page_title
stringlengths 1
91
| page_text
stringlengths 0
34.2k
|
|---|---|
Atropine/diphenoxylate | Diphenoxylate/atropine, also known as co-phenotrope, is a combination of the medications diphenoxylate and atropine, used to treat diarrhea. It should not be used in those in whom Clostridioides difficile infection is a concern. It is taken by mouth. Onset is typically within an hour.Side effects may include abdominal pain, angioedema, glaucoma, heart problems, feeling tired, dry mouth, and trouble seeing. It is unclear if use in pregnancy is safe and use when breastfeeding may result in side effects in the baby. It works by decreasing contractions of the bowel.The combination was approved for medical use in the United States in 1960. It is available as a generic medication. In 2019, it was the 339th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions. It is sold under the brand name Lomotil among others. The medication is in Schedule V in the United States.
Contraindications
Absolute contraindications are:
Patients under 6 years of age
Allergy to diphenoxylate or atropine
Diarrhea associated with pseudomembranous enterocolitis, diarrhea caused by antibiotic treatment, or diarrhea caused by enterotoxin-producing bacteria, such as Clostridium difficile
Obstructive jaundice
Side effects
The drug combination is generally safe in short-term use and with recommended dosage. In doses used for the treatment of diarrhea, whether acute or chronic, diphenoxylate has not produced addiction.
It may cause several side-effects, such as dry mouth, headache, constipation and blurred vision. Since it may also cause drowsiness or dizziness, it should not be used by motorists, operators of hazardous machinery, etc. It is not recommended for children under two years of age.
Interactions
Interactions with other drugs:
Antidepressants (e.g. Elavil, Prozac)
Monoamine oxidase inhibitors (e.g. Nardil, Parnate)
Opioid analgesics
Sedatives (e.g. Ambien, Sonata)Diarrhea that is caused by some antibiotics such as cefaclor, erythromycin or tetracycline can worsen.
Toxicity
It may cause serious health problems when overdosed. Signs and symptoms of adverse effects may include any or several of the following: convulsions, respiratory depression (slow or stopped breathing), dilated eye pupils, nystagmus (rapid side-to-side eye movements), erythema (flushed skin), gastrointestinal constipation, nausea, vomiting, paralytic ileus, tachycardia (rapid pulse), drowsiness and hallucinations. Symptoms of toxicity may take up to 12 hours to appear.
Treatment of overdose must be initiated immediately after diagnosis and may include the following: ingestion of activated charcoal, laxative and a counteracting medication (narcotic antagonist).
Mechanism of action
Diphenoxylate is anti-diarrheal and atropine is anticholinergic. A subtherapeutic amount of atropine sulfate is present to discourage deliberate overdosage. Atropine has no anti-diarrheal properties, but will cause tachycardia when overused. The medication diphenoxylate works by slowing down the movement of the intestines. In some cases it has been shown to ease symptoms of opiate withdrawal.
History
Diphenoxylate was developed in 1954 as part of US Navy and CIA-funded research on nonaddictive substitutes for codeine.
Society and culture
Names
The UK British Approved Name (BAN) generic name for diphenoxylate and atropine is co-phenotrope.As of 2018, the combination drug is marketed in the US and some other countries under the following brands: Atridol, Atrolate, Atrotil, Co-Phenotrope, Dhamotil, Dimotil, Intard, Logen, Lomanate, Lomotil, Lonox, and Reasec.
Legal status
In the United States, it is classified as a Schedule V controlled substance by federal law, and is available only for a medical purpose.
References
External links
"Atropine sulfate mixture with diphenoxylate hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Deferiprone | Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and had been licensed for use in the European Union for many years while awaiting approval in Canada and in the United States. On October 14, 2011, it was approved for use in the US under the FDAs accelerated approval program.The most common side effects include red-brown urine (showing that iron is being removed through the urine), nausea (feeling sick), abdominal pain (stomach ache) and vomiting. Less common but more serious side effects are agranulocytosis (very low levels of granulocytes, a type of white blood cell) and neutropenia (low levels of neutrophils, a type of white blood cell that fights infections).
Medical uses
Deferiprone monotherapy is indicated in the European Union for the treatment of iron overload in those with thalassaemia major when current chelation therapy is contraindicated or inadequate.Deferiprone in combination with another chelator is indicated in the European Union in those with thalassaemia major when monotherapy with any iron chelator is ineffective, or when prevention or treatment of life-threatening consequences of iron overload (mainly cardiac overload) justifies rapid or intensive correction.
Controversy
Deferiprone was at the center of a protracted struggle between Nancy Olivieri, a Canadian haematologist and researcher, and the Hospital for Sick Children and the pharmaceutical company Apotex, that started in 1996, and delayed approval of the drug in North America. Olivieris data suggested deferiprone leads to progressive hepatic fibrosis.
History
Deferiprone was approved for medical use in the European Union in August 1999.It was approved for medical use in the United States in October 2011. Generic versions were approved in August 2019.The safety and effectiveness of deferiprone is based on an analysis of data from twelve clinical studies in 236 participants. Participants in the study did not respond to prior iron chelation therapy. Deferiprone was considered a successful treatment for participants who experienced at least a 20 percent decrease in serum ferritin, a protein that stores iron in the body for later use. Half of the participants in the study experienced at least a 20 percent decrease in ferritin levels.
References
External links
"Deferiprone". Drug Information Portal. U.S. National Library of Medicine. |
Pimavanserin | Pimavanserin (ACP-103; BVF-036), sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinsons disease psychosis and is also being studied for the treatment of Alzheimer’s disease psychosis, schizophrenia, agitation, and major depressive disorder. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist.
Pharmacology
Pharmacodynamics
Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki 0.44 nM). Pimavanserin shows low binding to σ1 receptors (Ki 120 nM) and has no appreciable affinity (Ki >300 nM) to serotonin 5-HT2B, dopamine (including D2), muscarinic acetylcholine, histamine, or adrenergic receptors, or to calcium channels.Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor, with 40-fold selectivity for this site over the 5-HT2C receptor and no significant affinity or activity at the 5-HT2B receptor or dopamine receptors.
History
Development
Pimavanserin was developed by Acadia Pharmaceuticals.
Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics. The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012, and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of risperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms.The drug met expectations for a Phase III clinical trial for the treatment of Parkinsons disease psychosis, and has completed Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadias New Drug Application for pimavanserin.
FDA Approval
On April 29, 2016 Nuplazid (pimavanserin) was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. The non-binding advisory panel recommendation of 12-to-2 in support of approval that preceded the FDA approval action noted that the drug met an important need, despite its only providing modest benefits and posing serious safety issues.On June 29, 2018 the FDA approved new dosages of pimavanserin to treat hallucinations and delusions associated with Parkinson’s disease psychosis. A 34 mg capsule and 10 mg tablet formulation were approved. Previously, patients were required to take two 17 mg tablets to achieve the recommenced 34 mg dose per day. The 10 mg dose is indicated for patients also taking CYP3A4 inhibitors (eg. ketoconazole).
HARMONY-Trial
In a phase 3, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov number NTC03325556) pimavanserin was applicated in patients with dementia-related psychosis. The dementia was caused by Alzheimers disease, dementia with Lewy bodies, frontotemporal dementia, Parkinsons disease with dementia, or vascular dementia. The trial was stopped early for efficacy. Patients treated with pimavanserin had a relapse in 13%, without in 28% (hazard ratio 0.35; 95% CI = 0.17-0.73; p = 0.005). Longer and larger trials are suggested.
Controversy
On April 9, 2018, CNN reported that some in the FDA were concerned that Nuplazid was "risky" when it was approved and noted there have been a substantial number of deaths reported by those using the drug. The story further noted that the drug was approved based on a "six-week study of about 200 patients". The FDA began post-market monitoring of the drug to assess the validity of these claims. On September 20, 2018, the FDA stated their review "did not identify any new or unexpected safety findings with Nuplazid, or findings that are inconsistent with the established safety profile currently described in the drug label".
Research
Pimavanserin is under development for the treatment of major depressive disorder, schizophrenia, agitation, and psychiatric disorders. As of March 2022, pimavanserin is in phase 3 clinical trials for major depressive disorder and schizophrenia, phase 2 trials for agitation, and phase 1 trials for psychiatric disorders. It was also under development for the treatment of insomnia, drug-induced akathisia, and drug-induced dyskinesia, but development for these indications was discontinued.
See also
List of investigational antipsychotics
List of investigational antidepressants
Ketanserin
References
Further reading
McGuire, Donna (May 10, 2017). "New drug can ease Parkinsons psychosis". Chicago Tribune. p. 5 (section 5) – via Newspapers.com.
External links
Nuplazid (pimavanserin) Official Site
Pimanvaserin - AdisInsight |
Glucarpidase | Glucarpidase (Voraxaze) is a medication used for the treatment of elevated levels of methotrexate (defined as 1 micromol/L) during treatment of cancer patients who have impaired kidney function (and thus cannot reduce the drug to safe levels sufficiently after the drug has been given). Glucarpidase is an enzyme that inactivates methotrexate rapidly after injection. Because this agent reduces systemic levels of methotrexate and could therefore interfere with efficacy, it is not recommended for use in patients with normal or only slightly impaired kidney function or in whom serum levels are normal. The main antidote for methotrexate overdoses prior to the approval of this drug were high doses of folinic acid. However, this agent was not always sufficient at preventing kidney failure due to methotrexate. Glucarpidase also degrades folinic acid so the two should not be used together (within two hours of one another).
Glucarpidase, a recombinant form of the bacterial enzyme carboxypeptidase G2 converts methotrexate into glutamate and 2,4-diamino-N(10)-methylpteroic acid. These are generally much less toxic and are excreted largely by the liver. One case series in children has found that high-dose methotrexate therapy can be resumed after an instance of methotrexate-induced acute kidney injury successfully treated with glucarpidase.Adverse effects include mild and include numbness, tingling, flushing, nausea, vomiting, itching, and headache.
Society and culture
Legal status
In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Voraxaze, intended to reduce toxic plasma methotrexate concentration. The applicant for this medicinal product is SERB SAS. Glucarpidase was approved for medical use in the European Union in January 2022.
References
External links
"Glucarpidase". Drug Information Portal. U.S. National Library of Medicine. |
Zirgan | Zirgan (Russian: Зирган) is a rural locality (a selo) and the administrative centre of Zirgansky Selsoviet, Meleuzovsky District, Bashkortostan, Russia. The population was 4,125 as of 2010. There are 35 streets.
Geography
Zirgan is located 33 km north of Meleuz (the districts administrative centre) by road. Sabashevo is the nearest rural locality.
== References == |
Penciclovir | Penciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections. It is a nucleoside analogue which exhibits low toxicity and good selectivity. Because penciclovir is absorbed poorly when given orally (by mouth) it is more often used as a topical treatment. It is the active ingredient in the cold sore medications Denavir (NDC 0135-0315-52), Vectavir and Fenivir. Famciclovir is a prodrug of penciclovir with improved oral bioavailability.
Penciclovir was approved for medical use in 1996.
Medical use
In herpes labialis, the duration of healing, pain and detectable virus is reduced by up to one day, compared with the total duration of 2–3 weeks of disease presentation.
Mechanism of action
Penciclovir is inactive in its initial form. Within a virally infected cell a viral thymidine kinase adds a phosphate group to the penciclovir molecule; this is the rate-limiting step in the activation of penciclovir. Cellular (human) kinases then add two more phosphate groups, producing the active penciclovir triphosphate. This activated form inhibits viral DNA polymerase, thus impairing the ability of the virus to replicate within the cell.
The selectivity of penciclovir may be attributed to two factors. First, cellular thymidine kinases phosphorylate the parent form significantly less rapidly than does the viral thymidine kinase, so the active triphosphate is present at much higher concentrations in virally infected cells than in uninfected cells. Second, the activated drug binds to viral DNA polymerase with a much higher affinity than to human DNA polymerases. As a result, penciclovir exhibits negligible cytotoxicity to healthy cells.
The structure and mode of action of penciclovir are very similar to that of other nucleoside analogues, such as the more widely used aciclovir. A difference between aciclovir and penciclovir is that the active triphosphate form of penciclovir persists within the cell for a much longer time than the activated form of aciclovir, so the concentration within the cell of penciclovir will be higher given equivalent cellular doses.
See also
Nucleoside analogue
Famciclovir
== References == |
Isosorbide mononitrate | Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally less preferred than beta blockers or calcium channel blockers. It is taken by mouth.Common side effects include headache, low blood pressure with standing, blurry vision, and skin flushing. Serious side effects may include low blood pressure especially if also exposed to PDE5 inhibitors such as sildenafil. Use is not recommended in pregnancy. It is believed to work by relaxing smooth muscle within blood vessels.It was patented in 1971 and approved for medical use in 1981. It is available as a generic medication. In 2019, it was the 123rd most commonly prescribed medication in the United States, with more than 5 million prescriptions.
Medical uses
Isosorbide mononitrate is a nitrate-class drug used for the prevention of angina pectoris. The sublingual patch has an onset of five minutes and a duration of action of one hour. The oral, slow release tablet has an onset of thirty minutes, and a duration of 8 hours.
Adverse effects
The following adverse effects have been reported in studies with isosorbide mononitrate:
Very common: Headache predominates (up to 30%) necessitating withdrawal of 2 to 3% of patients, but the incidence reduces rapidly as treatment continues.Common: Tiredness, sleep disturbances (6%) and gastrointestinal disturbances (6%) have been reported during clinical trials with isosorbide mononitrate modified-release tablets, but at a frequency no greater than for placebo. Hypotension (4 to 5%), poor appetite (2.5%), nausea (1%)Adverse effects associated with the clinical use of the drug are as expected with all nitrate preparations. They occur mainly in the early stages of treatment.Hypotension (4%) with symptoms such as dizziness and nausea (1%) have been reported. In general, these symptoms disappear during long-term treatment.Other reactions that have been reported with isosorbide mononitrate-modified release tablets include tachycardia, vomiting, diarrhoea, vertigo, and heartburn.
Interactions
Sildenafil (Viagra). Concomitant administration of isosorbide mononitrate and sildenafil (Viagra) or other phosphodiesterase inhibitors (Tadalafil and Udenafil) can potentiate the vasodilatory effect of isosorbide mononitrate with the potential result of serious side-effects such as syncope or myocardial infarction. Life-threatening hypotension may also occur. Therefore, sildenafil should not be given to patients already receiving isosorbide mononitrate therapy.
Sulfhydryl-containing compounds. The metabolism of organic nitrates to nitric oxide is dependent on the presence of sulfhydryl groups in the muscle. The combination of oral N-acetylcysteine and a single dose of sustained-release isosorbide mononitrate 60 mg significantly prolonged the total exercise time in patients with angina pectoris and angiographically proven significant coronary artery disease, when compared with isosorbide mononitrate alone. Concomitant administration of other exogenous sources of sulfhydryl groups such as methionine and captopril may produce a similar interaction.
Phenylalkylamine calcium antagonists. The addition of a calcium channel blocker of the verapamil type, such as gallopamil 75 mg, has been shown to further improve left ventricular functional parameters when given in combination with isosorbide mononitrate in a sustained-release formulation.
Propranolol. The addition of isosorbide mononitrate to propranolol treatment in patients with cirrhosis and portal hypertension caused a marked fall in portal pressure, a reduction in hepatic blood flow, cardiac output and mean arterial blood pressure, but no additional change in azygos blood flow. The additional effect of isosorbide mononitrate was especially evident in patients whose portal pressure was not reduced by propranolol.
Calcium antagonists (general). Marked symptomatic orthostatic hypotension has been reported when calcium antagonists and organic nitrates were used in combination. Dose adjustments of either class of agent may be necessary.
Brand names
It is sold in the US by Lannett Company, under the trade name Monoket, and was also sold in the US under the name Imdur, and marketed in the UK under the trade names: Isotard, Monosorb, Chemydur. In India, this drug is available under the brand names of Ismo, Imdur, Isonorm, Monotrate, Solotrate, and Monit. In Russia it is occasionally used under the brand names Monocinque and Pektrol. In Australia, this drug is available under the brand name Duride.
References
External links
"Isosorbide mononitrate". Drug Information Portal. U.S. National Library of Medicine. |
Quazepam | Quazepam, sold under brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively (and uniquely) selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectively). Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.It was patented in 1970 and came into medical use in 1985.
Medical uses
Quazepam is used for short-term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as temazepam. It had a fewer incidence of side effects than temazepam, including less sedation, amnesia, and less motor-impairment. Usual dosage is 7.5 to 15 mg orally at bedtime.Quazepam is effective as a premedication prior to surgery.
Side effects
Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines. The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors.
Ataxia
Daytime somnolence
Hypokinesia
Cognitive and performance impairmentsIn September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Tolerance and dependence
Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as triazolam. Quazepam causes significantly less drug tolerance and less withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines. Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life. Short-acting hypnotics often cause next day rebound anxiety. Quazepam due to its pharmacological profile does not cause next day rebound withdrawal effects during treatment.No firm conclusions can be drawn, however, whether long-term use of quazepam does not produce tolerance as few, if any, long-term clinical trials extending beyond 4 weeks of chronic use have been conducted. Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died however, in the diazepam-treated monkeys. In addition it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long-acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines.
Special precautions
Benzodiazepines require special precaution if used in the during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.Quazepam and its active metabolites are excreted into breast milk.Accumulation of one of the active metabolites of quazepam, N-desalkylflurazepam, may occur in the elderly. A lower dose may be required in the elderly.
Elderly
Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next day impairments. However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long-acting metabolites. Thus the medical literature shows conflicts on quazepams side effect profile. A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects.
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including quazepam, the nonbenzodiazepine sedative/hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative/hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.
Interactions
The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the hypnotic effect of quazepam. If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.
Pharmacology
Quazepam is a trifluoroalkyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABAA α1 subunit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies.Quazepam is selective for type I benzodiazepine receptors containing the α1 subunit, similar to other drugs such as zaleplon and zolpidem. As a result, quazepam has little or no muscle relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABAA receptors and type2 GABAA receptors. Type1 GABAA receptors include the α1 subunit containing GABAA receptors which are responsible for hypnotic properties of the drug. Type 2 receptors include the α2, α3 and α5 subunits which are responsible for anxiolytic action, amnesia and muscle relaxant properties. Thus quazepam may have less side effects than other benzodiazepines but, it has a very long half-life of 25 hours which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam perhaps due to its subtype selectivity. The longer half-life of quazepam may have the advantage however, of causing less rebound insomnia than shorter acting subtype selective nonbenzodiazepines. However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkylflurazepam), binds unselectively to both type1 and type2 GABAA receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.
