label for control of bleeding in patients with severe thrombocytopenia, control of oral bleeding in patients with congenital and acquired coagulation disorders, control of perioperative bleeding associated with cardiac surgery, prevention of excessive bleeding in patients on anticoagulation therapy undergoing invasive dental procedures, and reduction of the risk of catastrophic hemorrhage in patients with acute promyelocytic leukemia.
References
Further reading
Alkjaersig N, Fletcher AP, Sherry S (April 1959). "xi-Aminocaproic acid: an inhibitor of plasminogen activation". The Journal of Biological Chemistry. 234 (4): 832–7. doi:10.1016/S0021-9258(18)70185-3. PMID 13654273.
Kang Y, Lewis JH, Navalgund A, Russell MW, Bontempo FA, Niren LS, Starzl TE (June 1987). "Epsilon-aminocaproic acid for treatment of fibrinolysis during liver transplantation". Anesthesiology. 66 (6): 766–73. doi:10.1097/00000542-198706000-00010. PMC 2965586. PMID 3296855.
External links
"Aminocaproic acid". Drug Information Portal. U.S. National Library of Medicine. |
Merrem | Merrem may refer to:
Meropenem, an antibiotic initially marketed under the trade name Merrem
Blasius Merrem (1761–1824), German naturalist, zoologist, ornithologist, mathematician, and herpetologist |
Alclometasone | Alclometasone is a synthetic corticosteroid for topical dermatologic use, possessing anti-inflammatory, antipruritic, and vasoconstrictive properties.The prodrug alclometasone dipropionate was originally marketed under the brand name Aclovate by GlaxoSmithKline as a topical cream and ointment. However, generic versions of the drug are available.
Medical uses
Alclometasone cream and ointment are indicated for the relief of corticosteroid-responsive dermatoses, including:
atopic dermatitis
eczema
psoriasis
allergic dermatitis
contact dermatitis
actinic dermatitis
kiss-type allergy
skin itchAlclometasone may be used on sensitive skin sites (face, skinfolds); in pediatric patients 1 year or older and in geriatric patients.
Contraindications
hypersensitivity to alclometasone or any of ingredients in pharmaceutical forms
cutaneous tuberculosis
chicken pox
perioral dermatitis
acne
rosacea
open wounds
trophic ulcers
viral infection of skin
skin manifestations of syphilis
Side effects
Adverse reactions (sometimes, less than 1-2% cases) include:
burning
itching
erythema
skin reddening
xerodermia
skin irritation
acne
hypopigmentation
prickly heat
folliculitis
white atrophy
hypertrichosis
reinfection of skin
Pharmacology
Alclometasone induces the production of lipocortins, formally known as annexins, which inhibit phospholipase A2 – the enzyme responsible for the synthesis of arachidonic acid. Without the oxidation of arachidonic acid, eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes, cant be produced.
Alclometasone also inhibits the release of pro-inflammatory mediators from leukocytes (e.g., cytokines, histamine, leukotrienes, serotonin).
Formulations
Alclometasone as Aclovate is supplied in:
Cream; Topical; 0.05%
Ointment; Topical; 0.05%
== References == |
Efgartigimod alfa | Efgartigimod alfa, sold under the brand name Vyvgart, is a medication used to treat myasthenia gravis.The most common side effects include respiratory tract infections, headache, and urinary tract infections.Efgartigimod alfa is a neonatal Fc receptor blocker and is a new class of medication. It is an antibody fragment that binds to the neonatal Fc receptor (FcRn), preventing FcRn from recycling immunoglobulin G (IgG) back into the blood. The medication causes a reduction in overall levels of IgG, including the abnormal acetylcholine receptor (AChR) antibodies that are present in myasthenia gravis. It was approved for medical use in the United States in December 2021, and in the European Union in August 2022.
Medical uses
Efgartigimod alfa is indicated for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody positive.
History
The safety and efficacy of efgartigimod alfa were evaluated in a 26-week clinical study of 167 participants with myasthenia gravis who were randomized to receive either efgartigimod alfa or placebo. The study showed that more participants with myasthenia gravis with antibodies responded to treatment during the first cycle of efgartigimod alfa (68%) compared to those who received placebo (30%) on a measure that assesses the impact of myasthenia gravis on daily function. More participants receiving efgartigimod alfa also demonstrated response on a measure of muscle weakness compared to placebo.
Pharmacodynamics
Efgartigimod alfa as a drug is an antibody fragment that binds to the neonatal Fc receptor. When this binding happens, the IgG recycling process is blocked. The amount of circulating IgG decreases and therefore prevents the acetylcholine receptors from being degraded by the autoantibodies that are responsible for the myasthenia gravis.
Pharmacokinetics
The drug is mainly metabolized via proteolytic enzymes. The termination half-life of Efgartigimod alfa is 80 to 120 hours.
Side effects
Side effects of efgartigimod alfa include respiratory tract infections, headache, urinary tract infection, numbness and tingling and muscle pain.
Society and culture
Legal status
The U.S. Food and Drug Administration (FDA) granted the application for efgartigimod alfa fast track and orphan drug designations. The FDA granted the approval of Vyvgart to Argenx BV.On 23 June 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 Vyvgart, intended for the treatment of anti‑acetylcholine receptor (AChR) antibody positive generalized myasthenia gravis. The applicant for this medicinal product is Argenx. Efgartigimod alfa was approved for medical use in the European Union in August 2022.
Names
Efgartigimod alfa is the international nonproprietary name (INN).
References
This article incorporates public domain material from the United States Department of Health and Human Services.
Further reading
Howard JF, Bril V, Vu T, Karam C, Peric S, Margania T, et al. (July 2021). "Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial". Lancet Neurol. 20 (7): 526–536. doi:10.1016/S1474-4422(21)00159-9. hdl:10067/1859580151162165141. PMID 34146511. S2CID 235456637.
External links
"Efgartigimod alfa". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03669588 for "An Efficacy and Safety Study of ARGX-113 in Patients With Myasthenia Gravis Who Have Generalized Muscle Weakness (ADAPT)" at ClinicalTrials.gov |
Gatifloxacin | Gatifloxacin (brand names Gatiflo, Tequin, and Zymar) is an antibiotic of the fourth-generation fluoroquinolone family, that like other members of that family, inhibits the bacterial enzymes DNA gyrase and topoisomerase IV.
It was patented in 1986 and approved for medical use in 1999.
Side effects
A Canadian study published in the New England Journal of Medicine in March 2006, claimed that Tequin can have significant side effects including dysglycemia. An editorial by
Jerry Gurwitz in the same issue called for the Food and Drug Administration (FDA) to consider giving Tequin a black box warning. This editorial followed distribution of a letter dated February 15 by Bristol-Myers Squibb to health care providers indicating action taken with the FDA to strengthen warnings for the medication. Subsequently, Bristol-Myers Squibb reported it would stop manufacture of Tequin, end sales of the drug after existing stockpiles were exhausted, and return all rights to Kyorin.By contrast, ophthalmic gatifloxacin is generally well tolerated. The observed systemic concentration of the drug following oral administration of 400 mg (0.01 ounces) gatifloxacin is approximately 800 times higher than that of the 0.5% gatifloxacin eye drop. Given as an eye drop, gatifloxacin has very low systemic exposure. Therefore, the systemic exposures resulting from the gatifloxacin ophthalmic solution are not likely to pose any risk for systemic toxicities.
Contraindications
Hypersensitivity
Society and culture
Availability
Gatifloxacin is currently available in the US and Canada only as an ophthalmic solution.In 2011, the Union Health and Family Welfare Ministry of India banned the manufacture, sale, and distribution of gatifloxacin because of its adverse side effects.In China, gatifloxacin is sold in tablet as well as in eye drop formulations.
Brand names
Bristol-Myers Squibb introduced gatifloxacin in 1999 under the proprietary name Tequin for the treatment of respiratory tract infections, having licensed the medication from Kyorin Pharmaceutical Company of Japan. Allergan produces it in eye-drop formulation under the names Zymar, Zymaxid and Zylopred. In many countries, gatifloxacin is also available as tablets and in various aqueous solutions for intravenous therapy.
== References == |
Trifluridine/tipiracil | Trifluridine/tipiracil, sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell that fights infection), feeling sick, tiredness and anemia (low red blood cell counts).
Medical uses
It is used as a third- or fourth-line treatment for metastatic colorectal cancer or gastric cancer, after chemotherapy and biologic therapy.
Contraindications
The combination caused harm to the fetus of pregnant animals, and it was not tested in pregnant women. Pregnant women should not take it, and women should not become pregnant while taking it.
Adverse effects
The combination severely suppresses bone marrow function, resulting in fewer red blood cells, white blood cells, and platelets, so many people taking it are at risk for infections, anemia, and blood loss from lack of clotting. It also causes digestive problems, with more than 10% of people experiencing loss of appetite, diarrhea, nausea, and vomiting. More than 10% of people experience fatigue and fever.Between 1 and 10% of people have skin and mucosa issues, like rashes and itchiness, or mouth sores, as well as skin sloughing, numbness, redness, and swelling of their palms and soles. Dizziness and confusion are common as well.
Interactions
Only in vitro interaction studies are available. In these, trifluridine used the concentrative nucleoside transporter 1 (CNT1) and equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), and tipiracil was transported by the solute carrier proteins SLC22A2 and SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of trifluridine and tipiracil. Trifluridine, being a thymidine phosphorylase inhibitor, could also interact with substrates of this enzyme such as zidovudine.
Pharmacology
Mechanism of action
The drug consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP; TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzymes activity. TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, thymidine triphosphate (dTTP). Inhibition of TS depletes the cell of dTTP and causes accumulation of deoxyuridine monophosphate (dUMP), which increases the likelihood that uracil gets misincorporated into the DNA. Also, subsequent phosphorylations of TF-TMP cause an increased level of TF-TTP within the cell, which results in it being incorporated into DNA. Even though the exact mechanism of how TFT causes DNA damage is not completely understood, it is hypothesized that the incorporation TF-TTP in DNA leads to DNA strand break formation.Tipiracil prevents the degradation of trifluridine via thymidine phosphorylase (TP) when taken orally and also has antiangiogenic properties.
History
Since the synthesis of 5-fluorouracil (5-FU) in 1957, fluoropyrimidines have been used to treat many types of cancer. Due to the drawbacks of 5-FU therapy, such as having to be administered over long periods of time via intravenous infusion and the development of resistance in tumors, more convenient and efficacious fluoropyrimidine therapy has been desired. The fluoropyrimidine component of this drug, trifluridine, was first synthesized in 1964 by Heidelberger et al.By the late 1960s, Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved to be disappointing. Its pharmacokinetic profile during these clinical trials showed that the drug exhibited a very short half-life while in serum (12 minutes post-injection). Adjustments in the dosing regimen improved its effects in small studies, but the effect was short-lived.Researchers later found out that trifluridine, when taken orally, was broken down into the inactive metabolites 5-trifluoromethyluracil and 5-trifluoromethyl-2,4(1H,3,H)-pyrimidinedione (FTY) during its extensive first pass metabolism in the liver via the enzyme thymidine phosphorylase. It was then hypothesized that orally administered FTD concentrations could be increased and maintained if the drug was given with a thymidine phosphorylase inhibitor.Trifluridine/tipiracil was approved by the U.S. FDA in September 2015, and by the European Medicines Agency in April 2016.
References
External links
"Tipiracil hydrochloride mixture with trifluridine". Drug Information Portal. U.S. National Library of Medicine. |
Dorzolamide | Dorzolamide, sold under the brand name Trusopt among others, is a medication used to treat high pressure inside the eye, including in cases of glaucoma. It is used as an eye drop. Effects begin within three hours and last for at least eight hours. It is also available as the combination dorzolamide/timolol.Common side effects include eye discomfort, eye redness, taste changes, and blurry vision. Serious side effects include Steven Johnson syndrome. Those allergic to sulfonamides may be allergic to dorzolamide. Use is not recommended in pregnancy or breastfeeding. It is a carbonic anhydrase inhibitor and works by decreasing the production of aqueous humour.Dorzolamide was approved for medical use in the United States in 1994. It is available as a generic medication. In 2017, it was the 281st most commonly prescribed medication in the United States, with more than one million prescriptions. It is a second-generation carbonic anhydrase inhibitor.
Medical uses
Dorzolamide hydrochloride is used to lower excessive intraocular pressure in open-angle glaucoma and ocular hypertension. This drug is able to cross the cornea, reach the ciliary body of the eye, and produce systemic effects on the carbonic anhydrase enzyme within the eye.
Side effects
Ocular stinging, burning, itching and bitter taste. It causes shallowing of the anterior chamber and leads to transient myopia. As a second generation carbonic anhydrase inhibitor, Dorzolamide avoids systemic effects associated with first generation carbonic anhydrase inhibitors such as Acetazolamide, Methazolamide, and Dichlorphenamide.
Pharmacodynamics
Dorzolamide lowers intraocular pressure by about 20%. Normally, carbonic anhydrase converts carbonic acid (H2CO3) into bicarbonate (HCO3), releasing a proton (H+) into solution. The H+ is then exchanged for sodium (Na+) ions, which facilitates the production of aqueous humor. By blocking the function of carbonic anhydrase, the Na+/H+ exchange is unable to occur, which leads to a decrease in Na+ in the cell and prevents aqueous humor production.
History
This drug, developed by Merck, was the first drug in human therapy (market introduction 1995) that resulted from structure-based drug design. It was developed to circumvent the systemic side effects of acetazolamide which has to be taken orally.
References
Further reading
Kubinyi H (1999). "Chance favors the prepared mind--from serendipity to rational drug design". J Recept Signal Transduct Res. 19 (1–4): 15–39. doi:10.3109/10799899909036635. PMID 10071748.
Plummer C, MacKay E, Gelatt K (2006). "Comparison of the effects of topical administration of a fixed combination of dorzolamide-timolol to monotherapy with timolol or dorzolamide on IOP, pupil size, and heart rate in glaucomatous dogs". Veterinary Ophthalmology. 9 (4): 245–9. doi:10.1111/j.1463-5224.2006.00469.x. PMID 16771760.
Grover S, Apushkin M, Fishman G (2006). "Topical dorzolamide for the treatment of cystoid macular edema in patients with retinitis pigmentosa". Am J Ophthalmol. 141 (5): 850–8. doi:10.1016/j.ajo.2005.12.030. PMID 16546110.
Almeida G, Faria e Souza S (2006). "Effect of topical dorzolamide on rabbit central corneal thickness". Braz J Med Biol Res. 39 (2): 277–81. doi:10.1590/S0100-879X2006000200015. PMID 16470316. |
Tiagabine | Tiagabine (trade name Gabitril) is an anticonvulsant medication produced by Cephalon that is used in the treatment of epilepsy. The drug is also used off-label in the treatment of anxiety disorders and panic disorder.
Medical uses
Tiagabine is approved by U.S. Food and Drug Administration (FDA) as an adjunctive treatment for partial seizures in individuals of age 12 and up. It may also be prescribed off-label by physicians to treat anxiety disorders and panic disorder as well as neuropathic pain (including fibromyalgia). For anxiety and neuropathic pain, tiagabine is used primarily to augment other treatments. Tiagabine may be used alongside selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or benzodiazepines for anxiety, or antidepressants, gabapentin, other anticonvulsants, or opioids for neuropathic pain. It is effective as monotherapy and combination therapy with other antiepileptic drugs in the treatment of partial seizure.The American Academy of Sleep Medicines 2017 clinical practice guidelines recommended against the use of tiagabine in the treatment of insomnia due to poor effectiveness and very low quality of evidence.
Side effects
Side effects of tiagabine are dose related. The most common side effect of tiagabine is dizziness. Other side effects that have been observed with a rate of statistical significance relative to placebo include asthenia, somnolence, nervousness, memory impairment, tremor, headache, diarrhea, and depression. Adverse effects such as confusion, aphasia (difficulty speaking clearly)/stuttering, and paresthesia (a tingling sensation in the bodys extremities, particularly the hands and fingers) may occur at higher dosages of the drug (e.g., over 8 mg/day). Tiagabine may induce seizures in those without epilepsy, particularly if they are taking another drug which lowers the seizure threshold. There may be an increased risk of psychosis with tiagabine treatment, although data is mixed and inconclusive. Tiagabine can also reportedly interfere with visual color perception.
Warning
CNS depression
Dermatologic reactions
Generalized weakness
Ophthalmic effects
Suicidal ideation
Overdose
Tiagabine overdose can produce neurological symptoms such as lethargy, single or multiple seizures, status epilepticus, coma, confusion, agitation, tremors, dizziness, dystonias/abnormal posturing, and hallucinations, as well as respiratory depression, tachycardia, hypertension, and hypotension. Overdose may be fatal especially if the victim presents with severe respiratory depression and/or unresponsiveness.
Pharmacology
Tiagabine increases the level of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, by blocking the GABA transporter 1 (GAT-1), and hence is classified as a GABA reuptake inhibitor (GRI).
Pharmacodynamics
Tiagabine is primarily used as an anticonvulsant in the treatment of epilepsy as a supplement. Although the exact mechanism by which Tiagabine exerts its antiseizure effect is unknown, it is thought to be related to its ability to increase the activity of gamma aminobutyric acid (GABA), the central nervous systems major inhibitory neurotransmitter. Tiagabine attaches to the GABA uptake carriers recognition sites. Tiagabine is thought to block GABA uptake into presynaptic neurons as a result of this action, allowing more GABA to be available for receptor binding on the surfaces of post-synaptic cells.
Monitoring Parameters
Seizure frequency, liver function tests , suicidality
History
Tiagabine was discovered at Novo Nordisk in Denmark in 1988 by a team of medicinal chemists and pharmacologists under the general direction of Claus Bræstrup. The drug was co-developed with Abbott Laboratories, in a 40/60 cost sharing deal, with Abbott paying a premium for licensing the IP from the Danish company.U.S. patents on tiagabine listed in the Orange Book expired in April 2016.
See also
CI-966
Deramciclane
Nipecotic acid
SKF-89976A
References
External links
Gabitril(manufacturers website) |
Cefpodoxime | Cefpodoxime is an oral, third-generation cephalosporin antibiotic. It is active against most Gram-positive and Gram-negative organisms. Notable exceptions include Pseudomonas aeruginosa, Enterococcus, and Bacteroides fragilis. Currently, it is only marketed as generic preparations in the US, according to the FDA Orange Book. It is commonly used to treat acute otitis media, pharyngitis, sinusitis, and gonorrhea. It also finds use as oral continuation therapy when intravenous cephalosporins (such as ceftriaxone) are no longer necessary for continued treatment.
Cefpodoxime inhibits cell wall synthesis by inhibiting the final transpeptidation step of peptidoglycan synthesis in cell walls. It has well established pharmacokinetic profile with absorption of 50%. It is indicated in community acquired pneumonia, uncomplicated skin and skin structure infections, and uncomplicated urinary tract infections.
It was patented in 1980 and approved for medical use in 1989.
Spectrum of bacterial susceptibility and resistance
Cefpodoxime has been used to fight pathogenic bacteria responsible for causing gonorrhoea, tonsillitis, pneumonia, and bronchitis. Representative pathogenic genera include Streptococcus, Haemophilus, and Neisseria. The following represents MIC susceptibility data for a few medically significant microorganisms.
Haemophilus influenzae: ≤0.03 – 1 μg/ml
Neisseria gonorrhoeae: 0.004 – 0.06 μg/ml
Streptococcus pyogenes: ≤0.004 – 2 μg/ml
Brand name
Zoetis markets cefpodoxime proxetil under the trade name Simplicef for veterinary use, Finecure, India markets the products under trade name Cefpo.Vantin (by Pfizer) in suspension or tablet form.
Toraxim (by Delta Pharma Ltd. Bangladesh)
Trucef (by Renata Limited, Bangladesh)
Tricef (by Alkaloid Skopje, North Macedonia)
Orelox (by Sanofi-Aventis)MAPDOX-CV: Cefpodoxime and Clavulanic acid combination
MONOTAX O (Cefpodoxime)/ MONOTAX CV (Cefpodoxime and Clavulanic acid combination) (by Zydus Healthcare Ltd.)
POSTPOD-50 (Cefpodoxime 50mg/5ml) (by Laafon Galaxy Pharmaceuticals)
References
External links
CID 6526396 from PubChem – cefpodoxime proxetil
Vantin Tablets and Oral Suspension Torpod (Torrent) Full U.S. Prescribing Information (from manufacturers website)
Simplicef (from manufacturers website)
https://web.archive.org/web/20190425082636/https://www.intaspharma.com/index.php?option=com_djcatalog2&view=itemstable&cid=3&Itemid=77 |
Abacavir | Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.Abacavir is generally well tolerated. Common side effects include vomiting, insomnia (trouble sleeping), fever, and feeling tired. Other common side effects include loss of appetite, headache, nausea (feeling sick), diarrhea, rash, and lethargy (lack of energy). More severe side effects include hypersensitivity, liver damage, and lactic acidosis. Genetic testing can indicate whether a person is at higher risk of developing hypersensitivity. Symptoms of hypersensitivity include rash, vomiting, and shortness of breath. Abacavir is in the NRTI class of medications, which work by blocking reverse transcriptase, an enzyme needed for HIV virus replication. Within the NRTI class, abacavir is a carbocyclic nucleoside.Abacavir was patented in 1988, and approved for use in the United States in 1998. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Abacavir is used together with other HIV medications, such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine. The combination abacavir/lamivudine is an essential medicine.
Medical uses
Abacavir, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. Abacavir should be used in combination with other antiretroviral agents.
Contraindications
Abacavir is contraindicated for people who have the HLA‑B*5701 allele or who have moderate or severe liver disease (hepatic impairment).
Side effects
Common adverse reactions include nausea, headache, fatigue, vomiting, diarrhea, Anorexia (symptom) (loss of appetite), and insomnia (trouble sleeping). Rare but serious side effects include hypersensitivity reaction such as rash, elevated AST and ALT, depression, anxiety, fever/chills, URI, lactic acidosis, hypertriglyceridemia, and lipodystrophy.<
Hypersensitivity syndrome
Hypersensitivity to abacavir is strongly associated with a specific allele at the human leukocyte antigen B locus namely HLA-B*5701. The mechanism for this hypersensitivity reaction is due to abacavir binding in the antigen-binding cleft of HLA-B*57:01, allowing alternative peptides to bind, which appear as "non-self" when presented to T cells. There is an association between the prevalence of HLA-B*5701 and ancestry. The prevalence of the allele is estimated to be 3.4 to 5.8 percent on average in populations of European ancestry, 17.6 percent in Indian Americans, 3.0 percent in Hispanic Americans, and 1.2 percent in Chinese Americans. There is significant variability in the prevalence of HLA-B*5701 among African populations. In African Americans, the prevalence is estimated to be 1.0 percent on average, 0 percent in the Yoruba from Nigeria, 3.3 percent in the Luhya from Kenya, and 13.6 percent in the Masai from Kenya, although the average values are derived from highly variable frequencies within sample groups.Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea, and diarrhea. Some patients may also develop a skin rash. Symptoms of AHS typically manifest within six weeks of treatment using abacavir, although they may be confused with symptoms of HIV, immune reconstitution syndrome, hypersensitivity syndromes associated with other drugs, or infection. The U.S. Food and Drug Administration (FDA) released an alert concerning abacavir and abacavir-containing medications on 24 July 2008, and the FDA-approved drug label for abacavir recommends pre-therapy screening for the HLA-B*5701 allele and the use of alternative therapy in subjects with this allele. Additionally, both the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group recommend use of an alternative therapy in individuals with the HLA-B*5701 allele.
Skin-patch testing may also be used to determine whether an individual will experience a hypersensitivity reaction to abacavir, although some patients susceptible to developing AHS may not react to the patch test.The development of suspected hypersensitivity reactions to abacavir requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients who do not possess the HLA-B*5701 allele. On 1 March 2011, the FDA informed the public about an ongoing safety review of abacavir and a possible increased risk of heart attack associated with the drug. A meta-analysis of 26 studies conducted by the FDA, however, did not find any association between abacavir use and heart attack
Immunopathogenesis
The mechanism underlying abacavir hypersensitivity syndrome is related to the change in the HLA-B*5701 protein product. Abacavir binds with high specificity to the HLA-B*5701 protein, changing the shape and chemistry of the antigen-binding cleft. This results in a change in immunological tolerance and the subsequent activation of abacavir-specific cytotoxic T cells, which produce a systemic reaction known as abacavir hypersensitivity syndrome.
Interaction
Abacavir, and in general NRTIs, do not undergo hepatic metabolism and therefore have very limited (to none) interaction with the CYP enzymes and drugs that effect these enzymes. That being said there are still few interactions that can affect the absorption or the availability of abacavir. Below are few of the common established drug and food interaction that can take place during abacavir co-administration:
Protease inhibitors such as tipranavir or ritonovir may decrease the serum concentration of abacavir through induction of glucuronidation. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.
Ethanol may result in increased levels of abacavir through the inhibition of alcohol dehydrogenase. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.
Methadone may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone.
Orlistat may decrease the serum concentration of antiretroviral drugs. The mechanism of this interaction is not fully established but it is suspected that it is due to the decreased absorption of abacavir by orlistat.
Cabozantinib: Drugs from the MRP2 inhibitor (Multidrug resistance-associated protein 2 inhibitors) family such as abacavir could increase the serum concentration of Cabozantinib.
Mechanism of action
Abacavir is a nucleoside reverse transcriptase inhibitor that inhibits viral replication. It is a guanosine analogue that is phosphorylated to carbovir triphosphate (CBV-TP). CBV-TP competes with the viral molecules and is incorporated into the viral DNA. Once CBV-TP is integrated into the viral DNA, transcription and HIV reverse transcriptase is inhibited.
Pharmacokinetics
Abacavir is given orally and is rapidly absorbed with a high bioavailability of 83%. Solution and tablet have comparable concentrations and bioavailability. Abacavir can be taken with or without food.Abacavir can cross the blood-brain barrier. Abacavir is metabolized primarily through the enzymes alcohol dehydrogenase and glucuronyl transferase to an inactive carboxylate and glucuronide metabolites. It has a half-life of approximately 1.5-2.0 hours. If a person has liver failure, abacavirs half life is increased by 58%.Abacavir is eliminated via excretion in the urine (83%) and feces (16%). It is unclear whether abacavir can be removed by hemodialysis or peritoneal dialysis.
History
Robert Vince and Susan Daluge along with Mei Hua, a visiting scientist from China, developed the medication in the 80s.Abacavir was approved by the U.S. Food and Drug Administration (FDA) on 18 December 1998, and is thus the fifteenth approved antiretroviral drug in the United States. Its patent expired in the United States on 26 December 2009.
Synthesis
References
Further reading
External links
"Abacavir". Drug Information Portal. U.S. National Library of Medicine.
"Abacavir sulfate". Drug Information Portal. U.S. National Library of Medicine.
Abacavir pathway on PharmGKB |
Patisiran | Patisiran, sold under the brand name Onpattro, is a medication used for the treatment of polyneuropathy in people with hereditary transthyretin-mediated amyloidosis, a fatal rare disease that is estimated to affect 50,000 people worldwide.It is the first small interfering RNA-based drug approved by the U.S. Food and Drug Administration (FDA) and the first drug approved by the FDA to treat this condition. It is a gene silencing drug that interferes with the production of an abnormal form of transthyretin. Patisiran utilizes a novel approach to target and reduce production of the TTR protein in the liver via the RNAi pathway.Patisiran was developed and is marketed by Alnylam. The FDA considers it to be a first-in-class medication.
History
Patisiran was granted orphan drug status, fast track designation, priority review and breakthrough therapy designation due to its novel mechanism and the rarity of the condition it treats. It was approved for medical use in the United States and in the European Union in August 2018. The per-patient cost is between US$451,430 and US$677,145 per year, depending on the number of vials needed.
Formulation
The siRNA active component of Patisiran is formulated into lipid nanoparticles, which protect the RNA and facilitate its delivery to target tissues. The lipid nanoparticle formulation includes buffer components, as well as the lipid components DLin-MC3-DMA, Distearoylphosphatidylcholine, cholesterol, and the PEGylated lipid DMG-PEG 2000.
Society and culture
Economics
As of 2020, there were 1050 people globally receiving patisiran, generating $65.5M in net-revenues for Alnylam Pharmaceuticals.
References
External links
"Patisiran". Drug Information Portal. U.S. National Library of Medicine. |
Tranexamic acid | Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken either orally or by injection into a vein.
Mechanism of action
Tranexamic acid is a synthetic analog of the amino acid lysine. It serves as an antifibrinolytic by reversibly binding four to five lysine receptor sites on plasminogen. This decreases the conversion of plasminogen to plasmin, preventing fibrin degradation and preserving the framework of fibrins matrix structure. Tranexamic acid has roughly eight times the antifibrinolytic activity of an older analogue, ε-aminocaproic acid. Tranexamic acid also directly inhibits the activity of plasmin with weak potency (IC50 = 87 mM), and it can block the active-site of urokinase plasminogen activator (uPA) with high specificity (Ki = 2 mM), one of the highest among all the serine proteases.Side effects are rare. Some include changes in color vision, blood clots, and allergic reactions. Greater caution is recommended in people with kidney disease. Tranexamic acid appears to be safe for use during pregnancy and breastfeeding. Tranexamic acid is an antifibrinolytic medication.Tranexamic acid was first made in 1962 by Japanese researchers Shosuke and Utako Okamoto. It is on the World Health Organizations List of Essential Medicines. Tranexamic acid is available as a generic drug.
Medical uses
Tranexamic acid is frequently used following major trauma. Tranexamic acid is used to prevent and treat blood loss in a variety of situations, such as dental procedures, heavy menstrual bleeding, and surgeries with high risk of blood loss.
Trauma
Tranexamic acid has been found to decrease the risk of death due to any cause in people who have significant bleeding due to trauma. It is most effective if taken within the first three hours following major trauma. It also decreases the risk of death if given within the first three hours of brain injury.
Menstrual bleeding
Tranexamic acid is sometimes used to treat heavy menstrual bleeding. When taken by mouth it both safely and effectively treats regularly occurring heavy menstrual bleeding and improves quality of life. Another study demonstrated that the dose does not need to be adjusted in females who are between ages 12 and 16.
Childbirth
Tranexamic acid is sometimes used (often in conjunction with oxytocin) to reduce bleeding after childbirth. Death due to postpartum bleeding is reduced in women receiving tranexamic acid.
Surgery
Tranexamic acid is sometimes used in orthopedic surgery to reduce blood loss, to the extent of reducing or altogether abolishing the need for perioperative blood transfusion. It is of proven value in clearing the field of surgery and reducing blood loss when given before or after surgery. Drain and number of transfusions are reduced.
In surgical corrections of craniosynostosis in children it reduces the need for blood transfusions.
In spinal surgery (e.g., scoliosis), correction with posterior spinal fusion using instrumentation, to prevent excessive blood loss.
In cardiac surgery, both with and without cardiopulmonary bypass (e.g., coronary artery bypass surgery), it is used to prevent excessive blood loss.
Dentistry
In the United States, tranexamic acid is FDA approved for short-term use in people with severe bleeding disorders who are about to have dental surgery. Tranexamic acid is used for a short period of time before and after the surgery to prevent major blood loss and decrease the need for blood transfusions.Tranexamic acid is used in dentistry in the form of a 5% mouth rinse after extractions or surgery in patients with prolonged bleeding time; e.g., from acquired or inherited disorders.In China, TXA is allowed in over-the-counter toothpastes, with six products using the drug. As of 2018, there are no limits on dosage, nor requirements for labeling the concentration. 0.05% TXA in toothpaste is allowed OTC in Hong Kong. <5% TXA in over-the-counter toothpaste is first patented and marketed by Lion Corporation in Japan, where it is still sold. Presence of unauthorized TXA has led to the Canadian recall of a Yunnan Baiyao toothpaste in 2019.
Hematology
There is not enough evidence to support the routine use of tranexamic acid to prevent bleeding in people with blood cancers. However, there are several trials that are currently assessing this use of tranexamic acid. For people with inherited bleeding disorders (e.g. von Willebrands disease), tranexamic acid is often given. It has also been recommended for people with acquired bleeding disorders (e.g., directly acting oral anticoagulants (DOACs)) to treat serious bleeding.