Pharmacokinetics
Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through feces. The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABAA receptors. The elimination half-life range of quazepam is between 27 and 41 hours.
Mechanism of action
Quazepam modulates specific GABAA receptors via the benzodiazepine site on the GABAA receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABAA receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep. Quazepam also has some anticonvulsant properties.
EEG and sleep
Quazepam has potent sleep inducing and sleep maintaining properties. Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow wave sleep. This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs.
Drug misuse
Quazepam is a drug with the potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.
References
External links
"Quazepam". Drug Information Portal. U.S. National Library of Medicine. |
Pentoxifylline | Pentoxifylline, also known as oxpentifylline, is a xanthine derivative used as a drug to treat muscle pain in people with peripheral artery disease. It is generic and sold under many brand names worldwide.
Medical uses
Its primary use in medicine is to reduce pain, cramping, numbness, or weakness in the arms or legs which occurs due to intermittent claudication, a form of muscle pain resulting from peripheral artery diseases. This is its only FDA, MHRA and TGA-labelled indication. However, pentoxifylline is also recommended for off-label use as an adjunct to compression bandaging for the treatment of chronic venous leg ulcers by the Scottish Intercollegiate Guidelines Network (SIGN) as this has been shown to improve healing rates.Pentoxifylline has been tested for use in sarcoidosis patients as an alternative or compliment to prednisone and other steroids, as the drug can inhibit excess levels of TNF-a, which is associated with granuloma formation.Pentoxifylline has also been used to treat immunologic reactions to leprosy with some success.Pentoxifylline has also been shown to be of benefit in alcoholic hepatitis, with some studies demonstrating a reduction in risk of hepatorenal syndrome.Pentoxifylline has been used to improve sperm quality and motility for in vitro fertilization and as safe oral drug in the treatment of male infertility and erectile dysfunctionAn interesting off-label indication of pentoxifylline is the supportive treatment of distal diabetic neuropathy, where it can be added, for example, to thioctic acid or gabapentin. Theoretically, it can (among other things) act prophylactically against ulcerative changes of the lower limbs associated with chronically decompensated diabetes. Patients with measurable impairment in arterial supply are more likely to benefit from adjunctive treatment with pentoxifylline. The administration of higher doses of pentoxifylline in hospitalization for complications of distal diabetic neuropathy is usually conditioned by the joint agreement of the neurologist with the physicians of internal medicine (diabetology and angiology).
Adverse effects
Common side effects are belching, bloating, stomach discomfort or upset, nausea, vomiting, indigestion, dizziness, and flushing. Uncommon and rare side effects include angina, palpitations, hypersensitivity, itchiness, rash, hives, bleeding, hallucinations, arrhythmias, and aseptic meningitis.Contraindications include intolerance to pentoxifylline or other xanthine derivatives, recent retinal or cerebral haemorrhage, and risk factors for haemorrhage.
Mechanism
Like other methylated xanthine derivatives, pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and blood clot formation. Pentoxifylline is also an antagonist at adenosine 2 receptors.
Research
There is some evidence that pentoxifylline can lower the levels of some biomarkers in non-alcoholic steatohepatitis but evidence is insufficient to determine if the drug is safe and effective for this use. Animal studies have been conducted exploring the use of pentoxifylline for erectile dysfunction and hearing loss. Human studies have been conducted for Peyronies disease.Pentoxifylline, in combination with tocopherol and clodronate, has been found to heal refractory osteoradionecrosis of the jaw,
and to be prophylactic against osteoradionecrosis.In a Cochrane systematic review on the use of pentoxifylline for intermittent claudication in 2015, the following was concluded "The quality of included studies was generally low, and very large variability between studies was noted in reported findings including duration of trials, doses of pentoxifylline and distances participants could walk at the start of trials. Most included studies did not report on randomisation techniques or how treatment allocation was concealed, did not provide adequate information to permit judgement of selective reporting and did not report blinding of outcome assessors. Given all these factors, the role of pentoxifylline in intermittent claudication remains uncertain, although this medication was generally well tolerated by participants".
See also
Lisofylline, an active metabolite of pentoxifylline
Propentofylline
Cilostazol, a PDE-3 inhibitor with better evidence for intermittent claudication on the Cochrane review cited above.
References
External links
Pentoxifylline MedlinePlus Drug Information |
Diclofenac/misoprostol | Diclofenac/misoprostol, sold under the brand name Arthrotec, is a fixed-dose combination medication that contains:
Diclofenac sodium: Nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties
Misoprostol: Gastrointestinal (GI) mucosal protective prostaglandin E1 analog.In the United Kingdom it is marketed by Pharmacia and it is indicated for prophylaxis against NSAID-induced gastroduodenal ulceration in people requiring diclofenac for rheumatoid arthritis or osteoarthritis.The American College of Rheumatology and a Canadian consensus report both recommend GI-protective agents such as misoprostol be combined with long term NSAID therapy and a review concluded that diclofenac/misoprostol is a cost effective treatment in patients requiring long term NSAID therapy who are at increased risk of developing gastropathy.
Contraindications
Arthrotec must not be taken during pregnancy, as it may deform or otherwise harm the fetus, or lead to miscarriage. This may be accompanied by potentially dangerous bleeding, possibly requiring surgery and potentially leading to infertility or death.
References
External links
"Diclofenac mixture with misoprostol". Drug Information Portal. U.S. National Library of Medicine. |
Tetanus vaccine | Tetanus vaccine, also known as tetanus toxoid (TT), is a toxoid vaccine used to prevent tetanus. During childhood, five doses are recommended, with a sixth given during adolescence.After three doses, almost everyone is initially immune, but additional doses every ten years are recommended to maintain immunity. A booster shot should be given within 48 hours of an injury to people whose immunization is out of date. For people with high-risk injuries who are not fully immunized, tetanus antitoxin may also be recommended.Confirming that pregnant women are up to date on tetanus immunization during each pregnancy can prevent both maternal and neonatal tetanus.
The vaccine is very safe, including during pregnancy and in those with HIV/AIDS.Redness and pain at the site of injection occur in between 25% and 85% of people. Fever, feeling tired, and minor muscle pain occurs in less than 10% of people. Severe allergic reactions occur in less than one in 100,000 people.A number of vaccine combinations include the tetanus vaccine, such as DTaP and Tdap, which contain diphtheria, tetanus, and pertussis vaccines, and DT and Td, which contain diphtheria and tetanus vaccines. DTaP and DT are given to children less than seven years old, while Tdap and Td are given to those seven years old and older. The lowercase d and p denote lower strengths of diphtheria and pertussis vaccines.Tetanus antiserum was developed in 1890, with its protective effects lasting a few weeks. The tetanus toxoid vaccine was developed in 1924, and came into common use for soldiers in World War II. Its use resulted in a 95% decrease in the rate of tetanus. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Effectiveness
Following vaccination, 95% of people are protected from diphtheria, 80% to 85% from pertussis, and 100% from tetanus. Globally deaths from tetanus in newborns decreased from 787,000 in 1988 to 58,000 in 2010, and 34,000 deaths in 2015 (a 96% decrease from 1988).In the 1940s, before the vaccine, there were about 550 cases of tetanus per year in the United States, which has decreased to about 30 cases per year in the 2000s. Nearly all cases are among those who have never received a vaccine, or adults who have not stayed up to date on their 10-year booster shots.
Pregnancy
Guidelines on prenatal care in the United States specify that women should receive a dose of the Tdap vaccine during each pregnancy, preferably between weeks 27 and 36, to allow antibody transfer to the fetus. All postpartum women who have not previously received the Tdap vaccine are recommended to get it prior to discharge after delivery. It is recommended for pregnant women who have never received the tetanus vaccine (i.e., neither DTP or DTaP, nor DT as a child or Td or TT as an adult) to receive a series of three Td vaccinations starting during pregnancy to ensure protection against maternal and neonatal tetanus. In such cases, Tdap is recommended to be substituted for one dose of Td, again preferably between 27 and 36 weeks of gestation, and then the series completed with Td.
Specific types
The first vaccine is given in infancy. The baby is injected with the DTaP vaccine, which is three inactive toxins in one injection. DTaP protects against diphtheria, pertussis, and tetanus. This vaccine is safer than the previously used DTP. Another option is DT, which is a combination of diphtheria and tetanus vaccines. This is given as an alternative to infants who have conflicts with the DTaP vaccine. Quadrivalent, pentavalent, and hexavalent formulations contain DTaP with one or more of the additional vaccines: inactivated polio virus vaccine (IPV), Haemophilus influenzae type b conjugate, Hepatitis B, with the availability varying in different countries.For the every ten-year booster Td or Tdap may be used, though Tdap is more expensive.
Schedule
Because DTaP and DT are administered to children less than a year old, the recommended location for injection is the anterolateral thigh muscle. However, these vaccines can be injected into the deltoid muscle if necessary.The World Health Organization (WHO) recommends six doses in childhood starting at six weeks of age. Four doses of DTaP are to be given in early childhood. The first dose should be around two months of age, the second at four months, the third at six, and the fourth from fifteen to eighteen months of age. There is a recommended fifth dose to be administered to four- to six-year-olds.Td and Tdap are for older children, adolescents, and adults and can be injected into the deltoid muscle. These are boosters and are recommended every ten years. It is safe to have shorter intervals between a single dose of Tdap and a dose of the Td booster.
Additional doses
Booster shots are important because lymphocyte production (antibodies) is not at a constant high rate of activity. This is because after the introduction of the vaccine when lymphocyte production is high, the production activity of white blood cells will start to decline. The decline in activity of the T-helper cells means that there must be a booster to help keep the white blood cells active.Td and Tdap are the booster shots given every ten years to maintain immunity for adults nineteen years of age to sixty-five years of age.Tdap is given as a one-time, first-time-only dose that includes the tetanus, diphtheria, and acellular pertussis vaccinations. This should not be administered to those who are under the age of eleven or over the age of sixty-five.Td is the booster shot given to people over the age of seven and includes the tetanus and diphtheria toxoids. However, Td has less of the diphtheria toxoid, which is why the "d" is lowercase and the "T" is capitalized.In 2020, the US Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) recommended that either tetanus and diphtheria toxoids (Td) vaccine or Tdap to be used for the decennial Td booster, tetanus prevention during wound management, and for additional required doses in the catch-up immunization schedule if a person has received at least one Tdap dose.
Side effects
Common side effects of the tetanus vaccine include fever, redness, and swelling with soreness or tenderness around the injection site (one of five people have redness or swelling). Body aches and tiredness have been reported following Tdap. Td / Tdap can cause painful swelling of the entire arm in one of 500 people.
Tetanus toxoid containing vaccines (DTaP, DTP, Tdap, Td, DT) may cause brachial neuritis at a rate of one out of every 100,000 to 200,000 doses.
Mechanism of action
The type of vaccination for this disease is called artificial active immunity. This type of immunity is generated when a dead or weakened version of the disease enters the body, causing an immune response which includes the production of antibodies. This is beneficial because it means that if the disease is ever introduced into the body, the immune system will recognize the antigen and produce antibodies more rapidly.
History
The first vaccine for passive immunology was discovered by a group of German scientists under the leadership of Emil von Behring in 1890.
The first inactive tetanus toxoid was discovered and produced in 1924. A more effective adsorbed version of the vaccine, created in 1938, was proven to be successful when it was used to prevent tetanus in the military during World War II. DTP (which is the combined vaccine for diphtheria, tetanus, and pertussis) was first used in 1948, and was continued until 1991, when it was replaced with an acellular form of the pertussis vaccine due to safety concerns. Half of those who received the DTP vaccine had redness, swelling, and pain around the injection site, which convinced researchers to find a replacement vaccine.
Two new vaccines were launched in 1992. These combined tetanus and diphtheria with acellular pertussis (TDaP or DTaP), which could be given to adolescents and adults (as opposed to previously when the vaccine was only given to children).
References
Further reading
Liang JL, Tiwari T, Moro P, Messonnier NE, Reingold A, Sawyer M, Clark TA (April 2018). "Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP)" (PDF). MMWR Recomm Rep. 67 (2): 1–44. doi:10.15585/mmwr.rr6702a1. ISSN 1057-5987. PMC 5919600. PMID 29702631.
Kahn KE, Black CL, Ding H, Williams WW, Lu PJ, Fiebelkorn AP, Havers F, DAngelo DV, Ball S, Fink RV, Devlin R (September 2018). "Influenza and Tdap Vaccination Coverage Among Pregnant Women - United States, April 2018" (PDF). MMWR Morb. Mortal. Wkly. Rep. 67 (38): 1055–1059. doi:10.15585/mmwr.mm6738a3. PMC 6188122. PMID 30260946.
World Health Organization (2018). The immunological basis for immunization series: module 3: tetanus: update 2018. World Health Organization (WHO). hdl:10665/275340. ISBN 9789241513616. License: CC BY-NC-SA 3.0 IGO.
Ramsay M (ed.). "Chapter 30: Tetanus". Immunisation against infectious disease. Public Health England.
Hamborsky J, Kroger A, Wolfe S, eds. (2015). "Chapter 21: Tetanus". Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC). ISBN 978-0990449119.
Roush SW, Baldy LM, Hall MA, eds. (March 2019). "Chapter 16: Tetanus". Manual for the surveillance of vaccine-preventable diseases. Atlanta GA: U.S. Centers for Disease Control and Prevention (CDC).
External links
"Td (Tetanus, Diphtheria) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). 17 August 2021.
"DTaP (Diphtheria, Tetanus, Pertussis) Vaccine Information Statement". Centers for Disease Control and Prevention (CDC). 17 August 2021.
"DTaP/Tdap/Td ACIP Vaccine Recommendations". Centers for Disease Control and Prevention (CDC). 28 January 2020.
"Tetanus Vaccine". Drug Information Portal. U.S. National Library of Medicine.
Tetanus Toxoid at the US National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus Vaccine at the US National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus-Pertussis Vaccine at the US National Library of Medicine Medical Subject Headings (MeSH)
Diphtheria-Tetanus-acellular Pertussis Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH) |
Ozenoxacin | Ozenoxacin, sold under the brand names Ozanex, Ozewid and Xepi, is a quinolone antibiotic used for the treatment of impetigo. A 1% topical cream is approved for treatment of impetigo in Canada and in the United States.Ozenoxacin is active against some bacteria that have developed resistance to fluoroquinolone antibiotics.
References
External links
"Ozenoxacin". Drug Information Portal. U.S. National Library of Medicine. |
Carisoprodol | Carisoprodol, sold under the brand name Soma among others, is a medication used for musculoskeletal pain. Use is only approved for up to three weeks. Effects generally begin within half an hour and last for up to six hours. It is taken orally.Common side effects include headache, dizziness, and sleepiness. Serious side effect may include addiction, allergic reactions, and seizures. In people with a sulfa allergy certain formulations may result in problems. Safety during pregnancy and breastfeeding is not clear. How it works is not clear. Some of its effects are believed to occur following being converted into meprobamate.Carisoprodol was approved for medical use in the United States in 1959. Its approval in Europe was withdrawn in 2008. It is available as a generic medication. In 2017, it was the 255th most commonly prescribed medication in the United States, with more than one million prescriptions. In the United States, it is a Schedule IV controlled substance.
Medical uses
Carisoprodol is meant to be used along with rest, physical therapy and other measures to relax muscles after strains, sprains and muscle injuries. It comes in tablet format and is taken by the mouth three times a day and before bed.
Side effects
The usual dose of 350 mg is unlikely to engender prominent side effects other than somnolence, and mild to significant euphoria or dysphoria, but the euphoria is generally short-lived due to the fast metabolism of carisoprodol into meprobamate and other metabolites; the euphoria derived is, according to new research, most likely due to carisoprodols inherent, potent anxiolytic effects that are far stronger than those produced by its primary metabolite, meprobamate, which is often misblamed for the drug-seeking associated with carisoprodol, as carisoprodol itself is responsible for the significantly more intense central nervous system effects than meprobamate alone. Carisoprodol has a qualitatively different set of effects to that of meprobamate (Miltown). The medication is well tolerated and without adverse effects in the majority of patients for whom it is indicated. In some patients, however, and/or early in therapy, carisoprodol can have the full spectrum of sedative side effects and can impair the patients ability to operate a firearm, motor vehicles, and other machinery of various types, especially when taken with medications containing alcohol, in which case an alternative medication would be considered. The intensity of the side effects of carisoprodol tends to lessen as therapy continues, as is the case with many other drugs. Other side effects include: dizziness, clumsiness, headache, fast heart rate, upset stomach, vomiting and skin rash.The interaction of carisoprodol with essentially all opioids, and other centrally acting analgesics, but especially codeine, those of the codeine-derived subgroup of the semisynthetic class (ethylmorphine, dihydrocodeine, hydrocodone, oxycodone, nicocodeine, benzylmorphine, the various acetylated codeine derivatives including acetyldihydrocodeine, dihydroisocodeine, nicodicodeine and others) which allows the use of a smaller dose of the opioid to have a given effect, is useful in general and especially where skeletal muscle injury and/or spasm is a large part of the problem. The potentiation effect is also useful in other pain situations and is also especially useful with opioids of the open-chain class, such as methadone, levomethadone, ketobemidone, phenadoxone and others. In recreational drug users, deaths have resulted from combining doses of hydrocodone and carisoprodol. Another danger of misuse of carisoprodol and opiates is the potential to aspirate while unconscious.Meprobamate and other muscle-relaxing drugs often were subjects of misuse in the 1950s and 60s. Overdose cases were reported as early as 1957, and have been reported on several occasions since then.Carisoprodol is metabolized by the liver and excreted by the kidneys so this drug must be used with caution with patients that have impaired hepatic or renal function. Because of potential for more severe side effects, this drug is on the list to avoid for elderly people.
Withdrawal
Carisoprodol, meprobamate, and related drugs such as tybamate, have the potential to produce physical dependence of the barbiturate type following periods of prolonged use. Withdrawal of the drug after extensive use may require hospitalization in medically compromised patients. In severe cases the withdrawal can mimic the symptoms of alcohol withdrawal including the potentially lethal status epilepticus.
Psychological dependence has also been linked to carisoprodol use although this is much less severe than with meprobamate itself (presumably due to the slower onset of effects). Psychological dependence is more common in those who use carisoprodol non-medically and those who have a history of substance use (particularly sedatives or alcohol). It may reach clinical significance before physiological tolerance and dependence have occurred and (as with benzodiazepines) has been demonstrated to persist to varying degrees of severity for months or years after discontinuation.
Discontinuation of carisoprodol, as with all GABA-ergics, can result in cognitive changes which persist for weeks, months, or rarely even years including greatly increased anxiety and depression, social withdrawal, hair-trigger agitation/aggression, chronic insomnia, new or aggravated (often illogical) phobias, reduced IQ, short term and long-term memory loss, and dozens of other sequelae. The effects, severity, and duration appear to be slightly dose-dependent but are mainly determined by the patients pattern of use (taken as prescribed, taken in bulk doses, mixed with other drugs, a combination of the above, etc.), genetic predisposition to substance use, and a history of substance use all increase the patients risk of persistent discontinuation syndrome symptoms.
Treatment for physical withdrawal generally involves switching the patient to a long-acting benzodiazepine such as diazepam or clonazepam then slowly titrating them off the replacement drug completely at a rate which is both reasonably comfortable for the patient but rapid enough for the managing physician to consider the rate of progress acceptable (overly rapid dose reduction greatly increases the risk of patient non-compliance such as the use of illicitly obtained alternative sedatives and/or alcohol). Psychotherapy and cognitive behavioral therapy have demonstrated moderate success in reducing the rebound anxiety which results upon carisoprodol discontinuation but only when combined with regular and active attendance to a substance use support group.Carisoprodol withdrawal can be life-threatening (especially in high dose users and those who attempt to quit "cold turkey"). Medical supervision is recommended, with gradual reduction of dose of carisoprodol or a substituted medication, typical of other depressant drugs.
Non-medical use
Combining a muscle relaxant like carisoprodol with opioids and benzodiazepines is referred to as "The Holy Trinity" as it has been reported to increase the power of the "high".Recreational users of carisoprodol usually seek its potentially heavy sedating, relaxant, and anxiolytic effects. Also, because of its potentiating effects on narcotics, it is often used in conjunction with many opioid drugs. Also it is not detected on standard drug testing screens. On 26 March 2010 the DEA issued a Notice of Hearing on proposed rule making in respect to the placement of carisoprodol in schedule IV of the Controlled Substances Act. The DEA ended up classifying it under schedule IV. Carisoprodol is sometimes mixed with date rape drugs.Many overdoses have resulted from recreational users combining these drugs to combine their individual effects without being aware of the enzyme-induction induced potentiation.
Overdose
As with other GABAergic drugs, combination with other GABAergic drugs, including alcohol, as well as with sedatives in general, possess a significant risk to the user in the form of overdose. Overdose symptoms are similar to those of other GABAergics including excessive sedation and unresponsiveness to stimuli, severe ataxia, amnesia, confusion, agitation, intoxication and inappropriate (potentially violent) behavior. Severe overdoses may present with respiratory depression (and subsequent pulmonary aspiration), coma, and death.Carisoprodol is not detected on all toxicology tests which may delay diagnosis of overdose. Overdose symptoms in combination with opiates are similar but are distinguished by the presentation of normal or pinpoint pupils, which are generally unresponsive to light. Carisoprodol (as with its metabolite meprobamate) is particularly dangerous in combination with alcohol. Flumazenil (the benzodiazepine antidote) is not effective in the management of carisoprodol overdose as carisoprodol acts at the barbiturate binding site. Treatment mirrors that of barbiturate overdoses and is generally supportive, including the administration of mechanical respiration and pressors as implicated (and in rare cases, bemegride). Total amnesia of the experience is not uncommon following recovery.In 2014 actress Skye McCole Bartusiak died of an overdose due to the combined effects of carisoprodol, hydrocodone and difluoroethane.
Pharmacology
Pharmacodynamics
Carisoprodol, has a chemical structure similar to Glutamate, a neurotransmitter, and dimethylglycine. Upon analysis, this pharmacological agent seems to be an agonist of the NMDA receptor, with an unknown [Km].
Because excess Glutamate causes excitotoxicity and neuronal apoptosis, Carisoprodol overdose may also lead to NMDA related toxicity, thus inducing seizures at high doses, and muscle relaxation upon administration.
Carisoprodols structural similarity to Meprobamate indicates GABAergic activity, including GABA A agonism, similar to the mechanism of benzodiazepines.
This will allow for further muscle relaxation and anxiety reduction. Therefore, Carisoprodol, at low to moderate dosages, may be clinically indicated for absent seizures, yet exacerbate Tonic-clonic seizures.
Pharmacokinetics
Carisoprodol has a rapid, 30-minute onset of action, with the aforementioned effects lasting about two to six hours. It is metabolized in the liver via the cytochrome P450 oxidase isozyme CYP2C19, excreted by the kidneys and has about an eight-hour half-life. In patients with low levels of CYP2C19 (poor metabolizers), standard doses can lead to increased concentrations of carisoprodol (up-to a four-fold increase). A considerable proportion of carisoprodol is metabolized to meprobamate, which is a known addictive substance; this could account for the addictive potential of carisoprodol (meprobamate levels reach higher peak plasma levels than carisoprodol itself following administration). As mentioned above, carisoprodol appears to have strong anxiolytic effects on its own; however, a large part of its effects also come from the fact that it is metabolized into meprobamate: at least a 25% of the carisoprodol administered will be transformed into meprobamate which means that meprobamate is 3.25× stronger than carisoprodol (although this rate varies from person to person according to their levels of CYP2C19 enzymes in their livers with some people having considerably higher levels) or, in other words, 200 mg of meprobamate (which is the lowest standard dose) is equivalent to 650 mg of carisoprodol. As such, meprobamate is believed to play a significant role in the effects of carisoprodol and meprobamates long half-life results in bioaccumulation following extended periods of carisoprodol administration.
It is slightly soluble in water and freely soluble in ethanol, chloroform and acetone. The drugs solubility is practically independent of pH.
History
On 1 June 1959, several American pharmacologists convened at Wayne State University in Detroit, Michigan to discuss a newly discovered structural analogue of meprobamate. The substitution of one hydrogen atom with an isopropyl group on one of the carbamyl nitrogens was intended to yield a drug with new pharmacological properties. It had been developed by Frank Berger at Wallace Laboratories and was named carisoprodol.Building on meprobamates pharmacological effects, carisoprodol was intended to have better muscle relaxing properties, less potential for addiction, and a lower risk of overdose. Carisoprodols effect profile did indeed turn out to differ significantly with respect to meprobamate, with carisoprodol possessing stronger muscle relaxant and analgesic effects.
Usage and legal status
Norway
Reports from Norway have shown carisoprodol has addictive potential as a prodrug of meprobamate and/or potentiator of hydrocodone, oxycodone, codeine, and similar drugs. In May 2008 it was taken off the market in Norway.
European Union
In the EU, the European Medicines Agency issued a release recommending member states suspend marketing authorization for this product in the treatment of acute (not chronic) back pain.As of November 2007, carisoprodol has been taken off the market in Sweden due to problems with dependence and side effects. The agency overseeing pharmaceuticals considered other drugs used with the same indications as carisoprodol to have the same or better effects without the risks of the drug.
United States
Until 12 December 2011, when the administrator of the Drug Enforcement Administration (DEA) issued the final ruling placing the substance carisoprodol into Schedule IV of the Controlled Substances Act (CSA), carisoprodol was not a controlled substance. The placement of carisoprodol into Schedule IV was effective 11 January 2012.Carisoprodol is available generically as 350 mg and, more recently, 250 mg tablets. Compounded tablets with acetaminophen and codeine are also available.
Canada
Federally, carisoprodol is a prescription drug (Schedule I, sub-schedule F1). Provincial regulations vary. It is no longer readily available.
Indonesia
In September 2013, carisoprodol was taken off the market due to problems with diversion, dependence and side effects.
In September 2017, one child died and 50 had seizures when PCC, which stands for "Paracetamol Caffeine Carisoprodol" was mixed (probably illicit) into childrens drinks in elementary and junior high schools in Kendari.
Notes
References
Further reading
External links
"Carisoprodol". Drug Information Portal. U.S. National Library of Medicine. |
Deferoxamine | Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an underlying genetic condition, and aluminium toxicity in people on dialysis. It is used by injection into a muscle, vein, or under the skin.Common side effects include pain at the site of injection, diarrhea, vomiting, fever, hearing loss, and eye problems. Severe allergic reactions including anaphylaxis and low blood pressure may occur. It is unclear if use during pregnancy or breastfeeding is safe for the baby. Deferoxamine is a siderophore from the bacteria Streptomyces pilosus.Deferoxamine was approved for medical use in the United States in 1968. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Deferoxamine is used to treat acute iron poisoning, especially in small children. This agent is also frequently used to treat hemochromatosis, a disease of iron accumulation that can be either genetic or acquired. Acquired hemochromatosis is common in patients with certain types of chronic anemia (e.g. thalassemia and myelodysplastic syndrome) who require many blood transfusions, which can greatly increase the amount of iron in the body. Treatment with iron-chelating drugs such as deferoxamine reduces mortality in persons with sickle cell disease or β‐thalassemia who are transfusion dependent.Administration for chronic conditions is generally accomplished by subcutaneous injection over a period of 8–12 hours each day. Administration of deferoxamine after acute intoxication may color the urine a pinkish red, a phenomenon termed "vin rosé urine". Apart from iron toxicity, deferoxamine can be used to treat aluminium toxicity (an excess of aluminium in the body) in select patients. In US, the drug is not FDA-approved for this use. Deferoxamine is also used to minimize doxorubicins cardiotoxic side effects and in the treatment of a patient with aceruloplasminemia. Deferoxamine maybe effective for improving neurologic outcomes in persons with intracranial hemorrhage, although the evidence supporting the efficacy and safety for this indication was weak.Some published manuscripts suggesting the use of deferoxamine for patients diagnosed with COVID-19 because of the high level of ferritin among them.
Adverse effects
It is unclear if use during pregnancy is safe for the baby.Chronic use of deferoxamine may increase the risk of hearing loss in patients with thalassemia major.Chronic use of deferoxamine may cause ocular symptoms, growth retardation, local reactions and allergy.
Mechanism
Deferoxamine is produced by removal of the trivalent iron moiety from ferrioxamine B, an iron-bearing sideramine produced by the actinomycetes, Streptomyces pilosus. Its discovery was a serendipitous result of research conducted by scientists at Ciba in collaboration with scientists at the Swiss Federal Institute of Technology in Zurich and the University Hospital in Freiburg, Germany Deferoxamine acts by binding free iron in the bloodstream and enhancing its elimination in the urine. By removing excess iron from persons with hemochromatosis, the agent reduces the damage done to various organs and tissues, such as the liver. Also, it speeds healing of nerve damage (and minimizes the extent of recent nerve trauma). Deferoxamine may modulate expression and release of inflammatory mediators by specific cell types.
Research
Deferoxamine is being studied as a treatment for spinal cord injury and intracerebral hemorrhage. It is also used to induce hypoxia-like environment in mesenchymal stem cells.
See also
Chelation therapy
== References == |
Soma | Soma may refer to:
Businesses and brands
SOMA (architects), a New York–based firm of architects
Soma (company), a company that designs eco-friendly water filtration systems
SOMA Fabrications, a builder of bicycle frames and other bicycle parts and accessories
Soma Festival, annual music and well-being festival in Northern Ireland
Soma, a brand of Chicos
Computing
SOMA Messenger, a cross-platform instant messaging and communication application
Service-oriented modeling and architecture, a framework for software design
Music
Bands and labels
Soma (band), an Australian dark ambient musical project
Soma (studio), a recording studio located in Chicago, Illinois
Soma Records (U.S. label), a Minneapolis record label
Soma Quality Recordings, a Scottish record label co-founded by Slam
Albums
Soma (Mallavoodoo album) (2006)
Soma (Steve Roach and Robert Rich album) (1992)
Soma (Windhand album) (2013)
Soma, a 2004 album by Eths
Soma, a 2021 album by Phaeleh
Songs
"Soma" (song), a 1993 song by the Smashing Pumpkins
"Soma", a 2009 song by Deadmau5 from For Lack of a Better Name
"Soma", a 2015 song by Northlane from Node
"Soma", a 2002 song by Project 86 from Truthless Heroes
"Soma", a 2007 song by Prometheus from Corridor of Mirrors
"Soma", a 2001 song by the Strokes from Is This It
"Soma", a 2012 song by 10 Years from Minus the Machine
"Soma", a 1984 song by Tuxedomoon
Organizations
A.T. Still University School of Osteopathic Medicine in Arizona, one of three medical schools in Arizona
Sharing of Ministries Abroad, an international Anglican charity
Society of Mutual Autopsy, a professional association of anthropologists
Student Osteopathic Medical Association, a national student organization of osteopathic medical students
Symphony Orchestra Musician Association, part of the Media, Entertainment and Arts Alliance, Australia
People
Stephen OMalley or SOMA (born 1974), experimental musician and graphic designer
Queen Soma, legendary founder of Kingdom of Funan in the 1st century
Leela Soma, Scottish-based writer, born in Madras
Soma Sara, founder of Everyones Invited, an anti-rape organisation based in the UK
Fictional
Soma, the freely distributed happiness drug in Brave New World
Soma, a character in Is It Wrong to Try to Pick Up Girls in a Dungeon?
Prince Soma, a character in Black Butler
Soma Cruz, the protagonist of Castlevania: Aria of Sorrow and Castlevania: Dawn of Sorrow
Soma Peries, a character in Mobile Suit Gundam 00
Soma Schicksal, a character in Gods Eater Burst
Soma Yukihira, the main protagonist in Food Wars!: Shokugeki no Soma
Jarlskona Soma, a character in Assassins Creed: Valhalla
Ryu Soma, a character in Argento Soma
Places
South Main, a neighbourhood in Vancouver, British Columbia, Canada
Soma, Gambia, a town in Gambia
Sama, South Khorasan or Somā, Iran
Sōma, Aomori, a village in Nakatsugaru District, Aomori Prefecture, Japan
Sōma, Fukushima, a city in Fukushima Prefecture, Japan
Sōma District, Fukushima, a district in Fukushima Prefecture, Japan
Soma, Manisa, a town and district of Manisa Province, Turkey
South of Market, San Francisco or SoMa, a neighborhood in San Francisco, California, U.S
SoMa, the 4th arrondissement part of Le Marais in Paris, France
Science
Soma (biology), the cell body of a neuron
Carisoprodol or Soma, a muscle relaxant drug
Other uses
Soma (deity), a Hindu deity
Soma (drink), a ritual drink in Indo-Iranian cultures
Sōma (surname)
Soma (video game), a 2015 survival horror science fiction video game
System Open Market Account, a monetary policy tool used by the US Federal Reserve System
Soma cube, a solid dissection puzzle invented by Piet Hein
Soma San Diego, a concert venue in San Diego, California
System Open Market Account, a pool of financial assets owned & operated by the US Federal Reserve, held as an emergency store of liquidity and used as collateral against liabilities
See also
Malmheim og Soma, a borough of Sandnes, Norway
Parisoma (disambiguation)
Som (disambiguation)
Sōma (disambiguation)
Sōma clan, a Japanese clan of Mutsu Province from the 16th century
Soma 0.5mg, a 2018 album by Taconafide
SomaFM, a listener-supported, commercial-free Internet radio station
Somatherapy, also Soma or SOMA, a therapy designed by Brazilian Roberto Freire
Somatic (disambiguation) |
Pitavastatin | Pitavastatin (usually as a calcium salt) is a member of the blood cholesterol lowering medication class of statins.Like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis.
It was patented in 1987 and approved for medical use in 2003. It is available in Japan, South Korea and in India. In the US, it received FDA approval in 2009.Kowa Pharmaceuticals, a subsidiary of Kowa Company, is the owner of the American patent to pitavastatin.
Medical uses
Like the other statins, pitavastatin is indicated for hypercholesterolaemia (elevated cholesterol) and for the prevention of cardiovascular disease.
A 2009 study of the 104-week LIVES trial found pitavastatin increased HDL cholesterol, especially in patients with HDL lower than 40 mg/dL, who had a 24.6% rise, in addition to greatly reducing LDL cholesterol 31.3%. HDL improved in patients who switched from other statins and rose over time. In the 70-month CIRCLE observational study, pitavastatin increased HDL more than atorvastatin.It has neutral or possibly beneficial effects on glucose control. As a consequence, pitavastatin is likely to be appropriate for patients with metabolic syndrome plus high LDL, low HDL and diabetes mellitus.
Side effects
Common statin-related side effects (headaches, stomach upset, abnormal liver function tests and muscle cramps) were similar to other statins. Pitavastatin is a lipophillic statin. Reports indicate that this statin may lead to fewer muscle side effects than other statins. One study found that coenzyme Q10 was not reduced as much as with certain other statins (though this is unlikely given the inherent chemistry of the HMG-CoA reductase pathway that all statin drugs inhibit).As opposed to other statins, there is evidence that pitavastatin improves insulin resistance in humans, with insulin resistance assessed by the homeostatic model assessment (HOMA-IR) method.Hyperuricemia or increased levels of serum uric acid have been reported with pitavastatin.
Metabolism and interactions
Most statins are metabolised in part by one or more hepatic cytochrome P450 enzymes, leading to an increased potential for drug interactions and problems with certain foods (such as grapefruit juice). The primary metabolism pathway of pitavastatin is glucuronidation. It is minimally metabolized by the CYP450 enzymes CYP2C9 and CYP2C8, but not by CYP3A4 (which is a common source of interactions in other statins). As a result, it is less likely to interact with drugs that are metabolized via CYP3A4, which might be important for elderly patients who need to take multiple medicines.
History
Pitavastatin (previously known as itavastatin, itabavastin, nisvastatin, NK-104 or NKS-104) was discovered in Japan by Nissan Chemical Industries and developed further by Kowa Pharmaceuticals, Tokyo. Pitavastatin was approved for use in the United States by the FDA on 08/03/2009 under the trade name Livalo. Pitavastatin has been also approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in UK on 17 August 2010. Zypitamag (pitavastatin magnesium), a pharmaceutical alternative to Livalo, was approved for use in the United States by the FDA in 2017.
Names
The drug is marketed in the United States under the trade names Livalo and Zypitamag, and in the European Union and Russia under the trade name Livazo.