Nosebleeds
The use of tranexamic acid, applied directly to the area that is bleeding or taken by mouth, appears useful to treat nose bleeding compared to packing the nose with cotton pledgets alone. It decreases the risk of rebleeding within 10 days.
Other uses
Tentative evidence supports the use of tranexamic acid in hemoptysis.
In hereditary angioedema
In hereditary hemorrhagic telangiectasia - Tranexamic acid has been shown to reduce frequency of epistaxis in patients with severe and frequent nosebleed episodes from hereditary hemorrhagic telangiectasia.
In melasma - tranexamic acid is sometimes used in skin whitening as a topical agent, injected into a lesion, or taken by mouth, both alone and as an adjunct to laser therapy; as of 2017 its safety seemed reasonable but its efficacy for this purpose was uncertain because there had been no large scale randomized controlled studies nor long term follow-up studies. It is allowed as a quasi-drug for skin whitening in Japan.
In hyphema - Tranexamic acid has been shown to be effective in reducing risk of secondary hemorrhage outcomes in people with traumatic hyphema.
Experimental uses
Tranexamic acid might alleviate neuroinflammation in some experimental settings.Tranexamic acid can be used in case of postpartum hemorrhage; it can decrease the risk of death due to bleeding by one third according to the WHO.
Contraindications
Allergic to tranexamic acid
History of seizures
History of venous or arterial thromboembolism or active thromboembolic disease
Severe kidney impairment due to accumulation of the medication, dose adjustment is required in mild or moderate kidney impairment
Adverse effects
Side effects are rare. Some reported adverse events include changes in color vision, blood clots, and allergic reactions such as anaphylaxis. Whether the risk of venous thromboembolism (blood clots) is actually increased is a matter of debate. The risk is mentioned in the product literature, and they were reported in post marketing experience. Despite this, and the inhibitory effect of tranexamic acid on blood clot breakdown, large studies of the use of tranexamic acid have not shown an increase in the risk of venous or arterial thrombosis, even in people who had previously experienced thrombosis under other circumstances.
Special populations
Tranexamic acid is categorized as pregnancy category B. No harm has been found in animal studies.
Small amounts appear in breast milk if taken during lactation. If it is required for other reasons, breastfeeding may be continued.
In kidney impairment, tranexamic acid is not well studied. However, due to the fact that it is 95% excreted unchanged in the urine, it should be dose adjusted in patients with renal impairment.
In liver impairment, dose change is not needed as only a small amount of the drug is metabolized through the liver.
Society and culture
Tranexamic acid was first synthesized in 1962 by Japanese researchers Shosuke and Utako Okamoto. It has been included in the WHO list of essential medicines.
Brand names
Tranexamic acid is marketed in the U.S. and Australia in tablet form as Lysteda and in Australia, Sweden and Jordan it is marketed in an IV form and tablet form as Cyklokapron, in the UK and Sweden as Cyclo-F. In the UK it is also marketed as Femstrual, in Asia as Transcam, in Bangladesh as Tracid, in India as Pause, in Pakistan as Transamin, in South America as Espercil, in Japan as Nicolda, in France, Poland, Belgium and Romania as Exacyl and in Egypt as Kapron. In the Philippines, its capsule form is marketed as Hemostan and in Israel as Hexakapron.
Approval
The U.S. Food and Drug Administration (FDA) approved tranexamic acid oral tablets (brand name Lysteda) for treatment of heavy menstrual bleeding on 13 November 2009.In March 2011 the status of tranexamic acid for treatment of heavy menstrual bleeding was changed in the UK, from PoM (Prescription only Medicines) to P (Pharmacy Medicines) and became available over the counter in UK pharmacies under the brand names of Cyklo-F and Femstrual, initially exclusively for Boots pharmacy, which has sparked some discussion about availability. (In parts of Europe it had then been available OTC for over a decade.) Regular liver function tests are recommended when using tranexamic acid over a long period of time.
References
External links
ISBT information on tranexamic acid
Tranexamic acid, UK patient information leaflet
CRASH-2: tranexamic acid and trauma patients
TXA central; site collating all clinical evidence for tranexamic acid by the London School of Hygiene & Tropical Medicine
"Tranexamic Acid". Drug Information Portal. U.S. National Library of Medicine. |
Cortisone | Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug; it is not synthesized in the adrenal glands. Cortisol is converted by the action of the enzyme corticosteroid 11-beta-dehydrogenase isozyme 2 into the inactive metabolite cortisone, particularly in the kidneys. Cortisone is converted back to the active steroid cortisol by the action of the enzyme 11β-Hydroxysteroid dehydrogenase type 1, particularly in the liver.
The term "cortisone" is frequently misused to mean either any corticosteroid or hydrocortisone, which is actually another name for cortisol. Many who speak of receiving a "cortisone shot" or taking "cortisone" are actually receiving hydrocortisone or one of many other, much more potent synthetic corticosteroids; it is unlikely that the drug administered is actually cortisone.
Cortisone can be administered as a prodrug, meaning it has to be converted by the body (specifically the liver, converting it into cortisol) after administration to be effective. It is used to treat a variety of ailments and can be administered intravenously, orally, intra-articularly (into a joint), or transcutaneously. Cortisone suppresses various elements of the immune system, thus reducing inflammation and attendant pain and swelling. Risks exist, in particular in the long-term use of cortisone. However, using cortisone only results in very mild activity, and very often more potent steroids are used instead.
Effects and uses
Cortisone itself is inactive. It must be converted to cortisol by the action of 11β-Hydroxysteroid dehydrogenase type 1. This primarily happens in the liver, the main site at which cortisone becomes cortisol after oral or systemic injection, and can thus have a pharmacological effect. After application to the skin or injection into a joint, local cells that express 11β-hydroxysteroid dehydrogenase type 1 instead convert it to active cortisol.
A cortisone injection may provide short-term pain relief and may reduce the swelling from inflammation of a joint, tendon, or bursa in, for example, the joints of the knee, elbow and shoulder and into a broken coccyx.Cortisone is also used by dermatologists to treat keloids, relieve the symptoms of eczema and atopic dermatitis, and stop the development of sarcoidosis.
Side effects
Oral use of cortisone has a number of potential systemic adverse effects, including asthma, hyperglycemia, insulin resistance, diabetes mellitus, osteoporosis, anxiety, depression, amenorrhoea, cataracts, glaucoma, Cushings syndrome, increased risk of infections and impaired growth. With topical application, it can lead to thinning of the skin, impaired wound healing, increased skin pigmentation, tendon rupture and skin infections (including abscesses).
History
Cortisone was first identified by the American chemists Edward Calvin Kendall and Harold L. Mason while researching at the Mayo Clinic. During the discovery process, cortisone was known as compound E (while cortisol was known as compound F).
In 1949, Philip S. Hench and colleagues discovered that large doses of injected cortisone were effective in the treatment of patients with severe rheumatoid arthritis. Kendall was awarded the 1950 Nobel Prize for Physiology or Medicine along with Philip Showalter Hench and Tadeusz Reichstein for the discovery of the structure and function of adrenal cortex hormones including cortisone. Both Reichstein and the team of O. Wintersteiner and J. Pfiffner had separately isolated the compound prior to the discovery made by Mason and Kendall, but failed to recognize its biological significance. Masons contributions to the crystallization and characterization of the compound have generally been forgotten outside of the Mayo Clinic.Cortisone was first produced commercially by Merck & Co. in 1948 or 1949. On September 30, 1949, Percy Julian announced an improvement in the process of producing cortisone from bile acids. This eliminated the need to use osmium tetroxide, a rare, expensive, and dangerous chemical. In the UK in the early 1950s, John Cornforth and Kenneth Callow at the National Institute for Medical Research collaborated with Glaxo to produce cortisone from hecogenin from sisal plants.
Production
Cortisone is one of several end-products of a process called steroidogenesis. This process starts with the synthesis of cholesterol, which then proceeds through a series of modifications in the adrenal gland to become any one of many steroid hormones. One end-product of this pathway is cortisol. For cortisol to be released from the adrenal gland, a cascade of signaling occurs. Corticotropin-releasing hormone released from the hypothalamus stimulates corticotrophs in the anterior pituitary to release ACTH, which relays the signal to the adrenal cortex. Here, the zona fasciculata and zona reticularis, in response to ACTH, secrete glucocorticoids, in particular cortisol. In various peripheral tissues, notably the kidneys, cortisol is inactivated to cortisone by the enzyme corticosteroid 11-beta-dehydrogenase isozyme 2. This is crucial because cortisol is a potent mineralocorticoid and would cause havoc with electrolyte levels (raising blood sodium and lowering blood potassium levels) and raise blood pressure if it were not inactivated in the kidneys.Because cortisone must be converted to cortisol before being active as a glucocorticoid, its activity is less than simply administering cortisol directly (80–90%).
Popular culture
Addiction to cortisone was the subject of the 1956 motion picture Bigger Than Life, produced by and starring James Mason. Though it was a box-office flop upon its initial release, many modern critics hail the film as a masterpiece and brilliant indictment of contemporary attitudes toward mental illness and addiction. In 1963, Jean-Luc Godard named it one of the ten greatest American sound films ever made.John F. Kennedy was regularly administered corticosteroids such as cortisone as a treatment for Addisons disease.
See also
Biology portal
Medicine portal
Central serous retinopathy
Corticosterol
Notes
Bibliography
Bonagura J., DVM; et al. (2000). Current Veterinary Therapy. Vol. 13. pp. 321–381.
Ingle DJ (October 1950). "The biologic properties of cortisone: a review". J. Clin. Endocrinol. Metab. 10 (10): 1312–54. doi:10.1210/jcem-10-10-1312. PMID 14794756.
Woodward R. B.; Sondheimer F.; Taub D. (1951). "The Total Synthesis of Cortisone". Journal of the American Chemical Society. 73 (8): 4057. doi:10.1021/ja01152a551. |
Bebtelovimab | Bebtelovimab is a monoclonal antibody developed by AbCellera and Eli Lilly as a treatment for COVID-19.Possible side effects include itching, rash, infusion-related reactions, nausea and vomiting.Bebtelovimab works by binding to the spike protein of the virus that causes COVID-19, similar to other monoclonal antibodies that have been authorized for the treatment of high-risk people with mild to moderate COVID-19 and shown a benefit in reducing the risk of hospitalization or death. Bebtelovimab is a neutralizing human immunoglobulin G1 (IgG1) monoclonal antibody, isolated from a patient who has recovered from the Coronavirus disease 2019 (COVID-19), directed against the spike (S) protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), that can potentially be used for immunization against COVID-19.Bebtelovimab was granted an emergency use authorization (EUA) by the US Food and Drug Administration (FDA) in February 2022. The EUA for bebtelovimab is for the treatment of mild to moderate COVID-19 in people aged 12 years of age and older weighing at least 40 kilograms (88 lb) with a positive COVID-19 test, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate.Bebtelovimab is not authorized for people who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19. Treatment with bebtelovimab has not been studied in people hospitalized due to COVID-19.
History
Bebtelovimab emerged from a collaboration between Eli Lilly and AbCellera. Bebtelovimab was discovered by AbCellera and the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center.
Society and culture
Names
Bebtelovimab is the proposed international nonproprietary name (pINN).
References
External links
"Bebtelovimab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT04634409 for "A Study of Immune System Proteins in Participants With Mild to Moderate COVID-19 Illness (BLAZE-4)" at ClinicalTrials.gov |
Zileuton | Zileuton (trade name Zyflo) is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation, used for the maintenance treatment of asthma. Zileuton was introduced in 1996 by Abbott Laboratories and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names Zyflo and Zyflo CR. The original immediate-release formulation, Zyflo, is taken four times per day. The extended-release formulation, Zyflo CR, is taken twice daily.
Although the 600 mg immediate release tablet (Zyflo) and extended release formulation of zileuton are still available (Zyflo CR), the 300 mg immediate release tablet was withdrawn from the U.S. market on February 12, 2008.
Pharmacotherapy
Indications and dosing
Zileuton is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is not indicated for use in the reversal of bronchospasm in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma.
The recommended dose of Zyflo is one 600 mg tablet, four times per day. The tablets may be split in half to make them easier to swallow. The recommended dose of Zyflo CR is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a daily dose of 2400 mg. Do not split Zyflo CR tablets in half.
Related compounds include montelukast (Singulair) and zafirlukast (Accolate). These two compounds are leukotriene receptor antagonists which block the action of specific leukotrienes, while zileuton inhibits leukotriene formation.
ResearchResearch on mice suggests that Zileuton used alone or in combination with imatinib may inhibit chronic myeloid leukemia (CML). It has also been researched in a mouse model of dementia.
Contraindications and warnings
The most serious side effect of Zyflo and Zyflo CR is a potential elevation of liver enzymes (in 2% of patients). Therefore, zileuton is contraindicated in patients with active liver disease or persistent hepatic function enzymes elevations greater than three times the upper limit of normal. Hepatic function should be assessed prior to initiating Zyflo CR, monthly for the first 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter.
Neuropsychiatric events, including sleep disorders and behavioral changes, may occur with Zyflo and Zyflo CR. Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using Zyflo or Zyflo CR.
Zileuton is a weak inhibitor of CYP1A2 and thus has three clinically important drug interactions, which include increasing theophylline, and propranolol levels. It has been shown to lower theophylline clearance significantly, doubling the AUC and prolonging half-life by nearly 25%. Because of theophyllines relation to caffeine (both being a methylxanthine, and theophylline being a metabolite of caffeine), caffeines metabolism and clearance may also be reduced, but there are no drug interaction studies between zileuton and caffeine. The R-isomer of warfarin metabolism and clearance is mainly affected by zileuton, while the S-isomer is not (because of metabolism via different enzymes). This can lead to an increase in prothrombin time.
Chemistry
Zileuton is an active oral inhibitor of the enzyme 5-lipoxygenase, which forms leukotrienes, 5-hydroxyeicosatetraenoic acid, and 5-oxo-eicosatetraenoic acid from arachidonic acid. The chemical name of zileuton is (±)-1-(1-Benzo[b]thien-2-ylethyl)-l-hydroxyurea.The molecular formula of zileuton is C11H12N2O2S with a molecular weight of 236.29. The formulation from the manufacturer is a racemic mixture of R(+) and S(-) enantiomers.
Pharmacokinetics
Following oral administration zileuton is rapidly absorbed with a mean time to peak blood serum concentration of 1.7 hours and an average half-life elimination of 2.5 hours. Blood plasma concentrations are proportional to dose, whereas the absolute bioavailability is unknown.
The apparent volume of distribution of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin, with minor binding to alpha-1-acid glycoprotein.
Elimination of zileuton is primarily through metabolites in the urine (~95%) with the feces accounting for the next largest amount (~2%). The drug is metabolized by the cytochrome P450 enzymes: CYP1A2, 2C9, and 3A4.
Adverse effects
The most common adverse reactions reported by patients treated with Zyflo CR were sinusitis (6.5%), nausea (5%), and pharyngolaryngeal pain (5%) vs. placebo, 4%, 1.5%, and 4% respectively.
Interactions
Drug interactions
Zileuton is a minor substrate of CYP1A2, 2C8/9, 3A4, and a weak inhibitor of CYP 1A2. The drug has been shown to increase the serum concentration or effects of theophylline, propranolol, and warfarin, although significant increase in prothrombin time is not obvious. It is advised that the doses of each medication be monitored and/or reduced accordingly.
Other interactions
The avoidance of alcohol is recommended due to increased risk of CNS depression as well as an increased risk of liver toxicity. In addition, the herbal supplement St. Johns wort may decrease the serum levels of zileuton.
Overdose/toxicology
Symptoms
Human experience of acute overdose with zileuton is limited. A patient in a clinical study took between 6.6 and 9.0 grams of zileuton immediate-release tablets in a single dose. Vomiting was inducted and the patient recovered without sequelae. Zileuton is not removed by dialysis.
The oral minimum lethal doses in mice and rats were 500-4000 and 300–1000 mg/kg, respectively (providing greater than 3 and 9 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose, respectively). In dogs, at an oral dose of 1000 mg/kg (providing in excess of 12 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose) no deaths occurred but nephritis was reported.
Treatment
Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with Zyflo CR.
See also
Lipoxygenase inhibitor
References
External links
Zyflo (manufacturers website)
Zyflo (patient information)
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm |
Kuvan | Kuvan or Kuvan Darya is a dry riverbed of what once was a tributary of the Syr river in Central Asia. The area is located west of Kzyl-Orda. It is an area of archaeological interest and was once home to tigers whose range extensed to the reedy shores of the Aral Sea. The area includes unusual kurgan burial sites. In the late 19th century there was some flow along the tributary before it petered out in marshlands.
== References == |
Tenecteplase | Tenecteplase, sold under the trade names TNKase, Metalyse and Elaxim, is an enzyme used as a thrombolytic drug.
Tenecteplase is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using an established mammalian cell line (Chinese hamster ovary cells). Tenecteplase is a 527 amino acid glycoprotein developed by introducing the following modifications to the complementary DNA (cDNA) for natural human tPA: a substitution of threonine 103 with asparagine, and a substitution of asparagine 117 with glutamine, both within the kringle 1 domain, and a tetra-alanine substitution at amino acids 296–299 in the protease domain.
Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus (blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. Tenecteplase has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
The abbreviation TNK is common for referring to tenecteplase, but abbreviating drug names is not best practice in medicine, and in fact "TNK" is one of the examples given on the Institute for Safe Medication Practices (ISMP) do-not-use list.
Research
Researchers at Newcastle University in Australia say they have had a significant breakthrough in treating stroke patients using the commonly used drug. The findings were published in the New England Medical Journal. Though safety has been established through previous clinical trials, there is ongoing debate about whether this is an effective treatment for ischemic stroke, and significant ongoing discussion between Emergency Physicians, Neurologists and Pharmacists about whether this treatment should be used for that indication.
The American Heart Association/American Stroke Association 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke supports considering tenecteplase over alteplase in patients without contraindication to intravenous thrombolytics.
Pharmacokinetics
Distribution: approximates plasma volume
Metabolism: Primarily hepatic
Half-life elimination: Biphasic: Initial: 20–24 minutes; Terminal: 90–130 minutes
Excretion: Clearance: Plasma: 99-119 mL/minute
Gallery
References
Further reading
External links
MedlinePlus DrugInfo uspdi-500145 |
Mirtazapine | Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of Mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth.Common side effects include sleepiness, dizziness, increased appetite and weight gain. Serious side effects may include mania, low white blood cell count, and increased suicide among children. Withdrawal symptoms may occur with stopping. It is not recommended together with an MAO inhibitor, although evidence supporting the danger of this combination has been refuted. It is unclear if use during pregnancy is safe. How it works is not clear, but it may involve blocking certain adrenergic and serotonin receptors. Chemically, it is a tetracyclic antidepressant (TeCA), and is closely related to mianserin. It also has strong antihistaminergic effects.Mirtazapine came into medical use in the United States in 1996. The patent expired in 2004, and generic versions are available. In 2019, it was the 106th most commonly prescribed medication in the United States, with more than 6 million prescriptions.
Medical uses
Depression
Mirtazapine is primarily used for major depressive disorder and other mood disorders. Onset of action appears faster than some selective serotonin reuptake inhibitors (SSRI) and similar to tricyclic antidepressants.In 2010, NICE recommended generic SSRIs as first line choices, as they are "equally effective as other antidepressants and have a favourable risk–benefit ratio." With respect to mirtazapine, it found: "There is no difference between mirtazapine and other antidepressants on any efficacy measure, although in terms of achieving remission mirtazapine appears to have a statistical though not clinical advantage. In addition, mirtazapine has a statistical advantage over selective serotonin reuptake inhibitors in terms of reducing symptoms of depression, but the difference is not clinically significant. However, there is strong evidence that patients taking mirtazapine are less likely to leave treatment early because of side effects, although this is not the case for patients reporting side effects or leaving treatment early for any reason."A 2011 Cochrane review that compared mirtazapine to other antidepressants found that, while it appears to have a faster onset in people for whom it works (measured at two weeks), its efficacy is about the same as other antidepressants after six weeks use.A 2012 review focused on antidepressants and sleep found that in many people with sleep disorders caused by depression, mirtazapine reduces the time it takes to fall asleep and increases the quality of sleep, but that in some people it can disturb sleep, especially at higher doses, causing restless leg syndrome in 8 to 28% of people and in rare cases causes REM sleep behavior disorder. This seemingly paradoxical dose–response curve of mirtazapine with respect to somnolence is owed to the exceptionally high affinity of the drug for the histamine H1, 5-HT2A, and 5-HT2C receptors; exhibiting near exclusive occupation of these receptors at doses ≤15 mg. However, at higher doses, inverse antagonism and constitutive activation of the α2A-, α2B-, and α2C-adrenergic receptors begins to offset activity at H1 receptors leading to decreased somnolence and even a subjective sensation of "activation" in treated patients.A 2018 analysis of 21 antidepressants found them to be fairly similar overall. It found tentative evidence for mirtazapine being in the more effective group and middle in tolerability.After one week of usage, mirtazapine was found to have an earlier onset of action compared to SSRIs.
Other
There is also some evidence supporting its use in treating the following conditions, for which it is sometimes prescribed off-label:
Doses of mirtazapine used for sleep range from 7.5 to 45 mg. Doses of 7.5 to 15 mg are recommended as mirtazapine may become more stimulating at higher doses.
Side effects
A 2011 Cochrane review found that, compared with other antidepressants, it is more likely to cause weight gain and sleepiness, but it is less likely to cause tremor than tricyclic antidepressants, and less likely to cause nausea and sexual dysfunction than SSRIs.Very common (≥10% incidence) adverse effects include constipation, dry mouth, sleepiness, increased appetite (17%) and weight gain (>7% increase in <50% of children).Common (1–10% incidence) adverse effects include weakness, confusion, dizziness, fasciculations (muscle twitches), peripheral edema (swelling, usually of the lower limbs), and negative lab results like elevated transaminases, elevated serum triglycerides, and elevated total cholesterol.Mirtazapine is not considered to have a risk of many of the side effects often associated with other antidepressants like the SSRIs, and may actually improve certain ones when taken in conjunction with them. (Those adverse effects include decreased appetite, weight loss, insomnia, nausea and vomiting, diarrhoea, urinary retention, increased body temperature, excessive sweating, pupil dilation and sexual dysfunction.)
In general, some antidepressants, especially selective serotonin reuptake inhibitors (SSRI), can paradoxically exacerbate some peoples depression or anxiety or cause suicidal ideation. Despite its sedating action, mirtazapine is also believed to be capable of this, so in the United States and certain other countries, it carries a black box label warning of these potential effects, especially for people under the age of 25.Mirtazapine may induce arthralgia (non-inflammatory joint pain)A case report published in 2000 noted an instance in which mirtazapine counteracted the action of clonidine, causing a dangerous rise in blood pressure.In a study comparing 32 antidepressants of all pharmacological classes, mirtazapine was one of the antidepressants most likely to cause nightmare disorder, sleepwalking, restless legs syndrome, night terrors and sleep paralysis.Mirtazapine has been associated with an increased risk of death compared to other antidepressants in several studies. However, it is more likely that the residual differences between people prescribed mirtazapine rather than an SSRI account for the difference in risk of mortality.
Withdrawal
Mirtazapine and other antidepressants may cause withdrawal symptoms upon cessation. A gradual and slow reduction in dose is recommended to minimize withdrawal symptoms. Effects of sudden cessation of treatment with mirtazapine may include depression, anxiety, tinnitus, panic attacks, vertigo, restlessness, irritability, decreased appetite, insomnia, diarrhea, nausea, vomiting, flu-like symptoms, allergy-like symptoms such as pruritus, headaches, and sometimes mania or hypomania.
Overdose
Mirtazapine is considered to be relatively safe in the event of an overdose, although it is considered slightly more toxic in overdose than most of the SSRIs (except citalopram). Unlike the tricyclic antidepressants, mirtazapine showed no significant cardiovascular adverse effects at 7 to 22 times the maximum recommended dose. Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to tricyclic antidepressants.Twelve reported fatalities have been attributed to mirtazapine overdose. The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.
Interactions
Concurrent use with inhibitors or inducers of the cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and/or CYP3A4 can result in altered concentrations of mirtazapine, as these are the main enzymes responsible for its metabolism. As examples, fluoxetine and paroxetine, inhibitors of these enzymes, are known to modestly increase mirtazapine levels, while carbamazepine, an inducer, considerably decreases them. Liver impairment and moderate chronic kidney disease have been reported to decrease the oral clearance of mirtazapine by about 30%; severe kidney disease decreases it by 50%.Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically, with a combination of venlafaxine and mirtazapine, sometimes referred to as "California rocket fuel". Several case reports document serotonin syndrome induced by the combination of mirtazapine with other agents (olanzapine, quetiapine, tramadol and venlafaxine).
According to information from the manufacturers, mirtazapine should not be started within two weeks of any monoamine oxidase inhibitor (MAOI) usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine.The addition of mirtazapine to a monoamine oxidase inhibitor (MAOI), while potentially having typical or idiosyncratic (unique to the individual) reactions not herein described, does not appear to cause serotonin syndrome. This is in accordance with the fact that the 5-HT2A receptor is the predominant serotonin receptor thought to be involved in the pathophysiology of serotonin syndrome (with the 5-HT1A receptor seeming to be protective). Mirtazapine is a potent 5-HT2A receptor antagonist, and cyproheptadine, a medication that shares this property, mediates recovery from serotonin syndrome and is an antidote against it.There is a possible interaction that results in a hypertensive crisis when mirtazapine is given to a patient that has already been on steady doses of clonidine. This involves a subtle consideration, when patients have been on chronic therapy with clonidine and suddenly stop the dosing, a rapid hypertensive rebound sometimes (20%) occurs from increased sympathetic outflow. Clonidines blood pressure lowering effects are due to stimulation of presynaptic α2 autoreceptors in the CNS which suppress sympathetic outflow. Mirtazapine itself blocks these same α2 autoreceptors, so the effect of adding mirtazapine to a patient stabilized on clonidine may precipitate withdrawal symptoms.
Pharmacology
Pharmacodynamics
Mirtazapine is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA), although the actual evidence in support of this label has been regarded as poor. It is a tetracyclic piperazine-azepine.Mirtazapine has antihistamine, α2-blocker, and antiserotonergic activity. It is specifically a potent antagonist or inverse agonist of the α2A-, α2B-, and α2C-adrenergic receptors, the serotonin 5-HT2A, 5-HT2C, and the histamine H1 receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. Similarly, mirtazapine has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most TCAs. In accordance, it has better tolerability and low toxicity in overdose. As an H1 receptor antagonist, mirtazapine is extremely potent, and is in fact the most potent of all the TCAs and TeCAs. Antagonism of the H1 receptor is by far the strongest activity of mirtazapine, with the drug acting as a selective H1 receptor antagonist at low concentrations.The (S)-(+) enantiomer of mirtazapine is responsible for antagonism of the serotonin 5-HT2A and 5-HT2C receptors, while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT3 receptor. Both enantiomers are involved in antagonism of the H1 and α2-adrenergic receptors, although the (S)-(+) enantiomer is the stronger antihistamine.Although not clinically relevant, mirtazapine has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC50 = 7.2 μM).
α2-Adrenergic receptor
Antagonism of the α2-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT1A receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapines classification as a NaSSA. Indirect α1 adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α2 heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin. Because of this, mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.
5-HT2 receptor
Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapines efficacy in the treatment of depressive states.
Mirtazapine increases dopamine release in the prefrontal cortex. Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. In addition, mirtazapines antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. Mirtazapine has been shown to lower drug seeking behaviour (more specifically to methamphetamine) in various human and animal studies. It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.Mirtazapine significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in affected individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to Ondansetron. In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), Monoamine oxidase inhibitors (MAOI), and some Tricyclic antidepressants (TCA) increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, nausea, and diarrhea, among others. Its reduced incidence of sexual dysfunction (such as loss of libido and anorgasmia) could be a product of negligible binding to the serotonin transporter (as is generally the cause of sexual dysfunction with most SSRIs) and antagonism of the 5-HT2A receptors; however, Mirtazapines high affinity towards and inverse agonism of the 5-HT2C receptors may greatly attenuate those pro-sexual factors (as evidenced by the pro-sexual effects of drugs like m-CPP and Lorcaserin which agonize 5-HT2C receptors in a reasonably selective manner). As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.Mirtazapine does not have pro-serotonergic activity and thus does not cause serotonin syndrome. This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor (MAOI), nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with mirtazapine alone, and mirtazapine has not been found to cause serotonin syndrome in overdose. However, there are a handful of case reports of serotonin syndrome occurring with mirtazapine in combination with serotonergic drugs like SSRIs, although such reports are very rare, and do not necessarily implicate mirtazapine as causative.
5-HT3 receptor
It is a potent 5-HT3 blocker. It may relieve chemotherapy-related and advanced cancer-related nausea.
H1 receptor
Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. A single 15 mg dose of mirtazapine to healthy volunteers has been found to result in over 80% occupancy of the H1 receptor and to induce intense sleepiness. After a short period of chronic treatment, however, the H1 receptor tends to desensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in affected individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor, mirtazapine has only low affinity for the muscarinic acetylcholine receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practice.
Pharmacokinetics
The oral bioavailability of mirtazapine is about 50%. It is found mostly bound to plasma proteins, about 85%. It is metabolized primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. One of its major metabolites is desmethylmirtazapine. The overall elimination half-life is 20–40 hours. It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted, and about 15% is eliminated in feces.: 430
Chemistry
Mirtazapine is a tetracyclic piperazinoazepine; mianserin was developed by the same team of organic chemists and mirtazapine differs from it via addition of a nitrogen atom in one of the rings.: 429 It is a racemic mixture of enantiomers. The (S)-(+)-enantiomer is known as esmirtazapine.
Analogues of mirtazapine include mianserin, setiptiline, and aptazapine.
Synthesis
A chemical synthesis of mirtazapine has been published. The first step of synthesis is a condensation reaction between the molecule 2-chloro 3-cyanopyridine and the molecule 1-methyl-3-phenylpiperazine.
History
Mirtazapine was first synthesized at Organon and published in 1989, was first approved for use in major depressive disorder in the Netherlands in 1994, and was introduced in the United States in 1996 under the brand name Remeron.: 429
Society and culture
Generic names
Mirtazapine is the English and French generic name of the drug and its INN, USAN, USP, BAN, DCF, and JAN. Its generic name in Spanish, Italian and Portuguese is mirtazapina and in German and Swedish is Mirtazapin.
Brand names
Mirtazapine is marketed under many brand names worldwide, including Adco-Mirteron, Afloyan, Amirel, Arintapin Smelt, Avanza, Axit, Azapin, Beron, Bilanz, Blumirtax, Calixta, Ciblex, Combar, Comenter, Depreram, Divaril, Esprital, Maz, Menelat, Mepirzapine, Merdaten, Meronin, Mi Er Ning, Milivin, Minelza, Minivane, Mirastad, Mirazep, Miro, Miron, Mirrador, Mirt, Mirta, Mirtabene, Mirtadepi, Mirtagamma, Mirtagen, Mirtalan, Mirtamor, Mirtamylan, Mirtan, Mirtaneo, Mirtapax, Mirtapil, Mirtapine, Mirtaron, Mirtastad, Mirtax, Mirtaz, Mirtazap, Mirtazapin, Mirtazapina, Mirtazapine, Mirtazapinum, Mirtazelon, Mirtazon, Mirtazonal, Mirtel, Mirtimash, Mirtin, Mirtine, Mirzapine, Mirzaten, Mirzest, Mitaprex, Mitaxind, Mitocent, Mitrazin, Mizapin, Motofen, Mytra, Norset, Noxibel, Pharmataz, Promyrtil, Rapizapine, Ramure, Razapina, Redepra, Reflex, Remergil, Remergon, Remeron, Remirta, Rexer, Saxib, Sinmaron, Smilon, Tazepin, Tazimed, Tetrazic, Tifona, U-Mirtaron, U-zepine, Valdren, Vastat, Velorin, Yarocen, Zania, Zapex, Zestat, Zismirt, Zispin, Zuleptan, and Zulin.
Research
The use of mirtazapine has been explored in several additional conditions:
Sleep apnea/hypopnea
Secondary symptoms of autistic spectrum conditions and other pervasive developmental disorders
Antipsychotic-induced akathisia.