References
External links
FDA approval history |
Sinecatechins | Sinecatechins (USAN, trade names Veregen and Polyphenon E) is a specific water extract of green tea leaves from Camellia sinensis that is the active ingredient in an ointment approved by the FDA in 2006 as a botanical drug to treat genital warts. Sinecatechins are mostly catechins, 55% of which is epigallocatechin gallate. It was the first botanical drug approved by the US FDA.
== References == |
Tazemetostat | Tazemetostat, sold under the brand name Tazverik, is a medication used for the treatment of adults and adolescents aged 16 years and older with metastatic (when cancer cells spread to other parts of the body) or locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) epithelioid sarcoma not eligible for complete resection (surgically removing all of a tissue, structure, or organ).The most common side effects are pain, fatigue, nausea, decreased appetite, vomiting and constipation. People taking tazemetostat are at increased risk of developing secondary malignancies including: T-cell lymphoblastic lymphoma (a type of blood cancer that affects the lymphatic system usually found in the lymph nodes), myelodysplastic syndrome (a disorder resulting from poorly formed or dysfunctional blood cells) and acute myeloid leukemia (a cancer of the blood and bone marrow).Tazemetostat is a cancer drug that acts as a potent selective EZH2 inhibitor. Tazemetostat blocks activity of the EZH2 methyltransferase, which may help keep the cancer cells from growing. Most cases of epithelioid sarcoma begin in the soft tissue under the skin of an extremity, though it can start in other areas of the body. Surgical removal is considered the main treatment when the cancer is localized to one area of the body. Chemotherapy or radiation may also be given. However, there is a high likelihood for local and regional spread of the disease even with treatment and approximately 50% of patients have metastatic disease at the time of diagnosis. Metastatic disease is considered life-threatening to the patient.According to the NCI Drug Dictionary, "tazemetostat is an orally available, small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of histone methyl transferase EZH2, with potential antineoplastic activity. Upon oral administration, tazemetostat selectively inhibits the activity of both wild-type and mutated forms of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 lysine 27 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased tumor cell proliferation in EZH2 mutated cancer cells. EZH2, which belongs to the class of histone methyltransferases (HMTs), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation."The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
History
The U.S. Food and Drug Administration (FDA) approved tazemetostat in January 2020, based on the results of a clinical trial (NCT02601950) enrolling 62 subjects with metastatic or locally advanced epithelioid sarcoma. During the clinical trial, subjects received 800 milligrams (mg) of tazemetostat twice a day until the disease progressed or the subject reached an unacceptable level of toxicity. Tumor response assessments were performed every eight weeks during the clinical trial. The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate). The overall response rate was 15%, with 1.6% of subjects having a complete response and 13% having a partial response. Of the nine subjects that had a response, six (67%) subjects had a response lasting six months or longer.The trial was conducted at 22 sites in France, United Kingdom, Taiwan, Italy, Canada, Belgium, and the United States.The FDA granted the application for tazemetostat accelerated approval and orphan drug designation. The FDA granted the approval of Tazverik to Epizyme Inc.
References
External links
"Tazemetostat". Drug Information Portal. U.S. National Library of Medicine. |
Chlorzoxazone | Chlorzoxazone (INN) is a centrally acting muscle relaxant used to treat muscle spasm and the resulting pain or discomfort. It can also be administered for acute pain in general and for tension headache (muscle contraction headache). It acts on the spinal cord by depressing reflexes. It is sold under the brand names Lorzone, Paraflex and Muscol and in combination form as Parafon Forte, a combination of chlorzoxazone and acetaminophen (paracetamol). Possible side effects include dizziness, lightheadedness, malaise, nausea, vomiting, and liver dysfunction. Used with acetaminophen it has added risk of hepatotoxicity,.
Like metaxalone, its mechanism of action is still in question. It is believed that metaxalone works by altering serotonin levels and acting as a mild MAO inhibitor. The mechanism of action of chlorzoaxazone is thought to act on Gaba-A & B receptors and voltage-gated calcium channels to a degree. General central nervous system depression is the only currently accepted aspect to its medical benefits. Elucidation of the exact mechanism of action is ongoing but there is limited study due to the existence of more effective, safe muscle relaxants (ex. diazepam, cyclobenzaprine, tizanidine), greatly limiting the potential benefit of identifying novel compounds which share chlorzoxazones mechanism of action.
See also
Zoxazolamine
References
Further reading
External links
"Chlorzoxazone". Drug Information Portal. U.S. National Library of Medicine.
Chloroxazone Safety Data Sheet Archived 2019-07-12 at the Wayback Machine
D.F. Marsh, U.S. Patent 2,895,877 (1959) |
Sebelipase alfa | Sebelipase alfa, sold under the brand name Kanuma, is a recombinant form of the enzyme lysosomal acid lipase (LAL) that is used as a medication for the treatment of lysosomal acid lipase deficiency (LAL-D). It is administered via intraveneous infusion. It was approved for medical use in the European Union and in the United States in 2015.
Medical uses
Sebelipase alfa is indicated for long-term enzyme replacement therapy (ERT) in people of all ages with lysosomal acid lipase (LAL) deficiency.
History
Sebelipase was developed by Synageva that became part of Alexion Pharmaceuticals in 2015. For its production, chickens are genetically modified to produce the recombinant form of LAL (rhLAL) in their egg white. After extraction and purification it becomes available as the medication. On 8 December 2015 the FDA announced that its approval came from two centers: The Center for Drug Evaluation and Research (CDER) approved the human therapeutic application of the medication, while the Center for Veterinary Medicine (CVM) approved the application for a recombinant DNA construct in genetically engineered chicken to produce rhLAL in their egg whites. At the time it gained FDA approval Kanuma was the first only drug manufactured in chicken eggs and intended for use in humans.Sebelipase alfa is an orphan drug; its effectiveness was published after a phase 3 trial in 2015. The disease of LAL affects < 0.2 in 10,000 people in the EU.
References
External links
"Sebelipase alfa". Drug Information Portal. U.S. National Library of Medicine. |
Bromfenac | Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID) marketed in the US as an ophthalmic solution (brand names Prolensa and Bromday, prior formulation brand name Xibrom, which has since been discontinued) by ISTA Pharmaceuticals for short-term, local use. Prolensa and Bromday are the once-daily formulation of bromfenac, while Xibrom was approved for twice-daily administration. In the European Union, the brand name is Yellox. Bromfenac is indicated for the treatment of ocular inflammation and pain after cataract surgery.
Medical uses
Bromfenac is indicated for the treatment of postoperative ocular inflammation following cataract extraction.The drug has been shown to reduce macular edema and thickness of the retina (an indicator for inflammation) and improve visual acuity after surgery.
Contraindications
Bromfenac is contraindicated for people with adverse reactions to NSAIDs, such as asthma or rashes.
Side effects
Bromfenac eye drops are generally well tolerated. Comparatively common side effects in clinical studies included abnormal sensations in eye (0.5% of people treated with bromfenac), mild to moderate erosion of the cornea (0.4%), eye pruritus (0.4%), eye pain (0.3%) and redness (0.3%). Serious side effects such as corneal perforation were not reported in studies but only during post-marketing in less than one patient in 1000.
Interactions
No systematic interaction studies have been performed. There are no known cases of interactions with antibiotic eye drops. Blood plasma levels remain very low during bromfenac therapy, so interactions with drugs taken by mouth are unlikely.
Pharmacology
Mechanism of action
As an NSAID, bromfenac works by inhibiting prostaglandin synthesis by blocking the cyclooxygenase (COX) enzymes. It preferably acts on COX-2 and only has a low affinity for COX-1.
Pharmacokinetics
Bromfenac is well absorbed through the cornea and reaches highest concentrations in the aqueous humour after 150 to 180 minutes, with a biological half-life of 1.4 hours and high drug levels being maintained for at least 12 hours. It is mainly concentrated in the aqueous humour and conjunctiva, and much less in the lens and vitreous body.Concentrations in the blood plasma are too low to be measured quantitatively. 99.8% of the substance are bound to plasma proteins. The enzyme mainly responsible for metabolization of bromfenac is CYP2C9, and metabolites include the lactam and several conjugated compounds. 82% are excreted via the urine, and 13% via the faeces.The high degree of penetration and potency of bromfenac can be attributed to the halogenation of the molecule: by adding a bromine the NSAID becomes highly lipophilic which allows for rapid, sustained drug levels in the ocular tissues.
Chemistry
Along with indomethacin, diclofenac and others, bromfenac belongs to the acetic acid group of NSAIDs. It is used in form of bromfenac sodium · 1.5 H2O (CAS number: 120638-55-3 ), which is soluble in water, methanol and aqueous bases, insoluble in chloroform and aqueous acids, and melts at 284 to 286 °C (543 to 547 °F) under decomposition.
History
For ophthalmic use, bromfenac has been prescribed more than 20,000,000 times across the world. As an eye drop, it has been available since 2000, starting in Japan where it was sold as Bronuck. It was first FDA approved for use in the United States in 2005, and it was marketed as Xibrom, twice-daily. In October 2010 Bromday received FDA approval as a new, once-daily formulation. More recently, in 2013, Prolensa has also been approved by the FDA. Bromfenac eye drops have been marketed in the European Union since 2011, and are available on worldwide markets with agreements from Bausch & Lomb, Croma-Pharma, and other companies.Bromfenac was formerly marketed in the United States by Wyeth-Ayerst in an oral formulation called Duract for short-term relief of pain (less than 10 days at a time). It was brought to market in July 1997, and was withdrawn 22 June 1998, following numerous reports of hepatotoxicity in patients who had taken the medication for longer than the recommended 10-day period.
References
External links
"Bromfenac". Drug Information Portal. U.S. National Library of Medicine.
"Bromfenac sodium". Drug Information Portal. U.S. National Library of Medicine. |
Kanuma | Kanuman may refer to:
Kanuma, Tochigi, a city in Tochigi Prefecture, Japan
Kanuma Station, a railway station
Eri Kanuma, Japanese actress Toshie Furuoya (born 1952)
Naoki Kanuma (born 1997), Japanese footballer
Kanuma, brand name of Sebelipase alfa, a drug |
Finerenone | Finerenone, sold under the brand name Kerendia, is a medication used to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes. Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA).Common side effects include hyperkalemia (high levels of potassium), hypotension (low blood pressure), and hyponatremia (low levels of sodium).Finerenone was approved for medical use in the United States in July 2021, and in the European Union in February 2022.
Medical uses
In the United States, finerenone is indicated to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes.In the European Union, finerenone is indicated for the treatment of chronic kidney disease (stage 3 and 4 with albuminuria) associated with type 2 diabetes in adults.
Pharmacology
Finerenone has less relative affinity to other steroid hormone receptors than currently available aldosterone antagonists such as eplerenone and spironolactone, which should result in fewer adverse effects like gynaecomastia, impotence, and low libido.Finerenone blocks mineralocorticoid receptors, which makes it a potassium-sparing diuretic.
This table compares inhibitory (blocking) concentrations (IC50, unit: nM) of three antimineralocorticoids. Mineralocorticoid receptor inhibition is responsible for the desired action of the drugs, whereas inhibition of the other receptors potentially leads to side effects. Lower values mean stronger inhibition.
The above-listed drugs have insignificant affinity for the estrogen receptor.Finerenone acts as an antagonist to mineralocorticoid receptors harboring the S810L mutation, unlike other traditional MR inhibitors such as spironolactone and eplerenone that incidentally act as agonists.
Adverse Effects
Finerenone may cause electrolyte imbalances that must be resolved by a healthcare professional. In the case of potassium, patients taking Finerenone may experience a higher level of potassium in the blood. Symptoms that correlate to this clinical finding include nausea, weakness, chest pain and loss of movement. Another common electrolyte imbalance which may occur for patients on Finerenone is that patients may have low sodium, which can manifest as headaches, confusion, weakness and feeling off balance for patients.
History
The efficacy of finerenone to improve kidney and heart outcomes was evaluated in a randomized, multicenter, double-blind, placebo-controlled study in adults with chronic kidney disease associated with type 2 diabetes. In this study, 5,674 participants were randomly assigned to receive either finerenone or a placebo.The study compared the two groups for the number of participants whose disease progressed to a composite (or combined) endpoint that included at least a 40% reduction in kidney function, progression to kidney failure, or kidney death. Results showed that 504 of the 2,833 participants who received finerenone had at least one of the events in the composite endpoint compared to 600 of the 2,841 participants who received a placebo.The U.S. Food and Drug Administration (FDA) granted the application for finerenone priority review and fast track designations. The FDA granted the approval of Kerendia to Bayer Healthcare.
Society and culture
Legal status
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 Kerendia, intended for the treatment of chronic kidney disease associated with type 2 diabetes in adults. The applicant for this medicinal product is Bayer AG. Finerenone was approved for medical use in the European Union in February 2022.
Research
In the Phase II ARTS-DN study, finerenone dose-dependently reduced urine albumin to creatinine ratio in patients with diabetic kidney disease. Based on these findings, finerenone is being studied in the large Phase III FIDELIO and FIGARO outcome studies designed to assess whether finerenone reduces risk of CKD progression and adverse cardiovascular events in patients with Chronic Kidney Disease and Type 2 Diabetes. These trials have enrolled more than 13,000 patients with primary completion of FIDELIO anticipated in 2020 and FIGARO IN 2021.
References
Further reading
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. (December 2020). "Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes". N Engl J Med. 383 (23): 2219–2229. doi:10.1056/NEJMoa2025845. PMID 33264825.
External links
"Finerenone". Drug Information Portal. U.S. National Library of Medicine. |
Ingenol mebutate | Ingenol mebutate, sold under the brand name Picato, is a substance that is found in the sap of the plant Euphorbia peplus, commonly known as milkweed, and is an inducer of cell death. A gel formulation of the drug has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the topical treatment of actinic keratosis. Two different strengths of the gel have been approved for use on either the face and scalp (0.015%) or the trunk and extremities (0.05%), respectively. In 2020 the drug was withdrawn from the market in the EU.
Adverse effects
Irritation of the application site is very common. The various types of irritation include redness, scaling, crusting, pain, severe itching, and sometimes infection. Additional possible side effects include eye irritation, such as periorbital edema (3% of patients in studies), headaches (2%) and nasopharyngitis (running nose, 2%).Allergic reactions, shingles, changes in pigmentation at application site, chemical conjunctivitis, and corneal burns may also occur.The European Medicines Agency recommended suspending the marketing authorisation of ingenol mebutate due to concerns regarding increased incidence of skin cancer in patients treated with topical ingenol mebutate compared to vehicle or imiquimod. Physicians were advised to refrain from prescribing ingenol and to use different treatment options. Subsequently, the marketing authorization holder requested withdrawal of the manufacturing authorization for commercial reasons. The withdrawal was granted and therefore, ingenol mebutate is no longer registered in the EU.
Interactions
As ingenol mebutate is not effectively absorbed through the skin and into the bloodstream, interactions with oral drugs are unlikely.
Chemistry
The substance is an ester of the diterpene ingenol and angelic acid. A 3-step semisynthesis of ingenol mebutate starting from ingenol was described by a chemical research group in Denmark in 2012. A 14-step synthesis of (+)-ingenol from (+)-3-carene, which is a relatively inexpensive constituent of turpentine, was published in July 2013.
Mechanism of action
The mechanism by which ingenol mebutate causes cell death is still not fully understood. One study on squamous cell carcinoma, the precursor of which is actinic keratosis, cultures found that the PKC/MEK/ERK signaling pathway is involved in causing cell death after treatment with ingenol mebutate. In addition, the interleukin decoy receptors IL1R2 and IL13RA2 were induced, resulting in a reduction in the long-term viability of the cells, which could help prevent recurrence.
Studies
Results from four multicenter, randomized, double-blind studies have shown that ingenol mebutate gel applied topically, for 2 to the trunk or 3 days to the face or scalp, is effective for field treatment of actinic keratoses.A twelve-month follow-up study was performed on actinic keratosis patients who had been treated with ingenol mebutate, 108 of which had been treated for face or scalp and 71 for trunk or extremities and the study found that of those treated for the face or scalp 46.1% had sustained clearance, and of those treated for the trunk 44.0% had sustained clearance for the period of the study.
Research
HIV
Ingenol mebutate has also been found to be useful for reactivating latent HIV virus in cells taken from individuals who have tested negative for signs of the disease following extended courses of anti-retroviral drugs, raising the possibility that this drug may be used to expose the last traces of virus, and thus potentially provide a permanent cure for HIV infection. Research is ongoing to determine whether the effects observed in vitro are also seen in animal models, with a view to eventual human trials for this application.
Tattoo removal
A placebo-controlled study on hairless mice found that 0.1% ingenol mebutate gel was able to remove two-week-old tattoos consistently. It was observed that the microspheres within the skin containing the dye would exude into the scab intact and slough off as the skin healed about 20 days after treatment began. This mechanism appears to be independent of ink color, unlike laser tattoo removal, which is less effective for certain colors. There are no reports of human trials having been conducted.
Skin cancer risk
Health Canada assessed twelve studies published in scientific and medical literature in order to determine the link between the use of ingenol mebutate and skin cancer. Health Canadas review found that six of the twelve studies had evidence of skin cancer with the use of ingenol mebutate. The European Medicines Agency (EMA) has also reviewed this safety issue. In April 2020, it concluded that ingenol mebutate may increase the risk of skin cancer and that its risks outweigh its benefits. On February 11, 2020, the manufacturer voluntarily withdrew the product from the European Union market.
References
External links
"Ingenol mebutate". Drug Information Portal. U.S. National Library of Medicine. |
Methylergometrine | Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and in the treatment of migraine. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.
It is on the World Health Organizations List of Essential Medicines.
Medical uses
Obstetric use
Methylergometrine is a smooth muscle constrictor that mostly acts on the uterus. It is most commonly used to prevent or control excessive bleeding following childbirth and spontaneous or elective abortion, and also to aid in expulsion of retained products of conception after a missed abortion (miscarriage in which all or part of the fetus remains in the uterus) and to help deliver the placenta after childbirth. It is available as tablets or injection (IM or IV) or in liquid form to be taken orally.
Migraine
Methylergometrine is sometimes used for both prevention and acute treatment of migraine. It is an active metabolite of methysergide. In the treatment of cluster headaches, methylergometrine has been initiated at a dose of 0.2 mg/day, rapidly increased to 0.2 mg three times per day, and increased to a maximum of 0.4 mg three times per day.
Contraindications
Methylergometrine is contraindicated in patients with hypertension and pre-eclampsia. It is also contraindicated in HIV positive patients taking protease inhibitors, delavirdine, and efavirenz (which is also an agonist at the 5-HT2A–mGlu2 receptor protomer and increases the chances of a patient experiencing hallucinations during methylergometrine therapy).
Side effects
Adverse effects include:
Nausea, vomiting, and diarrhea
Dizziness
Pulmonary hypertension
Coronary artery vasoconstriction
Severe systemic hypertension (especially in patients with pre-eclampsia)
ConvulsionsIn excessive doses, methylergometrine can also lead to cramping, respiratory depression and coma.
Interactions
Methylergometrine likely interacts with drugs that inhibit the liver enzyme CYP3A4, such as azole antifungals, macrolide antibiotics and many HIV drugs. It can also increase constriction of blood vessels caused by sympathomimetic drugs and other ergot alkaloids.
Pharmacology
Pharmacodynamics
Methylergometrine is an agonist or antagonist to serotonin, dopamine, and α-adrenergic receptors. Its specific binding and activation pattern on these receptors leads to a highly, if not completely, specific contraction of smooth uterus muscle via serotonin 5-HT2A receptors, while blood vessels are affected to a lesser extent compared to other ergot alkaloids. It has been found to interact with the serotonin 5-HT1A, 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, and 5-HT7 receptors.Methylergometrine is a synthetic analogue of ergometrine, a psychedelic alkaloid found in ergot, and many species of morning glory. Methylergometrine is a member of the ergoline family and chemically similar to LSD, ergine, ergometrine, and lysergic acid. According to Jonathan Ott, methylergometrine produces LSD-like psychedelic effects at doses of 2 mg and above. This can be attributed to due to its agonistic action at the 5-HT2A–mGlu2 receptor protomers. Clinical efficacy occurs around 200 µg, ten times lower than the hallucinogenic threshold.Methylergometrine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.
Chemistry
Methylergometrine, also known as d-lysergic acid 1-butanolamide, is a derivative of the ergoline and lysergamide classes and is structurally related to ergometrine (d-lysergic acid β-propanolamide) and lysergic acid diethylamide.
== References == |
Miglitol | Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to break down complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic control by preventing the digestion of carbohydrates (such as disaccharides, oligosaccharides, and polysaccharides) into monosaccharides which can be absorbed by the body.Miglitol, and other structurally-related iminosugars, inhibit glycoside hydrolase enzymes called alpha-glucosidases. Since miglitol works by preventing digestion of carbohydrates, it lowers the degree of postprandial hyperglycemia. It must be taken at the start of main meals to have maximal effect. Its effect will depend on the amount of non-monosaccharide carbohydrates in a persons diet.
In contrast to acarbose (another alpha-glucosidase inhibitor), miglitol is systemically absorbed; however, it is not metabolized and is excreted by the kidneys.
See also
Alpha-glucosidase inhibitor
Miglustat
Voglibose
== References == |
Obiltoxaximab | Obiltoxaximab, sold under the brand name Anthim, is a monoclonal antibody medication designed for the treatment of exposure to Bacillus anthracis spores (etiologic agent of anthrax).The medication was developed by Elusys Therapeutics, Inc.
Medical uses
Obiltoxaximab is indicated in combination with appropriate antibacterial drugs in all age groups for treatment of inhalational anthrax due to Bacillus anthracis. It is also indicated in all age groups for post-exposure prophylaxis of inhalational anthrax when alternative therapies are not appropriate or are not available.
Society and culture
Legal status
In March 2016, obiltoxaximab was approved by the U.S. Food and Drug Administration (FDA) for the treatment and prophylaxis of inhalational anthrax.On 17 September 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 obiltoxaximab, intended for the treatment or post-exposure prophylaxis of inhalational anthrax. The applicant for this medicinal product is SFL Pharmaceuticals Deutschland GmbH. It was approved for medical use in the European Union in November 2020.
References
External links
"Obiltoxaximab". Drug Information Portal. U.S. National Library of Medicine. |
Archpriest | The ecclesiastical title of archpriest or archpresbyter belongs to certain priests with supervisory duties over a number of parishes. The term is most often used in Eastern Orthodoxy and the Eastern Catholic Churches and may be somewhat analogous to a monsignor, vicar forane or dean in the Latin Church, but in the Eastern churches an archpriest wears an additional vestment and, typically, a pectoral cross, and becomes an archpriest via a liturgical ceremony.
The term may be used in the Latin Catholic Church in certain historical titles and may replace in popular usage the title of vicar forane, otherwise often known as a dean.
Antiquity
In ancient times, the archdeacon was the head of the deacons of a diocese, as is still the case in the Eastern Orthodox Church, while the archpriest was the chief of the presbyerate of the diocese, i.e. of the priests as a body. The latters duties included deputising for the bishop in spiritual matters when necessary.
Western Christianity
Latin Catholic Church
In the western Church, by the Middle Ages, the use of the title had evolved and became assigned to the priest of the principal parish among several local parishes. This priest had general charge of worship in this archpresbyterate, and the parishioners of the smaller parishes had to attend Sunday Mass and hold baptisms at the principal parish while the subordinate parishes instead held daily mass and homilies.
By the time of the Council of Trent the office of archpriest was replaced by the office of vicar forane, also known in English as "dean". The first recorded use of this meaning of the title comes from St Charles Borromeos reforms in his own diocese. Unlike vicars general and vicars episcopal, vicars forane are not prelates, which means they do not possess ordinary power. Their role is entirely supervisory, and they perform visitations for the bishop and report to the bishop or vicar general any problems in their territory.
Exceptionally, the pope on occasion raised a territory to the rank of archipresbyterate nullius, detached from any prelature, yet under a non-prelate, as happened in 1471 with the future abbacy (1583) and later (1828-1986) Diocese of Guastalla.
In the 16th and 17th centuries, during the persecution of Catholics in England, an archpriest was appointed by the Holy See as head of the Catholic Church in England, with authority over all of the secular clergy in the country.The title of archpriest has survived in Rome, in Malta and elsewhere, where it is now held by the rectors of the principal basilicas. However, the title is entirely honorary, reflecting the fact that these churches held archpriestly status in the past.
In Rome today, there are four archpriests, one for each of the four papal major basilicas; all of them are presently bishops :
Archbasilica of Saint John Lateran
Basilica of Saint Peter
Basilica of Saint Mary Major
Basilica of Saint Paul outside the WallsThe use of "archpriest" in the Latin Catholic Church should not be confused with "protopriest", the senior Cardinal-Priest in the College of Cardinals.
According to the specific historical tradition, many churches throughout the world, other than basilicas, are under the authority of a priest who bears the title of archpriest. However, the title is mostly honorary and today, such an archpriest has no control over subordinate clergy other than that of a parish priest over junior clergy assigned to assist him in meeting pastoral needs.
In the Latin Catholic Church, it was traditional in some localities for a priest to be assisted at his First Mass by another priest termed for the occasion the archpriest, who functioned as the deacon otherwise does. This was not a permanent title but referred only to the particular occasion.
Church of England
In the Church of England there is at least one archpriest, the Archpriest of Haccombe. The title is a survival of local practice of Latin Catholic Church prior to the Reformation. It was first employed in AD 1315 and has been held ever since. It was confirmed by an order in council on 1 April 1913 under King George V. The title reflects the fact that the archpriest has the right to sit beside the bishop and acknowledges no authority below that of the Archbishop of Canterbury, although today it is more appropriate to go through the usual channels of the churchs hierarchy. Haccombe is a village in Devon, near Newton Abbot, where the parish is combined with that of Stoke-in-Teignhead with Combe-in-Teignhead. There is an hereditary patron for the Church of St Blaise, Haccombe. The modern office most closely resembling that of archpriest is the role of rural dean (rural dioceses) or area dean (urban dioceses). Like the archpriest of old, these officers have supervisory duties, but not ordinary jurisdiction, and are entitled to carry out visitations of subordinate parishes when so commissioned. With this in mind, although the Archpriest of Haccombe holds a unique role in the Church of England, it is considered analogous with certain incumbencies which bear the title "Dean" regardless of whether or not their incumbent is the actual rural or area dean. One example of this historical oddity is the office of Dean of Bocking in Essex. The current Archpriest of St Blaise, Haccombe is the current incumbent, the Reverend Annie Church, the first female priest to hold this office in Haccombe.
Eastern Christianity
Archpriest, also protopope (Greek: πρωτοπαπᾶς, protopapas) or protopresbyter (Greek: πρωτοπρεσβύτερος, protopresbyteros), is a clerical rank, a title of honor given to non-monastic priests and is conferred by a bishop with the laying on of hands and prayer. An archpriest typically wears an epigonation, a vestment originally worn only by bishops; however, details vary locally, and in some places being given the epigonation is an honor that typically precedes being made an archpriest and in other places, it is an honor that is given to only some archpriests. An archpriest also wears a pectoral cross both as part of his street clothes and when vested.
The ceremony for making an archpriest is analogous to other clerical promotions bestowed with cheirothesia: at the little entrance of the divine liturgy, the candidate is conducted to the ambo in the middle of the church where the bishop is at the time, and the bishop blesses him and says a prayer addressed to Christ asking to "... endue our brother (name) with Thy Grace, and adorn him with virtue to stand at the head of the Presbyters of Thy people, and make him to be a good example to them that are with him ..."In the Russian tradition, protopresbyter is a higher rank than archpriest, as explained in a translation by the Orthodox Church in America:
Although entitled "for the making of a Protopresbyter" it is clear that what is now known as an "Archpriest" is what is usually meant. The rank of "Protopresbyter" as a distinction higher than "Archpriest" is a later addition. The same Order, naturally, is used for what is now called "Protopresbyter".
Other uses
The Unitarian Church of Transylvania is divided into five Archpriestships as a form of territorial governance, virtual dioceses.
See also
Archimandrite
Archpriest Controversy
Arnaud de Cervole, also known as "the Archpriest"
Archpriest of Hita
Protopope
Notes
References and sources
References
Sources
Cross, F. L., ed. (1957). Oxford Dictionary of the Christian Church. London: Oxford University Press; pp. 79–80
Further reading
Amanieu, A. (1935). "Archiprêtre", in: Dictionnaire de Droit Canonique. Coll. 1004–26. Includes good bibliography.
External links
"Archpriest in Catholic Encyclopedia". NewAdvent (organization). |
Epirubicin | Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.
Similarly to other anthracyclines, epirubicin acts by intercalating DNA strands.
Intercalation results in complex formation which inhibits DNA and RNA synthesis. It also triggers DNA cleavage by topoisomerase II, resulting in mechanisms that lead to cell death. Binding to cell membranes and plasma proteins may be involved in the compounds cytotoxic effects. Epirubicin also generates free radicals that cause cell and DNA damage.
Epirubicin is favoured over doxorubicin, the most popular anthracycline, in some chemotherapy regimens as it appears to cause fewer side-effects. Epirubicin has a different spatial orientation of the hydroxyl group at the 4 carbon of the sugar - it has the opposite chirality - which may account for its faster elimination and reduced toxicity. Epirubicin is primarily used against breast and ovarian cancer, gastric cancer, lung cancer and lymphomas.
Medical uses
Adjuvant therapy
The aim of Epirubicin as adjuvanted therapy is to eradicate micro metastasis and prolong disease free survival.
Vs standard adjuvant therapy
The Standard adjuvant therapy is a combination of cyclophosphamide, methotrexate and fluorouracil (CMF). In comparison to this the Epirubicin therapy contains fluorouracil/epirubicin/cyclophosphamide (FEC). Three large randomized studies have directly compared the epirubicin-containing regimen fluorouracil/epirubicin/cyclophosphamide (FEC) with CMF in the adjuvant setting. Trial one and two contained premenopausal node-positive women with breast cancer, Trial three pre- and postmenopausal women with node-positive or negative breast cancer. It was discovered that FEC is at least as effective as CMF in premenopausal women with node positive- or negative breast cancer and that FEC produced no additional benefit in terms of 5-year relapse-free or overall survival.
Dose response
Researchers discovered a benefit for epirubicin 100 mg (FEC 100) over epirubicin 50 mg (FEC 50). Patients with FEC100 treatment of the study were relapse-free and an overall survival rate at 5 years higher as in FEC 50 treatment. They also compared epirubicin 90 mg/m2 (EC 90) with epirubicin 120 mg/m2 (EC 120). After a mean follow up of 27 months elapse-free survival of patients who received EC 120 was significantly longer than that of patients who received EC 90. The combination of Epirubicin and tamoxifen lead to an increase survival in node-positive postmenopausal women with hormone receptor-positive breast tumours.
Advanced breast cancer
First-line therapy
Epirubicin monotherapy was shown to be therapeutically equivalent to doxorubicin monotherapy in patients who had to receive previous chemotherapy for advanced breast cancer.
There are several Combination therapies: 1. FEC: fluorouracil + cyclophosphamide + epirubicin; 2. FAC: fluorouracil + cyclophosphamide + doxorubicin. The median survival rates markedly better than those achieved with epirubicin monotherapy. Additionally the FEC treatment seems to be less toxic.
Second-line therapy
Patients with advanced breast cancer who experience disease progression after first-line therapy may respond to subsequent chemotherapy regimens; however, response rates and durations are generally lower than those seen after initial treatment with these regimens (FEC and FAC).
Dose escalation
A reduced dose intensity leads to reduced response rates . Equimolar doses of epirubicin and doxorubicin have been shown to be therapeutically equivalent in patients with metastatic breast cancer. Additionally the administration of more dose intensive epirubicin-containing regimens to patients with metastatic breast cancer has been associated with improved response rates, but not increased overall survival. It is suggested that it is necessary to at least double the dose of chemotherapy to detect a clinically relevant effect.
Pharmacology
Mechanism of action
The mechanism of action of epirubicin is similar to that of doxorubicin and other anthracycline drugs. The observed clinical differences between epirubicin and doxorubicin can be explained by the pharmacokinetic differences based on the different affinity to DNA and lipophilicity, as there is no indication that different mechanisms are involved in their activity.Epirubicin first forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs. (Pharmacia & Upjohn Company LLC, 1999) This inhibits replication and transcription and triggers DNA cleavage by topoisomerase II. Epirubicin then stabilizes the topoisomerase II-DNA complex, resulting in irreversible DNA strand breakage, leading to cell death. Epirubicin is also capable of generating cytotoxic free radicals, which are very reactive against DNA, cell membranes and mitochondria.Epirubicin exhibits activity in all phases of the cell cycle, but maximal cell kill occurs during the S and G2 phases of the cell cycle.
Pharmacokinetics
The pharmacokinetic properties of epirubicin can be described by a 3-compartment model, with half-lives for the initial (alpha), intermediate (beta) and terminal (gamma) elimination phases of approximately 3 minutes, 1 hour and 30 hours, respectively. Only the latter differs substantially compared to doxorubicin, as the terminal elimination half-life of doxorubicin is estimated to be approximately 40-70% longer than that of epirubicin. The pharmacokinetics of epirubicin appear to be linear for doses in the range of 40 – 150 mg/m2.The volume of distribution of epirubicin is found to be high and variable (1 000- 1 500), but similar to those reported for doxorubicin. This indicates extensive distribution into the tissue. The total plasma clearance of epirubicin is approximately 45 to 50 L/h/m2, which is almost 2-fold higher than that of doxorubicin. Area under the plasma concentration versus time curve values (adjusted for dose) are 1.3 to 1.7 times higher for doxorubicin than epirubicin following single-dose intravenous administration. Epirubicin shows a 77% binding to plasma proteins, predominantly albumin, which is not affected by drug concentration.
Metabolism
Epirubicin is rapidly metabolized by the liver to relatively or totally inactive metabolites: epirubicinol, 2 glucuronides and 4 aglycones. As plasma levels of epirubicinol are lower than those of the unchanged drug and the metabolite has an in vitro cytotoxic activity 10% of that of epirubicin, it is unlikely to reach in vivo concentration sufficient for cytotoxicity. No significant toxicity has been reported for the other metabolites.
Epirubicinol is the 13(S)-dihydro derivative formed via the reduction of the C-13 keto-group. Both the unchanged drug and epirubicinol can be conjugated with glucuronic acid, creating the 2 glucuronides. This glucuronidation pathway is unique to epirubicin metabolism in humans as epirubicin is the only anthracycline that serves as a substrate for beta-glucuronidation. This unique pathway might explain the better tolerability of this drug compared with doxorubicin.The 4 aglycones are formed by losing the amino sugar moiety through a hydrolytic process or redox process, creating the doxorubicin and doxorubicinol aglycones and 7-deoxy-doxorubicin and 7-deoxy-doxorubicinol aglycones, respectively.
Excretion
Epirubicin and its metabolites are primarily eliminated through biliary excretion. About 11 to 15% of the administered dose is eliminated as an unchanged drug, which makes up 6 to 7% of the excreted compounds, and metabolites.
Side effects
The most common side effects of the Epirubicin are alopecia, nausea/vomiting, cardiotoxicity, leukopenia, and stomatitis. Cardiotoxicity is a severe side effect and the exact pathway is still unknown. However, there is good evidence to suggest that cardiotoxicity is caused at least in part by the avid interaction of anthracyclines with iron, resulting in the formation of metal ion complexes. It was first observed in adult cancer patients as clinical congestive heart failure (CHF), characterized by pulmonary oedema, fluid overload, and effort intolerance, was initially reported in 1979 by Von Hoff et al. at 2.2% overall with a cumulative doxorubicin dose-dependent incidence of CHF of 3%, 7%, and 18% at 400, 550, and 700 mg/m2, respectively.There are a lot of adverse effects of epirubicin related with the dose-limiting. The major commun negative effects are fever, diarrhea, nausea and vomiting. More than 50% of patients without a right prophylactic antiemetics therapy experience nausea and vomiting the first 24 h after administration. That fact occurs if the epirubicin dose is between 50 to 75 mg/m2 single doses.Reversible alopecia and local cutaneous reactions are important adverse effects too. Those could be related with radiation recall and local reactions such as cellulitis, which cause development of tissue necrosis and pain if extravasation damage occurs.Another major adverse effects are cumulative dose-related cardiotoxicity and acute dose-limiting haematotoxicity. This last is related to mucositis, inflammation and ulceration in mouth or mucous membranes.Finally, the most adverse effect is secondary leukemia produced by breast cancer treated with epirubicin, particularly in those cases in which the patient receives concomitant alkylating agent therapy.