Drug withdrawal, dependence and detoxification
Negative, depressive and cognitive symptoms of schizophrenia (as an adjunct)
A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinsons disease psychosis (PDP). This is in alignment with recent findings that inverse agonists at the 5-HT2A receptors are efficacious in attenuating the symptoms of Parkinsons disease psychosis. As is supported by the common practice of prescribing low-dose quetiapine and clozapine for PDP at doses too low to antagonize the D2 receptor, but sufficiently high doses to inversely agonize the 5-HT2A receptors.
Eight case reports have been reported in five papers on the use of mirtazapine in the treatment of hives as of 2017.
Veterinary use
Mirtazapine also has some veterinary use in cats and dogs. Mirtazapine is sometimes prescribed as an appetite stimulant for cats or dogs experiencing loss of appetite due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats and dogs.Mirtazapine is indicated for bodyweight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions.There are two options for administration: tablets given orally, and an ointment applied topically to the inner surface of the ear.The most common side effects include signs of local irritation or inflammation at the site where the ointment is applied and behavioural changes (increased meowing, hyperactivity, disoriented state or inability to co-ordinate muscle movements, lack of energy/weakness, attention-seeking, and aggression).
References
External links
"Mirtazapine". Drug Information Portal. U.S. National Library of Medicine. |
Talazoparib | Talazoparib, sold under the brand name Talzenna, is an orally available poly ADP ribose polymerase (PARP) inhibitor developed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations. Talazoparib is similar to the first in class PARP inhibitor, olaparib. It was approved in October 2018, in the United States and June 2019, in the European Union for germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.
Side effects
The most serious side effects in studies were related to the blood forming system and included anaemia (low red blood cell count), neutropenia (low neutrophil blood cell count) and thrombocytopenia (low platelet count). Serious forms of these conditions (grade 3 to 4) occurred in 39%, 21% and 15% of patients, respectively. Other adverse effects such as headache, nausea, hair loss and fatigue were mostly mild.
Interactions
Combination with drugs that inhibit P-glycoprotein or BCRP may increase talazoparib concentrations in the body.
Mechanism of action
Talazoparib acts as an inhibitor of poly ADP ribose polymerase (PARP) which aids in single strand DNA repair. Cells that have BRCA1/2 mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage. Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib. However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.
Commercialization
Talazoparib was originally developed by BioMarin Pharmaceutical Inc. However, Medivation Inc. acquired all worldwide rights to talazoparib in August 2015, to expand their global oncology franchise. Medivation acquired talazoparib for $410 million with additional payments of up to $160 million in royalties and milestones. Under this agreement, Medivation assumed all financial responsibilities for the continued development, regulatory, and commercialization of talazoparib.
References
External links
"Talazoparib". Drug Information Portal. U.S. National Library of Medicine.
"Talazoparib tosylate". Drug Information Portal. U.S. National Library of Medicine. |
Elexacaftor/tezacaftor/ivacaftor | Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta (US) and Kaftrio (EU), is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.It is approved for use in the United States for people aged six years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene. It is also approved for use in Canada, the European Union and Australia.
Medical uses
The combination is indicated for the treatment of people aged six years and older who have cystic fibrosis with a F508del mutation or other mutations in the CFTR gene.
Side effects
The most common side effects affecting more than 5% of patients are headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis and blood bilirubin increased.
Interactions
Concomitant use with CYP3A inducers is not recommended. Dosage must be adjusted with moderate or strong CYP3A inhibitors.Other drugs with the potential for interaction include: warfarin, digoxin, statins, glyburide, nateglinide, repaglinide.
Pharmacology
Cystic fibrosis and CFTR
Cystic fibrosis is an autosomal recessive genetic disorder of the CFTR protein which reduces chloride and sodium ion transport through the cell membrane, causing thicker than normal mucus secretions. The CFTR protein is found in epithelial cells of the lung, liver, pancreas, digestive tract, and reproductive tracts. CFTR has a role in the production of mucus, sweat, and digestive fluids. The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts.
Mechanism of action
Elexacaftor/tezacaftor/ivacaftor is a tridrug treatment in which the medications work together to increase the transport of chloride and sodium ions, and reducing thick mucus production.
CFTR channel potentiator
Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the proteins ability to open chloride channels. Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein. Ivacaftors primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations. In the crystalline figure, you can see ivacaftor, shown as a gray ball and stick model on the bottom-right, bound to CFTR docked in a cleft formed by transmembrane helices at the protein-lipid interface.
CFTR correctors
Elexacaftor and Tezacaftor act as CFTR correctors to repair F508del processing by binding to the CFTR protein to increase the availability of CFTR protein on the cell surface. They work by modulating the position of the CFTR protein into the right position on the cell surface.The combination of increased CFTR protein in the correct position on the cell surface with ivacaftors potentiation of chloride channel opening results in increased transport of chloride and thinned mucus secretions.
Pharmacokinetics
Elexacaftor/tezacaftor/ivacaftor is primarily metabolized by CYP3A4 /5. This medication should be taken with a high fat meal to improve absorption through the gut. It is excreted as metabolites or unchanged mainly through feces and to a smaller extent urine. The mean effective half-life of elexacaftor, tezacaftor, and ivacaftor is 27.4 hours, 25.1 hours, and 15 hours, respectively.
History
A phase III trial showed people treated with elexacaftor/tezacaftor/ivacaftor improved in FEV1 at four weeks with sustained improvement at 24 weeks. Rate of pulmonary exacerbation was 63% lower and sweat chloride concentration was 41.8 mmol/L lower. Its effectiveness is dependent on the type of CF mutations the patient has.
Society and culture
Legal status
United States
The combination was approved for use in the United States in 2019 for people twelve years and older with cystic fibrosis who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population. In December 2020, after an additional clinical trial was completed, and FDA approval was expanded for 177 other cystic fibrosis mutations. FDA approval for children aged 6–11 was added in January 2021, after a third clinical trial was completed.The U.S. Food and Drug Administration (FDA) granted the application priority review, in addition to fast track, breakthrough therapy, and orphan drug designations. The drugs manufacturer Vertex Pharmaceuticals will receive a rare pediatric disease priority review voucher for having developed this therapy.
Australia
In March 2021, health regulators in Australia approved trikafta for patients aged 12 years and older with at least one copy of the F508del mutation. At the end of April 2022, it was placed on PBS, thus reducing the cost from tens of thousands of dollars a month, to tens of dollars a month.
Canada
In June 2020, Health Canada approved Trikafta for patients ages 12 and up. In September 2021, the provinces Alberta and Saskatchewan announced they will join Ontario in funding the medication. They will determine coverage on a case-by-case basis using criteria that has not yet been announced.
European Union
In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended its approval for the treatment of cystic fibrosis. It was approved for medical use in the European Union in August 2020.
Norway
On 25 April 2022, Beslutningsforum for nye metoder approved Kaftrio for treatment of cystic fibrosis.
New Zealand
In February 2022, Pharmac recommended, with medium priority, funding for patients age 12 and above.
Spain
In November 2021, the Spanish government approved the reimbursement of Kaftrio for patients ages 12 and older with at least one copy of the F508del mutation.
Economics
United States
The list price of a years treatment in the US is US$311,000. However, a 2020 report by Institute for Clinical and Economic Review found that the price has made the treatment not cost effective and that "an appropriate health-benefit price would range from $67,900–$85,500 per year".
Australia
Following the listing of Trikafta on the Pharmaceutical Benefits Scheme in 2022, the cost for CF patients 12 years or older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator gene is $42.50 per month, or $6.80 for concession card holders.
Research
CFTR mutations that are responsive to elexacaftor/tezacaftor/ivacaftor were determined by an in-vitro study of Fischer Rat Thyroid (FRT) cells that expressed mutant CFTR. Elexacaftor/tezacaftor/ivacaftor showed effectiveness with mutations where the CFTR protein was being successfully delivered to the cell surface.
References
External links
"Elexacaftor". Drug Information Portal. U.S. National Library of Medicine.
"Ivacaftor regimen with Tezacaftor". Drug Information Portal. U.S. National Library of Medicine. |
Desiccated thyroid extract | Desiccated thyroid, also known as thyroid extract, is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism. It is less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to 3 weeks to occur.Side effects may occur from excessive doses. This may include weight loss, fever, headache, anxiety, trouble sleeping, arrythmias, and heart failure. Other side effects may include allergic reactions. Use in pregnancy and breastfeeding is generally safe. Regular blood tests are recommended to verify the appropriateness of the dose. They contain a mixture of thyroxine (T4) and triiodothyronine (T3).Desiccated thyroid has been used since the late 1800s. It is usually made from pigs, sheep, or cows. It is available as a generic medication. In 2017, it was the 130th most commonly prescribed medication in the United States, with more than five million prescriptions. Usage has decreased since the 1960s.
Medical uses
The American Association of Clinical Endocrinologists and the Royal College of Physicians recommend against the use of thyroid extract for the treatment of hypothyroidism. Concerns include the potential for adverse effects from superphysiological levels of T3 and the absence of long-term safety data from randomized clinical trials. They recommend levothyroxine as the preferred treatment. Some practitioners refuse to use desiccated thyroid.About 65 mg of thyroid extract is equivalent to 100 μg of levothyroxine.Arguments against desiccated thyroid include:
Desiccated thyroid preparations have a greater variability from batch to batch than synthetic ones.
Desiccated thyroid has roughly a 4:1 ratio of thyroxine (T4) to triiodothyronine (T3). In humans, the ratio is 11:1.
A combination of various ratios of T4 and T3 might not provide benefits over T4 alone. Some controlled trials have shown inconsistent benefits of various ratios of T4 and T3.
The use of desiccated thyroid is usually accompanied with the practice of dosing according to symptoms instead of dosing to achieve "ideal" lab results (e.g. serum levels of TSH). While there is debate as to what the ideal serum levels are, dosing according to symptoms often results in higher dosages. Most endocrinologists are opposed to these higher dosages as there may be risks of hyperthyroidism and osteoporosis.
The preference for "natural" treatment seems to stem from philosophical belief as opposed to science.Arguments for desiccated thyroid include:
Desiccated thyroid contains all the natural thyroid hormones produced exclusively by the thyroid gland, including calcitonin which plays a crucial but still quite unclear role in promoting and sustaining bone density, however it is already used in therapy for osteoporosis when other treatments fail.
Desiccated thyroid therapy can be combined with synthetic thyroxine (T4) to balance out the T4/T3 correctly.
Chemistry
Desiccated thyroid has been described in the United States Pharmacopoeia for a century as the cleaned, dried, and powdered thyroid gland previously deprived of connective tissue and fat... obtained from domesticated animals that are used for food by man (USP XVI). In the last few decades, pork alone is the usual source. Before modern assays, the potency was specified only by iodine content ("not less than 0.17% and not more than 0.23%"), rather than hormonal content or activity.
History
The earliest oral treatment for hypothyroidism consisted of thyroid extract. George Redmayne Murray of the United Kingdom first described treatment of myxedema with thyroid extract in 1891, and published a description of long-term successful treatment (28 years) of a patient with myxedema (severe hypothyroidism) in 1920 His treatment was quickly adopted in North America and Europe. The first recorded American use dates to 1891 by a woman who was still taking it 52 years later at 84 years of age Desiccated thyroid extract is prepared from pig thyroid glands. The glands are dried (desiccated), ground to powder, combined with binder chemicals, and pressed into pills. This was a new use for parts that were previously unwanted slaughterhouse offal, and Armour and Company, the dominant American meatpacker in the 20th century, supplied the best-known brand of thyroid extract.Replacement by thyroid extract in hypothyroidism was one of the most effective treatments of any disease available to physicians before the middle of the 20th century, and in severe cases afforded dramatic relief of the myriad symptoms. The decision to treat was usually based on the presence of signs and symptoms of hypothyroidism because there were no accurate, readily available laboratory tests of thyroid function. Many less severe cases of hypothyroidism went untreated. Dosage was regulated by improvement of symptoms.
Desiccated Thyroid became a commercial treatment option in 1934 with Westhroid,. In the early 1960s, desiccated thyroid hormones (thyroid extract) began to be replaced by levothyroxine (synthetic T4), or by combinations of T4 and T3. Replacement occurred faster in the United Kingdom than in North America, but by the 1980s more patients were being prescribed synthetic T4 (levothyroxine) or synthetic T4/T3 combinations than desiccated thyroid extract.Several reasons have been identified as to why prescriptions changed from desiccated thyroid treatment.
Although thyroid extract was useful and usually effective, some patients continued to complain of fatigue, weight gain, or other symptoms. Dosing until the 1960s was often a matter of prolonged adjustment trials.
It was known that not all of the iodine content of thyroid extract was in the form of effective T4 and T3 and that actual content of available preparations varied more than the permitted 15%. It was hoped that better dosing precision with levothyroxine (synthetic) alone would increase the proportion of patients effectively treated. In 1980, a widely publicized investigation published in JAMA revealed continued large ranges of hormone content and potency in all of the available thyroid extracts on the American market.
By the 1960s, it was known that thyroxine was the essential hormone produced by the thyroid gland, and that most T3 was manufactured in other parts of the body by deiodination of thyroxine. It was demonstrated in hypothyroid animals and people that replacement of thyroxine alone corrected the measurable manifestations (laboratory test results) of hypothyroidism. By the 1970s doctors could measure T4, T3, and TSH in human blood with approximate accuracy and confirmed that treatment with thyroxine alone could produce normal blood levels of both T4 and T3, but desiccated thyroid caused supraphysiologic levels of T3. In the majority of patients normalization of these levels eliminated all signs and symptoms of hypothyroidism.
It was discovered that a healthy person varied the amount of T3 produced from T4 in response to changing needs and conditions and it seemed wiser not to bypass this control system by providing larger amounts of T3 than were naturally produced each day.
Furthermore, when T3 could be measured, it was discovered that thyroid extract and synthetic combinations of T4 and T3 produced significantly greater fluctuations of T3 throughout the day than occurred in healthy people or hypothyroid people treated with thyroxine alone.
Endocrinologists found that treatment with thyroxine alone worked as well or better than thyroid extract for the majority of patients, although even thyroxine did not reverse all the symptoms of a minority.Thyroid care changed in other ways as well. Accurate T4 and T3 measurements became widely used in the 1970s, and by the late 1980s, TSH measurement had become sensitive enough to detect mild degrees of hyperthyroidism and overtreatment. Blood levels of thyroid hormones and TSH were found to be the best predictors of objective benefits from thyroid replacement: those with the most severe measurable deficiency enjoyed the most dramatic and sustained benefits. It was also discovered that even mild hyperthyroidism as defined by a suppressed TSH level, whether due to disease or overtreatment, was associated with poorer bone density in women, and with higher rates of atrial fibrillation in elderly patients.
Names
This product is sometimes referred to as thyroid USP, thyroid BP. Brands differing only in binders and fillers.
References
External links
"Thyroid tablets". Drug Information Portal. U.S. National Library of Medicine. |
Norepinephrine (medication) | Norepinephrine, also known as noradrenaline, is a medication used to treat people with very low blood pressure. It is the typical medication used in sepsis if low blood pressure does not improve following intravenous fluids. It is the same molecule as the hormone and neurotransmitter norepinephrine. It is given by slow injection into a vein.Common side effects include headache, slow heart rate, and anxiety. Other side effects include an irregular heartbeat. If it leaks out of the vein at the site it is being given, norepinephrine can result in limb ischemia. If leakage occurs the use of phentolamine in the area affected may improve outcomes. Norepinephrine works by binding and activating alpha adrenergic receptors.Norepinephrine was discovered in 1946 and was approved for medical use in the United States in 1950. It is available as a generic medication.
Medical uses
Norepinephrine is used mainly as a sympathomimetic drug to treat people in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment.
Mechanism of action
It stimulates α1 and α2 adrenergic receptors to cause blood vessel contraction, thus increases peripheral vascular resistance and resulted in increased blood pressure. This effect also reduces the blood supply to gastrointestinal tract and kidneys. Norepinephrine acts on beta-1 adrenergic receptors, causing increase in heart rate and cardiac output. However, the elevation in heart rate is only transient, as baroreceptor response to the rise in blood pressure as well as enhanced vagal tone ultimately result in a sustained decrease in heart rate. Norepinephrine acts more on alpha receptors than the beta receptors.
Names
Norepinephrine is the INN while noradrenaline is the BAN.
References
External links
"Norepinephrine". Drug Information Portal. U.S. National Library of Medicine.
"Norepinephrine bitartrate". Drug Information Portal. U.S. National Library of Medicine. |
Prasterone | Prasterone, also known as dehydroepiandrosterone (DHEA) and sold under the brand names Intrarosa, Diandrone, and Gynodian Depot among others, is a medication as well as over-the-counter dietary supplement which is used to correct DHEA deficiency due to adrenal insufficiency or old age, as a component of menopausal hormone therapy, to treat painful sexual intercourse due to vaginal atrophy, and to prepare the cervix for childbirth, among other uses. It is taken by mouth, by application to the skin, in through the vagina, or by injection into muscle.Side effects of prasterone in women include symptoms of masculinization like oily skin, acne, increased hair growth, voice changes, and increased sexual desire, headaches, insomnia, and others. The compound is a naturally occurring prohormone of androgens and estrogens and hence is an agonist of the androgen and estrogen receptors, the respective biological targets of androgens like testosterone and estrogens like estradiol. Prasterone also has a variety of activities of its own, including neurosteroid and other activities.DHEA, the active ingredient of prasterone, was discovered in 1934. An association between DHEA levels and aging was first reported in 1965. The compound started being used as a medication in the late 1970s and as a supplement in the early 1980s. The marketing of prasterone over-the-counter as a supplement is allowed in the United States but is banned in many other countries.
Medical uses
Deficiency
DHEA and DHEA sulfate (DHEA-S) are produced by the adrenal glands. In people with adrenal insufficiency such as in Addisons disease, there may be deficiency of DHEA and DHEA-S. In addition, levels of these steroids decrease throughout life and are 70 to 80% lower in the elderly relative to levels in young adults. Prasterone can be used to increase DHEA and DHEA-S levels in adrenal insufficiency and older age. Although there is deficiency of these steroids in such individuals, clinical benefits of supplementation, if any, are uncertain, and there is insufficient evidence at present to support the use of prasterone for such purposes.
Menopause
Prasterone is sometimes used as an androgen in menopausal hormone therapy. In addition to prasterone itself, a long-lasting ester prodrug of prasterone, prasterone enanthate, is used in combination with estradiol valerate for the treatment of menopausal symptoms under the brand name Gynodian Depot.
Vaginal atrophy
Prasterone, under the brand name Intrarosa, is approved in the United States in a vaginal insert formulation for the treatment of atrophic vaginitis. The mechanism of action of prasterone for this indication is unknown, though it may involve local metabolism of prasterone into androgens and estrogens.
Sexual desire
Prasterone has been used orally at a dosage of 10 mg/day to increase sexual desire in women.
Childbirth
As the sodium salt of prasterone sulfate (brand names Astenile, Mylis, Teloin), an ester prodrug of prasterone, prasterone is used in Japan as an injection for the treatment of insufficient cervical ripening and cervical dilation during childbirth.
Available forms
Prasterone was previously marketed as a pharmaceutical medication under the brand name Diandrone in the form of a 10 mg oral tablet in the United Kingdom.
Side effects
Prasterone is produced naturally in the human body, but the long-term effects of its use are largely unknown. In the short term, several studies have noted few adverse effects. In a study by Chang et al., prasterone was administered at a dose of 200 mg/day for 24 weeks with slight androgenic effects noted. Another study utilized a dose up to 400 mg/day for 8 weeks with few adverse events reported. A longer-term study followed patients dosed with 50 mg of prasterone for 12 months with the number and severity of side effects reported to be small. Another study delivered a dose of 50 mg of prasterone for 10 months with no serious adverse events reported.As a hormone precursor, there have been reports of side effects possibly caused by the hormone metabolites of prasterone.It is not known whether prasterone is safe for long-term use. Some researchers believe prasterone supplements might actually raise the risk of breast cancer, prostate cancer, heart disease, diabetes, and stroke. Prasterone may stimulate tumor growth in types of cancer that are sensitive to hormones, such as some types of breast, uterine, and prostate cancer. Prasterone may increase prostate swelling in men with benign prostatic hyperplasia (BPH), an enlarged prostate gland.Prasterone is a steroid hormone. High doses may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL cholesterol, which could raise the risk of heart disease. Other reported side effects include acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin. It may also alter the bodys regulation of blood sugar.Prasterone may promote tamoxifen resistance in breast cancer. It may also increase the risk of uterine and prostate cancers due to metabolism into estrogens and androgens, respectively. Patients on hormone replacement therapy may have more estrogen-related side effects when taking prasterone. This supplement may also interfere with other medicines, and potential interactions between it and drugs and herbs are possible.Prasterone is possibly unsafe for individuals experiencing pregnancy, breastfeeding, hormone sensitive conditions, liver problems, diabetes, depression or mood disorders, polycystic ovarian syndrome (PCOS), or cholesterol problems.Prasterone has been reported to possess few or no side effects even at very high dosages (e.g., 50 times the recommended over-the-counter supplement dosage). However, it may cause masculinization and other androgenic side effects in women and gynecomastia and other estrogenic side effects in men.
Pharmacokinetics
Oral uptake of prasterone is excellent. Its volume of distribution is 17.0-38.5L (whereas it is 8.5-9.3L for its active metabolite DHEA-S). Prasterone (DHEA) has a biological half-life of 15-38 min (whereas it is 7-22h for DHEA-S). 51-73% of DHEA-S and its metabolites are excreted via the renal route.
Prasterone is metabolized into androgens and estrogens in the body, including androstenedione, testosterone, estrone, estradiol, and estriol. The transformation of prasterone into androgens and estrogens is tissue-specific, for instance occurring in the liver, fat, vagina, prostate gland, skin, and hair follicles (as well as other tissues).
Metabolism
Prasterone is also reversibly transformed into its active metabolite prasterone sulfate (DHEA-S) by steroid sulfotransferase (specifically SULT1E1 and SULT2A1), which in turn can be converted back into prasterone by steroid sulfatase. Interconversion takes place in both adrenal and peripheral tissues.It is transformed into androstenedione by 3β-hydroxysteroid dehydrogenase (3β-HSD), and into androstenediol by 17β-hydroxysteroid dehydrogenase (17β-HSD). Then, androstenedione and androstenediol can be converted into testosterone by 17β-HSD and 3β-HSD, respectively. Subsequently, testosterone can be metabolized into dihydrotestosterone by 5α-reductase.In addition, androstenedione and testosterone can be converted into estrone and estradiol by aromatase, respectively.
Dose-response of hormone levels
At a high dosage of 1,600 mg/day orally for 4 weeks, treatment of postmenopausal women with prasterone has been found to increase serum levels of DHEA by 15-fold, testosterone by 9-fold, DHEA-S, androstenedione, and DHT all by 20-fold, and estrone and estradiol both by 2-fold.Although prasterone can reliably increase testosterone levels in women, this isnt similarly the case in men. A high dosage of 1,600 mg/day prasterone in men for 4 weeks was found to increase DHEA and androstenedione levels but did not significantly affect testosterone levels.
Dosing
In clinical studies of prasterone supplementation, dosages have ranged from 20 to 1,600 mg per day.In people with adrenal insufficiency, oral dosages of 20 to 50 mg/day prasterone have been found to restore DHEA and DHEA-S levels to physiological levels seen in young healthy adults. Conversely, oral dosages of 100 to 200 mg/day prasterone have been found to result in supraphysiological levels of DHEA and DHEA-S.Micronization of prasterone has been found to significantly increase levels of DHEA-S achieved with oral administration, but to produce no significant change in levels of DHEA or testosterone levels achieved.
Chemistry
Prasterone, also known as androst-5-en-3β-ol-17-one, is a naturally occurring androstane steroid and a 17-ketosteroid. It is closely related structurally to androstenediol (androst-5-ene-3β,17β-diol), androstenedione (androst-4-ene-3,17-dione), and testosterone (androst-4-en-17β-ol-3-one). Prasterone is the δ5 (5(6)-dehydrogenated) analogue of epiandrosterone (5α-androstan-3β-ol-17-one), and is also known as 5-dehydroepiandrosterone (5-DHEA) or δ5-epiandrosterone. A positional isomer of prasterone which may have similar biological activity is 4-dehydroepiandrosterone (4-DHEA).
Derivatives
Prasterone is used medically as the C3β esters prasterone enanthate and prasterone sulfate. The C19 demethyl analogue of prasterone is 19-nordehydroepiandrosterone (19-nor-DHEA), which is a prohormone of nandrolone (19-nortestosterone). The 5α-reduced and δ1 (1(2)-dehydrogenated) analogue of prasterone is 1-dehydroepiandrosterone (1-DHEA or 1-androsterone), which is a prohormone of 1-testosterone (δ1-DHT or dihydroboldenone). Fluasterone (3β-dehydroxy-16α-fluoro-DHEA) is a derivative of prasterone with minimal or no hormonal activity but other biological activities preserved.
History
DHEA was discovered, via isolation from male urine, by Adolf Butenandt and Hans Dannenbaum in 1934, and the compound was isolated from human blood plasma by Migeon and Plager in 1954. DHEA sulfate, the 3β-sulfate ester of DHEA, was isolated from urine in 1944, and was found by Baulieu to be the most abundant steroid hormone in human plasma in 1954. From its discovery in 1934 until 1959, DHEA was referred to by a number of different names in the literature, including dehydroandrosterone, transdehydroandrosterone, dehydroisoandrosterone, and androstenolone. The name dehydroepiandrosterone, also known as DHEA, was first proposed by Fieser in 1949, and subsequently became the most commonly used name of the hormone. For decades after its discovery, DHEA was considered to be an inactive compound that served mainly as an intermediate in the production of androgens and estrogens from cholesterol. In 1965, an association between DHEA sulfate levels and aging was reported by De Nee and Vermeulen. Following this, DHEA became of interest to the scientific community, and numerous studies assessing the relationship between DHEA and DHEA sulfate levels and aging were conducted.Prasterone, the proposed INN and recommended INN of DHEA and the term used when referring to the compound as a medication, were published in 1970 and 1978, respectively. The combination of 4 mg estradiol valerate and 200 mg prasterone enanthate in an oil solution was introduced for use in menopausal hormone therapy by intramuscular injection under the brand name Gynodian Depot in Europe by 1978. In the early 1980s, prasterone became available and was widely sold over-the-counter as a non-prescription supplement in the United States, primarily as a weight loss aid. It was described as a "miracle drug", with supposed anti-aging, anti-obesity, and anti-cancer benefits. This continued until 1985, when the marketing of prasterone was banned by the Food and Drug Administration (FDA) due to a lack of evidence for health benefits and due to the long-term safety and risks of the compound being unknown at the time. Subsequently, prasterone once again became available over-the-counter as a dietary supplement in the United States following the passage of the Dietary Supplement Health and Education Act of 1994. Conversely, it has remained banned as a supplement in Canada, the United Kingdom, Australia, and New Zealand.In 2001, Genelabs submitted a New Drug Application of prasterone for the treatment of systemic lupus erythematosus (SLE) to the FDA. It had the tentative brand names Anastar, Aslera, and Prestara. However, this application was not approved, and while development of prasterone for SLE in both the United States and Europe continued until up to 2010, the medication was ultimately never approved for the treatment of this condition. In 2016, the FDA approved prasterone in an intravaginal gel formulation for the treatment of painful sexual intercourse due to vulvovaginal atrophy in the United States under the brand name Intrarosa. This was the first prasterone-containing medication to be approved by the FDA in this country.
Society and culture
Generic names
Prasterone is the generic name of DHEA in English and Italian and its International Nonproprietary Name, United States Adopted Name and Italian Common Name, while its generic name is prasteronum in Latin, prastérone in French and its French popular name, and prasteron in German.
Marketing
In the United States, prasterone or prasterone sulfate have been advertised, under the names DHEA and DHEA-S, with claims that they may be beneficial for a wide variety of ailments. Prasterone and prasterone sulfate are readily available in the United States, where they are sold as over-the-counter dietary supplements.In 1996, reporter Harry Wessel of the Orlando (Florida) Sentinel wrote about DHEA that "Thousands of people have gotten caught up in the hoopla and are buying the stuff in health food stores, pharmacies and mail-order catalogs" but that "such enthusiasm is viewed as premature by many in the medical field." He noted that "National publications such as Time, Newsweek and USA Today have run articles recently about the hormone, while several major publishers have come out with books touting it." His column was widely syndicated and reprinted in other U.S. newspapers.
The product was being "widely marketed to and used by bodybuilders," Dr. Paul Donahue wrote in 2012 for King Features syndicate.
Regulation
By country
Australia
In Australia, a prescription is required to buy prasterone, where it is also comparatively expensive compared to off-the-shelf purchases in US supplement shops. Australian customs classify prasterone as an "anabolic steroid[s] or precursor[s]" and, as such, it is only possible to carry prasterone into the country through customs if one possesses an import permit which may be obtained if one has a valid prescription for the hormone.
Canada
In Canada, prasterone is a Controlled Drug listed under Section 23 of Schedule IV of the Controlled Drugs and Substances Act and as such is available by prescription only.
United Kingdom
Prasterone is listed as an anabolic steroid and is thus a class C controlled drug.
United States
Prasterone is legal to sell in the United States as a dietary supplement. It is currently grandfathered in as an "Old Dietary Ingredient" being on sale prior to 1994. Prasterone is specifically exempted from the Anabolic Steroid Control Act of 1990 and 2004.
Sports and athletics
Prasterone is banned from use in athletic competition.
It is a prohibited substance under the World Anti-Doping Code of the World Anti-Doping Agency, which manages drug testing for Olympics and other sports.
Yulia Efimova, who holds the world record pace for both the 50-meter and 200-meter breaststroke, and won the bronze medal in the 200-meter breaststroke in the 2012 London Olympic Games, tested positive for prasterone in an out-of-competition doping test.
Rashard Lewis, then with the Orlando Magic, tested positive for prasterone and was suspended 10 games before the start of the 2009–10 season.
In 2016 MMA fighter Fabio Maldonado revealed he was taking prasterone during his time with the UFC.
In January 2011, NBA player O. J. Mayo was given a 10-game suspension after testing positive for prasterone. Mayo termed his use of prasterone as "an honest mistake," saying the prasterone was in an over-the-counter supplement and that he was unaware the supplement was banned by the NBA. Mayo was the seventh player to test positive for performance-enhancing drugs since the league began testing in 1999.
Olympic 400-meter champion Lashawn Merritt tested positive for prasterone in 2010 and was banned from the sport for 21 months.
Tennis player Venus Williams had permission from the International Tennis Federation to use DHEA along with hydrocortisone as a treatment for "adrenal insufficiency," but it was revoked in 2016 by the World Anti-Doping Agency, which believed DHEA use would enhance Williams athletic performance.
Research
Anabolic uses
A meta-analysis of intervention studies shows that prasterone supplementation in elderly men can induce a small but significant positive effect on body composition that is strictly dependent on prasterone conversion into its bioactive metabolites such as androgens or estrogens. Evidence is inconclusive in regards to the effect of prasterone on strength in the elderly. In middle-aged men, no significant effect of prasterone supplementation on lean body mass, strength, or testosterone levels was found in a randomized placebo-controlled trial.
Cancer
There is no evidence prasterone is of benefit in treating or preventing cancer.
Cardiovascular disease
A review in 2003 found the then-extant evidence sufficient to suggest that low serum levels of DHEA-S may be associated with coronary heart disease in men, but insufficient to determine whether prasterone supplementation would have any cardiovascular benefit.Prasterone may enhance G6PD mRNA expression, confounding its inhibitory effects.
Lupus
There is some evidence of short-term benefit in those with systemic lupus erythematosus but little evidence of long-term benefit or safety. Prasterone was under development for the treatment of systemic lupus erythematosus in the United States and Europe in the 1990s and 2000s and reached phase III clinical trials and preregistration for this indication, respectively, but ultimately development was not continued past 2010.
Memory
Prasterone supplementation has not been found to be useful for memory function in normal middle aged or older adults. It has been studied as a treatment for Alzheimers disease, but there is no evidence that it is effective or ineffective. More research is needed to determine its benefits.
Mood
A few small, short term clinical studies have found that prasterone improves mood but its long-term efficacy and safety, and how it compares to antidepressants, was unknown as of 2015.