Toxicity
Epirubicins toxicity is according to the NCI-CTEP Common Toxicity Criteria, version 2.0. In some studies, patient toxicity reviews were obtained by a diary with the important information before and after each cycle of chemotherapy and their consequences.Common toxicities are neutropenia (<1 × 109 cells/L) without any death related and in lesser mesures anemia and thrombocytopenia.The most acute dose-limiting toxicity of epirubicin is bone marrow suppression, irreversible cardiotoxicity such as an important chronic cumulative dose-limiting toxicity illness and myelosuppression. The last one is associated with leukopenia, the decrease in the number of leukocytes (white blood cells) in the blood.
Chemistry
Epirubicin is a 4-epi-isomer of doxorubicin and a derivative of daunorubicin. As an anthracycline antibiotic it belongs to several chemical classes such as: aminoglycosides, tetracene quinones, p-quinones, primary alpha-hydroxy ketone and tertiary alpha-hydroxy ketones. Due to numerous ionisable groups, it has multiple pka (pKa1 = 9.17 (phenol); pKa2 = 9.93 (amine); pKa3 = 12.67 (hydroxyl)) and is soluble in a variety of solvents (DMSO 125 mg/mL; Ethanol 120 mg/mL; In water, 93 mg/L at 25 °C (est)). It has a melting point of 344.53 and a boiling point of 810.3±65.0 °C at 760 mmHg.Its shelf life (def. as the time it takes to degrade 10% from the initial concentration) has been documented as at least 14 and 180 days at 25 °C and 4 °C, respectively in a 0.9% sodium chloride solution in polypropylene syringes.
Synthesis
There are multiple ways of synthesizing epirubicin depending on which starting material is used as a precursor.
Daunorubicin
One pathway starts from Daunorubicin, a common byproduct found in fermentation, since it is relatively easily available and already structurally similar to the product (only requiring minor alterations).
Firstly, the amine group is protected using trifluoroacetic acid to stop it from further reactions. Next the hydroxyl group needs to be changed from an equatorial position to an axial, this is achieved by firstly oxidizing an intermediate sulfoxy salt to a keto group (losing the optical center) followed by a stereo-specific reduction using sodium borohydride to give the hydroxide group in the axial position.
Secondly, the focus shifts to carbon number 13 where it is necessary to add a hydroxide group which is achieved by bromination followed by a reaction with an alkali salt of formic acid and water to give the final product.
There is an older variant of this pathway which involves first splitting the Daunorubicin, into daunomycin one and daunosamine methyl ether, using methanol. Analogous reactions are performed to get the two hydroxyl groups onto their positions and the rings are then recombined and the protecting groups released. The drawbacks are more chemicals are used and daunomycin one and daunosamine need to be separated first.
13-daunorubicinol
The second pathway startsfrom 13-daunorubicinol (hydroxyl group on carbon 13 instead of Daunorubicins keto group). Firstly, the amine group is protected using trifluoroacetic acid then both the hydroxyl groups at positions 4 and 13 are oxidized simultaneously to keto groups again using DMSO, but a different alkylating agent. The reduction to alcohol is performed with a derivative of a borohydride of an alkali metal with formula MHBL3, where M=Li, Na, K; L=AlkO, AlkCOO, ArCOO. The subsequent halogenation is performed with a complex halogenating agent where an H or a chain of up to 4 carbons is combined with Cl, I or Br. The final hydrolysis is analogous to the one in the first pathway.
Development history
The first trial of epirubicin in humans was published in 1980. Upjohn applied for approval by the U.S. Food and Drug Administration (FDA) in node-positive breast cancer in 1984, but was turned down because of lack of data. In 1999 Pharmacia (who had by then merged with Upjohn) received FDA approval for the use of epirubicin as a component of adjuvant therapy in node-positive patients.
Patent protection for epirubicin expired in August 2007.
== References == |
Vericiguat | Vericiguat, sold under the brand name Verquvo, is a medication used to reduce the risk of cardiovascular death and hospitalization in certain patients with heart failure after a recent acute decompensation event. It is taken by mouth.Common side effects include low blood pressure and low red cell count (anemia).Vericiguat is a soluble guanylate cyclase (sGC) stimulator. It was approved for medical use in the United States in January 2021, and for use in the European Union in July 2021.
Medical uses
Vericiguat is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure following a prior hospitalization for heart failure or need for outpatient intravenous diuretics, in adults with symptomatic chronic heart failure and an ejection fraction of less than 45%.
Adverse effects
Vericiguat causes harm to the unborn baby and should not be given to pregnant women. It is also not known how vericiguat passes into breastmilk, therefore patients should not take vericiguat The most common side effects of vericiguat include low blood pressure and anemia. Patients taking other soluble guanylate cyclase inhibitors should also not be taking vericiguat.
Pharmacology
Vericiguat is a direct stimulator of soluble guanylate cyclase enzyme, an important enzyme in vascular smooth muscle cells. Specifically, vericiguat will bind to the beta-subunit of the target site on the soluble guanylate cyclase enzyme. Soluble guanylate cyclase enzymes catalyzes the formation of cyclic GMP upon interaction with nitric oxide to activate a number of downstream signaling cascade which can compensate for defects in this pathway and resulting losses in regulatory myocardial and vascular cellular processes due to cardiovascular complications.
Pharmacokinetics
After vericiguat is administered (100 mg by mouth once daily), the average steady state and Cmax and AUC for patients with cardiovascular failure is 350 mcg/L and 6,680 mcg/h/L with a Tmax of one hour. Vericiguat has a positive food effect, and therefore patients are advised to consume food with the drug for an oral bioavailability of 93%. Vericiguat is extensively protein-bound in plasma . Vericiguat is primarily metabolized via phase II conjugation reactions, with a minor CYP-mediated oxidative metabolite. The major metabolite is glucuronidated and inactive. The typical half-life profile for patients with heart failure is 30 hours. Vericiguat has a decreased clearance and was observed to have a 1.6 g/L clearance in patients with systolic heart failure.
History
The U.S. Food and Drug Administration (FDA) approved vericiguat based on evidence from a clinical trial (NCT02861534) which consisted of 5,050 participants aged 23 to 98 years old with worsening heart failure. The trial was conducted at 694 sites in 42 countries in Europe, Asia, North and South America. The trial enrolled participants with symptoms of worsening heart failure. Participants were randomly assigned to receive vericiguat or a placebo pill once a day. Neither the participants nor the health care professionals knew if the participants were given vericiguat or placebo pill until after the trial was complete. It was awarded a fast track designation on January 19th, 2021.
Society and culture
Legal status
On 20 May 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 vericiguat, intended for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction. The applicant for this medicinal product is Bayer AG. Vericiguat was approved for medical use in the European Union in July 2021.
References
Further reading
Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, et al. (May 2020). "Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction". N Engl J Med. 382 (20): 1883–1893. doi:10.1056/NEJMoa1915928. PMID 32222134.
External links
"Vericiguat". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02861534 for "A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction (HFrEF) (MK-1242-001) (VICTORIA)" at ClinicalTrials.gov |
Alcaine | Alcaine is a municipality located in the province of Teruel, Aragon, Spain. According to the 2004 census (INE), the municipality had a population of 65 inhabitants.
== References == |
Clorazepate | Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a majoritive prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.It was patented in 1965 and approved for medical use in 1967.
Medical uses
Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant. It is also used as a premedication.Clorazepate is prescribed principally in the treatment of alcohol withdrawal and epilepsy, although it is also a useful anxiolytic because of its long half-life. The normal starting dosage range of Clorazepate is 15 to 60 mg per day. The drug is to be taken two to four times per day. Dosages as high as 90 to 120 mg per day may be used in the treatment of acute alcohol withdrawal. In the United States and Canada, Clorazepate is available in 3.75, 7.5, and 15 mg capsules or tablets. In Europe, tablet formations are 5 mg, 10 mg, 20 mg and 50 mg. Clorazepate SD (controlled release) is available and may have a reduced incidence of adverse effects. The sustained-release formulation of clorazepate has some advantages in that, if a dose is missed, less profound fluctuations in blood plasma levels occur, which may be helpful to some people with epilepsy at risk of break-through seizures.
Adverse effects
Adverse effects of clorazepate include tolerance, dependence, withdrawal reactions, cognitive impairment, confusion, anterograde amnesia, falls in the elderly, ataxia, hangover effects, and drowsiness. It is unclear whether cognitive deficits resulting from the long-term use of benzodiazepines return to normal or persist indefinitely after withdrawal from benzodiazepines. Benzodiazepines are also known to cause or worsen depression. Paradoxical effects including excitement and paradoxical worsening of seizures can sometimes result from the use of benzodiazepines. Children, the elderly, individuals with a history of alcohol use disorder or a history of aggressive behavior and anger are at greater risk of developing paradoxical reactions to benzodiazepines.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 non-medical use, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Tolerance, dependence and withdrawal
Delirium has been noted from discontinuation from clorazepate.
A benzodiazepine dependence occurs in approximately one third of patients who take benzodiazepines for longer than 4 weeks, which is characterised by a withdrawal syndrome upon dose reduction. When used for seizure control, tolerance may manifest itself with an increased rate of seizures as well an increased risk of withdrawal seizures. In humans, tolerance to the anticonvulsant effects of clorazepate occurs frequently with regular use. Due to the development of tolerance, benzodiazepines are, in general, not considered appropriate for the long-term management of epilepsy; increasing the dose may result only in the developing of tolerance to the higher dose combined with worsened adverse effects. Cross-tolerance occurs between benzodiazepines, meaning that, if individuals are tolerant to one benzodiazepine, they will display a tolerance to equivalent doses of other benzodiazepines. Withdrawal symptoms from benzodiazepines include a worsening of pre-existing symptoms as well as the appearance of new symptoms that were not pre-existing. The withdrawal symptoms may range from mild anxiety and insomnia to severe withdrawal symptoms such as seizures and psychosis. Withdrawal symptoms can be difficult in some cases to differentiate between pre-existing symptoms and withdrawal symptoms. Use of high doses, long-term use and abrupt or over-rapid withdrawal increases increase the severity of withdrawal syndrome. However, tolerance to the active metabolite of clorazepate may occur more slowly than with other benzodiazepines. Regular use of benzodiazepines causes the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhea.
Interactions
All sedatives or hypnotics e.g. other benzodiazepines, barbiturates, antiepileptic drugs, alcohol, antihistamines, opioids, neuroleptics, sleep aids are likely to magnify the effects of clorazepate on the central nervous system. Drugs that may interact with clorazepate include, digoxin, disulfiram, fluoxetine, isoniazid, ketoconazole, levodopa, metoprolol, hormonal contraceptives, probenecid, propranolol, rifampin, theophylline, valproic acid. Selective serotonin reuptake inhibitors, cimetidine, macrolide antibiotics and antimycotics inhibit the metabolism of benzodiazepines and may result in increased plasma levels with resultant enhancement of adverse effects. Phenytoin, phenobarbital, and carbamazepine have the opposite effect, with coadministration leading to increased metabolism and decreased therapeutic effects of clorazepate.
Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.Clorazepate if used late in pregnancy, the third trimester, causes a definite risk of severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.Special precaution is required when using clorazepate in the elderly because the elderly metabolise clorazepate more slowly, which may result in excessive drug accumulation. Additionally the elderly are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even when blood plasma levels are the same. Use of benzodiazepines in the elderly is only recommended for 2 weeks and it is also recommended that half of the usual daily dose is prescribed.
Pharmacology
Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam. Clorazepate is a long-acting benzodiazepine drug. Clorazepate produces the active metabolite desmethyl-diazepam, which is a partial agonist of the GABAA receptor and has a half life of 20 – 179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam. Clorazepate exerts its pharmacological properties via increasing the opening frequency of the chloride ion channel of GABAA receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABAA receptors. Clorazepate, like other benzodiazepines, is widely distributed and is highly bound to plasma proteins; clorazepate also crosses readily over the placenta and into breast milk. Peak plasma levels of the active metabolite desmethyl-diazepam are seen between 30 minutes and 2 hours after oral administration of clorazepate. Clorazepate is completely metabolised to desmethyl-diazepam in the gastrointestinal tract and thus the pharmacological properties of clorazepate are largely due to desmethyldiazepam.
Chemistry
Clorazepate is used in the form of a dipotassium salt. It is unusual among benzodiazepines in that it is freely soluble in water.
Clorazepate can be synthesized starting from 2-amino-5-chlorobenzonitrile, which upon reaction with phenylmagnesium bromide is transformed into 2-amino-5-chlorbenzophenone imine. Reacting this with aminomalonic ester gives a heterocyclization product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one. Upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt, chlorazepate.
Legal status
In the United States, clorazepate is listed under Schedule IV of the Controlled Substances Act.
References
External links
Rx-List.com - Clorazepate
Inchem.org - Clorazepate |
Calcipotriol/betamethasone dipropionate | Calcipotriol/betamethasone dipropionate, sold under the brand name Taclonex among others, is a fixed-dose combination medication of the synthetic vitamin D3 analog calcipotriol (also known as calcipotriene) and the synthetic corticosteroid betamethasone dipropionate for the treatment of plaque psoriasis. It is used in the form of ointment, topical suspension, gel, aerosol, and foam.
Medical uses
Calcipotriol/betamethasone dipropionate (Cal/BD) is a topical medication for the treatment of trunk, limb, and scalp plaque psoriasis. This medication is available in ointment, gel, aerosol, or foam, formulations. The ointment formulation was FDA approved in 2004, and is indicated for the once daily topical treatment of plaque-type psoriasis vulgaris amenable to topical therapy. The foam formulation was approved by the FDA in 2015, and is indicated for the topical treatment of plaque psoriasis in patients twelve years of age and older.In all pivotal trials of calcipotriol/betamethasone dipropionate ointment, topical suspension, or foam, treatment success or achievement of clear or almost clear disease was defined by Investigators Global Assessment, an alternative to the Psoriasis Area and Severity Index (PASI) score.
OintmentIn an international, double-blind, parallel group study of 1603 participants with psoriasis (affecting at least 10% of one or more body regions), more patients on once-daily calcipotriol/betamethasone dipropionate ointment had controlled disease, defined as having absence or very mild disease at 4 weeks (56.3%) compared with Cal 50 μg/g (22.3%). In addition, a retrospective analysis of data from six phase 3, double-blind studies found that more patients treated with calcipotriol/betamethasone dipropionate ointment achieved PASI 75 than patients treated with individual components, regardless of baseline disease severity.
FoamThe foam formulation has been studied in two pivotal, randomized, double-blind trials in patients with mild to severe plaque psoriasis. In the first study (randomized, phase 2) of 302 patients with body and scalp psoriasis, more patients treated with calcipotriol/betamethasone dipropionate (Cal/BD) foam achieved clear or almost clear disease (45%) according to the IGA by 4 weeks compared with Cal 50 mcg/g or BD 0.5 mg/g (15% and 31%, respectively). In a second study (randomized, phase 3) of patients with psoriasis on the body (N=426), a significantly greater proportion of patients treated with once-daily Cal/BD foam achieved clear or almost clear disease (53.3%) vs. those receiving the vehicle control (4.8%). Mean modified PASI score was also significantly lower for patients treated with Cal/BD foam compared with vehicle (2.0 vs 5.5, respectively, at week 4), and itch relief was significantly greater in patients using the Cal/BD foam beginning at day 3. A recent study compared the Cal/BD foam formulation with the ointment formulation in patients with mild to severe psoriasis. At 4 weeks, significantly more patients achieved treatment success, defined as clear or almost clear disease according to the IGA with Cal/BD foam (54.6%) versus the ointment (43.0%). However, pronounced itch relief occurred quickly and was maintained throughout the 4-week study duration with both formulations.
Contraindications
Calcipotriol/betamethasone dipropionate is contraindicated in patients with hypersensitivity to either glucocorticoids or vitamin D or disorders in calcium metabolism. This drug is also contraindicated for patients with erythrodermic, exfoliative, or pustular psoriasis.
Adverse effects
A number of clinical studies have been conducted to investigate possible adverse events of this fixed combination corticosteroid and vitamin D analog. Safety and tolerability of calcipotriol/betamethasone dipropionate (Cal/BD) ointment has been assessed in a combined total of 2448 patients, exposed to treatment for 4 or 8 weeks (median weekly dose of 24.5 g). The most common adverse events for patients receiving Cal/BD were pruritus (3.1%), headache (2.8%), and nasopharyngitis (2.3%). Lesional/perilesional adverse events, defined as an adverse event located ≤2 cm from the lesional border, were reported by 8.7% of patients treated with Cal/BD ointment. Median time to onset of lesional/perilesional adverse events was 7 days.Adverse events during treatment with the foam formulation have been evaluated in three 4-week randomized, multicenter, prospective vehicle- and/or active-controlled clinical trials of subjects with plaque psoriasis. The median weekly dose was 24.8 g. Application site irritation, application site pruritus (itching), folliculitis (inflammation of hair follicles), skin hypopigmentation (loss of skin color), hypercalcemia (increased blood calcium levels), urticaria, and exacerbation of psoriasis were reported in <1% of subjects. Local long-term adverse effects of continuous steroid exposure may include skin atrophy, stretch marks, telangiectasia (spider veins), dryness, local infections, and miliaria ("prickly heat").
Pharmacology
Pharmacodynamics
A number of clinical studies have been conducted to research possible adverse effects of this drug combination, which can be expected from experiences with corticosteroids and vitamin D analogs.
Hypothalamic-pituitary-adrenal axis suppression
In a small study of calcipotriol/betamethasone dipropionate (Cal/BD) ointment once-daily for 4 weeks, no patients (N=11 tested) demonstrated adrenal suppression defined as 30-minute post-stimulation cortisol level ≤18 mcg/dL. In two other studies of Cal/BD ointment, 1 patient of 19 (5.3%) had adrenal suppression, as did 5 patients of 32 (15.6%) after 4 weeks of treatment. In the latter study, it may be noted that patients used Cal/BD ointment on the body in addition to Cal/BD topical suspension on the scalp.Potential effects on hypothalamic-pituitary-adrenal (HPA axis) function of the foam formulation were evaluated in a clinical trial of adults (N=35) with moderate to severe plaque psoriasis covering a mean of 18% of the body surface area of the trunk and limbs and 50% of the scalp. The foam was applied once daily to all lesions on the trunk, limbs and scalp for 4 weeks. Mean (range) weekly exposure was 62 (13.5–113) g. After 4 weeks, no patient exhibited adrenal suppression, defined as a cortisol level ≤497 nmol/L 30 minutes after adrenocorticotropic hormone challenge. Lack of adrenal suppression over the course of four weeks does not preclude the possibility of HPA axis suppression during prolonged exposure.