References
Further reading
Keppel Hesselink JM (December 1997). "[Prasterone (dihydroepiandrosterone): a modern source of eternal youth?]". Ned Tijdschr Geneeskd (in Dutch). 141 (51): 2484–7. PMID 9555138.
Zelissen PM, Thijssen JH (October 2001). "[Role of prasterone (dehydroepiandrosterone) in substitution therapy for adrenocortical insufficiency]". Ned Tijdschr Geneeskd (in Dutch). 145 (42): 2018–22. PMID 11695098.
Pope, JE; Cupp, MJ; Tracy, TS (2003). Dehydroepiandrosterone (DHEA) (Prasterone). Dietary Supplements. Totowa, NJ: Humana Press. pp. 123–147. doi:10.1007/978-1-59259-303-3_8 (inactive 31 July 2022). ISBN 9781592593033.{{cite book}}: CS1 maint: DOI inactive as of July 2022 (link)
Kocis P (November 2006). "Prasterone". Am J Health Syst Pharm. 63 (22): 2201–10. doi:10.2146/ajhp060100. PMID 17090740.
Mendivil Dacal JM, Borges VM (April 2009). "[Dehydroepiandrosterone (DHEA), review of its efficiency in the managing of the libido decrease and other symptoms of aging]". Actas Urol Esp (in Spanish). 33 (4): 390–401. doi:10.4321/s0210-48062009000400009. PMID 19579890.
Alkatib AA, Cosma M, Elamin MB, Erickson D, Swiglo BA, Erwin PJ, Montori VM (October 2009). "A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency". J. Clin. Endocrinol. Metab. 94 (10): 3676–81. doi:10.1210/jc.2009-0672. PMID 19773400.
Panjari M, Davis SR (June 2010). "DHEA for postmenopausal women: a review of the evidence". Maturitas. 66 (2): 172–9. doi:10.1016/j.maturitas.2009.12.017. PMID 20089375.
Oberbeck R, Kobbe P (2010). "Dehydroepiandrosterone (DHEA): a steroid with multiple effects. Is there any possible option in the treatment of critical illness?". Curr. Med. Chem. 17 (11): 1039–47. doi:10.2174/092986710790820570. PMID 20156161.
Prati A, Santagni S, Rattighieri E, Campedelli A, Ricchieri F, Chierchia E, Despini G, Genazzani AR, Genazzani AD (June 2014). "[The putative role and use of DHEA and its association with the hormone replacement therapy]". Minerva Ginecol (in Italian). 66 (3): 313–24. PMID 24971788.
Genazzani AR, Pluchino N (August 2010). "DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence". Climacteric. 13 (4): 314–6. doi:10.3109/13697137.2010.492496. PMID 20540592. S2CID 5578070.
Luci M, Valenti G, Maggio M (September 2010). "[Dehydroepiandrosterone [DHEA(S)]: anabolic hormone?]". Recenti Prog Med (in Italian). 101 (9): 333–44. hdl:11381/2436727. PMID 21268370.
Gleicher N, Barad DH (May 2011). "Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)". Reprod. Biol. Endocrinol. 9: 67. doi:10.1186/1477-7827-9-67. PMC 3112409. PMID 21586137.
Davis SR, Panjari M, Stanczyk FZ (June 2011). "Clinical review: DHEA replacement for postmenopausal women". J. Clin. Endocrinol. Metab. 96 (6): 1642–53. doi:10.1210/jc.2010-2888. PMID 21411558.
Panjari M, Davis SR (September 2011). "Vaginal DHEA to treat menopause related atrophy: a review of the evidence". Maturitas. 70 (1): 22–5. doi:10.1016/j.maturitas.2011.06.005. PMID 21733647.
Traish AM, Kang HP, Saad F, Guay AT (November 2011). "Dehydroepiandrosterone (DHEA)--a precursor steroid or an active hormone in human physiology". J Sex Med. 8 (11): 2960–82, quiz 2983. doi:10.1111/j.1743-6109.2011.02523.x. PMID 22032408.
Savineau JP, Marthan R, Dumas de la Roque E (March 2013). "Role of DHEA in cardiovascular diseases". Biochem. Pharmacol. 85 (6): 718–26. doi:10.1016/j.bcp.2012.12.004. PMID 23270992.
Labrie F, Labrie C (April 2013). "DHEA and intracrinology at menopause, a positive choice for evolution of the human species". Climacteric. 16 (2): 205–13. doi:10.3109/13697137.2012.733983. PMID 23126249. S2CID 6546179.
Rutkowski K, Sowa P, Rutkowska-Talipska J, Kuryliszyn-Moskal A, Rutkowski R (July 2014). "Dehydroepiandrosterone (DHEA): hypes and hopes". Drugs. 74 (11): 1195–207. doi:10.1007/s40265-014-0259-8. PMID 25022952. S2CID 26554413.
Peixoto C, Devicari Cheda JN, Nardi AE, Veras AB, Cardoso A (2014). "The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review". Curr Drug Targets. 15 (9): 901–14. doi:10.2174/1389450115666140717111116. PMID 25039497.
Elraiyah T, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Altayar O, Prokop L, Montori VM, Murad MH (October 2014). "Clinical review: The benefits and harms of |
Prasterone | systemic dehydroepiandrosterone (DHEA) in postmenopausal women with normal adrenal function: a systematic review and meta-analysis". J. Clin. Endocrinol. Metab. 99 (10): 3536–42. doi:10.1210/jc.2014-2261. PMC 5393492. PMID 25279571.
Maggio M, De Vita F, Fisichella A, Colizzi E, Provenzano S, Lauretani F, Luci M, Ceresini G, DallAglio E, Caffarra P, Valenti G, Ceda GP (January 2015). "DHEA and cognitive function in the elderly". J. Steroid Biochem. Mol. Biol. 145: 281–92. doi:10.1016/j.jsbmb.2014.03.014. PMID 24794824. S2CID 33768697.
Pluchino N, Drakopoulos P, Bianchi-Demicheli F, Wenger JM, Petignat P, Genazzani AR (January 2015). "Neurobiology of DHEA and effects on sexuality, mood and cognition". J. Steroid Biochem. Mol. Biol. 145: 273–80. doi:10.1016/j.jsbmb.2014.04.012. PMID 24892797. S2CID 12382989.
Warner M, Gustafsson JA (January 2015). "DHEA - a precursor of ERβ ligands". J. Steroid Biochem. Mol. Biol. 145: 245–7. doi:10.1016/j.jsbmb.2014.08.003. PMID 25125389. S2CID 26043868.
Lang K, Burger-Stritt S, Hahner S (January 2015). "Is DHEA replacement beneficial in chronic adrenal failure?". Best Pract. Res. Clin. Endocrinol. Metab. 29 (1): 25–32. doi:10.1016/j.beem.2014.09.007. PMID 25617170.
Vuksan-Ćusa B, Šagud M, Radoš I (March 2016). "The role of dehydroepiandrosterone (DHEA) in schizophrenia". Psychiatr Danub. 28 (1): 30–3. PMID 26938818.
Prough RA, Clark BJ, Klinge CM (April 2016). "Novel mechanisms for DHEA action". J. Mol. Endocrinol. 56 (3): R139–55. doi:10.1530/JME-16-0013. PMID 26908835.
Qin JC, Fan L, Qin AP (May 2016). "The effect of dehydroepiandrosterone (DHEA) supplementation on women with diminished ovarian reserve (DOR) in IVF cycle: Evidence from a meta-analysis". J Gynecol Obstet Biol Reprod (Paris). 46: 1–7. doi:10.1016/j.jgyn.2016.01.002. PMID 27212610.
Ohnaka K (July 2016). "[Dehydroepiandrosterone (DHEA) and bone metabolism]". Clin Calcium (in Japanese). 26 (7): 987–93. PMID 27346309.
Handelsman DJ, Matsumoto AM, Gerrard DF (January 2017). "Doping Status of DHEA Treatment for Female Athletes with Adrenal Insufficiency". Clin J Sport Med. 27 (1): 78–85. doi:10.1097/JSM.0000000000000300. PMID 26844622. S2CID 24168278.
Qin JC, Fan L, Qin AP (January 2017). "The effect of dehydroepiandrosterone (DHEA) supplementation on women with diminished ovarian reserve (DOR) in IVF cycle: Evidence from a meta-analysis". J Gynecol Obstet Hum Reprod. 46 (1): 1–7. doi:10.1016/j.jgyn.2016.01.002. PMID 28403950.
Labrie F, Martel C, Bélanger A, Pelletier G (April 2017). "Androgens in women are essentially made from DHEA in each peripheral tissue according to intracrinology". J. Steroid Biochem. Mol. Biol. 168: 9–18. doi:10.1016/j.jsbmb.2016.12.007. PMID 28153489. S2CID 2620899.
Triantafyllidou O, Sigalos G, Vlahos N (June 2017). "Dehydroepiandrosterone (DHEA) supplementation and IVF outcome in poor responders". Hum Fertil (Camb). 20 (2): 80–87. doi:10.1080/14647273.2016.1262065. PMID 27927044. S2CID 3425127.
Archer DF, Labrie F, Montesino M, Martel C (November 2017). "Comparison of intravaginal 6.5mg (0.50%) prasterone, 0.3mg conjugated estrogens and 10μg estradiol on symptoms of vulvovaginal atrophy". J. Steroid Biochem. Mol. Biol. 174: 1–8. doi:10.1016/j.jsbmb.2017.03.014. PMID 28323042. S2CID 140206697.
External links
"Prasterone". Drug Information Portal. U.S. National Library of Medicine. |
Chattem | Chattem, Inc. is an American, Chattanooga, Tennessee-based, producer and marketer of over-the-counter healthcare products, toiletries, dietary supplements, topical analgesics, and medicated skin care products. Originally named the Chattanooga Medicine Company, the company’s brand portfolio holds twenty-two brands including Allegra, Gold Bond, Flexall, IcyHot, Rolaids, Sun-In, Pamprin, Dexatrim, Aspercreme, and Selsun Blue. The company produces two-thirds of its products at its Chattanooga production facilities with the remaining produced by third-party producers. The company is a subsidiary of the French multinational pharmaceutical company Sanofi.
The company’s brands are sold nationally through mass merchandiser, drug and food retailers. In 2005, 70% of the firms sales were made through its top ten customers, which include Wal-Mart, Walgreens, and Kroger. Sales to Wal-Mart constituted 36% of Chattem’s total sales in 2005. Chattem supports these sales with a forty-five-person sales force and broadcast media advertising. Chattem has market penetration in the United States, Europe, Canada, Latin America, and the Caribbean.
History
Chattem was founded by Zeboim Cartter Patten as the Chattanooga Medicine Company in 1879. The company incorporated in 1909 and has remained in Chattanooga, Tennessee, to this day.
During World War II, the Chattanooga Medicine Company turned into a major supplier of K-Rations to the US Army, producing 34 million rations from 1942 to 1945, earning 5 "E" Awards for support of war efforts.
The firm adopted Chattem as its name and went public in 1969.
Chattem’s top and bottom lines grew significantly from 1989 through 1992. The source of this growth was the company’s strategy of purchasing under-marketed consumer brands and aggressively marketing those in its portfolio. In 1993, Chattem experienced a 14% decline in sales from the loss of Warner-Lambert’s Rolaids business. To fund a one-time special dividend in 1994, $75 million in high-yield bonds were issued.
In January 2013, Chattem acquired the full rights to Rolaids, which had seen its brand wounded under the ownership of Johnson & Johnsons McNeil Consumer Healthcare with a series of product recalls and quality control issues throughout 2010 that ended with most of the Rolaids line discontinued. In September, 2013 Chattem returned Rolaids to the market with new trade dress, though production of Rolaids is not expected to return to Chattanooga.
In March 2014, Chattem sold Dexatrim to NVE Pharmaceuticals.
Recent events
In October 2006, Chattem announced it would acquire five brands for $410 million as a result of the merger between Johnson & Johnson and the consumer healthcare business of Pfizer. These brands are:
ACT Anti-Cavity Mouthwash
Unisom
Cortizone 10
Kaopectate
Balmex-Diaper Rash OintmentPending the US government’s approval of the merger of Johnson & Johnson and Pfizer Consumer Healthcare, Chattem will acquire five brands divested from the firms. Chattem has announced it expects to take possession of the brands around January 2007. These mature brands will provide $150 million in additional revenue to Chattem per year.On December 21, 2009, Paris-based (France) Sanofi, the worlds fourth largest drugmaker, said it was acquiring Chattem in a $1.9 billion cash deal. Sanofi said the acquisition would be completed by the first quarter of 2010.
Current brands
Chattem manufactures many over-the-counter healthcare products. They are marketed in three categories: pain relief, skin & hair care, and health & wellness.
Pain relief
Arthritis Hot
Aspercreme
Capzasin
Cortizone 10
Flexall
Icy Hot
Sportscreme
Skin & hair care
Gold Bond
Gold Bond Ultimate
Selsun Blue
Health & wellness
ACT Oral Care
Allegra
Kaopectate
Nasacort
Rolaids
Unisom
Unisom Natural Nights
Xyzal
References
== External links == |
Benazepril | Benazepril, sold under the brand name Lotensin among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combinations benazepril/hydrochlorothiazide and benazepril/amlodipine.Common side effects include feeling tired, dizziness, cough, and light-headedness with standing. Serious side effects may include kidney problems, low blood pressure, high blood potassium, and angioedema. Use in pregnancy may harm the baby, while use when breastfeeding may be safe. It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.Benazepril was patented in 1981 and came into medical use in 1990. It was created by the chemist Mahesh Desai. It is available as a generic medication. In 2019, it was the 130th most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Structure Activity Relationship
Benazepril Hydrochlorides OCh2Ch3 group must be metabolized in order to inhibit the ACE Enzyme to form Benazeprilat, which is the active form of the molecule. The bulky cyclic structure is resistant to hydrolysis. A special note about the molecule is that the nitrogen within the ring makes the bulky cyclic structure especially harder to break down, and can account for the drugs PK profile, in which the duration of action is 24 hours.
Medical uses
It is useful for high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. Other reasonable initial options include angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics.
Side effects
The most common side effects patients experience are a headache or a chronic cough. The chronic cough develops in about 20% of patients treated, and those patients that experience it find it develops after a few months of use. Anaphylaxis, angioedema, and elevation of potassium levels are more serious side effects that can also occur.
Contraindications
Benazepril should be discontinued during pregnancy and in women planning to become pregnant, as it can harm the fetus.
Dosage forms
It is also available in combination with hydrochlorothiazide, under the trade name Lotensin HCT, and with amlodipine (Lotrel).
Veterinary use
Under the brand names Fortekor (Novartis) and VetACE (Jurox Animal Health), benazepril is used to treat congestive heart failure in dogs and chronic kidney failure in cats and dogs.
References
External links
"Benazepril". Drug Information Portal. U.S. National Library of Medicine. |
Vantas | Vantas may refer to:
Karkat and Kankri Vantas, characters from the webcomic Homestuck
Vertically aligned carbon nanotube arrays (VANTAs)
Histrelin acetate, a drug sold under the brand name Vantas
Vantas, a cancelled brand of Exeed TX SUVs in North America |
Fulvestrant | Fulvestrant, sold under the brand name Faslodex among others, is a medication used to treat hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression as well as HR-positive, HER2-negative advanced breast cancer in combination with palbociclib in women with disease progression after endocrine therapy. It is given by injection into a muscle.Fulvestrant is a selective estrogen receptor degrader (SERD) and was first-in-class to be approved. It works by binding to the estrogen receptor and destabilizing it, causing the cells normal protein degradation processes to destroy it.Fulvestrant was approved for medical use in the United States in 2002.
Medical uses
Breast cancer
Fulvestrant is used for the treatment of hormone receptor positive metastatic breast cancer or locally advanced unresectable disease in postmenopausal women; it is given by injection. A 2017 Cochrane review found it is as safe and effective as first line or second line endocrine therapy.It is also used to treat ER-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib in women with disease progression after first-line endocrine therapy.Due to the medications having a chemical structure similar to that of estrogen, it can interact with immunoassays for blood estradiol concentrations and show falsely elevated results. This can improperly lead to discontinuing the treatment.
Early puberty
Fulvestrant has been used in the treatment of peripheral precocious puberty in girls with McCune–Albright syndrome.
Available forms
Fulvestrant is provided in a castor oil solution also containing alcohol, benzyl alcohol, and benzyl benzoate. It is supplied at a concentration of 250 mg/5 mL.
Contraindications
Fulvestrant should not be used in women with kidney failure or who are pregnant.
Side effects
Very common (occurring in more than 10% of people) adverse effects include nausea, injection site reactions, weakness, and elevated transaminases. Common (between 1% and 10%) adverse effects include urinary tract infections, hypersensitivity reactions, loss of appetite, headache, blood clots in veins, hot flushes, vomiting, diarrhea, elevated bilirubin, rashes, and back pain. In a large clinical trial, the incidence of venous thromboembolism (VTE) with fulvestrant was 0.9%.
Pharmacology
Pharmacodynamics
Fulvestrant is an antiestrogen which acts as an antagonist of the estrogen receptor (ER) and additionally as a selective estrogen receptor degrader (SERD). It works by binding to the estrogen receptor and making it more hydrophobic, which makes the receptor unstable and misfold, which in turn leads normal processes inside the cell to degrade it.In addition to its antiestrogenic activity, fulvestrant is an agonist of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (10–100 nM, relative to 3–6 nM for estradiol).
Pharmacokinetics
Fulvestrant after an intramuscular injection is slowly absorbed and maximal levels (Cmax) are reached after 5 days on average with a range of 2 to 19 days. The elimination half-life of fulvestrant with intramuscular injection is 40 to 50 days. This is 40 times longer than the half-life of fulvestrant by intravenous injection, indicating that its long half-life with intramuscular injection is due to slow absorption from the injection site. Levels of fulvestrant with 500 mg/month by intramuscular injection (and a single additional 500 mg loading dose on day 15 of therapy) in postmenopausal women with advanced breast cancer were 25.1 ng/mL (25,100 pg/mL) at peak and 28.0 ng/mL (28,000 pg/mL) at trough with a single dose and 28.0 ng/mL (28,000 pg/mL) at peak and 12.2 ng/mL (12,200 pg/mL) at trough after multiple doses at steady state.Fulvestrant does not cross the blood–brain barrier in animals and may not in humans as well. Accordingly, no effects of fulvestrant on brain function have been observed in preclinical or clinical research. Fulvestrant is highly (99%) bound to plasma proteins. It is bound to very low density lipoprotein, low density lipoprotein, and high density lipoprotein, but not to sex hormone-binding globulin.Fulvestrant appears to be metabolized along similar pathways as endogenous steroids; CYP3A4 may be involved, but non-cytochrome P450 routes appear to be more important. It does not inhibit any cytochrome P450 enzymes. Elimination is almost all via feces.Fulvestrant can form colloidal aggregates at certain concentration ranges and this can limit its activity as well as produce bell-shaped concentration–response curves.
Chemistry
Fulvestrant, also known as 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estradiol, is a synthetic estrane steroid and a derivative of estradiol. An alkyl-sulfinyl moiety was added to the endogenous estrogen receptor ligand.It was discovered through rational drug design, but was selected for further development via phenotypic screening.
History
Fulvestrant was the first selective estrogen receptor degrader to be approved. It was approved in the United States in 2002 and in Europe in 2004.
Society and culture
NICE evaluation
The U.K. National Institute for Health and Clinical Excellence (NICE) said in 2011 that it found no evidence Faslodex was significantly better than existing treatments, so its widespread use would not be a good use of resources for the countrys National Health Service. The first months treatment of Faslodex, which starts with a loading dose, costs £1,044.82 ($1,666), and subsequent treatments cost £522.41 a month. In the 12 months ending June 2015, the UK price (excluding VAT) of a months supply of anastrozole (Arimidex), which is off patent, cost 89 pence/day, and letrozole (Femara) cost £1.40/day.
Patent extension
The original patent for Faslodex expired in October 2004. Drugs subject to pre-marketing regulatory review are eligible for patent extension, and for this reason AstraZeneca got an extension of the patent to December 2011.
AstraZeneca has filed later patents. A generic version of Faslodex has been approved by the FDA. However, this does not mean that the product will necessarily be commercially available - possibly because of drug patents and/or drug exclusivity. A later patent for Faslodex expires in January 2021. Atossa Genetics has a patent for the administration of fulvestrant into the breast via a microcatheter invented by Susan Love.
Research
Fulvestrant was studied in endometrial cancer but results were not promising and as of 2016 development for this use was abandoned.Because fulvestrant cannot be given orally, efforts have been made to develop SERD drugs that can be taken by mouth, including brilanestrant and elacestrant. The clinical success of fulvestrant also led to efforts to discover and develop a parallel drug class of selective androgen receptor degraders (SARDs).ZB716, or fulvestrant-3-boronic acid, is an oral prodrug of fulvestrant which is under development.
References
External links
"Fulvestrant". Drug Information Portal. U.S. National Library of Medicine. |
Ciltacabtagene autoleucel | Ciltacabtagene autoleucel, sold under the brand name Carvykti, is a medication used to treat multiple myeloma.The most common adverse reactions include pyrexia, cytokine release syndrome, hypogammaglobulinemia, musculoskeletal pain, fatigue, infections, diarrhea, nausea, encephalopathy, headache, coagulopathy, constipation, and vomiting. Additional common side effects include neutropenia (low levels of neutrophils), lymphopenia and leucopenia (low levels of lymphocytes or other white blood cells), anemia (low levels of red blood cells), thrombocytopenia (low levels of blood platelets), hypotension (low blood pressure), pain of the muscles and bones, high level of liver enzymes, upper respiratory tract infection (nose and throat infection), diarrhea, hypokalemia (low level of potassium), hypocalcemia (low levels of calcium), hypophosphatemia (low levels of phosphate in the blood), nausea, headache, cough, tachycardia (rapid heartbeat), encephalopathy (a brain disorder), edema (fluid retention), decreased appetite, chills, fever, tiredness, as well as cytokine release syndrome (a potentially life-threatening condition that can cause fever, vomiting, shortness of breath, pain and low blood pressure).Ciltacabtagene autoleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using the recipients own T-cells, which are collected and genetically modified, and infused back into the recipient.Ciltacabtagene autoleucel was approved for medical use in the United States in February 2022, and in the European Union in May 2022.
Medical uses
In the US, ciltacabtagene autoleucel is indicated for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.In the EU it is indicated for the treatment of adults with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.
History
The safety and efficacy of ciltacabtagene autoleucel were evaluated in CARTITUDE-1 (NCT03548207), an open label, multicenter clinical trial evaluating ciltacabtagene autoleucel in 97 participants with relapsed or refractory multiple myeloma who received at least three prior lines of therapy which included a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody and who had disease progression on or after the last chemotherapy regimen; 82% had received four or more prior lines of antimyeloma therapy.The U.S. Food and Drug Administration (FDA) granted the application for ciltacabtagene autoleucel priority review, breakthrough therapy, and orphan drug designations.
Society and culture
Legal status
On 24 March 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 Carvykti, intended for the treatment of adults with relapsed and refractory multiple myeloma. The applicant for this medicinal product is Janssen-Cilag International NV. Ciltacabtagene autoleucel was approved for medical use in the European Union in May 2022.
References
External links
"Ciltacabtagene autoleucel". Drug Information Portal. U.S. National Library of Medicine. |
Eflornithine | Eflornithine, sold under the brand name Vaniqa among others, is a medication used to treat African trypanosomiasis (sleeping sickness) and excessive hair growth on the face in women. Specifically it is used for the 2nd stage of sleeping sickness caused by T. b. gambiense and may be used with nifurtimox. It is used by injection or applied to the skin.Common side effects when applied as a cream include rash, redness, and burning. Side effects of the injectable form include bone marrow suppression, vomiting, and seizures. It is unclear if it is safe to use during pregnancy or breastfeeding. It is recommended typically for children over the age of 12.Eflornithine was developed in the 1970s and came into medical use in 1990. It is on the World Health Organizations List of Essential Medicines. In the United States the injectable form can be obtained from the Centers for Disease Control and Prevention. In regions of the world where the disease is common eflornithine is provided for free by the World Health Organization.
Medical uses
Sleeping sickness
Sleeping sickness, or trypanosomiasis, is treated with pentamidine or suramin (depending on subspecies of parasite) delivered by intramuscular injection in the first phase of the disease, and with melarsoprol and eflornithine intravenous injection in the second phase of the disease. Efornithine is commonly given in combination with nifurtimox, which reduces the treatment time to 7 days of eflornithine infusions plus 10 days of oral nifurtimox tablets.Eflornithine is also effective in combination with other drugs, such as melarsoprol and nifurtimox. A study in 2005 compared the safety of eflornithine alone to melarsoprol and found eflornithine to be more effective and safe in treating second-stage sleeping sickness Trypanosoma brucei gambiense. Eflornithine is not effective in the treatment of Trypanosoma brucei rhodesiense due to the parasites low sensitivity to the drug. Instead, melarsoprol is used to treat Trypanosoma brucei rhodesiense. Another randomized control trial in Uganda compared the efficacy of various combinations of these drugs and found that the nifurtimox-eflornithine combination was the most promising first-line theory regimen.A randomized control trial was conducted in Congo, Côte dIvoire, the Democratic Republic of the Congo, and Uganda to determine if a 7-day intravenous regimen was as efficient as the standard 14-day regimen for new and relapsing cases. The results showed that the shortened regimen was efficacious in relapse cases, but was inferior to the standard regimen for new cases of the disease.Nifurtimox-eflornithine combination treatment (NECT) is an effective regimen for the treatment of second stage gambiense African trypanosomiasis.
Trypanosome resistance
After its introduction to the market in the 1980s, eflornithine has replaced melarsoprol as the first line medication against Human African trypanosomiasis (HAT) due to its reduced toxicity to the host. Trypanosoma brucei resistant to eflornithine was reported as early as the mid-1980s.The gene TbAAT6, conserved in the genome of Trypanosomes, is believed to be responsible for the transmembrane transporter that brings eflornithine into the cell. The loss of this gene due to specific mutations causes resistance to eflornithine in several trypanosomes. If eflornithine is prescribed to a patient with Human African trypanosomiasis caused by a trypanosome that contains a mutated or ineffective TbAAT6 gene, then the medication will be ineffective against the disease. Resistance to eflornithine has increased the use of melarsoprol despite its toxicity, which has been linked to the deaths of 5% of recipient HAT patients.
Excess facial hair in women
The topical cream is indicated for treatment of facial hirsutism in women. It is the only topical prescription treatment that slows the growth of facial hair. It is applied in a thin layer twice daily, a minimum of eight hours between applications. In clinical studies with Vaniqa, 81% percent of women showed clinical improvement after twelve months of treatment. Positive results were seen after eight weeks. However, discontinuation of the cream caused regrowth of hair back to baseline levels within 8 weeks.Vaniqa treatment significantly reduces the psychological burden of facial hirsutism.
Chemo preventative therapy
It has been noted that ornithine decarboxylase (ODC) exhibits high activity in tumor cells, promoting cell growth and division, while absence of ODC activity leads to depletion of putrescine, causing impairment of RNA and DNA synthesis. Typically, drugs that inhibit cell growth are considered candidates for cancer therapy, so eflornithine was naturally believed to have potential utility as an anti-cancer agent. By inhibiting ODC, eflornithine inhibits cell growth and division of both cancerous and noncancerous cells.
However, several clinical trials demonstrated minor results. It was found that inhibition of ODC by eflornithine does not kill proliferating cells, making eflornithine ineffective as a chemotherapeutic agent. The inhibition of the formation of polyamines by ODC activity can be ameliorated by dietary and bacterial means because high concentrations are found in cheese, red meat, and some intestinal bacteria, providing reserves if ODC is inhibited. Although the role of polyamines in carcinogenesis is still unclear, polyamine synthesis has been supported to be more of a causative agent rather than an associative effect in cancer.Other studies have suggested that eflornithine can still aid in some chemoprevention by lowering polyamine levels in colorectal mucosa, with additional strong preclinical evidence available for application of eflornithine in colorectal and skin carcinogenesis. This has made eflornithine a supported chemopreventive therapy specifically for colon cancer in combination with other medications. Several additional studies have found that eflornithine in combination with other compounds decreases the carcinogen concentrations of ethylnitrosourea, dimethylhydrazine, azoxymethane, methylnitrosourea, and hydroxybutylnitrosamine in the brain, spinal cord, intestine, mammary gland, and urinary bladder.
Contraindications
Topical
Topical use is contraindicated in people hypersensitive to eflornithine or to any of the excipients.Throughout clinical trials, data from a limited number of exposed pregnancies indicate that there is no clinical evidence that treatment with Vaniqa adversely affects pregnant women or fetuses.
By mouth
When taken by mouth the risk-benefit should be assessed in people with impaired renal function or pre-existing hematologic abnormalities, as well as those with eighth-cranial-nerve impairment.
Adequate and well-controlled studies with eflornithine have not been performed regarding pregnancy in humans. Eflornithine should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. However, since African trypanosomiasis has a high mortality rate if left untreated, treatment with eflornithine may justify any potential risk to the fetus.
Side effects
Eflornithine is not genotoxic; no tumour-inducing effects have been observed in carcinogenicity studies, including one photocarcinogenicity study. No teratogenic effects have been detected.
Topical
The topical form of elflornithine is sold under the brand name Vaniqa. The most frequently reported side effect is acne (7–14%). Other side effects commonly (> 1%) reported are skin problems, such as skin reactions from in-growing hair, hair loss, burning, stinging or tingling sensations, dry skin, itching, redness or rash.
Intravenous
The intravenous dosage form of eflornithine is sold under the brand name Ornidyl. Most side effects related to systemic use through injection are transient and reversible by discontinuing the drug or decreasing the dose. Hematologic abnormalities occur frequently, ranging from 10 to 55%. These abnormalities are dose-related and are usually reversible. Thrombocytopenia is thought to be due to a production defect rather than to peripheral destruction. Seizures were seen in approximately 8% of patients, but may be related to the disease state rather than the drug. Reversible hearing loss has occurred in 30–70% of patients receiving long-term therapy (more than 4–8 weeks of therapy or a total dose of >300 grams); high-frequency hearing is lost first, followed by middle- and low-frequency hearing. Because treatment for African trypanosomiasis is short-term, patients are unlikely to experience hearing loss.
Interactions
Topical
No interaction studies with the topical form have been performed.
Mechanism of action
Description
Eflornithine is a "suicide inhibitor," irreversibly binding to ornithine decarboxylase (ODC) and preventing the natural substrate ornithine from accessing the active site (Figure 1). Within the active site of ODC, eflornithine undergoes decarboxylation with the aid of cofactor pyridoxal 5-phosphate (PLP). Because of its additional difluoromethyl group in comparison to ornithine, eflornithine is able to bind to a neighboring Cys-360 residue, permanently remaining fixated within the active site.During the reaction, eflornithines decarboxylation mechanism is analogous to that of ornithine in the active site, where transamination occurs with PLP followed by decarboxylation. During the event of decarboxylation, the fluoride atoms attached to the additional methyl group pull the resulting negative charge from the release of carbon dioxide, causing a fluoride ion to be released. In the natural substrate of ODC, the ring of PLP accepts the electrons that result from the release of CO2.
The remaining fluoride atom that resides attached to the additional methyl group creates an electrophilic carbon that is attacked by the nearby thiol group of Cys-360, allowing eflornithine to remain permanently attached to the enzyme following the release of the second fluoride atom and transimination.
Evidence
The reaction mechanism of Trypanosoma bruceis ODC with ornithine was characterized by UV-VIS spectroscopy in order to identify unique intermediates that occurred during the reaction. The specific method of multiwavelength stopped-flow spectroscopy utilized monochromatic light and fluorescence to identify five specific intermediates due to changes in absorbance measurements. The steady-state turnover number, kcat, of ODC was calculated to be 0.5 s−1 at 4 °C. From this characterization, the rate-limiting step was determined to be the release of the product putrescine from ODCs reaction with ornithine.
In studying the hypothetical reaction mechanism for eflornithine, information collected from radioactive peptide and eflornithine mapping, high pressure liquid chromatography, and gas phase peptide sequencing suggested that Lys-69 and Cys-360 are covalently bound to eflornithine in T. brucei ODCs active site. Utilizing fast-atom bombardment mass spectrometry (FAB-MS), the structural conformation of eflornithine following its interaction with ODC was determined to be (S)-((2-(1-pyrroline-methyl) cysteine, a cyclic imine adduct. Presence of this particular product was supported by the possibility to further reduce the end product to (S)-((2-pyrrole) methyl) cysteine in the presence of NaBH4 and oxidize the end product to (S)-((2-pyrrolidine) methyl) cysteine (Figure 2).
Active site
Eflornithines suicide inhibition of ODC physically blocks the natural substrate ornithine from accessing the active site of the enzyme (Figure 3). There are two distinct active sites formed by the homodimerization of ornithine decarboxylase. The size of the opening to the active site is approximately 13.6 Å. When these openings to the active site are blocked, there are no other ways through which ornithine can enter the active site. During the intermediate stage of eflornithine with PLP, its position near Cys-360 allows an interaction to occur. As the phosphate of PLP is stabilized by Arg 277 and a Gly-rich loop (235-237), the difluoromethyl group of eflornithine is able to interact and remain fixated to both Cys-360 and PLP prior to transimination.
As shown in the figure, the pyrroline ring interferes with ornithines entry (Figure 4). Eflornithine will remain permanently bound in this position to Cys-360. As ODC has two active sites, two eflornithine molecules are required to completely inhibit ODC from ornithine decarboxylation.
History
Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth, as well as in the treatment of African trypanosomiasis (sleeping sickness), especially the West African form (Trypanosoma brucei gambiense).
Hirsutism
In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.
Sleeping sickness treatment
The drug was registered for the treatment of gambiense sleeping sickness on November 28, 1990. However, in 1995 Aventis (now Sanofi-Aventis) stopped producing the drug, whose main market was African countries, because it did not make a profit.In 2001, Aventis and the WHO formed a five-year partnership, during which more than 320,000 vials of pentamidine, over 420,000 vials of melarsoprol, and over 200,000 bottles of eflornithine were produced by Aventis, to be given to the WHO and distributed by the association Médecins sans Frontières (also known as Doctors Without Borders) in countries where sleeping sickness is endemic.
According to Médecins sans Frontières, this only happened after "years of international pressure," and coinciding with the period when media attention was generated because of the launch of another eflornithine-based product (Vaniqa, for the prevention of facial-hair in women), while its life-saving formulation (for sleeping sickness) was not being produced.
From 2001 (when production was restarted) through 2006, 14 million diagnoses were made. This greatly contributed to stemming the spread of sleeping sickness, and to saving nearly 110,000 lives.
Society and culture
Available forms
Vaniqa is a cream, which is white to off-white in colour. It is supplied in tubes of 30 g and 60 g in Europe. Vaniqa contains 15% w/w eflornithine hydrochloride monohydrate, corresponding to 11.5% w/w anhydrous eflornithine (EU), respectively 13.9% w/w anhydrous eflornithine hydrochloride (U.S.), in a cream for topical administration.
Ornidyl, intended for injection, was supplied in the strength of 200 mg eflornithine hydrochloride per ml.
Market
Vaniqa, granted marketing approval by the US FDA, as well as by the European Commission among others, is currently the only topical prescription treatment that slows the growth of facial hair. Besides being a non-mechanical and non-cosmetic treatment, it is the only non-hormonal and non-systemic prescription option available for women with facial hirsutism. Vaniqa is marketed by Almirall in Europe, SkinMedica in the US, Triton in Canada, Medison in Israel, and Menarini in Australia.Ornidyl, the injectable form of eflornithine hydrochloride, is licensed by Sanofi-Aventis, but is currently discontinued in the US.
In other animals
Eflornithine is effective in mice. Bacchi et al. 1980 found the drug to be curative in T. b. brucei infection of mouse and it is generally without toxicity. Klug et al. 2016 are of the opinion that this demonstrates good promise for oral treatment. However although Jansson et al. 2008 also effectively treated mice with it they found the pharmacokinetics of oral administration in rats very negative. Brun et al. 2010 are of the opinion that Janssons results have killed the prospects for oral treatment.
References
External links
History of Drug Development for African Sleeping Sickness |
Bromocriptine | Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinsons disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.
It was patented in 1968 and approved for medical use in 1975.
Medical uses
Bromocriptine is used to treat acromegaly and conditions associated with hyperprolactinemia like amenorrhea, infertility, hypogonadism, and prolactin-secreting adenomas. It is also used to prevent ovarian hyperstimulation syndrome and to treat Parkinsons disease.Since the late 1980s it has been used, off-label, to reduce the symptoms of cocaine withdrawal but the evidence for this use is poor.A quick-release formulation of bromocriptine, Cycloset, is also used to treat type 2 diabetes. When administered within 2 hours of awakening, it increases hypothalamic dopamine level and as a result decreases hepatic glucose production. It therefore acts as an adjunct to diet and exercise to improve glycemic control.
Side effects
Most frequent side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre. Vasospasms with serious consequences such as myocardial infarction and stroke that have been reported in connection with the puerperium, appear to be extremely rare events. Peripheral vasospasm (of the fingers or toes) can cause Raynauds Phenomenon.
Bromocriptine use has been anecdotally associated with causing or worsening psychotic symptoms (its mechanism is in opposition of most antipsychotics, whose mechanisms generally block dopamine receptors). It should be understood, however, that the greater affinity bromocriptine and many similar antiparkinsons drugs have for the D2S receptor form (considered to be mostly present at inhibitory D2 autoreceptor locatations) relative to the D2L form, sufficiently low partial agonist activity (ie where a molecule binding to a receptor induces limited effects while preventing a stronger ligand like dopamine from binding), and, possibly, the functional selectivity of a particular drug may generate antidopaminergic effects that are more similar than oppositional in nature to antipsychotics.
Pulmonary fibrosis has been reported when bromocriptine was used in high doses for the treatment of Parkinsons disease.Use to suppress milk production after childbirth was reviewed in 2014 and it was concluded that in this context a causal association with serious cardiovascular, neurological or psychiatric events could not be excluded with an overall incidence estimated to range between 0.005% and 0.04%. Additional safety precautions and stricter prescribing rules were suggested based on the data. It is a bile salt export pump inhibitor.After long-term use of dopamine agonists, a withdrawal syndrome may occur during dose reduction or discontinuation with the following possible side effects: anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. For some individuals, these withdrawal symptoms are short-lived and they make a full recovery, for others a protracted withdrawal syndrome may occur with withdrawal symptoms persisting for months or years.
Pharmacology
Pharmacodynamics
Bromocriptine is a partial agonist of the dopamine D2 receptor. It also interacts with other dopamine receptors and with various serotonin and adrenergic receptors. Bromocriptine has additionally been found to inhibit the release of glutamate by reversing the GLT1 glutamate transporter.As an antagonist of the serotonin 5-HT2B receptor, bromocriptine has not been associated with cardiac valvulopathy. This is in contrast to other ergolines acting instead as 5-HT2B receptor agonists such as cabergoline and pergolide but is similar to lisuride which likewise acts as a 5-HT2B receptor antagonist.
Chemistry
Like all ergopeptides, bromocriptine is a cyclol; two peptide groups of its tripeptide moiety are crosslinked, forming the >N-C(OH)< juncture between the two rings with the amide functionality.
Bromocriptine is a semisynthetic derivative of a natural ergot alkaloid, ergocryptine (a derivative of lysergic acid), which is synthesized by bromination of ergocryptine using N-bromosuccinimide.
History
Bromocriptine was discovered by scientists at Sandoz in 1965 and was first published in 1968; it was first marketed under the brand name Parlodel.A quick-release formulation of bromocriptine was approved by the FDA in 2009.
Society and culture
Brand names
As of July 2017, bromocriptine was marketed under many brand names worldwide, including Abergin, Barlolin, Brameston, Brocriptin, Brom, Broma-Del, Bromergocryptine, Bromergon, Bromicon, Bromocorn, Bromocriptin, Bromocriptina, Bromocriptine, Bromocriptine mesilate, Bromocriptine mesylate, Bromocriptine methanesulfonate, Bromocriptini mesilas, Bromocriptinmesilat, Bromodel, Bromokriptin, Bromolac, Bromotine, Bromtine, Brotin, Butin, Corpadel, Cripsa, Criptine, Criten, Cycloset, Degala, Demil, Deparo, Deprolac, Diacriptin, Dopagon, Erenant, Grifocriptina, Gynodel, kirim, Kriptonal, Lactodel, Medocriptine, Melen, Padoparine, Palolactin, Parlodel, Pravidel, Proctinal, Ronalin, Semi-Brom, Serocriptin, Serocryptin, Suplac, Syntocriptine, Umprel, Unew, Updopa, Upnol B, and Volbro.As of July 2017 it was also marketed as a combination drug with metformin as Diacriptin-M, and as a veterinary drug under the brand Pseudogravin.
References
External links
MedlinePlus DrugInfo medmaster-a682079
https://www.drugs.com/pro/bromocriptine.html |
Mitomycins | The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.
Biosynthesis
In general, the biosynthesis of all mitomycins proceeds via combination of 3-amino-5-hydroxybenzoic acid (AHBA), D-glucosamine, and carbamoyl phosphate, to form the mitosane core, followed by specific tailoring steps. The key intermediate, AHBA, is a common precursor to other anticancer drugs, such as rifamycin and ansamycin.
Specifically, the biosynthesis begins with the addition of phosphoenolpyruvate (PEP) to erythrose-4-phosphate (E4P) with a yet undiscovered enzyme, which is then ammoniated to give 4-amino-3-deoxy-D-arabino heptulosonic acid-7-phosphate (aminoDHAP). Next, DHQ synthase catalyzes a ring closure to give 4-amino3-dehydroquinate (aminoDHQ), which then undergoes a double oxidation via aminoDHQ dehydratase to give 4-amino-dehydroshikimate (aminoDHS). The key intermediate, 3-amino-5-hydroxybenzoic acid (AHBA), is made via aromatization by AHBA synthase.
Synthesis of the key intermediate, 3-amino-5-hydroxy-benzoic acid.
The mitosane core is synthesized as shown below via condensation of AHBA and D-glucosamine, although no specific enzyme has been characterized that mediates this transformation. Once this condensation has occurred, the mitosane core is tailored by a variety of enzymes. Both the sequence and the identity of these steps are yet to be determined.
Complete reduction of C-6 – Likely via F420-dependent tetrahydromethanopterin (H4MPT) reductase and H4MPT:CoM methyltransferase
Hydroxylation of C-5, C-7 (followed by transamination), and C-9a. – Likely via cytochrome P450 monooxygenase or benzoate hydroxylase
O-Methylation at C-9a – Likely via SAM dependent methyltransferase
Oxidation at C-5 and C8 – Unknown
Intramolecular amination to form aziridine – Unknown
Carbamoylation at C-10 – Carbamoyl transferase, with carbamoyl phosphate (C4P) being derived from L-citrulline or L-arginine
Biological effects
In the bacterium Legionella pneumophila, mitomycin C induces competence for transformation. Natural transformation is a process of DNA transfer between cells, and is regarded as a form of bacterial sexual interaction. In the fruit fly Drosophila melanogaster, exposure to mitomycin C increases recombination during meiosis, a key stage of the sexual cycle. In the plant Arabidopsis thaliana, mutant strains defective in genes necessary for recombination during meiosis and mitosis are hypersensitive to killing by mitomycin C.
Medicinal uses and research
Mitomycin C has been shown to have activity against stationary phase persisters caused by Borrelia burgdorferi, a factor in lyme disease. Mitomycin C is used to treat pancreatic and stomach cancer, and is under clinical research for its potential to treat gastrointestinal strictures, wound healing from glaucoma surgery, corneal excimer laser surgery and endoscopic dacryocystorhinostomy.
== References == |
Insulin lispro | Insulin lispro, sold under the brand name Humalog among others, is a modified type of medical insulin used to treat type 1 and type 2 diabetes. Typically it is taken around the time of eating. It is used by injection under the skin or within an insulin pump. Onset of effects typically occurs within 30 minutes and lasts about 5 hours. Often a longer-acting insulin like insulin NPH is also needed.Common side effects include low blood sugar. Other serious side effects may include low blood potassium. Use in pregnancy and breastfeeding is generally safe. It works the same as human insulin by increasing the amount of glucose that tissues take in and decreasing the amount of glucose made by the liver.Insulin lispro was first approved for use in the United States in 1996. It is a manufactured form of human insulin where an amino acid has been switched. In 2019, it was the 65th most commonly prescribed medication in the United States, with more than 11 million prescriptions.
Medical uses
Insulin lispro is used to treat people with type 1 diabetes or type 2 diabetes. People doing well on regular insulin should not generally be changed to insulin lispro.
Side effects
Common side effects include skin irritation at the site of injection, hypoglycemia, hypokalemia, and lipodystrophy. Other serious side effects include anaphylaxis, and hypersensitivity reactions.
Contraindications
Do not administer insulin lispro during episodes of hypoglycemia, or if a person has a hypersensitivity to insulin lispro or any of its excipients.
Mechanism of action
Through recombinant DNA technology, the final lysine and proline residues on the C-terminal end of the B-chain are reversed. This modification does not alter receptor binding, but blocks the formation of insulin dimers and hexamers. This allows larger amounts of active monomeric insulin to be immediately available for postprandial injections.
Chemistry
It is a manufactured form of human insulin where the amino acids lysine and proline have been switched at the end of the B chain of the insulin molecule. This switch of amino acids mimics Insulin-like growth factor 1 which also has lysine (K) and proline (P) in that order at positions 27 and 28.
Cost
In the United States, the price of for a vial of Humalog increased from US$35 in 2001 to US$234 2015, or US$10.06 and US$29.36 per 100 units. In April 2019, Eli Lilly and Company announced they would produce a version selling for US$137.35 per vial, about half the then-current cost. The chief executive said that this was a contribution "to fix the problem of high out-of-pocket costs for Americans living with chronic conditions", but Patients for Affordable Drugs Now said this was just a public relations move, as "other countries pay US$20 for a vial of insulin."The cost in the United Kingdom was between £1.66 and £1.96 per 100 units, in 2017.
History
Insulin lispro (brand name Humalog) was granted marketing authorization in the European Union in April 1996, and it was approved for use in the United States in June 1996.Insulin lispro (brand name Liprolog) was granted marketing authorization in the European Union in May 1997, and again in August 2001.Combination drugs combining insulin lispro and other forms of insulin were approved for use in the United States in December 1999.Insulin lispro Sanofi was granted marketing authorization as a biosimilar in the European Union in July 2017.Insulin lispro injection (brand name Admelog) was approved for use in the United States in December 2017.In January 2020, the Committee for Medicinal Products for Human Use (CHMP) in the European Union recommended granting of a marketing authorization for insulin lispro acid (brand name Lyumjev) for the treatment of diabetes mellitus in adults. Insulin lispro (Lyumjev) was approved for use in the European Union in March 2020, and in the United States on 18 June 2020 as reported by Medscape.
References
External links
"Insulin lispro". Drug Information Portal. U.S. National Library of Medicine. |
Methocarbamol | Methocarbamol, sold under the brand name Robaxin among others, is a medication used for short-term musculoskeletal pain. It may be used together with rest, physical therapy, and pain medication. It is less preferred in low back pain. It has limited use for rheumatoid arthritis and cerebral palsy. Effects generally begin within half an hour. It is taken by mouth or injection into a vein.Common side effect include headaches, sleepiness, and dizziness. Serious side effects may include anaphylaxis, liver problems, confusion, and seizures. Use is not recommended in pregnancy and breastfeeding. Because of risk of injury, skeletal muscle relaxants should generally be avoided in geriatric patients. Methocarbamol is a centrally acting muscle relaxant. How it works is unclear, but it does not appear to affect muscles directly.Methocarbamol was approved for medical use in the United States in 1957. It is available as a generic medication. It is relatively inexpensive as of 2016. In 2019, it was the 136th most commonly prescribed medication in the United States, with more than 4 million prescriptions.
Medical use
Methocarbamol is a muscle relaxant used to treat acute, painful musculoskeletal spasms in a variety of musculoskeletal conditions. However, there is limited and inconsistent published research on the medications efficacy and safety in treating musculoskeletal conditions, primarily neck and back pain.Methocarbamol injection may have a beneficial effect in the control of the neuromuscular spasms of tetanus. It does not, however, replace the current treatment regimen.It is not useful in chronic neurological disorders, such as cerebral palsy or other dyskinesias.Currently, there is some suggestion that muscle relaxants may improve the symptoms of rheumatoid arthritis; however, there is insufficient data to prove its effectiveness as well as answer concerns regarding optimal dosing, choice of muscle relaxant, adverse effects, and functional status.
Comparison to similar agents
The clinical effectiveness of methocarbamol compared to other muscle relaxants is not well-known. One trial of methocarbamol versus cyclobenzaprine, a well-studied muscle relaxant, in those with localized muscle spasm found there was no significant differences in their effects on improved muscle spasm, limitation of motion, or limitation of daily activities.
Contraindications
There are few contraindications to methocarbamol. They include:
Hypersensitivity to methocarbamol or to any of the injection components.
For the injectable form, suspected kidney failure or renal pathology, due to large content of polyethylene glycol 300 that can increase pre-existing acidosis and urea retention.
Side effects
Methocarbamol is a centrally acting skeletal muscle relaxant that has significant adverse effects, especially on the central nervous system.Potential side effects of methocarbamol include:
Most commonly drowsiness, blurred vision, headache, nausea, and skin rash.
Possible clumsiness (ataxia), upset stomach, flushing, mood changes, trouble urinating, itchiness, and fever.
Both tachycardia (fast heart rate) and bradycardia (slow heart rate) have been reported.
Hypersensitivity reactions and anaphylatic reactions are also reported.
May cause respiratory depression when combined with benzodiazepines, barbiturates, codeine, or other muscle relaxants.
May cause urine to turn black, blue or green.While the product label states that methocarbamol can cause jaundice, there is minimal evidence to suggest that methocarbamol causes liver damage. During clinical trials of methocarbamol, there were no laboratory measurements of liver damage indicators, such as serum aminotransferase (AST/ALT) levels, to confirm hepatotoxicity. Although unlikely, it is impossible to rule out that methocarbamol may cause mild liver injury with use.
Elderly
Skeletal muscle relaxants are associated with an increased risk of injury among older adults. Methocarbamol appeared to be less sedating than other muscle relaxants, most notably cyclobenzaprine, but had similar increased risk of injury. Methocarbamol is cited along with "most muscle relaxants" in the 2012 Beers Criteria as being "poorly tolerated by older adults, because of anticholinergic adverse effects, sedation, increased risk of fractures," noting that "effectiveness dosages tolerated by older adults is questionable."
Pregnancy
Methocarbamol is labeled by the FDA as a pregnancy category C medication. The teratogenic effects of the medication are not known and should be given to pregnant women only when clearly indicated.
Overdose
There is limited information available on the acute toxicity of methocarbamol. Overdose is used frequently in conjunction with CNS depressants such as alcohol or benzodiazepines and will have symptoms of nausea, drowsiness, blurred vision, hypotension, seizures, and coma. There are reported deaths with an overdose of methocarbamol alone or in the presence of other CNS depressants.
Abuse
Unlike other carbamates such as meprobamate and its prodrug carisoprodol, methocarbamol has greatly reduced abuse potential. Studies comparing it to the benzodiazepine lorazepam and the antihistamine diphenhydramine, along with placebo, find that methocarbamol produces increased "liking" responses and some sedative-like effects; however, at higher doses dysphoria is reported. It is considered to have an abuse profile similar to, but weaker than, lorazepam.
Interactions
Methocarbamol may inhibit the effects of pyridostigmine bromide. Therefore, methocarbamol should be used with caution in those with myasthenia gravis taking anticholinesterase medications.Methocarbamol may disrupt certain screening tests as it can cause color interference in laboratory tests for 5-hydroxy-indoleacetic acid (5-HIAA) and in urinary testing for vanillylmandelic acid (VMA) using the Gitlow method.
Pharmacology
Mechanism of action
The mechanism of action of methocarbamol has not currently been established. Its effect is thought to be localized to the central nervous system rather than a direct effect on skeletal muscles. It has no effect on the motor end plate or the peripheral nerve fiber. The efficacy of the medication is likely related to its sedative effect. Alternatively, methocarbamol may act via inhibition of acetylcholinesterase, similarly to carbamate.
Pharmacokinetics
In healthy individuals, the plasma clearance of methocarbamol ranges between 0.20 and 0.80 L/h/kg. The mean plasma elimination half-life ranges between 1 and 2 hours, and the plasma protein binding ranges between 46% and 50%. The elimination half-life was longer in the elderly, those with kidney problems, and those with liver problems.
Metabolism
Methocarbamol is the carbamate derivative of guaifenesin, but does not produce guaifenesin as a metabolite, because the carbamate bond is not hydrolyzed metabolically; its metabolism is by Phase I ring hydroxylation and O-demethylation, followed by Phase II conjugation. All the major metabolites are unhydrolyzed carbamates. Small amounts of unchanged methocarbamol are also excreted in the urine.
Society and culture
Methocarbamol was approved as a muscle relaxant for acute, painful musculoskeletal conditions in the United States in 1957. Muscle relaxants are widely used to treat low back pain, one of the most frequent health problems in industrialized countries. Currently, there are more than 3 million prescriptions filled yearly. Methocarbamol and orphenadrine are each used in more than 250,000 U.S. emergency department visits for lower back pain each year. In the United States, low back pain is the fifth most common reason for all physician visits and the second most common symptomatic reason. In 80% of primary care visits for low back pain, at least one medication was prescribed at the initial office visit and more than one third were prescribed two or more medications. The most commonly prescribed drugs for low back pain included skeletal muscle relaxants. Cyclobenzaprine and methocarbamol are on the U.S. Medicare formulary, which may account for the higher use of these products.
Economics
The generic formulation of the medication is relatively inexpensive, costing less than the alternative metaxalone in 2016.
Marketing
Methocarbamol without other ingredients is sold under the brand name Robaxin in the U.K., U.S., Canada and South Africa; it is marketed as Lumirelax in France, Ortoton in Germany and many other names worldwide. In combination with other active ingredients it is sold under other names: with acetaminophen (paracetamol), under trade names Robaxacet and Tylenol Body Pain Night; with ibuprofen as Robax Platinum; with acetylsalicylic acid as Robaxisal in the U.S. and Canada. However, in Spain the tradename Robaxisal is used for the paracetamol combination instead of Robaxacet. These combinations are also available from independent manufacturers under generic names.
Research
Although opioids are a typically first line in treatment of severe pain, several trials suggest that methocarbamol may improve recovery and decrease hospital length of stay in those with muscles spasms associated with rib fractures. However, methocarbamol was less useful in the treatment of acute traumatic pain in general.Long-term studies evaluating the risk of development of cancer in using methocarbamol have not been performed. There are currently no studies evaluating the effect of methocarbamol on mutagenesis or fertility.The safety and efficacy of methocarbamol has not been established in pediatric individuals below the age of 16 except in tetanus.
References
External links
"Methocarbamol". Drug Information Portal. U.S. National Library of Medicine. |
Brimonidine/timolol | Brimonidine/timolol, sold under the brand name Combigan, is a fixed-dose combination medication eye drop indicated for the treatment of glaucoma. It is a combination of brimonidine (an α2 adrenergic agonist) and timolol (a β adrenergic blocker), in concentrations of 0.2% and 0.5% respectively. Both substances work by decreasing the synthesis of aqueous humor.
Combigan is marketed and sold by Allergan. It has been approved by regulatory authorities in Europe, Canada, and the United States for reduction of intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. Although clinical studies showed that the IOP-lowering effect was slightly greater (1-2 mmHg) with concomitant administration of 0.5% timolol twice daily and 0.2% brimonidine tartrate three times daily than with Combigan twice daily, the safety profile of latter was more favorable.
Medical uses
Combigan (brimonidine tartrate/timolol maleate) 0.2%/0.5% is used to reduce IOP in patients with glaucoma or ocular hypertension who need adjunctive or replacement therapy. The recommended dosage is one drop administered to the affected eye(s) twice a day, approximately every 12 hours.Both brimonidine 0.2% and timolol 0.5% are commonly used ophthalmic solutions for lowering IOP. Timolol 0.5% is dosed one drop once or twice daily, while brimonidine 0.2% is dosed one drop three times daily. For patients who need more than one medication to lower IOP, the fixed combination product offers the advantages of reducing the number of drops and medication bottles, improving patient compliance, and decreasing ocular exposure to preservatives in ophthalmic solutions.
Adverse effects
The most common adverse effects affecting 5 to 15% of the patients include allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging. 1 to 5% of the patients in clinical trials experienced asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial punctate keratitis, and visual disturbance.
Contraindications
Contraindications of Combigan include the following: reactive airway disease including bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, secondary or third degree atrioventricular block, overt cardiac failure, cardiogenic shock, age less than 2 years, and hypersensitivity to any component of Combigan.
Pharmacology
Combigan is composed of brimonidine, a selective alpha-2 adrenergic receptor agonist, and timolol, a non-selective beta-adrenergic receptor inhibitor. Elevated IOP is considered the only modifiable risk factor in the pathogenesis of glaucoma. Brimonidine exerts its ocular hypotensive effect by decreasing aqueous humor production and increasing uveoscleral outflow, while timolol acts by reducing aqueous humor production. Combigan has a fast onset of action, and the peak IOP lowering effect occurs at two hours after administration.
Preclinical studies
No carcinogenic effects were found with brimonidine tartrate in mice or rats. With timolol maleate, 300 mg/kg/day in rats (equivalent to about 42,000 times systemic exposure following the maximum recommended ocular dose in human [MRHOD]) was associated with significantly increased incidence of adrenal pheochromocytomas in a two-year study; in a lifetime study in mice, 500 mg/kg/day (equivalent to about 71,000 times systemic exposure following the MRHOD) but not 5 or 50 mg/kg/day (about 700 or 7,000 times systemic exposure following the MRHOD) of timolol maleate was associated with significantly increased incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas.
Neither brimonidine tartrate nor timolol maleate was mutagenic in in vitro and in vivo studies. Reproduction and fertility studies in rats did not reveal any adverse effects on male or female fertility with brimonidine tartrate or timolol maleate.
Clinical trials
Two prospective, randomized, double-blinded, phase III clinical trials were conducted at 53 sites in the United States to compare the IOP-lowering efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol maleate fixed combination twice daily with 0.2% brimonidine tartrate three times daily or 0.5% timolol maleate twice daily in patients aged 18 or older who had ocular hypertension or glaucoma. When assessed over a 3-month period, pooled results from a total of 1159 patients showed significantly greater mean IOP decrease from baseline with the brimonidine/timolol combination (4.9-7.6 mmHg) than with brimonidine monotherapy (3.1-5.5 mmHg) or timolol monotherapy (4.3-6.2 mmHg) across all follow-up visits. Similar efficacy results were reported during 12-month follow-up: mean IOP decrease from baseline was 4.4-7.6 mmHg with brimonidine/timolol combination, compared to 2.7-5.5 mmHg with brimonidine and 3.9-6.2 mmHg with timolol. The incidence of treatment-related adverse events with the brimonidine/timolol combination was lower than that with brimonidine monotherapy but higher than that with timolol monotherapy.A 12-week prospective, randomized, double-blinded study in 371 glaucoma and ocular hypertension patients with inadequate IOP control on monotherapy compared the efficacy and safety of 0.2% brimonidine tartrate/0.5% timolol fixed combination twice daily with the concomitant use of 0.2% brimonidine tartrate twice daily and timolol 0.5% twice daily. The IOP-lowering effect of the fixed combination group was shown to be non-inferior to that of concomitant therapy. Incidence of adverse events was similar between groups.
Society and culture
Commercial aspects
Allergan is the New Drug Application (NDA) holder of brimonidine tartrate/timolol maleate ophthalmic solution 0.2%/0.5%, which is sold under the COMBIGAN® trademark. The New Drug Application (NDA) for Combigan was approved by the US Food and Drug Administration (FDA) in October 2007. Allergan, Plc is a global specialty pharmaceutical company which develops, manufactures, markets and distributes branded pharmaceutical products, aesthetic products, biosimilar and over-the-counter pharmaceutical products. In 2015, Actavis, Plc acquired Allergan, Inc. for approximately $77 billion and subsequently changed its name to Allergan, Plc. In 2015, the global revenues for Alphagan and Combigan totaled $411.1 million ($285 million from the US market), which accounted for 2.7% of Allergans total net revenues.Allergan holds at least six active patents protecting Combigan from generic competition. Several generic companies challenged the validity of the patents and filed Abbreviated New Drug Applications (ANDA) seeking market entry. Allergan responded by filing a lawsuit against the ANDA filers. In Allergan, Inc. v. Sandoz, Inc., the US Court of Appeals for the Federal Circuit ruled that Allergans composition-related patent claims were invalid based on obviousness, because brimonidine and timolol had already been marketed in the claimed concentrations. However, Allergans method claim (US Patent No. 7,030,149), which states "reducing the number of daily topical ophthalmic doses of brimonidine administered topically to an eye of a person in need thereof for the treatment of glaucoma or ocular hypertension from 3 to 2 times a day without loss of efficacy", was held to be non-obvious. As a result, generic companies are prevented from marketing generic versions of Combigan until its patent expiration in 2022.Combigan is supplied in 5 mL, 10 mL, and 15 mL bottles. In the United States, the cash price of one 5-mL eye dropper of Combigan ranges from $160 to $190.
== References == |
Vincristine | Vincristine, also known as leurocristine and marketed under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkins disease, neuroblastoma, and small cell lung cancer among others. It is given intravenously.Most people experience some side effects from vincristine treatment. Commonly it causes a change in sensation, hair loss, constipation, difficulty walking, and headaches. Serious side effects may include neuropathic pain, lung damage, or low white blood cells which increases the risk of infection. Use during pregnancy may result in birth defects. It works by stopping cells from dividing properly. It is vital that it not be given intrathecally, as this causes paralysis and in most cases, death.Vincristine was first isolated in 1961. It is on the World Health Organizations List of Essential Medicines. It is a vinca alkaloid that can be obtained from the Madagascar periwinkle Catharanthus roseus.
Medical uses
Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkins lymphoma as part of the chemotherapy regimen CHOP R-CVP, Hodgkins lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen in acute lymphoblastic leukemia (ALL), and in treatment for nephroblastoma. It is also used to induce remission in ALL with dexamethasone and L-Asparaginase, and in combination with prednisone to treat childhood leukemia. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP).
Side effects
The main side effects of vincristine are chemotherapy-induced peripheral neuropathy, hyponatremia, constipation, and hair loss.
Vincristine induced neuropathy is the main dose limiting side effect. Chemotherapy-induced peripheral neuropathy can be severe, and may be a reason to reduce or avoid using vincristine. The symptoms of this are progressive and enduring tingling numbness, pain and hypersensitivity to cold, beginning in the hands and feet and sometimes affecting the arms and legs. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) should avoid the taking of vincristine. A 2021 study has suggested that Anakinra can reduce the neuropathy.Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death. Several patients have survived after aggressive and immediate intervention. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.
Children may do better following this injury. One child, who was aggressively treated at the time of the injection, recovered almost completely with only mild neurological deficits.
A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine and methotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.The overuse of vincristine may also lead to drug resistance by overexpression of the p-glycoprotein pump (Pgp). There is an attempt to overcome resistance by the addition of derivatives and substituents to the vincristine molecule.
Mechanism of action
Vincristine works partly by binding to the tubulin protein, stopping the tubulin dimers from polymerizing to form microtubules, causing the cell to be unable to separate its chromosomes during the metaphase. The cell then undergoes apoptosis.
The vincristine molecule inhibits leukocyte production and maturation. A downside, however, to Vincristine is that it does not only affect the division of cancer cells. It affects all rapidly dividing cell types, making it necessary for the very specific administration of the drug.
Pharmacology
The natural extraction of vincristine from Catharanthus roseus is produced at a percent yield of less than 0.0003%. For this reason, alternate methods to produce synthetic vincristine are being used. Vincristine is created through the semi-synthesis coupling of indole alkaloids vindoline and catharanthine in the vinca plant. It can also now be synthesized through a stereocontrolled total synthesis technique which retains the correct stereochemistry at C18 and C2. The absolute stereochemistry at these carbons is responsible for vincristines anticancer activity.The liposome encapsulation of vincristine enhances the efficacy of the vincristine drug while simultaneously decreasing the neurotoxicity associated with it. Liposome encapsulation increases vincristines plasma concentration and circulation lifetime in the body, and allows the drug to enter cells more easily.