Effects on calcium metabolism
In patients treated with both calcipotriol/betamethasone dipropionate (Cal/BD) ointment on the body and Cal/BD topical suspension on the scalp (n=35), 1 patient (2.9%) had elevated urinary calcium levels after 4 weeks of treatment.Three studies of Cal/BD topical suspension have evaluated treatment effects on calcium metabolism. In 2 of the 3 trials (n=32 and n=43), elevated urinary calcium levels outside the normal range were observed in 2 patients each. In the third trial (n=109), no clinically relevant changes in urinary calcium were reported.Potential effects on calcium metabolism have been evaluated in three randomized, multicenter, prospective, vehicle- and/or active-controlled trials of the foam formulation enrolling 564 adults with plaque psoriasis. The foam was applied once daily for four weeks. In these trials, three subjects had serum calcium levels elevated above the upper limit of normal. Urinary calcium elevations above normal were reported in 17 subjects.In a published multicenter, open-label, single-arm trial of the foam formulation, 35 adults with plaque psoriasis applied the foam once daily to all lesions on the trunk, limbs, and scalp for four weeks. No elevations of serum calcium, urinary calcium, or the ratio of urinary calcium to creatinine above the upper limit of normal were observed.
History
The combination was developed by LEO Pharma. To combine them, new non-aqueous non-alcohol formulations had to be found to avoid mutual degradation of the two active substances while also achieving the desired skin absorption. The ointment formulation (Taclonex) was approved in 2006, by the US Food and Drug Administration (FDA) for the treatment of psoriasis vulgaris in adults 18 years and older. The topical suspension formulation (Taclonex) was approved in 2008, by the FDA for the treatment of plaque psoriasis of the scalp and body in adults 18 years and older. In 2014, the FDA also approved the topical suspension formulation for the treatment of plaque psoriasis of the scalp in adolescents aged 12 to 17 years. The foam formulation (Enstilar) was approved in October 2015, by the U.S. Food and Drug Administration. The ointment and topical suspension formulation (Daivobet) were also approved in 2010 by the European Medicines Agency for the treatment of plaque psoriasis where it is possible to use a topical medication (ointment), and for the treatment of scalp psoriasis or mild to moderate plaque psoriasis on the body (topical suspension).
References
Further reading
External links
"Betamethasone dipropionate mixture with calcipotriene". Drug Information Portal. U.S. National Library of Medicine. |
Hexavalent vaccine | A hexavalent vaccine, or 6-in-1 vaccine, is a combination vaccine with six individual vaccines conjugated into one, intended to protect people from multiple diseases. The term usually refers to the childrens vaccine that protects against diphtheria, tetanus, pertussis, poliomyelitis, haemophilus B, and hepatitis B, which is used in more than 90 countries around the world including in Europe, Canada, Australia, and New Zealand.
Formulations
The generic vaccine is known as diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus, haemophilus b conjugate [meningococcal protein conjugate] and hepatitis b [recombinant] vaccine. The liquid vaccine is also known in abbreviated form as DTaP-HepB-IPV-Hib or DTPa-HepB-IPV-Hib. Branded formulations include Hexavac, Hexaxim, Hexyon, and Vaxelis manufactured by Sanofi Pasteur.
There is a two-part formulation known in abbreviated form as DTaP-IPV-HepB/Hib or DTPa-HBV-IPV/Hib. It consists of a suspension of diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliomyelitis (DTaP-IPV-HepB or DTPa-HBV-IPV) vaccine that is used to reconstitute a lyophilised (freeze-dried) Haemophilus influenzae type B (Hib) powder. A branded formulation with a 3-antigen pertussis component, Infanrix hexa, is manufactured by GlaxoSmithKline.
EU approval
On 23 October 2000, the European Commission issued marketing approval for Hexavac and for Infanrix hexa.Marketing approval for Hexavac was suspended in November 2005, on the advice of the agencys Committee for Medicinal Products for Human Use (CHMP) in view of the variability of its long-term protection against hepatitis B. In April 2012, the manufacturer Sanofi Pasteur voluntarily withdrew the product from the market. The European Commission formally withdrew marketing permission on 28 June 2012.On 21 June 2012, the European Medicines Agency (EMA) issued a positive first opinion on Hexaxim for use outside the EU, in cooperation with the World Health Organization (WHO), but later withdrew the opinion.On 17 April 2013, marketing approval in the EU was granted to Hexyon and to Hexacima.On 15 February 2016, marketing approval in the EU was granted to Vaxelis.
US approval
On 21 December 2018, the U.S. Food and Drug Administration (FDA) licensed a hexavalent combined diphtheria and tetanus toxoids and acellular pertussis (DTaP) adsorbed, inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib) conjugate (meningococcal protein conjugate) and hepatitis B (HepB) (recombinant) vaccine, DTaP-IPV-Hib-HepB (Vaxelis), for use as a three-dose series in infants at ages two, four, and six months. On 26 June 2019, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) voted to include DTaP-IPV-Hib-HepB in the federal Vaccines for Children Program (VFC).
== References == |
Ivermectin | Ivermectin (, EYE-vər-MEK-tin) is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, today it is used to treat infestations including head lice, scabies, river blindness (onchocerciasis), strongyloidiasis, trichuriasis, ascariasis and lymphatic filariasis. It works through many mechanisms to kill the targeted parasites, and can be taken orally, or applied to the skin for external infestations. It belongs to the avermectin family of medications.William Campbell and Satoshi Ōmura won the 2015 Nobel Prize in Physiology or Medicine for its discovery and applications. It is on the World Health Organizations List of Essential Medicines, and is approved by the U.S. Food and Drug Administration as an antiparasitic agent. In 2018, it was the 420th most commonly prescribed medication in the United States, with more than 100,000 prescriptions. It is available as a generic medicine.During the COVID-19 pandemic, misinformation has been widely spread claiming that ivermectin is beneficial for treating and preventing COVID-19. Such claims are not backed by credible scientific evidence. Multiple major health organizations, including the Food and Drug Administration, U.S. Centers for Disease Control, the European Medicines Agency, and the World Health Organization have stated that ivermectin is not authorized or approved to treat COVID-19.
Medical uses
Ivermectin is used to treat human diseases caused by roundworms and ectoparasites.
Worm infections
For river blindness (onchocerciasis) and lymphatic filariasis, ivermectin is typically given as part of mass drug administration campaigns that distribute the drug to all members of a community affected by the disease. For river blindness, a single oral dose of ivermectin (150 micrograms per kilogram of body weight) clears the body of larval Onchocerca volvulus worms for several months, preventing transmission and disease progression. Adult worms survive in the skin and eventually recover to produce larval worms again; to keep the worms at bay, ivermectin is given at least once per year for the 10–15-year lifespan of the adult worms. For lymphatic filariasis, oral ivermectin (200 micrograms per kilogram body weight) is part of a combination treatment given annually: ivermectin, diethylcarbamazine citrate and albendazole in places without onchocerciasis; and ivermectin and albendazole in places with onchocerciasis.The World Health Organization (WHO) considers ivermectin the drug of choice for strongyloidiasis. Most cases are treated with two daily doses of oral ivermectin (200 μg per kg body weight), while severe infections are treated with five to seven days of ivermectin. Ivermectin is also the primary treatment for Mansonella ozzardi and cutaneous larva migrans. The U.S. Centers for Disease Control and Prevention (CDC) recommends ivermectin, albendazole, or mebendazole as treatments for ascariasis. Ivermectin is sometimes added to albendazole or mebendazole for whipworm treatment, and is considered a second-line treatment for gnathostomiasis.
Mites and insects
Ivermectin is also used to treat infection with parasitic arthropods. Scabies – infestation with the mite Sarcoptes scabiei – is most commonly treated with topical permethrin or oral ivermectin. For most scabies cases, ivermectin is used in a two dose regimen: a first dose kills the active mites, but not their eggs. Over the next week, the eggs hatch, and a second dose kills the newly hatched mites. For severe "crusted scabies", the U.S. Centers for Disease Control and Prevention (CDC) recommends up to seven doses of ivermectin over the course of a month, along with a topical antiparasitic. Both head lice and pubic lice can be treated with oral ivermectin, an ivermectin lotion applied directly to the affected area, or various other insecticides. Ivermectin is also used to treat rosacea and blepharitis, both of which can be caused or exacerbated by Demodex folliculorum mites.
Contraindications
The only absolute contraindication to the use of ivermectin is hypersensitivity to the active ingredient or any component of the formulation. In children under the age of five or those who weigh less than 15 kilograms (33 pounds), there is limited data regarding the efficacy or safety of ivermectin, though the available data demonstrate few adverse effects. However, the American Academy of Pediatrics cautions against use of ivermectin in such patients, as the blood-brain barrier is less developed, and thus there may be an increased risk of particular CNS side effects such as encephalopathy, ataxia, coma, or death. Such patients should be monitored very closely when given ivermectin. The American Academy of Family Physicians also recommends against use in these patients, given a lack of sufficient data to prove drug safety. Ivermectin is secreted in very low concentration in breast milk. It remains unclear if ivermectin is safe during pregnancy.
Adverse effects
Side effects, although uncommon, include fever, itching, and skin rash when taken by mouth; and red eyes, dry skin, and burning skin when used topically for head lice. It is unclear if the drug is safe for use during pregnancy, but it is probably acceptable for use during breastfeeding.Ivermectin is considered relatively free of toxicity in standard doses (around 300 µg/kg). Based on the data drug safety sheet for ivermectin, side effects are uncommon. However, serious adverse events following ivermectin treatment are more common in people with very high burdens of larval Loa loa worms in their blood. Those who have over 30,000 microfilaria per milliliter of blood risk inflammation and capillary blockage due to the rapid death of the microfilaria following ivermectin treatment.One concern is neurotoxicity after large overdoses, which in most mammalian species may manifest as central nervous system depression, ataxia, coma, and even death, as might be expected from potentiation of inhibitory chloride channels.Since drugs that inhibit the enzyme CYP3A4 often also inhibit P-glycoprotein transport, the risk of increased absorption past the blood-brain barrier exists when ivermectin is administered along with other CYP3A4 inhibitors. These drugs include statins, HIV protease inhibitors, many calcium channel blockers, lidocaine, the benzodiazepines, and glucocorticoids such as dexamethasone.During the course of a typical treatment, ivermectin can cause minor aminotransferase elevations. In rare cases it can cause mild clinically apparent liver disease.To provide context for the dosing and toxicity ranges, the LD50 of ivermectin in mice is 25 mg/kg (oral), and 80 mg/kg in dogs, corresponding to an approximated human-equivalent dose LD50 range of 2.02-43.24 mg/kg, which is far in excess of its FDA-approved usage (a single dose of 0.150-0.200 mg/kg to be used for specific parasitic infections). While ivermectin has also been studied for use in COVID-19, and while it has some ability to inhibit SARS-CoV-2 in vitro, achieving 50% inhibition in vitro was found to require an estimated oral dose of 7.0 mg/kg (or 35x the maximum FDA-approved dosage), high enough to be considered ivermectin poisoning. Despite insufficient data to show any safe and effective dosing regimen for ivermectin in COVID-19, doses have been taken far in excess of FDA-approved dosing, leading the CDC to issue a warning of overdose symptoms including nausea, vomiting, diarrhea, hypotension, decreased level of consciousness, confusion, blurred vision, visual hallucinations, loss of coordination and balance, seizures, coma, and death. The CDC advises against consuming doses intended for livestock or doses intended for external use and warns that increasing misuse of ivermectin-containing products is resulting in an increasing rate of harmful overdoses.
Veterinary use
Ivermectin is routinely used to control parasitic worms in the gastrointestinal tract of ruminant animals. These parasites normally enter the animal when it is grazing, pass the bowel, and set and mature in the intestines, after which they produce eggs that leave the animal via its droppings and can infest new pastures. Ivermectin is only effective in killing some of these parasites, this is because of an increase in anthelmintic resistance. This resistance has arisen from the persistent use of the same anthelmintic drugs for the past 40 years.In dogs, ivermectin is routinely used as prophylaxis against heartworm. Dogs with defects in the P-glycoprotein gene (MDR1), often collie-like herding dogs, can be severely poisoned by ivermectin. The mnemonic "white feet, dont treat" refers to Scotch collies that are vulnerable to ivermectin. Some other dog breeds (especially the Rough Collie, the Smooth Collie, the Shetland Sheepdog, and the Australian Shepherd), also have a high incidence of mutation within the MDR1 gene (coding for P-glycoprotein) and are sensitive to the toxic effects of ivermectin. Clinical evidence suggests kittens are susceptible to ivermectin toxicity. A 0.01% ivermectin topical preparation for treating ear mites in cats is available.Ivermectin is sometimes used as an acaricide in reptiles, both by injection and as a diluted spray. While this works well in some cases, care must be taken, as several species of reptiles are very sensitive to ivermectin. Use in turtles is particularly contraindicated.A characteristic of the antinematodal action of ivermectin is its potency: for instance, to combat Dirofilaria immitis in dogs, ivermectin is effective at 0.001 milligram per kilogram of body weight when administered orally.For dogs, the insecticide spinosad may have the effect of increasing the toxicity of ivermectin.
Pharmacology
Mechanism of action
Ivermectin and its related drugs act by interfering with the nerve and muscle functions of helminths and insects. The drug binds to glutamate-gated chloride channels common to invertebrate nerve and muscle cells. The binding pushes the channels open, which increases the flow of chloride ions and hyper-polarizes the cell membranes, paralyzing and killing the invertebrate. Ivermectin is safe for mammals (at the normal therapeutic doses used to cure parasite infections) because mammalian glutamate-gated chloride channels only occur in the brain and spinal cord: the causative avermectins usually do not cross the blood–brain barrier, and are unlikely to bind to other mammalian ligand-gated channels.
Pharmacokinetics
Ivermectin can be given by mouth, topically, or via injection. It does not readily cross the blood–brain barrier of mammals due to the presence of P-glycoprotein (the MDR1 gene mutation affects the function of this protein). Crossing may still become significant if ivermectin is given at high doses, in which case brain levels peak 2–5 hours after administration. In contrast to mammals, ivermectin can cross the blood–brain barrier in tortoises, often with fatal consequences.
Chemistry
Fermentation of Streptomyces avermitilis yields eight closely related avermectin homologues, of which B1a and B1b form the bulk of the products isolated. In a separate chemical step, the mixture is hydrogenated to give ivermectin, which is an approximately 80:20 mixture of the two 22,23-dihydroavermectin compounds.Ivermectin is a macrocyclical lactone.
History
The avermectin family of compounds was discovered by Satoshi Ōmura of Kitasato University and William Campbell of Merck. In 1970, Ōmura isolated a strain of Streptomyces avermitilis from woodland soil near a golf course along the south east coast of Honshu, Japan. Ōmura sent the bacteria to William Campbell, who showed that the bacterial culture could cure mice infected with the roundworm Heligmosomoides polygyrus. Campbell isolated the active compounds from the bacterial culture, naming them "avermectins" and the bacterium Streptomyces avermitilis for the compounds ability to clear mice of worms (in Latin: a without, vermis worms). Of the various avermectins, Campbells group found the compound "avermectin B1" to be the most potent when taken orally. They synthesized modified forms of avermectin B1 to improve its pharmaceutical properties, eventually choosing a mixture of at least 80% 22,23-dihydroavermectin B1a and up to 20% 22,23-dihydroavermectin B1b, a combination they called "ivermectin".The discovery of ivermectin has been described as a combination of "chance and choice." Merck was looking for a broad-spectrum anthelmintic, which ivermectin is indeed; however, Campbell noted that they "...also found a broad-spectrum agent for the control of ectoparasitic insects and mites."Merck began marketing ivermectin as a veterinary antiparasitic in 1981. By 1986, ivermectin was registered for use in 46 countries and was administered massively to cattle, sheep and other animals. By the late 1980s, ivermectin was the bestselling veterinary medicine in the world. Following its blockbuster success as a veterinary antiparasitic, another Merck scientist, Mohamed Aziz, collaborated with the World Health Organization to test the safety and efficacy of ivermectin against onchocerciasis in humans. They found it to be highly safe and effective, triggering Merck to register ivermectin for human use as "Mectizan" in France in 1987. A year later, Merck CEO Roy Vagelos agreed that Merck would donate all ivermectin needed to eradicate river blindness. In 1998, that donation would be expanded to include ivermectin used to treat lymphatic filariasis.Ivermectin earned the title of "wonder drug" for the treatment of nematodes and arthropod parasites. Ivermectin has been used safely by hundreds of millions of people to treat river blindness and lymphatic filariasis.Half of the 2015 Nobel Prize in Physiology or Medicine was awarded jointly to Campbell and Ōmura for discovering avermectin, "the derivatives of which have radically lowered the incidence of river blindness and lymphatic filariasis, as well as showing efficacy against an expanding number of other parasitic diseases".
Society and culture
COVID-19 misinformation
Economics
The initial price proposed by Merck in 1987 was US$6 per treatment, which was unaffordable for patients who most needed ivermectin. The company donated hundreds of millions of courses of treatments since 1988 in more than 30 countries. Between 1995 and 2010, using donated ivermectin to prevent river blindness, the program is estimated to have prevented seven million years of disability at a cost of US$257 million.Ivermectin is considered an inexpensive drug. As of 2019, ivermectin tablets (Stromectol) in the United States were the least expensive treatment option for lice in children at approximately US$9.30, while Sklice, an ivermectin lotion, cost around US$300 for 120 mL (4 US fl oz).As of 2019, the cost effectiveness of treating scabies and lice with ivermectin has not been studied.
Brand names
It is sold under the brand names Heartgard, Sklice and Stromectol in the United States, Ivomec worldwide by Merial Animal Health, Mectizan in Canada by Merck, Iver-DT in Nepal by Alive Pharmaceutical and Ivexterm in Mexico by Valeant Pharmaceuticals International. In Southeast Asian countries, it is marketed by Delta Pharma Ltd. under the trade name Scabo 6. The formulation for rosacea treatment is sold under the brand name Soolantra. While in development, it was assigned the code MK-933 by Merck.