History
Having been used as a folk remedy for centuries, studies in the 1950s revealed that the rosy periwinkle Catharanthus roseus contained over 120 alkaloids, many of which are biologically active, the two most significant being vincristine and vinblastine. Its use for being anti-tumor, anti-mutagenic are well documented in ancient system of medicine of Ayurveda and folk culture of Madagascar and Southern Africa. Although it was not found to be anti-diabetic in double blinded controlled studies. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone marrow) led to its study in mice with leukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skellysolve-B defatting agent and an acid benzene extract led to a fraction termed "fraction A". This fraction was further treated with aluminium oxide, chromatography, trichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.Vincristine was approved by the US Food and Drug Administration (FDA) in July 1963 under the trade name Oncovin and was marketed by Eli Lilly Company. The drug was initially discovered by a team at Lilly Research Laboratories where it was demonstrated that vincristine cured artificially induced leukemia in mice. Vincristine also induced remission of acute leukemias of childhood.Production of vincristine required one ton of dried periwinkle leaves to produce one ounce of vincristine. Periwinkle was grown on a ranch in Texas.
Society and culture
Suppliers
Until recently, two generic drug makers were suppliers of vincristine in the United States: Teva and Pfizer. In 2019 Teva stopped producing vincristine, leaving Pfizer as the only company in production. Teva has said that they will restart production, and expect it to be available in 2020.
Shortage
In October 2019 an impending shortage was reported; no adequate substitute is known for treating childhood-cancers. By 2022, the shortage of vincristine continued.
Controversy
Pharmaceutical bioprospecting
Vincristines origins are debated as an example of pharmaceutical bioprospecting in the fields of ethnobotany and ethnomedicine. Some consider the Catharanthus roseus plant from which vincristine is derived, and its folk remedies to be endemic to Madagascar, and that Madagascar was denied royalties from vincristine sales. However, Catharanthus roseus has a documented history in folk medicine treatments in other locations. In 1963, Lilly researchers acknowledged that the plant was used in Brazil to treat hemorrhage, scurvy, toothaches, and chronic wounds; in the British West Indies to treat diabetic ulcers; and in the Philippines and South Africa as an oral hypoglycemic agent – but not as a treatment for cancer.Catharanthus roseus has been a cosmopolitan species since before the Industrial Revolution and the plants use in folk remedies suggested general bioactivity for diabetes treatment, not cancer. In the mid-eighteenth century, botanist Judith Sumner recorded the arrival of Catharanthus roseus at Londons Chelsea Physic Garden from the Jardin des plantes in Paris. Its unclear how the plant first arrived in Paris and the details of its origins in Madagascar beyond reports of its transport from Madagascar by early European explorers. Vincristine was initially distributed at cost to increase accessibility, though later switched to a for-profit model to recover the costs of production and development. According to Michael Brown, vincristine may not be a tidy example of pharmaceutical bioprospecting, but it demonstrates how pharmaceuticals with a history of use in folk medicine have intellectual property claims which are difficult to untangle.Since ethnobotanical studies and pharmaceutical bioprospecting depend on traditional knowledge from indigenous communities, the process of sourcing botanical and biological knowledge raises issues of the proper representation of the indigenous and local knowledge.
Vincristine and confusion with other drugs in administration
Vincristine has been involved in a number of medical errors. If given into the spine (intrathecal) it causes paralysis and usually death. Multiple instances of it being given wrongly, having been confused with other drugs, have occurred.
Research
In 2012, the FDA approved a liposomal formulation of vincristine branded as Marqibo. Marqibo was voluntarily withdrawn from the US market in November, 2021.A nano-particle bound version of vincristine was under development as of 2014.
References
External links
"Vincristine". Drug Information Portal. U.S. National Library of Medicine.
Vincristine and vinblastine
Description and Natural History of the Periwinkle
The Boger Route to (−)-Vindoline |
Dicloxacillin | Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).It was patented in 1961 and approved for medical use in 1968.
Medical uses
Dicloxacillin is used to treat mild-to-moderate staphylococcal infections. To decrease the development of resistance, dicloxacillin is recommended to treat infections that are suspected or proven to be caused by beta-lactamase-producing bacteria.Dicloxacillin is similar in pharmacokinetics, antibacterial activity, and indications to flucloxacillin, and the two agents are considered interchangeable. It is believed to have lower incidence of severe hepatic adverse effects than flucloxacillin, but a higher incidence of renal adverse effects.Dicloxacillin is used for the treatment of infections caused by susceptible bacteria. Specific approved indications include:
Staphylococcal skin infections and cellulitis – including impetigo, otitis externa, folliculitis, boils, carbuncles, and mastitis
Pneumonia (adjunct)
Osteomyelitis, septic arthritis, throat infections, streptococcus
Septicaemia
Empirical treatment for endocarditis
Surgical prophylaxis
Available forms
Dicloxacillin is commercially available as the sodium salt, dicloxacillin sodium, in capsules and as a powder for reconstitution.
Contraindications
Dicloxacillin is contraindicated in those with a previous history of allergy (hypersensitivity/anaphylactic reaction) to any penicillins.
Adverse effects
Common adverse drug reactions (ADRs) associated with the use of dicloxacillin include: diarrhea, nausea, rash, urticaria, pain and inflammation at injection site, superinfection (including candidiasis), allergy, and transient increases in liver enzymes and bilirubin.On rare occasions, cholestatic jaundice (also referred to as cholestatic hepatitis) has been associated with dicloxacillin therapy. The reaction may occur up to several weeks after treatment has stopped, and takes weeks to resolve. The estimated incidence is 1 in 15,000 exposures, and is more frequent in people over 55 years old, females, and those with treatment longer than 2 weeks.It should be used with caution and monitored in the elderly, particularly with intravenous administration, due to a risk of thrombophlebitis.Dicloxacillin can also lower the effectiveness of birth control pills and pass into breast milk.
Interactions
Dicloxacillin has potential interactions with following drugs:
Warfarin
Methotrexate
Tetracyclines
Resistance
Despite dicloxacillin being insensitive to beta-lactamases, some organisms have developed resistance to other narrow-spectrum β-lactam antibiotics including methicillin. Such organisms include methicillin-resistant Staphylococcus aureus (MRSA).
Mechanism of action
Like other β-lactam antibiotics, dicloxacillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria.
Medicinal chemistry
Dicloxacillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the isoxazolyl group on the side chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side-chain steric hindrance. Thus, it is able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamase
See also
Beta-lactam antibiotic
Flucloxacillin
== References == |
Difluprednate | Difluprednate is a corticosteroid, It is chemically a butyrate ester of 6(alpha),9(alpha)-difluoro prednisolone acetate. Accordingly, difluprednate is sometimes abbreviated DFBA, for difluoroprednisolone butyrate acetate.
Approval
On June 24, 2008, the US Food and Drug Administration (FDA) approved difluprednate for the treatment of post-operative ocular inflammation and pain. It is marketed by Alcon under the tradename Durezol.
Clinical trials
Difluprednate ophthalmic emulsion 0.05% is also being studied in other ocular inflammatory diseases, including a phase 3 study evaluating difluprednate for the treatment of anterior uveitis
== References == |
Dimercaprol | Dimercaprol, also called British anti-Lewisite (BAL), is a medication used to treat acute poisoning by arsenic, mercury, gold, and lead. It may also be used for antimony, thallium, or bismuth poisoning, although the evidence for those uses is not very strong. It is given by injection into a muscle.Common side effects include high blood pressure, pain at the site of the injection, vomiting, and fever. It is not recommended for people with peanut allergies as it is typically formulated as a suspension in peanut oil. It is unclear if use in pregnancy is safe for the baby. Dimercaprol is a chelator and works by binding with heavy metals. It has a very pungent odor.
Dimercaprol was first made during World War II. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, and it is an essential drug. It is also used as an antidote to the chemical weapon Lewisite. Nonetheless, because it can have serious adverse effects, researchers have also pursued development of less toxic analogues, such as succimer.
Wilsons disease is a genetic disorder in which copper builds up inside the liver and other tissues. Dimercaprol is a copper chelating agent that has been approved by the FDA to treat Wilsons disease.Dimercaprol also shows effectiveness against snakebite by potently antagonizing the activity of Zn2+-dependent snake venom metalloproteinases in vitro.
Mechanism of action
Arsenic and some other heavy metals act by chelating with adjacent thiol residues on metabolic enzymes, creating a chelate complex that inhibits the affected enzymes activity. Dimercaprol competes with the thiol groups for binding the metal ion, which is then excreted in the urine.Dimercaprol is itself toxic, with a narrow therapeutic range and a tendency to concentrate arsenic in some organs. Other drawbacks include the need to administer it by painful intramuscular injection. Serious side effects include nephrotoxicity and hypertension.
Dimercaprol has been found to form stable chelates in vivo with many other metals including inorganic mercury, antimony, bismuth, cadmium, chromium, cobalt, gold, and nickel. However, it is not necessarily the treatment of choice for toxicity to these metals. Dimercaprol has been used as an adjunct in the treatment of the acute encephalopathy of lead toxicity. It is a potentially toxic drug, and its use may be accompanied by multiple side effects. Although treatment with dimercaprol will increase the excretion of cadmium, there is a concomitant increase in renal cadmium concentration, so that its use in case of cadmium toxicity is to be avoided. It does, however, remove inorganic mercury from the kidneys; but is not useful in the treatment of alkylmercury or phenylmercury toxicity. Dimercaprol also enhances the toxicity of selenium and tellurium, so it is not to be used to remove these elements from the body.
History
The original name of dimercaprol reflects its origins as a compound secretly developed by British biochemists at Oxford University during World War II as an antidote for lewisite, a now-obsolete arsenic-based chemical warfare agent.
See also
EDTA
2,3-Dimercapto-1-propanesulfonic acid
Dimercaptosuccinic acid
DMSA scan
Penicillamine
Heavy metal poisoning
References
External links
"Dimercaprol". Drug Information Portal. U.S. National Library of Medicine. |
Linezolid | Linezolid is an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia although it may be used for a variety of other infections including drug-resistant tuberculosis. It is used either by injection into a vein or by mouth.When given for short periods, linezolid is a relatively safe antibiotic. It can be used in people of all ages and in people with liver disease or poor kidney function. Common side effects with short-term use include headache, diarrhea, rash, and nausea. Serious side effects may include serotonin syndrome, bone marrow suppression, and high blood lactate levels, particularly when used for more than two weeks. If used for longer periods it may cause nerve damage, including optic nerve damage, which may be irreversible.As a protein synthesis inhibitor, linezolid works by suppressing bacterial protein production. This either stops growth or results in bacterial death. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique in that it blocks the initiation of protein production, rather than one of the later steps. As of 2014, bacterial resistance to linezolid has remained low. Linezolid is a member of the oxazolidinone class of medications.Linezolid was discovered in the mid-1990s, and was approved for commercial use in 2000. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies linezolid as critically important for human medicine. Linezolid is available as a generic medication.
Medical uses
The main use of linezolid is the treatment of severe infections caused by aerobic Gram-positive bacteria that are resistant to other antibiotics; it should not be used against bacteria that are sensitive to drugs with a narrower spectrum of activity, such as penicillins and cephalosporins. In both the popular press and the scientific literature, linezolid has been called a "reserve antibiotic"—one that should be used sparingly so that it will remain effective as a drug of last resort against potentially intractable infections.In the United States, the indications for linezolid use approved by the U.S. Food and Drug Administration (FDA) are the treatment of vancomycin-resistant Enterococcus faecium infections, with or without bacterial invasion of the bloodstream; nosocomial pneumonia (hospital-acquired) and community-acquired pneumonia caused by S. aureus or S. pneumoniae; complicated skin and skin structure infections (cSSSI) caused by susceptible bacteria, including diabetic foot infection, unless complicated by osteomyelitis (infection of the bone and bone marrow); and uncomplicated skin and soft tissue infections caused by S. pyogenes or S. aureus. The manufacturer advises against the use of linezolid for community-acquired pneumonia or uncomplicated skin and soft tissue infections caused by MRSA. In the United Kingdom, pneumonia and cSSSIs are the only indications noted in the product labeling.Linezolid appears to be as safe and effective for use in children and newborns as it is in adults.
Skin and soft tissue infections
A large meta-analysis of randomized controlled trials found linezolid to be more effective than glycopeptide antibiotics (such as vancomycin and teicoplanin) and beta-lactam antibiotics in the treatment of skin and soft tissue infections (SSTIs) caused by Gram-positive bacteria, and smaller studies appear to confirm its superiority over teicoplanin in the treatment of all serious Gram-positive infections.In the treatment of diabetic foot infections, linezolid appears to be cheaper and more effective than vancomycin. In a 2004 open-label study, it was as effective as ampicillin/sulbactam and amoxicillin/clavulanic acid, and far superior in patients with foot ulcers and no osteomyelitis, but with significantly higher rates of adverse effects. A 2008 meta-analysis of 18 randomized controlled trials, however, found that linezolid treatment failed as often as other antibiotics, regardless of whether patients had osteomyelitis.Some authors have recommended that combinations of cheaper or more cost-effective drugs (such as co-trimoxazole with rifampicin or clindamycin) be tried before linezolid in the treatment of SSTIs when susceptibility of the causative organism allows it.
Pneumonia
No significant difference appears in treatment success rates between linezolid, glycopeptides, or appropriate beta-lactam antibiotics in the treatment of pneumonia. Clinical guidelines for the treatment of community-acquired pneumonia developed by the American Thoracic Society and the Infectious Diseases Society of America recommend that linezolid be reserved for cases in which MRSA has been confirmed as the causative organism, or when MRSA infection is suspected based on the clinical presentation. The guidelines of the British Thoracic Society do not recommend it as first-line treatment, but rather as an alternative to vancomycin. Linezolid is also an acceptable second-line treatment for community-acquired pneumococcal pneumonia when penicillin resistance is present.U.S. guidelines recommend either linezolid or vancomycin as the first-line treatment for hospital-acquired (nosocomial) MRSA pneumonia. Some studies have suggested that linezolid is better than vancomycin against nosocomial pneumonia, particularly ventilator-associated pneumonia caused by MRSA, perhaps because the penetration of linezolid into bronchial fluids is much higher than that of vancomycin. Several issues in study design have been raised, however, calling into question results that suggest the superiority of linezolid. Regardless, linezolids advantages include its high oral bioavailability—which allows easy switching to oral therapy—and the fact that poor kidney function is not an obstacle to use. In contrast, achieving the correct dosage of vancomycin in patients with kidney failure is very difficult.
Other
It is traditionally believed that so-called "deep" infections—such as osteomyelitis or infective endocarditis—should be treated with bactericidal antibiotics, not bacteriostatic ones. Nevertheless, preclinical studies were conducted to assess the efficacy of linezolid for these infections, and the drug has been used successfully to treat them in clinical practice. Linezolid appears to be a reasonable therapeutic option for infective endocarditis caused by multi-resistant Gram-positive bacteria, despite a lack of high-quality evidence to support this use. Results in the treatment of enterococcal endocarditis have varied, with some cases treated successfully and others not responding to therapy. Low- to medium-quality evidence is also mounting for its use in bone and joint infections, including chronic osteomyelitis, although adverse effects are a significant concern when long-term use is necessary.In combination with other drugs, linezolid has been used to treat tuberculosis. The optimal dose for this purpose has not been established. In adults, daily and twice-daily dosing have been used to good effect. Many months of treatment are often required, and the rate of adverse effects is high regardless of dosage. There is not enough reliable evidence of efficacy and safety to support this indication as a routine use.Linezolid has been studied as an alternative to vancomycin in the treatment of febrile neutropenia in cancer patients when Gram-positive infection is suspected. It is also one of few antibiotics that diffuse into the vitreous humor, and may therefore be effective in treating endophthalmitis (inflammation of the inner linings and cavities of the eye) caused by susceptible bacteria. Again, there is little evidence for its use in this setting, as infectious endophthalmitis is treated widely and effectively with vancomycin injected directly into the eye.
Infections of the central nervous system
In animal studies of meningitis caused by Streptococcus pneumoniae, linezolid was found to penetrate well into cerebrospinal fluid, but its effectiveness was inferior to that of other antibiotics. There does not appear to be enough high-quality evidence to support the routine use of linezolid to treat bacterial meningitis. Nonetheless, it has been used successfully in many cases of central nervous system infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a reasonable choice for this indication when treatment options are limited or when other antibiotics have failed. The guidelines of the Infectious Diseases Society of America recommend linezolid as the first-line drug of choice for VRE meningitis, and as an alternative to vancomycin for MRSA meningitis. Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system, although very few cases of such infections have been published (as of 2009).
Catheter-related infections
In March 2007, the FDA reported the results of a randomized, open-label, phase III clinical trial comparing linezolid to vancomycin in the treatment of catheter-related bloodstream infections. Patients treated with vancomycin could be switched to oxacillin or dicloxacillin if the bacteria that caused their infection was found to be susceptible, and patients in both groups (linezolid and vancomycin) could receive specific treatment against Gram-negative bacteria if necessary. The study itself was published in January 2009.Linezolid was associated with significantly greater mortality than the comparator antibiotics. When data from all participants were pooled, the study found that 21.5% of those given linezolid died, compared to 16% of those not receiving it. The difference was found to be due to the inferiority of linezolid in the treatment of Gram-negative infections alone or mixed Gram-negative/Gram-positive infections. In participants whose infection was due to Gram-positive bacteria alone, linezolid was as safe and effective as vancomycin. In light of these results, the FDA issued an alert reminding healthcare professionals that linezolid is not approved for the treatment of catheter-related infections or infections caused by Gram-negative organisms, and that more appropriate therapy should be instituted whenever a Gram-negative infection is confirmed or suspected.
Specific populations
In adults and children over the age of 12, linezolid is usually given every 12 hours, whether orally or intravenously. In younger children and infants, it is given every eight hours. No dosage adjustments are required in the elderly, in people with mild-to-moderate liver failure, or in those with impaired kidney function. In people requiring hemodialysis, care should be taken to give linezolid after a session, because dialysis removes 30–40% of a dose from the body; no dosage adjustments are needed in people undergoing continuous hemofiltration, although more frequent administration may be warranted in some cases. According to one study, linezolid may need to be given more frequently than normal in people with burns affecting more than 20% of body area, due to increased nonrenal clearance of the drug.Linezolid is in U.S. pregnancy category C, meaning there have been no adequate studies of its safety when used by pregnant women, and although animal studies have shown mild toxicity to the fetus, the benefits of using the drug may outweigh its risks. It also passes into breast milk, although the clinical significance of this (if any) is unknown.
Spectrum of activity
Linezolid is effective against all clinically important Gram-positive bacteria—those whose cell wall contains a thick layer of peptidoglycan and no outer membrane—notably Enterococcus faecium and Enterococcus faecalis (including vancomycin-resistant enterococci), Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus, MRSA), Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, the viridans group streptococci, Listeria monocytogenes, and Corynebacterium species (the latter being among the most susceptible to linezolid, with minimum inhibitory concentrations routinely below 0.5 mg/L). Linezolid is also highly active in vitro against several mycobacteria. It appears to be very effective against Nocardia, but because of high cost and potentially serious adverse effects, authors have recommended that it be combined with other antibiotics or reserved for cases that have failed traditional treatment.Linezolid is considered bacteriostatic against most organisms—that is, it stops their growth and reproduction without actually killing them—but has some bactericidal (killing) activity against streptococci. Some authors have noted that, despite its bacteriostatic effect in vitro, linezolid "behaves" as a bactericidal antibiotic in vivo because it inhibits the production of toxins by staphylococci and streptococci. It also has a post-antibiotic effect lasting one to four hours for most bacteria, meaning that bacterial growth is temporarily suppressed even after the drug is discontinued.
Gram-negative bacteria
Linezolid has no clinically significant effect on most Gram-negative bacteria. Pseudomonas and the Enterobacteriaceae, for instance, are not susceptible. In vitro, it is active against Pasteurella multocida, Fusobacterium, Moraxella catarrhalis, Legionella, Bordetella, and Elizabethkingia meningoseptica, and moderately active (having a minimum inhibitory concentration for 90% of strains of 8 mg/L) against Haemophilus influenzae. It has also been used to great effect as a second-line treatment for Capnocytophaga infections.
Comparable antibiotics
Linezolids spectrum of activity against Gram-positive bacteria is similar to that of the glycopeptide antibiotic vancomycin, which has long been the standard for treatment of MRSA infections, and the two drugs are often compared. Other comparable antibiotics include glycopeptide antibiotics such as teicoplanin (trade name Targocid), dalbavancin (Dalvance), and telavancin (Vibativ); quinupristin/dalfopristin (Synercid, a combination of two streptogramins, not active against E. faecalis); daptomycin (Cubicin, a lipopeptide); and ceftobiprole (Zevtera, a 5th-generation cephalosporin). Linezolid is the only one that can be taken by mouth for the treatment of systemic infections. In the future, oritavancin and iclaprim may be useful oral alternatives to linezolid—both are in the early stages of clinical development.
Adverse effects
When used for short periods, linezolid is a relatively safe drug. Common side effects of linezolid use (those occurring in more than 1% of people taking linezolid) include diarrhea (reported by 3–11% of clinical trial participants), headache (1–11%), nausea (3–10%), vomiting (1–4%), rash (2%), constipation (2%), altered taste perception (1–2%), and discoloration of the tongue (0.2–1%). It has also been known to cause thrombocytopenia. Fungal infections such as thrush and vaginal candidiasis may also occur as linezolid suppresses normal bacterial flora and opens a niche for fungi (so-called antibiotic candidiasis). Less common (and potentially more serious) adverse effects include allergic reactions, pancreatitis, and elevated transaminases, which may be a sign of liver damage. Unlike some antibiotics, such as erythromycin and the quinolones, linezolid has no effect on the QT interval, a measure of cardiac electrical conduction. Adverse effects in children are similar to those that occur in adults.Like nearly all antibiotics, linezolid has been associated with Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis, although the latter is uncommon, occurring in about one in two thousand patients in clinical trials. C. difficile appears to be susceptible to linezolid in vitro, and linezolid was even considered as a possible treatment for CDAD.
Long-term use
Bone marrow suppression, characterized particularly by thrombocytopenia (low platelet count), may occur during linezolid treatment; it appears to be the only adverse effect that occurs significantly more frequently with linezolid than with glycopeptides or beta-lactams. It is uncommon in patients who receive the drug for 14 days or fewer, but occurs much more frequently in patients who receive longer courses or who have renal failure. A 2004 case report suggested that pyridoxine (a form of vitamin B6) could reverse the anemia and thrombocytopenia caused by linezolid, but a later, larger study found no protective effect.Long-term use of linezolid has also been associated with chemotherapy-induced peripheral neuropathy, a progressive and enduring often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs. Chemotherapy drugs associated with CIPN include thalidomide, the epothilones such as ixabepilone, the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin. and optic neuropathy, which is most common after several months of treatment and may also be irreversible. Although the mechanism of injury is still poorly understood, mitochondrial toxicity has been proposed as a cause; linezolid is toxic to mitochondria, probably because of the similarity between mitochondrial and bacterial ribosomes. Lactic acidosis, a potentially life-threatening buildup of lactic acid in the body, may also occur due to mitochondrial toxicity. Because of these long-term effects, the manufacturer recommends weekly complete blood counts during linezolid therapy to monitor for possible bone marrow suppression, and recommends that treatment last no more than 28 days. A more extensive monitoring protocol for early detection of toxicity in seriously ill patients receiving linezolid has been developed and proposed by a team of researchers in Melbourne, Australia. The protocol includes twice-weekly blood tests and liver function tests; measurement of serum lactate levels, for early detection of lactic acidosis; a review of all medications taken by the patient, interrupting the use of those that may interact with linezolid; and periodic eye and neurological exams in patients set to receive linezolid for longer than four weeks.The adverse effects of long-term linezolid therapy were first identified during postmarketing surveillance. Bone marrow suppression was not identified during Phase III trials, in which treatment did not exceed 21 days. Although some participants of early trials did experience thrombocytopenia, it was found to be reversible and did not occur significantly more frequently than in controls (participants not taking linezolid). There have also been postmarketing reports of seizures, and, as of 2009, a single case each of Bells palsy (paralysis of the facial nerve) and kidney toxicity. Evidence of protein synthesis inhibition in mammalian cells by linezolid has been published.
Interactions
Linezolid is a weak, non-selective, reversible monoamine oxidase inhibitor (MAOI), and should not be used concomitantly with other MAOIs, large amounts of tyramine-rich foods (such as pork, aged cheeses, alcoholic beverages, or smoked and pickled foods), or serotonergic drugs. There have been postmarketing reports of serotonin syndrome when linezolid was given with or soon after the discontinuation of serotonergic drugs, particularly selective serotonin reuptake inhibitors (SSRIs) such as paroxetine and sertraline. It may also enhance the blood pressure-increasing effects of sympathomimetic drugs such as pseudoephedrine or phenylpropanolamine. It should also not be given in combination with pethidine (meperidine) under any circumstance due to the risk of serotonin syndrome.
Linezolid does not inhibit or induce the cytochrome P450 (CYP) system, which is responsible for the metabolism of many commonly used drugs, and therefore does not have any CYP-related interactions.
Pharmacology
Pharmacodynamics
Linezolid, like other oxazolidinones, is a bacterial protein synthesis inhibitor and a weak, non-selective, reversible monoamine oxidase inhibitor. As a protein synthesis inhibitor, linezolid stops the growth and reproduction of bacteria by disrupting translation of messenger RNA (mRNA) into proteins in bacterial ribosomes. Linezolid inhibits translation at the first step of protein synthesis, initiation, unlike most other protein synthesis inhibitors, which inhibit elongation. It does so by preventing the formation of the initiation complex, composed of the 30S and 50S subunits of the ribosome, tRNA, and mRNA. Linezolid binds to the 23S portion of the 50S subunit (the center of peptidyl transferase activity), close to the binding sites of chloramphenicol, lincomycin, and other antibiotics. Due to this unique mechanism of action, cross-resistance between linezolid and other protein synthesis inhibitors is highly infrequent or nonexistent.In 2008, the crystal structure of linezolid bound to the 50S subunit of a ribosome from the archaean Haloarcula marismortui was elucidated by a team of scientists from Yale University and deposited in the Protein Data Bank. Another team in 2008 determined the structure of linezolid bound to a 50S subunit of Deinococcus radiodurans. The authors proposed a refined model for the mechanism of action of oxazolidinones, finding that linezolid occupies the A site of the 50S ribosomal subunit, inducing a conformational change that prevents tRNA from entering the site and ultimately forcing tRNA to separate from the ribosome.
Pharmacokinetics
One of the advantages of linezolid is that it has an absolute oral bioavailability of 100% due to its rapid and complete absorption after oral administration; in other words, the entire dose reaches the bloodstream, as if it had been given intravenously. This means that people receiving intravenous linezolid may be switched to oral linezolid as soon as their condition allows it, whereas comparable antibiotics (such as vancomycin and quinupristin/dalfopristin) can only be given intravenously.
Taking linezolid with food somewhat slows its absorption, but the area under the curve is not affected.Linezolids plasma protein binding is approximately 31% (range 4–32%) and its volume of distribution at steady state averages 36.1–47.3 liters in healthy adult volunteers. Peak plasma concentrations (Cmax) are reached one to two hours after administration of the drug. Linezolid is readily distributed to all tissues in the body apart from bone matrix and white adipose tissue. Notably, the concentration of linezolid in the epithelial lining fluid (ELF) of the lower respiratory tract is at least equal to, and often higher than, that achieved in serum (some authors have reported bronchial fluid concentrations up to four times higher than serum concentrations), which may account for its efficacy in treating pneumonia. However, a meta-analysis of clinical trials found that linezolid was not superior to vancomycin, which achieves lower concentrations in the ELF. Cerebrospinal fluid (CSF) concentrations vary; peak CSF concentrations are lower than serum ones, due to slow diffusion across the blood–brain barrier, and trough concentrations in the CSF are higher for the same reason. The average half-life is three hours in children, four hours in teenagers, and five hours in adults.Linezolid is metabolized in the liver, by oxidation of the morpholine ring, without involvement of the cytochrome P450 system. This metabolic pathway leads to two major inactive metabolites (which each account for around 45% and 10% of an excreted dose at steady state), one minor metabolite, and several trace metabolites, none of which accounts for more than 1% of an excreted dose. Clearance of linezolid varies with age and gender; it is fastest in children (which accounts for the shorter half-life), and appears to be 20% lower in women than in men. There is a strong correlation between linezolid clearance and creatinine clearance.
Chemistry
At physiological pH (7.4), linezolid exists in an uncharged state. It is moderately water-soluble (approximately 3 mg/mL), with a logP of 0.55.
The oxazolidinone pharmacophore—the chemical "template" essential for antimicrobial activity—consists of a 1,3-oxazolidin-2-one moiety with an aryl group at position 3 and an S-methyl group, with another substituent attached to it, at position 5 (the R-enantiomers of all oxazolidinones are devoid of antibiotic properties). In addition to this essential core, linezolid also contains several structural characteristics that improve its effectiveness and safety. An acetamide substituent on the 5-methyl group is the best choice in terms of antibacterial efficacy, and is used in all of the more active oxazolidinones developed thus far; in fact, straying too far from an acetamide group at this position makes the drug lose its antimicrobial power, although weak to moderate activity is maintained when some isosteric groups are used. A fluorine atom at the 3′ position practically doubles in vitro and in vivo activity, and the electron-donating nitrogen atom in the morpholine ring helps maintain high antibiotic potency and an acceptable safety profile.The anticoagulant rivaroxaban (Xarelto) bears a striking structural similarity to linezolid; both drugs share the oxazolidinone pharmacophore, differing in only three areas (an extra ketone and chlorothiophene, and missing the fluorine atom). However this similarity appears to carry no clinical significance.
Synthesis
Linezolid is a completely synthetic drug: it does not occur in nature (unlike erythromycin and many other antibiotics) and was not developed by building upon a naturally occurring skeleton (unlike most beta-lactams, which are semisynthetic). Many approaches are available for oxazolidinone synthesis, and several routes for the synthesis of linezolid have been reported in the chemistry literature. Despite good yields, the original method (developed by Upjohn for pilot plant-scale production of linezolid and eperezolid) is lengthy, requires the use of expensive chemicals—such as palladium on carbon and the highly sensitive reagents methanesulfonyl chloride and n-butyllithium—and needs low-temperature conditions. Much of the high cost of linezolid has been attributed to the expense of its synthesis. A somewhat more concise and cost-effective route better suited to large-scale production was patented by Upjohn in 1998.Later syntheses have included an "atom-economical" method starting from D-mannitol, developed by Indian pharmaceutical company Dr. Reddys and reported in 1999, and a route starting from (S)-glyceraldehyde acetonide (prepared from ascorbic acid), developed by a team of researchers from Hunan Normal University in Changsha, Hunan, China. On 25 June 2008, during the 12th Annual Green Chemistry and Engineering Conference in New York, Pfizer reported the development of their "second-generation" synthesis of linezolid: a convergent, green synthesis starting from (S)-epichlorohydrin, with higher yield and a 56% reduction in total waste.
Resistance
Acquired resistance to linezolid was reported as early as 1999, in two patients with severe, multidrug-resistant Enterococcus faecium infection who received the drug through a compassionate use program. Linezolid-resistant Staphylococcus aureus was first isolated in 2001.In the United States, resistance to linezolid has been monitored and tracked since 2004 through a program named LEADER, which (as of 2007) was conducted in 60 medical institutions throughout the country. Resistance has remained stable and extremely low—less than one-half of one percent of isolates overall, and less than one-tenth of one percent of S. aureus samples. A similar, worldwide program—the "Zyvox Annual Appraisal of Potency and Spectrum Study", or ZAAPS—has been conducted since 2002. As of 2007, overall resistance to linez |
Linezolid | olid in 23 countries was less than 0.2%, and nonexistent among streptococci. Resistance was only found in Brazil, China, Ireland, and Italy, among coagulase-negative staphylococci (0.28% of samples resistant), enterococci (0.11%), and S. aureus (0.03%). In the United Kingdom and Ireland, no resistance was found in staphylococci collected from bacteremia cases between 2001 and 2006, although resistance in enterococci has been reported. Some authors have predicted that resistance in E. faecium will increase if linezolid use continues at current levels or increases. Nevertheless, linezolid continues to be an important antimicrobial agent with near-complete activity (0.05% resistance).
Mechanism
The intrinsic resistance of most Gram-negative bacteria to linezolid is due to the activity of efflux pumps, which actively "pump" linezolid out of the cell faster than it can accumulate.Gram-positive bacteria usually develop resistance to linezolid as the result of a point mutation known as G2576T, in which a guanine base is replaced with thymine in base pair 2576 of the genes coding for 23S ribosomal RNA. This is the most common mechanism of resistance in staphylococci, and the only one known to date in isolates of E. faecium. Other mechanisms have been identified in Streptococcus pneumoniae (including mutations in an RNA methyltransferase that methylates G2445 of the 23S rRNA and mutations causing increased expression of ABC transporter genes) and in Staphylococcus epidermidis.
History
The oxazolidinones have been known as monoamine oxidase inhibitors since the late 1950s. Their antimicrobial properties were discovered by researchers at E.I. duPont de Nemours in the 1970s. In 1978, DuPont patented a series of oxazolidinone derivatives as being effective in the treatment of bacterial and fungal plant diseases, and in 1984, another patent described their usefulness in treating bacterial infections in mammals. In 1987, DuPont scientists presented a detailed description of the oxazolidinones as a new class of antibiotics with a novel mechanism of action. Early compounds were found to produce liver toxicity, however, and development was discontinued.Pharmacia & Upjohn (now part of Pfizer) started its own oxazolidinone research program in the 1990s. Studies of the compounds structure–activity relationships led to the development of several subclasses of oxazolidinone derivatives, with varying safety profiles and antimicrobial activity. Two compounds were considered drug candidates: eperezolid (codenamed PNU-100592) and linezolid (PNU-100766). In the preclinical stages of development, they were similar in safety and antibacterial activity, so they were taken to Phase I clinical trials to identify any difference in pharmacokinetics. Linezolid was found to have a pharmacokinetic advantage—requiring only twice-daily dosage, while eperezolid needed to be given three times a day to achieve similar exposure—and therefore proceeded to further trials. The U.S. Food and Drug Administration (FDA) approved linezolid on 18 April 2000. Approval followed in Brazil (June 2000), the United Kingdom (January 2001), Japan and Canada (April 2001), Europe (throughout 2001), and other countries in Latin America and Asia.As of 2009, linezolid was the only oxazolidinone antibiotic available. Other members of this class have entered development, such as posizolid (AZD2563), ranbezolid (RBx 7644), and radezolid (RX-1741). In 2014, the FDA approved tedizolid phosphate, a second-generation oxazolidinone derivative, for acute bacterial skin and skin structure infection.
Society and culture
Economics
Linezolid was quite expensive in 2009; a course of treatment may cost one or two thousand U.S. dollars for the drug alone, not to mention other costs (such as those associated with hospital stay). With the medication becoming generic the price has decreased. In India as of 2015 a month of linezolid, as would be used to treat tuberculosis cost about US$60.However, because intravenous linezolid may be switched to an oral formulation (tablets or oral solution) without jeopardizing efficacy, people may be discharged from hospital relatively early and continue treatment at home, whereas home treatment with injectable antibiotics may be impractical. Reducing the length of hospital stay reduces the overall cost of treatment, even though linezolid may have a higher acquisition cost—that is, it may be more expensive—than comparable antibiotics.
Studies have been conducted in several countries with different health care system models to assess the cost-effectiveness of linezolid compared to glycopeptides such as vancomycin or teicoplanin. In most countries, linezolid was more cost-effective than comparable antibiotics for the treatment of hospital-acquired pneumonia and complicated skin and skin structure infections, either due to higher cure and survival rates or lower overall treatment costs.In 2009, Pfizer paid $2.3 billion and entered a corporate integrity agreement to settle charges that it had misbranded and illegally promoted four drugs, and caused false claims to be submitted to government healthcare programs for uses that had not been approved by the United States Food and Drug Administration. $1.3 billion was paid to settle criminal charges of illegally marketing the anti-inflammatory valdecoxib, while $1 billion was paid in civil fines regarding illegal marketing of three other drugs, including Zyvox.
Brand names
References
External links
"Linezolid". Drug Information Portal. U.S. National Library of Medicine. |
Cefditoren | Cefditoren also known as cefditoren pivoxil (trade names Zostom-O, Meiact, and Spectracef) is a broad-spectrum antibiotic, taken by mouth to treat pneumonia and other infections. It is a third-generation oral cephalosporin with a broad spectrum of activity against bacterial pathogens, including both Gram-positive and Gram-negative bacteria, and it is effective against some antibiotic-resistant bacteria because it is not susceptible to hydrolysis by many common beta-lactamases. The United States Food and Drug Administration approved cefditoren pivoxil for adults and adolescents (12 years of age or older) in 2001. In 2018 Zuventus Healthcare received approval for cefditoren pivoxil dry powder for suspension (100 mg / 5mL) for the treatment of mild to moderate infection in children (2 months to 12 years of age) which are caused by susceptible strains of the designated microorganisms.Cefditoren pivoxil may also reduce lung inflammation and epithelial damage by a non-bactericidal mechanism. It was patented in 1984 and approved for medical use in 1994.
Structure
Like other cephalosporins, cefditoren has a β-lactam ring at the 7 position of cephalosporin ring that is responsible for its inhibitory action on bacterial cell wall synthesis. In addition to the cephem nucleus common to all cephalosporins, cefditoren has an aminothiazole group that enhances its activity against Gram-negative organisms, a methylthiazole group that enhances its activity against Gram-positive organisms, a methoxyimino group that gives it stability against β-lactamases, and a pivoxil ester group that enhances oral bioavailability.
Antimicrobial activity
The spectrum of cefditoren includes both Gram-positive and Gram-negative bacterial species. It has strong antimicrobial activity because of its high affinity for penicillin binding protein 2X, which responsible for cephalosporin resistance when mutated. Cefditoren pivoxil high intrinsic activity against Streptococcus pneumoniae, including penicillin-resistant strains. Cefditoren holds a balanced antimicrobial spectrum that includes the three major pathogens of community-acquired lower-respiratory tract infections: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
Aerobic Gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible strains, including β-lactamase-producing strains), Streptococcus pneumoniae, Streptococcus pyogenes
Aerobic Gram-negative microorganisms: Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains.
Pharmacokinetics
Absorption
Oral bioavailability: following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following 200 mg dose and occur 1.5 to 3 hours following dosing. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under
fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%.
Distribution
Binding of cefditoren to plasma proteins averages 88%, and the mean volume of distribution of cefditoren at steady state is 9.3L. Cefditoren has been shown to penetrate into bronchial mucosa, epithelial lining fluid, skin blister fluid and tonsillar tissue and clinically relevant concentrations against common pathogens are achieved in these tissues for at least 4 hours.
Metabolism and Excretion
Cefditoren is predominantly eliminated by the kidneys as unchanged drug and has a renal clearance of 4.1–5.6 L/h after multiple doses; its elimination half-life is 1.5 hours.
Medical uses
Cefditoren pivoxil is indicated to treat uncomplicated skin and skin structure infections, community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, pharyngitis, and tonsillitis, acute maxillary sinusitis, otitis media (indications may differ in some countries).
Spectrum of bacterial susceptibility
Cefditoren pivoxil has a broad spectrum of activity and has been used to treat bacterial infections of the skin and respiratory tract, including bronchitis, pneumonia, and tonsillitis. The following represents minimum inhibitory concentration data for several medically significant microorganisms.
Haemophilus influenzae: ≥0.063 – 0.25 μg/ml
Staphylcoccus aureus: 0.25 – >128 μg/ml (not includes methicillin-resistant Staphylococcus aureus)
Streptococcus pyogenes: ≤0.004 – 2 μg/mlCefditoren does not have antibacterial activity against Pseudomonas aeruginosa.
Dosage and administration
Adults and Adolescents (≥12 Years)
Community-acquired pneumonia: 400 mg twice daily for 14 days
Acute bacterial exacerbation of chronic bronchitis: 400 mg twice daily for 10 days
Pharyngitis/tonsillitis, otitis media, sinusitis: 200 mg twice daily for 10 days
Uncomplicated skin and skin structure infections: 200 mg twice daily for 10 days
Children (2 months to 12 years of age)
Pneumonia, otitis media or sinusitis: 3 mg/kg/dose, 3 times a day, after meals. The dosage may be increased up to 6 mg/kg/dose as needed, but not exceed the maximum dose for adults.
For children with diseases other than above: 3 mg/kg/dose, 3 times a day after meals. The dosage may be adjusted according to the disease or the patients age and symptoms, but not exceed the maximum dose for adults. Safety in low birth weight infants and newborns has not been established.
Pregnancy
Pregnancy Category B
Cefditoren pivoxil was not teratogenic up to the highest doses tested in rats and rabbits. In rats, this dose was 1000 mg/kg/day, which is approximately 24 times a human dose of 200 mg twice daily based on mg/m2/day. In rabbits, the highest dose tested was 90 mg/kg/day, which is approximately four times a human dose of 200 mg twice daily based on mg/m2/day. This dose produced severe maternal toxicity and resulted in fetal toxicity and abortions.
In a postnatal development study in rats, cefditoren pivoxil produced no adverse effects on postnatal survival, physical and behavioral development, learning abilities, and reproductive capability at sexual maturity when tested at doses of up to 750 mg/kg/day, the highest dose tested. This is approximately 18 times a human dose of 200 mg twice daily based on mg/m2/day. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Geriatric use
Of the 2675 patients in clinical studies who received cefditoren pivoxil 200 mg twice daily, 308 (12%) were >65 years of age. Of the 2159 patients in clinical studies who received cefditoren pivoxil 400 mg twice daily, 307 (14%) were >65 years of age. No clinically significant differences in effectiveness or safety were observed between older and younger patients. No dose adjustments are necessary in geriatric patients with normal renal function. This drug is substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
International approvals
Cefditoren pivoxil is available as 200 and 400 mg tablets in the United States. It was marketed under the trade name Spectracef by Vansen Pharma Inc. Cefditoren is also marketed under the name Meiact by Meiji Seika Pharma Co., Ltd. In India it is marketed under the brand name Zostum-O by Zuventus Healthcare.
Proprietary Preparations and Countries
US:Spectracef; India:Zostum-O; Japan:Meiact; Russia:Spectracef; China:Meiact; Greece:Spectracef; Indonesia:Meiact; Italy:Giasion; Mexico:Spectracef; Portugal:Meiact; Thailand:Meiact; Turkey: Cftiten, Meiact; Sefporin Spain: Spectracef, Meiact.
Contraindications
In patients with known allergy to the cephalosporin class of antibiotics or any of its components.
Patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of cefditoren causes renal excretion of carnitine.
Safety and tolerability
Cefditoren pivoxil is generally well-tolerated, with most adverse events being of mild-to-moderate severity and self-limiting. Gastrointestinal adverse events (e.g., diarrhoea, nausea and abdominal pain) were the most commonly reported adverse events, although they seldom led to treatment discontinuation.
In a post-marketing surveillance evaluating safety in 2006 children with acute otitis media treated with cefditoren (median daily dose: 10.0 mg/kg with a median total treatment period of 7 days), the incidence of adverse reactions was 1.79%, without unexpected or serious adverse drug reactions reported. The most frequent adverse drug reaction was diarrhea (1.30%) that resolved or subsided during treatment or after discontinuation or completion of therapy in all cases.
Data from the clinical studies carried out with cefditoren in the treatment of pharyngotonsillitis from 2007 to 2010 in Japan showed that the percentage of adverse events was very low and diarrhea was the most frequent event. In the largest study (734 children), the incidence of adverse reactions was 1.50% (11 events in 11 patients), with 3 events of diarrhea and three of hematuria in urinalysis without clinical symptoms. In a study carried out in children in Thailand comparing cefditoren (66 patients) with amoxicillin/clavulanic acid (72 patients) for 10 days in the treatment of acute bacterial rhinosinusitis, the most frequent adverse event was diarrhea, with significant (P = 0.02) differences in the percentages found for both compounds (4.5% with cefditoren vs. 18.1% for amoxicillin/clavulanic acid).
Guidelines
Japanese Guidelines
Japanese guidelines for the management of respiratory infectious diseases in children recommend cefditoren pivoxil as an initial antimicrobial therapy in children (2 months and older).
A panel of 70 pulmonologists, coordinated by 9 experts in respiratory care recommendations
A consensus on appropriate prescribing in lower respiratory tract infection therapy was appraised by Delphi exercise, based on a panel of 70 pulmonologists, coordinated by a scientific committee of nine experts in respiratory medical care.
Amongst 3rd-generation oral cephalosporins, cefditoren pivoxil has the highest intrinsic activity against Streptococcus pneumoniae, penicillin-resistant strains included.
Amongst 3rd-generation oral cephalosporins, the spectrum of cefditoren is particularly balanced, includes both Gram-positive and Gram-negative species.
The experts expressed the opinion that, due to its high intrinsic activity, cefditoren appears as an appropriate agent for either the treatment of lower respiratory tract infections and for parenteral to oral switch therapy as well.
Ideal for switch therapy
The characteristics of oral antibiotics to be considered for the switch therapy (parenteral to oral antibiotic) are: (i) similar antimicrobial spectrum, (ii) high bioavailability, (iii) administration time 12–24 hours, (iv) good tolerability
The expert panel reached a high level of consensus on cefditoren pivoxil as the most appropriate option for the switch therapy from parenteral third-generation cephalosporins (like cefotaxime or ceftriaxone) to oral therapy, because of the similar spectrum and the highest intrinsic activity.
References
External links
Drug Approval Package
Manufacturers Product website
Manufacturers prescribing information for Spectracef |
Boniva | Boniva may refer to:
Boniva, a company acquired by software company SSA Global Technologies in August 2005
Ibandronic acid (marketed as Boniva), a potent bisphosphonate drug used in the prevention and treatment of osteoporosis |
Smallpox vaccine | The smallpox vaccine is the first vaccine to be developed against a contagious disease. In 1796, the British doctor Edward Jenner demonstrated that an infection with the relatively mild cowpox virus conferred immunity against the deadly smallpox virus. Cowpox served as a natural vaccine until the modern smallpox vaccine emerged in the 20th century. From 1958 to 1977, the World Health Organization (WHO) conducted a global vaccination campaign that eradicated smallpox, making it the only human disease to be eradicated. Although routine smallpox vaccination is no longer performed on the general public, the vaccine is still being produced to guard against bioterrorism, biological warfare, and monkeypox.The term vaccine derives from the Latin word for cow, reflecting the origins of smallpox vaccination. Edward Jenner referred to cowpox as variolae vaccinae (smallpox of the cow). The origins of the smallpox vaccine became murky over time, especially after Louis Pasteur developed laboratory techniques for creating vaccines in the 19th century. Allan Watt Downie demonstrated in 1939 that the modern smallpox vaccine was serologically distinct from cowpox, and vaccinia was subsequently recognized as a separate viral species. Whole-genome sequencing has revealed that vaccinia is most closely related to horsepox, and the cowpox strains found in Great Britain are the least closely related to vaccinia.
Types
As the oldest vaccine, the smallpox vaccine has gone through several generations of medical technology. From 1796 to the 1880s, the vaccine was transmitted from one person to another through arm-to-arm vaccination. Smallpox vaccine was successfully maintained in cattle starting in the 1840s, and calf lymph vaccine became the leading smallpox vaccine in the 1880s. First-generation vaccines grown on the skin of live animals were widely distributed in the 1950s–1970s to eradicate smallpox. Second-generation vaccines were grown in chorioallantoic membrane or cell cultures for greater purity, and they were used in some areas during the smallpox eradication campaign. Third-generation vaccines are based on attenuated strains of vaccinia and saw limited use prior to the eradication of smallpox.All three generations of vaccine are available in stockpiles. First and second-generation vaccines contain live unattenuated vaccinia virus and can cause serious side effects in a small percentage of recipients, including death in 1–10 people per million vaccinations. Third-generation vaccines are much safer due to the milder side effects of the attenuated vaccinia strains. Second and third-generation vaccines are still being produced, with manufacturing capacity being built up in the 2000s due to fears of bioterrorism and biological warfare.
First-generation
The first-generation vaccines are manufactured by growing live vaccinia virus in the skin of live animals. Most first-generation vaccines are calf lymph vaccines that were grown on the skin of cows, but other animals were also used, including sheep. The development of freeze-dried vaccine in the 1950s made it possible to preserve vaccinia virus for long periods of time without refrigeration, leading to the availability of freeze-dried vaccines such as Dryvax.: 115 The vaccine is administered by multiple puncture of the skin (scarification) with a bifurcated needle that holds vaccine solution in the fork. The skin should be cleaned with water rather than alcohol, as the alcohol could inactivate the vaccinia virus.: 292 If alcohol is used, it must be allowed to evaporate completely before the vaccine is administered.: 292 Vaccination results in a skin lesion that fills with pus and eventually crusts over. This manifestation of localized vaccinia infection is known as a vaccine "take" and demonstrates immunity to smallpox. After 2–3 weeks, the scab will fall off and leave behind a vaccine scar.First generation vaccines consist of live, unattenuated vaccinia virus. One-third of first-time vaccinees develop side effects significant enough to miss school, work, or other activities, or have difficulty sleeping. 15–20% of children receiving the vaccine for the first time develop fevers of over 102 °F (39 °C). The vaccinia lesion can transmit the virus to other people. Rare side effects include postvaccinal encephalitis and myopericarditis. Many countries have stockpiled first generation smallpox vaccines. In a 2006 predictive analysis of casualties if there were a mass vaccination of the populations of Germany and the Netherlands, it was estimated that a total of 9.8 people in the Netherlands and 46.2 people in Germany would die from uncontrolled vaccinia infection after being vaccinated with the New York City Board of Health strain. More deaths were predicted for vaccines based other strains: Lister (55.1 Netherlands, 268.5 Germany) and Bern (303.5 Netherlands, 1,381 Germany).
Second-generation
The second-generation vaccines consist of live vaccinia virus grown in the chorioallantoic membrane or cell culture. The second-generation vaccines are also administered through scarification with a bifurcated needle, and they carry the same side effects as the first-generation vaccinia strain that was cloned. However, the use of eggs or cell culture allows for vaccine production in a sterile environment, while first-generation vaccine contains skin bacteria from the animal that the vaccine was grown on.Ernest William Goodpasture, Alice Miles Woodruff, and G. John Buddingh grew vaccinia virus on the chorioallantoic membrane of chicken embryos in 1932. The Texas Department of Health began producing egg-based vaccine in 1939 and started using it in vaccination campaigns in 1948.: 588 Lederle Laboratories began selling its Avianized smallpox vaccine in the United States in 1959. Egg-based vaccine was also used widely in Brazil, New Zealand, and Sweden, and on a smaller scale in many other countries. Concerns about temperature stability and avian sarcoma leukosis virus prevented it from being used more widely during the eradication campaign, although no increase in leukemia was seen in Brazil and Sweden despite the presence of ASLV in the chickens.: 588 Vaccinia was first grown in cell culture in 1931 by Thomas Milton Rivers. The WHO funded work in the 1960s at the Dutch National Institute for Public Health and the Environment (RVIM) on growing the Lister/Elstree strain in rabbit kidney cells and tested it in 45,443 Indonesian children in 1973, with comparable results to the same strain of calf lymph vaccine.: 588–589 Two other cell culture vaccines were developed from the Lister strain in the 2000s: Elstree-BN (Bavarian Nordic) and VV Lister CEP (Chicken Embryo Primary, Sanofi Pasteur). Lister/Elstree-RVIM was stockpiled in the Netherlands, and Elstree-BN was sold to some European countries for stockpiles. However, Sanofi dropped its own vaccine after it acquired Acambis in 2008.
ACAM2000 is a vaccine developed by Acambis, which was acquired by Sanofi Pasteur in 2008, before selling the smallpox vaccine to Emergent Biosolutions in 2017. Six strains of vaccinia were isolated from 3,000 doses of Dryvax and found to exhibit significant variation in virulence. The strain with the most similar virulence to the overall Dryvax mixture was selected and grown in MRC-5 cells to make the ACAM1000 vaccine. After a successful Phase I trial of ACAM1000, the virus was passaged three times in Vero cells to develop ACAM2000, which entered mass production at Baxter. The United States ordered over 200 million doses of ACAM2000 in 1999–2001 for its stockpile, and production is ongoing to replace expired vaccine.
Third-generation
The third-generation vaccines are based on attenuated vaccinia viruses that are much less virulent and carry lesser side effects. The attenuated viruses may be replicating or non-replicating.Modified vaccinia Ankara (MVA, German: Modifiziertes Vakziniavirus Ankara) is a replication-incompetent variant of vaccinia that was developed in West Germany through serial passage. The original Ankara strain of vaccinia was maintained at the vaccine institute in Ankara, Turkey on donkeys and cows. The Ankara strain was taken to West Germany in 1953, where Herrlich and Mayr grew it on chorioallantoic membrane at the University of Munich. After 572 serial passages, the vaccinia virus had lost over 14% of its genome and could no longer replicate in human cells. MVA was used in West Germany in 1977–1980, but the eradication of smallpox ended the vaccination campaign after only 120,000 doses.MVA stimulates the production of fewer antibodies than replicating vaccines. During the smallpox eradication campaign, MVA was considered to be a pre-vaccine that would be administered before a replicating vaccine to reduce the side effects, or an alternative vaccine that could be safely given to people at high risk from a replicating vaccine.: 585 Japan evaluated MVA and rejected it due to its low immunogenicity, deciding to develop its own attenuated vaccine instead. In the 2000s, MVA was tested in animal models at much higher dosages. When MVA is given to monkeys at 40 times the dosage of Dryvax, it stimulates a more rapid immune response while still causing lesser side effects.
MVA-BN (also known as: Imvanex in the European Union; Imvamune in Canada; and Jynneos) is a vaccine manufactured by Bavarian Nordic by growing MVA in cell culture. Unlike replicating vaccines, MVA-BN is administered by injection via the subcutaneous route and does not result in a vaccine "take." It is safer for immunocompromised patients and those who are at risk from a vaccinia infection. MVA-BN has been approved in the European Union, Canada, and the United States. Clinical trials have found that MVA-BN is safer and just as immunogenic as ACAM2000.LC16m8 is a replicating attenuated strain of vaccinia that is manufactured by Kaketsuken in Japan. Working at the Chiba Serum Institute in Japan, So Hashizume passaged the Lister strain 45 times in primary rabbit kidney cells, interrupting the process after passages 36, 42, and 45 to grow clones on chorioallantoic membrane and select for pock size. The resulting variant was designated LC16m8 (Lister clone 16, medium pocks, clone 8). Unlike the severely-damaged MVA, LC16m8 contains every gene that is present in the ancestral vaccinia. However, a single-nucleotide deletion truncates membrane protein B5R from a residue length of 317 to 92. Although the truncated protein decreases production of extracellular enveloped virus, animal models have shown that antibodies against other membrane proteins are sufficient for immunity. LC16m8 was approved in Japan in 1975 after testing in over 50,000 children. Vaccination with LC16m8 results in a vaccine "take," but safety is similar to MVA.
Safety
Vaccinia is infectious, which improves its effectiveness, but causes serious complications for people with impaired immune systems (for example chemotherapy and AIDS patients) or history of eczema, and is not considered safe for pregnant women. A woman planning on conceiving should not receive smallpox immunization. Vaccines that only contain attenuated vaccinia viruses (an attenuated virus is one in which the pathogenicity has been decreased through serial passage) have been proposed, but some researchers have questioned the possible effectiveness of such a vaccine. According to the US Centers for Disease Control and Prevention (CDC), "within 3 days of being exposed to the virus, the vaccine might protect you from getting the disease. If you still get the disease, you might get much less sick than an unvaccinated person would. Within 4 to 7 days of being exposed to the virus, the vaccine likely gives you some protection from the disease. If you still get the disease, you might not get as sick as an unvaccinated person would."In May 2007, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the U.S. Food and Drug Administration (FDA) voted unanimously that a new live virus vaccine produced by Acambis, ACAM2000, is both safe and effective for use in persons at high risk of exposure to smallpox virus. However, due to the high rate of serious adverse effects, the vaccine will only be made available to the CDC for the Strategic National Stockpile.
Stockpiles
Since smallpox has been eradicated, the public is not routinely vaccinated against the disease. The World Health Organization maintained a stockpile of 200 million doses in 1980, to guard against reemergence of the disease, but 99% of the stockpile was destroyed in the late 1980s when smallpox failed to return. After the September 11 attacks in 2001, many governments began building up vaccine stockpiles again for fear of bioterrorism. Several companies sold off their stockpiles of vaccines manufactured in the 1970s, and production of smallpox vaccines resumed. Aventis Pasteur discovered a stockpile from the 1950s and donated it to the U.S. government.Stockpiles of newer vaccines must be repurchased periodically since they carry expiration dates. The United States had received 269 million doses of ACAM2000 and 28 million doses of MVA-BN by 2019, but only 100 million doses of ACAM2000 and 65,000 doses of MVA-BN were still available from the stockpile at the start of the 2022 monkeypox outbreak. First-generation vaccines have no specified expiration date and remain viable indefinitely in deep freeze. The U.S. stockpile of WetVax was manufactured in 1956–1957 and maintained since then at −4 °F (−20 °C), and it was still effective when tested in 2004. Replicating vaccines also remain effective even at 1:10 dilution, so a limited number of doses can be stretched to cover a much larger population.
History
Variolation
The mortality of the severe form of smallpox – variola major – was very high without vaccination, up to 35% in some outbreaks. A method of inducing immunity known as inoculation, insufflation or "variolation" was practiced before the development of a modern vaccine and likely occurred in Africa and China well before the practice arrived in Europe. It may also have occurred in India, but this is disputed; other investigators contend the ancient Sanskrit medical texts of India do not describe these techniques. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. Inoculation for smallpox does not appear to have been widespread in China until the reign era of the Longqing Emperor (r. 1567–1572) during the Ming Dynasty. In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years".Variolation was also practiced throughout the latter half of the 17th century by physicians in Turkey, Persia, and Africa. In 1714 and 1716, two reports of the Ottoman Empire Turkish method of inoculation were made to the Royal Society in England, by Emmanuel Timoni, a doctor affiliated with the British Embassy in Constantinople, and Giacomo Pylarini. Source material tells us on Lady Mary Wortley Montagu; "When Lady Mary was in the Ottoman Empire, she discovered the local practice of inoculation against smallpox called variolation." In 1718 she had her son, aged five variolated. He recovered quickly. She returned to London and had her daughter variolated in 1721 by Charles Maitland, during an epidemic of smallpox. This encouraged the British Royal Family to take an interest and a trial of variolation was carried out on prisoners in Newgate Prison. This was successful and in 1722 Caroline of Ansbach, the Princess of Wales, allowed Maitland to vaccinate her children. The success of these variolations assured the British people that the procedure was safe.
Stimulated by a severe epidemic, variolation was first employed in North America in 1721. The procedure had been known in Boston since 1706, when preacher Cotton Mather learned it from Onesimus, a man he held as a slave, who – like many of his peers – had been inoculated in Africa before they were kidnapped. This practice was widely criticized at first. However, a limited trial showed six deaths occurred out of 244 who were variolated (2.5%), while 844 out of 5980 died of natural disease (14%), and the process was widely adopted throughout the colonies.The inoculation technique was documented as having a mortality rate of only one in a thousand. Two years after Kennedys description appeared, March 1718, Dr. Charles Maitland successfully inoculated the five-year-old son of the British ambassador to the Turkish court under orders from the ambassadors wife Lady Mary Wortley Montagu, who four years later introduced the practice to England.An account from letter by Lady Mary Wortley Montagu to Sarah Chiswell, dated 1 April 1717, from the Turkish Embassy describes this treatment:
The small-pox so fatal and so general amongst us is here entirely harmless by the invention of ingrafting (which is the term they give it). There is a set of old women who make it their business to perform the operation. Every autumn in the month of September, when the great heat is abated, people send to one another to know if any of their family has a mind to have the small-pox. They make parties for this purpose, and when they are met (commonly fifteen or sixteen together) the old woman comes with a nutshell full of the matter of the best sort of small-pox and asks what veins you please to have opened. She immediately rips open that you offer to her with a large needle (which gives you no more pain than a common scratch) and puts into the vein as much venom as can lye upon the head of her needle, and after binds up the little wound with a hollow bit of shell, and in this manner opens four or five veins. … The children or young patients play together all the rest of the day and are in perfect health till the eighth. Then the fever begins to seize them and they keep their beds two days, very seldom three. They have very rarely above twenty or thirty in their faces, which never mark, and in eight days time they are as well as before the illness. … There is no example of any one that has died in it, and you may believe I am very well satisfied of the safety of the experiment since I intend to try it on my dear little son. I am patriot enough to take pains to bring this useful invention into fashion in England, and I should not fail to write to some of our doctors very particularly about it if I knew any one of them that I thought had virtue enough to destroy such a considerable branch of their revenue for the good of mankind, but that distemper is too beneficial to them not to expose to all their resentment the hardy wight that should undertake to put an end to it. Perhaps if I live to return I may, however, have courage to war with them.
Early vaccination
In the early empirical days of vaccination, before Louis Pasteurs work on establishing the germ theory and Joseph Listers on antisepsis and asepsis, there was considerable cross-infection. William Woodville, one of the early vaccinators and director of the London Smallpox Hospital is thought to have contaminated the cowpox matter – the vaccine – with smallpox matter and this essentially produced variolation. Other vaccine material was not reliably derived from cowpox, but from other skin eruptions of cattle.During the earlier days of empirical experimentation in 1758, American Calvinist Jonathan Edwards died from a smallpox inoculation. Some of the earliest statistical and epidemiological studies were performed by James Jurin in 1727 and Daniel Bernoulli in 1766. In 1768, Dr John Fewster reported that variolation induced no reaction in persons who had had cowpox.
Edward Jenner was born in Berkeley, England as an orphan. As a young child, Jenner was variolated with the other schoolboys through parish funds, but nearly died due to the seriousness of his infection. Fed purgative medicine and going through the bloodletting process, Jenner was put in one of the variolation stables until he recovered. At the age of 13, he was apprenticed to apothecary Daniel Ludlow and later surgeon George Hardwick in nearby Sodbury. He observed that people who caught cowpox while working with cattle were known not to catch smallpox. Jenner assumed a causal connection but the idea was not taken up at that time. From 1770 to 1772 Jenner received advanced training in London at St Georges Hospital and as the private pupil of John Hunter, then returned to set up practice in Berkeley.Perhaps there was already an informal public understanding of some connection between disease resistance and working with cattle. The "beautiful milkmaid" seems to have been a frequent image in the art and literature of this period. But it is known for certain that in the years following 1770, at least six people in England and Germany (Sevel, Jensen, Jesty 1774, Rendall, Plett 1791) tested successfully the possibility of using the cowpox vaccine as an immunization for smallpox in humans.
Jenner sent a paper reporting his observations to the Royal Society in April 1797. It was not submitted formally and there is no mention of it in the Societys records. Jenner had sent the paper informally to Sir Joseph Banks, the Societys president, who asked Everard Home for his views. Reviews of his rejected report, published for the first time in 1999, were skeptical and called for further vaccinations. Additional vaccinations were performed and in 1798 Jenner published his work entitled An Inquiry into the Causes and Effects of the Variolae Vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire and Known by the Name of Cow Pox. It was an analysis of 23 cases including several individuals who had resisted natural exposure after previous cowpox. It is not known how many Jenner vaccinated or challenged by inoculation with smallpox virus; e.g. Case 21 included several children and adults. Crucially all of at least four whom Jenner deliberately inoculated with smallpox virus resisted it. These included the first and last patients in a series of arm-to-arm transfers. He concluded that cowpox inoculation was a safe alternative to smallpox inoculation, but rashly claimed that the protective effect was lifelong. This last proved to be incorrect. Jenner also tried to distinguish between True cowpox which produced the desired result and Spurious cowpox which was ineffective and/or produced severe reaction. Modern research suggests Jenner was trying to distinguish between effects caused by what would now be recognised as non-infectious vaccine, a different virus (e.g. paravaccinia/milkers nodes), or contaminating bacterial pathogens. This caused confusion at the time, but would become important criteria in vaccine development. A further source of confusion was Jenners belief that fully effective vaccine obtained from cows originated in an equine disease, which he mistakenly referred to as grease. This was criticised at the time but vaccines derived from horsepox were soon introduced and later contributed to the complicated problem of the origin of vaccinia virus, the virus in present-day vaccine.: 165–78 The introduction of the vaccine to the New World took place in Trinity, Newfoundland, in 1798 by Dr. John Clinch, boyhood friend and medical colleague of Jenner. The first smallpox vaccine in the United States was administered in 1799. The physician Valentine Seaman gave his children a smallpox vaccination using a serum acquired from Jenner. By 1800, Jenners work had been published in all the major European languages and had reached Benjamin Waterhouse in the United States – an indication of rapid spread and deep interest.: 262–67 Despite some concern about the safety of vaccination the mortality using carefully selected vaccine was close to zero, and it was soon in use all over Europe and the United States.
In 1804 the Balmis Expedition, an official Spanish mission commanded by Francisco Javier de Balmis, sailed to spread the vaccine throughout the Spanish Empire, first to the Canary Islands and on to Spanish Central America. While his deputy, José Salvany, took vaccine to the west and east coasts of Spanish South America, Balmis sailed to Manila in the Philippines and on to Canton and Macao on the Chinese coast. He returned to Spain in 1806. The vaccine was not carried in the form of flasks, but in the form of 22 orphaned boys, who were carriers of the live cowpox virus. After arrival, "other Spanish governors and doctors used enslaved girls to move the virus between islands, using lymph fluid harvested from them to inoculate their local populations".The first state to introduce compulsory vaccinations was the Principality of Lucca and Piombino on September 25, 1806. On August 26, 1807, Bavaria introduced a similar measure. Baden followed in 1809, Prussia in 1815, Württemberg in 1818, Sweden in 1816, England in 1867 and the German Empire in 1874 through the Reichs Vaccination Act. In Lutheran Sweden, the Protestant clergy played a pioneering role in voluntary smallpox vaccination as early as 1800. The first vaccination was carried out in Liechtenstein in 1801, and from 1812 it was mandatory to vaccinate.The question of who first tried cowpox inoculation/vaccination cannot be answered with certainty. Most, but still limited, information is available for Benjamin Jesty, Peter Plett and John Fewster. In 1774 Jesty, a farmer of Yetminster in Dorset, observing that the two milkmaids living with his family were immune to smallpox, inoculated his family with cowpox to protect them from smallpox. He attracted a certain amount of local criticism and ridicule at the time then interest waned. Attention was later drawn to Jesty, and he was brought to London in 1802 by critics jealous of Jenners prominence at a time when he was applying to Parliament for financial reward. During 1790–92 Peter Plett, a teacher from Holstein, reported limited results of cowpox inoculation to the Medical Faculty of the University of Kiel. However, the Faculty favoured variolation and took no action. John Fewster, a surgeon friend of Jenners from nearby Thornbury, discussed the possibility of cowpox inoculation at meetings as early as 1765. He may have done some cowpox inoculations in 1796 at about the same time that Jenner vaccinated Phipps. However, Fewster, who had a flourishing variolation practice, may have considered this option but used smallpox instead. He thought vaccination offered no advantage over variolation, but maintained friendly contact with Jenner and certainly made no claim of priority for vaccination when critics attacked Jenners reputation. It seems clear that the idea of using cowpox instead of smallpox for inoculation was considered, and actually tried in the late |
Smallpox vaccine | 18th century, and not just by the medical profession. Therefore, Jenner was not the first to try cowpox inoculation. However, he was the first to publish his evidence and distribute vaccine freely, provide information on selection of suitable material, and maintain it by arm-to-arm transfer. The authors of the official World Health Organization (WHO) account Smallpox and its Eradication assessing Jenners role wrote:: 264
Publication of the Inquiry and the subsequent energetic promulgation by Jenner of the idea of vaccination with a virus other than variola virus constituted a watershed in the control of smallpox for which he, more than anyone else deserves the credit.
As vaccination spread, some European countries made it compulsory. Concern about its safety led to opposition and then repeal of legislation in some instances.: 236–40 Compulsory infant vaccination was introduced in England by the 1853 Vaccination Act. By 1871, parents could be fined for non-compliance, and then imprisoned for non-payment.: 202–13 This intensified opposition, and the 1898 Vaccination Act introduced a conscience clause. This allowed exemption on production of a certificate of conscientious objection signed by two magistrates. Such certificates were not always easily obtained and a further Act in 1907 allowed exemption by a statutory declaration which could not be refused. Although theoretically still compulsory, the 1907 Act effectively marked the end of compulsory infant vaccination in England.: 233–38
In the United States vaccination was regulated by individual states, the first to impose compulsory vaccination being Massachusetts in 1809. There then followed sequences of compulsion, opposition and repeal in various states. By 1930 Arizona, Utah, North Dakota and Minnesota prohibited compulsory vaccination, 35 states allowed regulation by local authorities, or had no legislation affecting vaccination, whilst in ten states, including Washington, D.C. and Massachusetts, infant vaccination was compulsory.: 292–93 Compulsory infant vaccination was regulated by only allowing access to school for those who had been vaccinated. Those seeking to enforce compulsory vaccination argued that the public good overrode personal freedom, a view supported by the U.S. Supreme Court in Jacobson v. Massachusetts in 1905, a landmark ruling which set a precedent for cases dealing with personal freedom and the public good.Louis T. Wright, an African-American Harvard Medical School graduate (1915), introduced, while serving in the Army during World War I, intradermal, smallpox vaccination for the soldiers.
Developments in production
Until the end of the 19th century, vaccination was performed either directly with vaccine produced on the skin of calves or, particularly in England, with vaccine obtained from the calf but then maintained by arm-to-arm transfer; initially in both cases vaccine could be dried on ivory points for short-term storage or transport but increasing use was made of glass capillary tubes for this purpose towards the end of the century. During this period there were no adequate methods for assessing the safety of the vaccine and there were instances of contaminated vaccine transmitting infections such as erysipelas, tetanus, septicaemia and tuberculosis. In the case of arm-to-arm transfer there was also the risk of transmitting syphilis. Although this did occur occasionally, estimated as 750 cases in 100 million vaccinations,: 122 some critics of vaccination e.g. Charles Creighton believed that uncontaminated vaccine itself was a cause of syphilis. Smallpox vaccine was the only vaccine available during this period, and so the determined opposition to it initiated a number of vaccine controversies that spread to other vaccines and into the 21st century.Sydney Arthur Monckton Copeman, an English Government bacteriologist interested in smallpox vaccine investigated the effects on the bacteria in it of various treatments, including glycerine. Glycerine was sometimes used simply as a diluent by some continental vaccine producers. However, Copeman found that vaccine suspended in 50% chemically pure glycerine and stored under controlled conditions contained very few "extraneous" bacteria and produced satisfactory vaccinations. He later reported that glycerine killed the causative organisms of erysipelas and tuberculosis when they were added to the vaccine in "considerable quantity", and that his method was widely used on the continent. In 1896, Copeman was asked to supply "extra good calf vaccine" to vaccinate the future Edward VIII.Vaccine produced by Copemans method was the only type issued free to public vaccinators by the English Government Vaccine Establishment from 1899. At the same time the 1898 Vaccination Act banned arm-to-arm vaccination, thus preventing transmission of syphilis by this vaccine. However, private practitioners had to purchase vaccine from commercial producers. Although proper use of glycerine reduced bacterial contamination considerably the crude starting material, scraped from the skin of infected calves, was always heavily contaminated and no vaccine was totally free from bacteria. A survey of vaccines in 1900 found wide variations in bacterial contamination. Vaccine issued by the Government Vaccine Establishment contained 5,000 bacteria per gram, while commercial vaccines contained up to 100,000 per gram. The level of bacterial contamination remained unregulated until the Therapeutic Substances Act, 1925 set an upper limit of 5,000 per gram, and rejected any batch of vaccine found to contain the causative organisms of erysipelas or wound infections. Unfortunately glycerolated vaccine soon lost its potency at ambient temperatures which restricted its use in tropical climates. However, it remained in use into the 1970s where a satisfactory cold chain was available. Animals continued to be widely used by vaccine producers during the smallpox eradication campaign. A WHO survey of 59 producers, some of whom used more than one source of vaccine, found that 39 used calves, 12 used sheep and 6 used water buffalo, whilst only 3 made vaccine in cell culture and 3 in embryonated hens eggs.: 543–45 English vaccine was occasionally made in sheep during World War I but from 1946 only sheep were used.In the late 1940s and early 1950s, Leslie Collier, an English microbiologist working at the Lister Institute of Preventive Medicine, developed a method for producing a heat-stable freeze-dried vaccine in powdered form. Collier added 0.5% phenol to the vaccine to reduce the number of bacterial contaminants but the key stage was to add 5% peptone to the liquid vaccine before it was dispensed into ampoules. This protected the virus during the freeze drying process. After drying the ampoules were sealed under nitrogen. Like other vaccines, once reconstituted it became ineffective after 1–2 days at ambient temperatures. However, the dried vaccine was 100% effective when reconstituted after 6 months storage at 37 °C (99 °F) allowing it to be transported to, and stored in, remote tropical areas. Colliers method was increasingly used and, with minor modifications, became the standard for vaccine production adopted by the WHO Smallpox Eradication Unit when it initiated its global smallpox eradication campaign in 1967, at which time 23 of 59 manufacturers were using the Lister strain.: 545, 550 In a letter about landmarks in the history of smallpox vaccine, written to and quoted from by Derrick Baxby, Donald Henderson, chief of the Smallpox Eradication Unit from 1967 to 1977 wrote; "Copeman and Collier made an enormous contribution for which neither, in my opinion ever received due credit".Smallpox vaccine was inoculated by scratches into the superficial layers of the skin, with a wide variety of instruments used to achieve this. They ranged from simple needles to multi-pointed and multi-bladed spring-operated instruments specifically designed for the purpose.A major contribution to smallpox vaccination was made in the 1960s by Benjamin Rubin, an American microbiologist working for Wyeth Laboratories. Based on initial tests with textile needles with the eyes cut off transversely half-way he developed the bifurcated needle. This was a sharpened two-prong fork designed to hold one dose of reconstituted freeze-dried vaccine by capillarity. Easy to use with minimum training, cheap to produce ($5 per 1000), using one quarter as much vaccine as other methods, and repeatedly re-usable after flame sterilization, it was used globally in the WHO Smallpox Eradication Campaign from 1968.: 472–73, 568–72 Rubin estimated that it was used to do 200 million vaccinations per year during the last years of the campaign. Those closely involved in the campaign were awarded the "Order of the Bifurcated Needle". This, a personal initiative by Donald Henderson, was a lapel badge, designed and made by his daughter, formed from the needle shaped to form an "O". This represented "Target Zero", the objective of the campaign.
Eradication of smallpox
Smallpox was eradicated by a massive international search for outbreaks, backed up with a vaccination program, starting in 1967. It was organised and co-ordinated by a World Health Organization (WHO) unit, set up and headed by Donald Henderson. The last case in the Americas occurred in 1971 (Brazil), south-east Asia (Indonesia) in 1972, and on the Indian subcontinent in 1975 (Bangladesh). After two years of intensive searches, what proved to be the last endemic case anywhere in the world occurred in Somalia, in October 1977.: 526–37 A Global Commission for the Certification of Smallpox Eradication chaired by Frank Fenner examined the evidence from, and visited where necessary, all countries where smallpox had been endemic. In December 1979 they concluded that smallpox had been eradicated; a conclusion endorsed by the WHO General Assembly in May 1980.: 1261–62 However, even as the disease was being eradicated there still remained stocks of smallpox virus in many laboratories. Accelerated by two cases of smallpox in 1978, one fatal (Janet Parker), caused by an accidental and unexplained containment breach at a laboratory at the University of Birmingham Medical School, the WHO ensured that known stocks of smallpox virus were either destroyed or moved to safer laboratories. By 1979, only four laboratories were known to have smallpox virus. All English stocks held at St Marys Hospital, London were transferred to more secure facilities at Porton Down and then to the U.S. at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia in 1982, and all South African stocks were destroyed in 1983. By 1984, the only known stocks were kept at the CDC in the U.S. and the State Research Center of Virology and Biotechnology (VECTOR) in Koltsovo, Russia.: 1273–76 These states report that their repositories are for possible anti-bioweaponry research and insurance if some obscure reservoir of natural smallpox is discovered in the future.
Anti-terrorism preparation
Among more than 270,000 US military service members vaccinated with smallpox vaccine between December 2002, and March 2003, eighteen cases of probable myopericarditis were reported (all in first-time vaccinees who received the NYCBOH strain of vaccinia virus), an incidence of 7.8 per 100,000 during the 30 days they were observed. All cases were in young, otherwise healthy adult white men and all survived.In 2002, the United States government started a program to vaccinate 500,000 volunteer health care professionals throughout the country. Recipients were healthcare workers who would be first-line responders in the event of a bioterrorist attack. Many healthcare workers refused or did not pursue vaccination, worried about vaccine side effects, compensation and liability. Most did not see an immediate need for the vaccine. Some healthcare systems refused to participate, worried about becoming a destination for smallpox patients in the event of an epidemic. Fewer than 40,000 actually received the vaccine.On April 21, 2022, Public Services and Procurement Canada published a notice of tender seeking to stockpile 500,000 doses of smallpox vaccine in order to protect against a potential accidental or intentional release of the eradicated virus. On May 6, the contract was awarded to Bavarian Nordic for their Imvamune vaccine. These were deployed by the Public Health Agency of Canada for targeted vaccination in response to the 2022 monkeypox outbreak.
Origin
The origin of the modern smallpox vaccine has long been unclear, but horsepox was identified in the 2010s as the most likely ancestor.: 9 Edward Jenner had obtained his vaccine from a cow, so he named the virus vaccinia, after the Latin word for cow. Jenner believed that both cowpox and smallpox were viruses that originated in the horse and passed to the cow,: 52–53 and some doctors followed his reasoning by inoculating their patients directly with horsepox. The situation was further muddied when Louis Pasteur developed techniques for creating vaccines in the laboratory in the late 19th century. As medical researchers subjected viruses to serial passage, inadequate recordkeeping resulted in the creation of laboratory strains with unclear origins.: 4 By the late 19th century, it was unknown whether the vaccine originated from cowpox, horsepox, or an attenuated strain of smallpox.In 1939, Allan Watt Downie showed that the vaccinia virus was serologically distinct from the "spontaneous" cowpox virus. This work established vaccinia and cowpox as two separate viral species. The term vaccinia now refers only to the smallpox vaccine, while cowpox no longer has a Latin name. The development of whole genome sequencing in the 1990s made it possible to compare orthopoxvirus genomes and identify their relationships with each other. The horsepox virus was sequenced in 2006 and found to be most closely related to vaccinia. In a phylogenetic tree of the orthopoxviruses, horsepox forms a clade with vaccinia strains, and cowpox strains form a different clade.Horsepox is extinct in the wild, and the only known sample was collected in 1976. Because the sample was collected at the end of the smallpox eradication campaign, scientists considered the possibility that horsepox is a strain of vaccinia that had escaped into the wild. However, as more smallpox vaccines were sequenced, older vaccines were found to be more similar to horsepox than modern vaccinia strains. A smallpox vaccine manufactured by Mulford in 1902 is 99.7% similar to horsepox, closer than any previously known strain of vaccinia. Modern Brazilian vaccines with a documented introduction date of 1887, made from material collected in an 1866 outbreak of "cowpox" in France, are more similar to horsepox than other strains of vaccinia. Five smallpox vaccines manufactured in the United States in 1859–1873 are most similar to each other and horsepox, as well as the 1902 Mulford vaccine. One of the 1859–1873 vaccines was identified as a novel strain of horsepox, containing a complete gene from the 1976 horsepox sample that has deletions in vaccinia.
Terminology
The word "vaccine" is derived from Variolae vaccinae (i.e. smallpox of the cow), the term devised by Jenner to denote cowpox and used in the long title of his An enquiry into the causes and effects of Variolae vaccinae, known by the name of cow pox. Vaccination, the term which soon replaced cowpox inoculation and vaccine inoculation, was first used in print by Jenners friend, Richard Dunning in 1800. Initially, the terms vaccine/vaccination referred only to smallpox, but in 1881 Louis Pasteur proposed at the 7th International Congress of Medicine that to honour Jenner the terms be widened to cover the new protective inoculations being introduced. According to some sources the term was first introduced by Jenners friend Richard Dunning in 1800.
References
Further reading
External links
Smallpox US Centers for Disease Control and Prevention
Smallpox Center for Infectious Disease Research and Policy
"Monkeypox Update: FDA Authorizes Emergency Use of Jynneos Vaccine to Increase Vaccine Supply". U.S. Food and Drug Administration. 10 August 2022. |
Vosoritide | Vosoritide, sold under the brand name Voxzogo, is a medication used for the treatment of achondroplasia.The most common side effects include injection site reactions (such as swelling, redness, itching, or pain), vomiting, and decreased blood pressure.Achondroplasia is a genetic condition that causes severely short stature and disproportionate growth. The average height of an adult with achondroplasia is approximately four feet. People with achondroplasia have a genetic mutation that causes a certain growth regulation gene called fibroblast growth factor receptor 3 to be overly active, which prevents normal bone growth. Vosoritide works by binding to a specific receptor called natriuretic peptide receptor-B that reduces the growth regulation genes activity and stimulates bone growth.Vosoritide was approved for medical use in the European Union in August 2021, and in the United States in November 2021.
Medical uses
In the European Union, vosoritide is indicated for the treatment of achondroplasia in people two years of age and older whose epiphyses are not closed.In the United States, vosoritide is indicated to increase growth in children five years of age and older with achondroplasia and open epiphyses (growth plates).
Mechanism of action
Vosoritide works by binding to a receptor (target) called natriuretic peptide receptor type B (NPR-B), which reduces the activity of fibroblast growth factor receptor 3 (FGFR3). FGFR3 is a receptor that normally down-regulates cartilage and bone growth when activated by one of the proteins known as acidic and basic fibroblast growth factor. It does so by inhibiting the development (cell proliferation and differentiation) of chondrocytes, the cells that produce and maintain the cartilaginous matrix which is also necessary for bone growth. Children with achondroplasia have one of several possible FGFR3 mutations resulting in constitutive (permanent) activity of this receptor, resulting in overall reduced chondrocyte activity and thus bone growth.The protein C-type natriuretic peptide (CNP), naturally found in humans, reduces the effects of over-active FGFR3. Vosoritide is a CNP analogue with the same effect but prolonged half-life, allowing for once-daily administration.
Chemistry
Vosoritide is an analog of CNP. It is a peptide consisting of the amino acids proline and glycine plus the 37 C-terminal amino acids from natural human CNP. The complete peptide sequence is
PGQEHPNARK YKGANKKGLS KGCFGLKLDR IGSMSGLGCwith a disulfide bridge between positions 23 and 39 (underlined). The drug must be administered by injection as it would be rendered ineffective by the digestive system if taken by mouth.
History
Vosoritide was developed by BioMarin Pharmaceutical and, being the only available causal treatment for this condition, got orphan drug status in the US as well as the European Union. It was in Phase II clinical trials in around 2015.The safety and efficacy of vosoritide in improving growth were evaluated in a year-long, double-blind, placebo-controlled, phase III study in participants five years and older with achondroplasia who have open epiphyses. In the study, 121 participants were randomly assigned to receive either vosoritide injections under the skin or a placebo. Researchers measured the participants annualized growth velocity, or rate of height growth, at the end of the year. Participants who received vosoritide grew an average 1.57 centimeters taller compared to those who received a placebo. The U.S. Food and Drug Administration (FDA) granted the approval of Voxzogo to BioMarin.
Society and culture
Controversy
Some people with achondroplasia, as well as parents of children with this condition, have reacted to vosoritides study results by saying that dwarfism is not a disease and consequently does not need treatment.
Research
Vosoritide has resulted in increased growth in a clinical trial with 26 children. The ten children receiving the highest dose grew 6.1 centimetres (2.4 in) in six months, compared to 4.0 centimetres (1.6 in) in the six months before the treatment (p=0.01). The body proportions, more specifically the ratio of leg length to upper body length – which is lower in achondroplasia patients than in the average population – was not improved by vosoritide, but not worsened either.As of September 2015, it is not known whether the effect of the drug will last long enough to result in normal body heights, or whether it will reduce the occurrence of achondroplasia associated problems such as ear infections, sleep apnea or hydrocephalus. This, together with the safety of higher doses, is to be determined in further studies.
References
External links
"Vosoritide". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03197766 for "A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia" at ClinicalTrials.gov |
Glibenclamide | Glibenclamide, also known as glyburide, is an antidiabetic medication used to treat type 2 diabetes. It is recommended that it be taken together with diet and exercise. It may be used with other antidiabetic medication. It is not recommended for use by itself in type 1 diabetes. It is taken by mouth.Common side effects include nausea and heartburn. Serious side effects may include angioedema and low blood sugar. It is generally not recommended during pregnancy but can be used during breastfeeding. It is in the sulfonylureas class of medications and works by increasing the release of insulin from the pancreas.Glibenclamide was discovered in 1969 and approved for medical use in the United States in 1984. It is available as a generic medication. In 2019, it was the 254th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Medical uses
Glibenclamide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.It is not as good as either metformin or insulin in those who have gestational diabetes.
Side effects
Frequently reported side effects include: nausea, heartburn, weight gain, and bloating. The medication is also a major cause of medication-induced hypoglycemia. The risk is greater than with other sulfonylureas.Glibenclamide may be not recommended in those with G6PD deficiency, as it may cause acute hemolysis.
Pregnancy and breastfeeding
It is generally not recommended during pregnancy but can be used during breastfeeding.
Mechanism of action
The medication works by binding to and inhibiting the ATP-sensitive potassium channels (KATP) inhibitory regulatory subunit sulfonylurea receptor 1 (SUR1) in pancreatic beta cells. This inhibition causes cell membrane depolarization, opening voltage-dependent calcium channels. This results in an increase in intracellular calcium in the pancreatic beta cell and subsequent stimulation of insulin release.After a cerebral ischemic insult, the blood–brain barrier is broken and glibenclamide can reach the central nervous system. Glibenclamide has been shown to bind more efficiently to the ischemic hemisphere. Moreover, under ischemic conditions SUR1, the regulatory subunit of the KATP- and the NCCa-ATP-channels, is expressed in neurons, astrocytes, oligodendrocytes, endothelial cells and by reactive microglia.As per the research papers, this sulphonylurea drugs also has extra hepatic effects. It works by inhibiting the enzyme Carnityl Acyl Transferase I (CAT-I) indirectly which is present in the mitochondria. This prevents the transport of long chain fatty acids into the mitochondria for beta-oxidation. This prevents hyperglycemia for which it is prescribed.
History
It was developed in 1966 in a cooperative study between Boehringer Mannheim (now part of Roche) and Hoechst (now part of Sanofi-Aventis).
Society and culture
Names
Glibenclamide is available as a generic medication, is manufactured by many pharmaceutical companies and is sold under many brand names including Gliben-J, Daonil, Diabeta, Euglucon, Gilemal, Glidanil, Glybovin, Glynase, Maninil, Micronase and Semi-Daonil. It is also available in a fixed-dose combination drug with metformin that is sold under various trade names, e.g. Bagomet Plus, Benimet, Glibomet, Gluconorm, Glucored, Glucovance, Metglib and many others.
References
External links
"Glyburide". Drug Information Portal. U.S. National Library of Medicine. |
Beyaz | Beyaz may refer to:
Beyaz, Iran, a village in Kerman Province, Iran
Beyaz Show, Turkish talk show
Beyazıt Öztürk, the host, also known as Beyaz
Beyaz peynir, Turkish cuisine
Eren Beyaz, Turkish basketball player
Beyaz (drug), an oral contraceptive
Beyazıt Öztürk |
Tezepelumab | Tezepelumab, sold under the brand name Tezspire, is a human monoclonal antibody used for the treatment of asthma. Tezepelumab blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine that has been suggested to be critical in the initiation and persistence of airway inflammation.The most common side effects include arthralgia (joint pain) and pharyngitis (sore throat).Tezepelumab was approved for medical use in the United States in December 2021, and in the European Union in September 2022.
Medical uses
Tezepelumab is indicated for the add-on maintenance treatment of people aged twelve years and older with severe asthma.
History
Two main studies including over 1,500 adults and adolescents with inadequately controlled asthma showed that tezepelumab was effective in reducing the number of severe asthma flare‑ups.
Society and culture
Legal status
On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tezspire, intended as add-on treatment in adult and adolescent patients with severe asthma. The applicant for this medicinal product is AstraZeneca AB. Tezepelumab was approved for medical use in the European Union in September 2022.
Research
It is being studied for the treatment of chronic obstructive pulmonary disease, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria and eosinophilic esophagitis (EoE).In phase III trials, tezepelumab demonstrated efficacy compared to placebo for patients with severe, uncontrolled asthma.Structural studies by X-ray crystallography showed that tezepelumab competes against a critical part of the TSLPR binding site on TSLP.
References
External links
"Tezepelumab". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02054130 for "Study to Evaluate the Efficacy and Safety of MEDI9929 (AMG 157) in Adult Subjects With Inadequately Controlled, Severe Asthma" at ClinicalTrials.gov
Clinical trial number NCT03347279 for "Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma (NAVIGATOR)" at ClinicalTrials.gov |
Enoxaparin sodium | Enoxaparin sodium, sold under the brand name Lovenox among others, is an anticoagulant medication (blood thinner). It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following certain types of surgery. It is also used in those with acute coronary syndrome (ACS) and heart attacks. It is given by injection just under the skin or into a vein. It is also used during hemodialysis.Common side effects include bleeding, fever, and swelling of the legs. Bleeding may be serious especially in those who are undergoing a spinal tap. Use during pregnancy appears to be safe for the baby. Enoxaparin is in the low molecular weight heparin family of medications.Enoxaparin was first made in 1981 and approved for medical use in 1993. It is on the World Health Organizations List of Essential Medicines. Enoxaparin is sold under several brand names and is available as a generic medication. Enoxaparin is made from heparin. In 2017, it was the 299th most commonly prescribed medication in the United States, with more than one million prescriptions.
Medical uses
Treatment of unstable angina (UA) and non-Q-wave myocardial infarction (NQMI), administered concurrently with aspirin
DVT and pulmonary embolism prophylaxis in bed-ridden patients
DVT prophylaxis in knee replacement surgery
DVT prophylaxis in hip replacement surgery
DVT prophylaxis in abdominal surgery
Treatment of DVT with or without pulmonary embolism
Treatment of DVT inpatient, with ST-segment elevation myocardial infarction (STEMI)
Bridging treatment for those with INR below therapeutic range
Monitoring
Enoxaparin has predictable absorption, bioavailability, and distribution therefore monitoring is not typically done. However, there are instances where monitoring may be beneficial for special populations, for example individuals with kidney insufficiency or those that are obese. In this case, anti-Xa units can be measured and dosing adjusted accordingly.
Reversal agent
Protamine sulfate is less effective at reversing enoxaparin compared to heparin, with a maximum neutralization of approximately 60% of the anti-factor Xa effect.
Pregnancy
Enoxaparin is a FDA pregnancy category B drug which means enoxaparin is not expected to cause harm to an unborn baby when used during pregnancy. This statement is based on reproductive studies involving pregnant rats and rabbits. No birth defects or toxic effects to an unborn fetus due to enoxaparin were observed during these animals studies. However a humans response to enoxaparin might be different from that of a small animal, therefore enoxaparin should be used during pregnancy only if there is a definite need.
Enoxaparin does not cross the placenta therefore it is unlikely an unborn baby would be exposed to it.
Some fetal deaths have been reported by women who used enoxaparin during pregnancy, but it is unclear if enoxaparin caused these deaths.
Pregnant woman on enoxaparin should be monitored on a regular basis for bleeding and/or "excessive anticoagulation" especially when the delivery date is approaching. The risk of hemorrhage is higher during delivery if the person is still using enoxaparin and this could endanger the life of the baby and/or the mother.
The multiple-dose vials of the brand name enoxaparin (Lovenox) contain 15 mg benzyl alcohol per 1 mL as a preservative. Premature infants who have been given large amounts of benzyl alcohol (99–405 mg/kg/day) have experienced "gasping syndrome".
Although enoxaparin is used to prevent blood clots, pregnancy alone can raise a womans risk of clotting.
Side effects
Uncommon (<1%)
In people with unstable angina or non-Q-wave myocardial infarction:
Atrial fibrillation, heart failure, lung edema, pneumonia: ≥ 0.5%vCommon (>1%)
Thrombocytopenia, i.e. can be associated with heparin-induced thrombocytopenia (0.5-5.0% of persons treated for at least five days)
Elevations in serum aminotransferases: 5.9%-6.1%
In people undergoing abdominal or colorectal surgery:
Bleeding, anemia, ecchymosis: ≥ 2%
In persons undergoing hip or knee replacement:
Fever, nausea, anemia, edema, peripheral edema: ≥ 2%
In persons with severely restricted mobility during acute illness:
Dyspnea, thrombocytopenia, confusion, diarrhea, nausea: ≥ 2%
In people being treated for deep vein thrombosis:
Injection site hemorrhage, injection site pain, hematuria: ≥ 2%Frequency under investigation
Local reactions: local irritation, pain, hematoma, ecchymosis, erythema
Bleeding
Hyperkalemia
Transaminitis
Hemorrhage
Boxed warning
The FDA issued a revision to the boxed warning for enoxaparin in October 2013. The revision recommends exercising caution regarding when spinal catheters are placed and removed in persons taking enoxaparin for spinal puncture or neuroaxial anesthesia. It may be necessary to delay anticoagulant dosing in these persons in order to decrease the risk for spinal or epidural hematomas, which can manifest as permanent or long-term paralysis. Persons at risk for hematomas may present with indwelling epidural catheters, concurrent use of medications that worsen bleeding states such as non-steroidal anti-inflammatory drugs (NSAIDs), or a past medical history of epidural or spinal punctures, spinal injury, or spinal deformations. The FDA recommends that at-risk persons be monitored for bleeding and neurological changes.
Pharmacology
Mechanism of action
Enoxaparin binds to and potentiates antithrombin (a circulating anticoagulant) to form a complex that irreversibly inactivates clotting factor Xa. It has less activity against factor IIa (thrombin) compared to unfractionated heparin (UFH) due to its low molecular weight.
Pharmacokinetics
Absorption: Bioavailability (subcutaneous injection) ~ 100%Distribution: Volume of distribution (anti-Factor Xa activity) = 4.3 litersMetabolism: Enoxaparin is metabolized in the liver into low molecular weight species by either or both desulfation and depolymerization.Elimination: A single dose of a subcutaneous injection of enoxaparin has an elimination half-life of 4.5 hours. Approximately 10–40% of the active and inactive fragments from a single dose are excreted by the kidneys. Dose adjustments based on kidney function are necessary in persons with reduced kidney function.
Drug class
Enoxaparin belongs to the class of drugs known as low molecular weight heparins. Other drugs in this class include dalteparin, fondaparinux and tinzaparin.
Biosimilars
In September 2016, Inhixa and Thorinane were approved for use in the European Union. Thorinane was withdrawn from the market in October 2019.In March 2017, Enoxaparin BECAT, Laboratorios ROVI (Spain) obtained marketing authorization in twenty six countries in Europe. The product is now available in Europe.In October 2020, Noromby and Noromby HP, were approved for medical use in Canada.In November 2020, and Inclunox HP were approved for medical use in Canada.In December 2020, Redesca and Redesca HP were approved for medical use in Canada.
References
External links
"Enoxaparin sodium". Drug Information Portal. U.S. National Library of Medicine. |
Nexafed | Nexafed is a formulation of pseudoephedrine developed by Acura Pharmaceuticals used to deter the use of the pseudoephedrine contained in the product for illicit methamphetamine synthesis. Nexafed uses a polymer matrix that forms a thick gel when hydrated, preventing the extraction of pseudoephedrine. Nexafed is the only meth-resistant formulation of pseudoephedrine that shows therapeutic equivalence to Sudafed.It is sold at various pharmacies in the US, including Fruth Pharmacy and Kroger, particularly in communities where illicit methamphetamine production is an issue.
References
== External links == |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.