Research
Parasitic disease
Ivermectin has been researched in laboratory animals, as a potential treatment for trichinosis.
Tropical diseases
As of 2016 ivermectin was studied as a potential antiviral agent against chikungunya and yellow fever. In chikungunya, ivermectin showed a wide in vitro safety margin as an antiviral.Ivermectin is also of interest in the prevention of malaria, as it is toxic to both the malaria plasmodium itself and the mosquitos that carry it. A direct effect on malaria parasites could not be shown in an experimental infection of volunteers with Plasmodium falciparum. Use of ivermectin at higher doses necessary to control malaria is probably safe, though large clinical trials have not yet been done to definitively establish the efficacy or safety of ivermectin for prophylaxis or treatment of malaria. Mass drug administration of a population with ivermectin to treat and prevent nematode infestation is effective for eliminating malaria-bearing mosquitos and thereby reducing infection with residual malaria parasites.One alternative to ivermectin is moxidectin, which has been approved by the Food and Drug Administration for use in people with river blindness. Moxidectin has a longer half-life than ivermectin and may eventually supplant ivermectin as it is a more potent microfilaricide, but there is a need for additional clinical trials, with long-term follow-up, to assess whether moxidectin is safe and effective for treatment of nematode infection in children and women of childbearing potential.There is tentative evidence that ivermectin kills bedbugs, as part of integrated pest management for bedbug infestations. However, such use may require a prolonged course of treatment which is of unclear safety.
NAFLD
In 2013, ivermectin was demonstrated as a novel ligand of the farnesoid X receptor, a therapeutic target for nonalcoholic fatty liver disease.
COVID-19
During the COVID-19 pandemic, ivermectin was researched for possible utility in preventing and treating COVID-19, but no good evidence of benefit was found.
See also
Notes
References
External links
"Ivermectin". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on October 19, 2021.
The Carter Center River Blindness (Onchocerciasis) Control Program
"ivermectin (Rx) Stromectol". Medscape. Archived from the original on October 19, 2021.
"Ivermectin Topical". MedlinePlus. Archived from the original on October 19, 2021. |
Pilocarpine | Pilocarpine is a medication used to reduce pressure inside the eye and treat dry mouth. As eye drops it is used to manage angle closure glaucoma until surgery can be performed, ocular hypertension, primary open angle glaucoma, and to bring about constriction of the pupil following its dilation. However, due to its side effects it is no longer typically used in the long term management. Onset of effects with the drops is typically within an hour and lasts for up to a day. By mouth it is used for dry mouth as a result of Sjögren syndrome or radiation therapy.Common side effects of the eye drops include irritation of the eye, increased tearing, headache, and blurry vision. Other side effects include allergic reactions and retinal detachment. Use is generally not recommended during pregnancy. Pilocarpine is in the miotics family of medication. It works by activating cholinergic receptors of the muscarinic type which cause the trabecular meshwork to open and the aqueous humor to drain from the eye.Pilocarpine was isolated in 1874 by Hardy and Gerrard and has been used to treat glaucoma for more than 100 years. It is on the World Health Organizations List of Essential Medicines. It was originally made from the South American plant Pilocarpus.
Medical uses
Pilocarpine stimulates the secretion of large amounts of saliva and sweat. It is used to prevent or treat dry mouth, particularly in Sjögren syndrome, but also as a side effect of radiation therapy for head and neck cancer.It may be used to help differentiate Adie syndrome from other causes of unequal pupil size.It may be used to treat a form of dry eye called aqueous deficient dry eye (ADDE)
Surgery
Pilocarpine is sometimes used immediately before certain types of corneal grafts and cataract surgery. It is also used prior to YAG laser iridotomy. In ophthalmology, pilocarpine is also used to reduce symptomatic glare at night from lights when the patient has undergone implantation of phakic intraocular lenses; the use of pilocarpine would reduce the size of the pupils, partially relieving these symptoms. The most common concentration for this use is pilocarpine 1%. Pilocarpine is shown to be just as effective as apraclonidine in preventing intraocular pressure spikes after laser trabeculoplasty.
Presbyopia
In 2021, the US Food and Drug Administration approved pilocarpine hydrochloride as an eyedrop treatment for presbyopia, age-related difficulty with near-in vision. It works by causing the pupils to constrict, increasing depth of field, similar to the effect of pinhole glasses. Marketed as Vuity, the effect lasts for more than 6 hours.
Other
Pilocarpine is used to stimulate sweat glands in a sweat test to measure the concentration of chloride and sodium that is excreted in sweat. It is used to diagnose cystic fibrosis.
Adverse effects
Use of pilocarpine may result in a range of adverse effects, most of them related to its non-selective action as a muscarinic receptor agonist. Pilocarpine has been known to cause excessive salivation, sweating, bronchial mucus secretion, bronchospasm, bradycardia, vasodilation, and diarrhea. Eye drops can result in brow ache and chronic use in miosis. It can also cause temporary blurred vision or darkness of vision, temporary shortsightedness, hyphema and retinal detachment.
Pharmacology
Pilocarpine is a drug that acts as a muscarinic receptor agonist. It acts on a subtype of muscarinic receptor (M3) found on the iris sphincter muscle, causing the muscle to contract - resulting in pupil constriction (miosis). Pilocarpine also acts on the ciliary muscle and causes it to contract. When the ciliary muscle contracts, it opens the trabecular meshwork through increased tension on the scleral spur. This action facilitates the rate that aqueous humor leaves the eye to decrease intraocular pressure. Paradoxically, when pilocarpine induces this ciliary muscle contraction (known as an accommodative spasm) it causes the eyes lens to thicken and move forward within the eye. This movement causes the iris (which is located immediately in front of the lens) to also move forward, narrowing the Anterior chamber angle. Narrowing of the anterior chamber angle increases the risk of increased intraocular pressure.
Society and culture
Preparation
Plants in the genus Pilocarpus are the only known sources of pilocarpine, and commercial production is derived entirely from the leaves of Pilocarpus microphyllus (Maranham Jaborandi). This genus grows only in South America, and Pilocarpus microphyllus is native to several states in northern Brazil.Pilocarpine is extracted from the powdered leaf material in a multi-step process. First the material is treated with ethanol acidified with hydrochloric acid, and the solvents removed under reduced pressure. The resultant aqueous residue is neutralized with ammonia and put aside until the resin has completely settled. It is then filtered and concentrated by sugar solution to a small volume, made alkaline with ammonia, and finally extracted with chloroform. The solvent is removed under reduced pressure.
Trade names
Pilocarpine is available under several trade names such as: Diocarpine (Dioptic), Isopto Carpine (Alcon), Miocarpine (CIBA Vision), Ocusert Pilo-20 and -40 (Alza), Pilopine HS (Alcon), Salagen (MGI Pharma), Scheinpharm Pilocarpine (Schein Pharmaceutical), Timpilo (Merck Frosst), and Vuity (AbbVie).
Research
Pilocarpine is used to induce chronic epilepsy in rodents, commonly rats, as a means to study the disorders physiology and to examine different treatments. Smaller doses may be used to induce salivation in order to collect samples of saliva, for instance, to obtain information about IgA antibodies.
Veterinary
Pilocarpine is given in moderate doses (about 2 mg) to induce emesis in cats that have ingested foreign plants, foods, or drugs. One feline trial determined it was effective, even though the usual choice of emetic is xylazine.
References
External links
"Pilocarpine". Drug Information Portal. U.S. National Library of Medicine. |
Podophyllotoxin | Podophyllotoxin (PPT) is the active ingredient in Podofilox, which is a medical cream that is used to treat genital warts and molluscum contagiosum. It is not recommended in HPV infections without external warts. It can be applied either by a healthcare provider or the person themselves.It is a non-alkaloid toxin lignin extracted from the roots and rhizomes of Podophyllum species. A less refined form known as podophyllum resin is also available, but has greater side effects.Podophyllotoxin was first isolated in pure form in 1880 by Valerian Podwyssotzki (1818 – 28 January 1892), a Polish-Russian privatdozent at the University of Dorpat (now: Tartu, Estonia) and assistant at the Pharmacological Institute there.It is on the World Health Organizations List of Essential Medicines.
Medical uses
Podophyllotoxin possesses a large number of medical applications, as it is able to stop replication of both cellular and viral DNA by binding necessary enzymes. It can additionally destabilize microtubules and prevent cell division. Because of these interactions it is considered an antimitotic drug, although modern medicine instead use less orally toxic derivatives when such effect is wanted.Podophyllotoxin cream is commonly prescribed as a potent topical antiviral. It is used for the treatment of HPV infections with external warts as well as molluscum contagisum infections. 0.5% PPT cream is prescribed for twice daily applications for 3 days followed by 4 days with no application, this weekly cycle is repeated for 4 weeks. It can also be prescribed as a gel, as opposed to cream. PPT is also sold under the names condyline and warticon.
Adverse effects
The most common side effects of podophyllotoxin cream are typically limited to irritation of tissue surrounding the application site, including burning, redness, pain, itching, swelling. Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow, for these reasons it is recommended that application be done in a way that limits contact with surrounding, uninfected tissueNeither podophyllin resin nor podophyllotoxin lotions or gels are used during pregnancy because these medications have been shown to be embroytoxic in both mice and rats. Additionally, antimitotic agents are not typically recommended during pregnancy. Additionally, it has not been determined if podophyllotoxin can pass into breast milk from topical applications and therefore it is not recommended for breastfeeding women.Podophyllotoxin cream is safe for topical use; however, it can cause CNS depression as well as enteritis if ingested. The podophyllum resin from which podophyllotoxin is derived has the same effect.
Mechanism of action
Podophyllotoxin destabilizes microtubules by binding tubulin and thus preventing cell division. In contrast, some of its derivatives display binding activity to the enzyme topoisomerase II (Topo II) during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary DNA break caused by the enzyme, disrupts the reparation of the break through which the double-stranded DNA passes, and consequently stops DNA unwinding and replication. Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells. The mutually exclusive cross-resistance patterns of these mutants provide a highly specific means to distinguish the two kinds of podophyllotoxin derivatives. Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.Furthermore, podophyllotoxin is classified as an arytetralin lignan for its ability to bind and deactivate DNA. It and its derivates bind Topo II and prevent its ability to catalyze rejoining of DNA that has been broken for replication. Lastly, experimental evidence has shown that these arytetralin lignans can interact with cellular factors to create chemical DNA adducts, thus further deactivating DNA.
Chemistry
Structural characteristic
The structure of podophyllotoxin was first elucidated in the 1930s. Podophyllotoxin bears four consecutive chiral centers, labelled C-1 through C-4 in the following image. The molecule also contains four almost planar fused rings. The podophyllotoxin molecule includes a number of oxygen containing functional groups: an alcohol, a lactone, three methoxy groups, and an acetal.
Derivatives of podophyllotoxin are synthesized as properties of the rings and carbon 1 through 4 are diversified. For example, ring A is not essential to antimitotic activity. Aromatization of ring C leads to loss of activity, possibly from ring E no longer being placed on the axial position. In addition, the stereochemistry at C-2 and C-3 configures a trans-lactone, which has more activity than the cis counterpart. Chirality at C-1 is also important as it implies an axial position for ring E.
Biosynthesis
The biosynthetic route of podophyllotoxin was not completely eludicidated for many years; however, in September 2015, the identity of the six missing enzymes in podophyllotoxin biosynthesis were reported for the first time. Several prior studies have suggested a common pathway starting from coniferyl alcohol being converted to (+)-pinoresinol in the presence of a one-electron oxidant through dimerization of stereospecific radical intermediate. Pinoresinol is subsequently reduced in the presence of co-factor NADPH to first lariciresinol, and ultimately secoisolariciresinol. Lactonization on secoisolariciresinol gives rise to matairesinol. Secoisolariciresinol is assumed to be converted to yatein through appropriate quinomethane intermediates, leading to podophyllotoxin.
A sequence of enzymes involved has been reported to be dirigent protein (DIR), to convert coniferyl alcohol to (+)-pinocresol, which is converted by pinocresol-lariciresinol reductase (PLR) to (-)-secoisolariciresinol, which is converted by sericoisolariciresinol dehydrogenase (SDH) to (-)-matairesinol, which is converted by CYP719A23 to (-)-pluviatolide, which is likely converted by Phex13114 (OMT1) to (-)-yatein, which is converted by Phex30848 (2-ODD) to (-)-deoxypodophyllotoxin. Though not proceeding through the last step of producing podophyllotoxin itself, a combination of six genes from the mayapple enabled production of the etoposide aglycone in tobacco plants.
Chemical synthesis
Podophyllotoxin has been successfully synthesized in a laboratory; however, synthesis mechanisms require many steps, resulting resulted in low overall yield. It therefore remains more efficient to obtain podophyllotoxin from natural sources.Four routes have been used to synthesize podophyllotoxin with varying success: an oxo ester route, lactonization of a dihydroxy acid, cyclization of a conjugate addition product, and a Diels-Alder reaction.
Derivatives
Podophyllotoxin and its derivatives are used as cathartic, purgative, antiviral agent, vesicant, antihelminthic, and antitumor agents. Podophyllotoxin derived antitumor agents include etoposide and teniposide. These drugs have been successfully used in therapy against numerous cancers including testicular, breast, pancreatic, lung, stomach, and ovarian cancers.
Natural abundance
Podophyllotoxin is present at concentrations of 0.3% to 1.0% by mass in the rhizome of the American mayapple (Podophyllum peltatum). Another common source is the rhizome of Sinopodophyllum hexandrum Royle (Berberidaceae).
It is biosynthesized from two molecules of coniferyl alcohol by phenolic oxidative coupling and a series of oxidations, reductions and methylations.
References
== Further reading == |
Cefixime | Cefixime, sold under the brand name Suprax among others, is an antibiotic medication used to treat a number of bacterial infections. These infections include otitis media, strep throat, pneumonia, urinary tract infections, gonorrhea, and Lyme disease. For gonorrhea typically only one dose is required. In the United States it is a second-line treatment to ceftriaxone for gonorrhea. It is taken by mouth.Common side effects include diarrhea, abdominal pain, and nausea. Serious side effects may include allergic reactions and Clostridium difficile diarrhea. It is not recommended in people with a history of a severe penicillin allergy. It appears to be relatively safe during pregnancy. It is in the third-generation cephalosporin class of medications. It works by disrupting the bacterias cell wall resulting in its death.Cefixime was patented in 1979 and approved for medical use in the United States in 1989. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication in the United States.
Medical uses
Cefixime treats infections of the:
Urinary tract: Uncomplicated urinary tract infections caused by susceptible isolates of Escherichia coli and Proteus mirabilis.
Ear: Otitis media caused by Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes.
Throat: Tonsillitis and pharyngitis caused by Streptococcus pyogenes.
Chest and lungs: Chronic bronchitis caused by Streptococcus pneumoniae and Haemophilus influenzae.
Cervix and urethra: Gonorrhea (cervical/urethral) caused by susceptible isolates of Neisseria gonorrhoeae (penicillinase-and non-penicillinase-producing isolates).
Skin and soft tissue infection: effective against group A and B beta-hemolytic streptococci. However, Staphylococcus aureus, coagulase-negative staphylococci and enterococci are resistant.It is also used to treat typhoid fever.
Spectrum of bacterial susceptibility
Cefixime is a broad spectrum cephalosporin antibiotic and is commonly used to treat bacterial infections of the ear, urinary tract, and upper respiratory tract. The following represents MIC susceptibility data for a few medically significant microorganisms:
Escherichia coli: 0.015 µg/mL – 4 µg/mL
Haemophilus influenzae: ≤0.004 µg/mL – >4 µg/mL
Proteus mirabilis: ≤0.008 µg/mL – 0.06 µg/mL
Streptococcus pneumoniae: 0.12 µg/mL
Staphylococcus aureus: >128 µg/mL (Resistant)
Enterobacter spp. : >128 µg/mL (Resistant)
Mechanism of action
The bactericidal action of Cefixime is due to the inhibition of cell wall synthesis. It binds to one of the penicillin binding proteins (PBPs) which inhibits the final transpeptidation step of the peptidoglycan synthesis in the bacterial cell wall, thus inhibiting biosynthesis and arresting cell wall assembly resulting in bacterial cell death.
Absorption
Only 40–50% is absorbed from the GI tract (oral bioavailability). Absorption may be slowed but not decreased when taken with food. Average peak concentration after administration of oral suspension is approximately 25–50% greater than the peak concentration following oral tablet or capsules administration.Distribution
It has high concentrations in bile and urine. It can cross the placenta and its protein binding capacity is 65%.It is always better to perform appropriate cultures and susceptibility studies to determine the causative organism and its sensitivity to cefixime.
Contraindications
Cefixime is contraindicated in patients with known sensitivity or allergies to cephalosporin class of antibiotics. As Cefixime is a third generation cephalosporin, it is not contraindicated for patients with a true penicillin allergy.
Adverse effects
Adverse drug reactions include diarrhea, dyspepsia, nausea and vomiting. Hypersensitivity reactions like skin rashes, urticaria and Stevens–Johnson syndrome have been reported. Though thrombocytopenia has been reported for many cephalosporins, it has not been reported for cefixime.
There is no specific antidote for Cefixime overdosage. Gastric lavage may be performed. Dialysis will not remove Cefixime in significant quantities.
Drug interactions
Alcohol – No major interaction has been observed between cefixime and alcohol.
History
It was sold under the trade name Suprax 125 in the United States until 2003, when it was taken off the market by drug manufacturer Wyeth after its patent expired. Lupin started selling Suprax in the United States in 2007, and it is available in different formulations and strengths.
Marketing
Cefixime is marketed under many trade names worldwide; examples include Pancef, Caricef, Taxim o, Texit,Ofex, Cef-3, Denvar, 3-C, Cefim, Magnett, Oroken, Ofiken, Fix-A, and Zifi. In India it is marketed as Zifi 200 and is commonly counterfeited.
References
External links
"Cefixime". Drug Information Portal. U.S. National Library of Medicine. |
Oxytocin | Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin is released into the bloodstream as a hormone in response to sexual activity and during labour. It is also available in pharmaceutical form. In either form, oxytocin stimulates uterine contractions to speed up the process of childbirth. In its natural form, it also plays a role in bonding with the baby and milk production. Production and secretion of oxytocin is controlled by a positive feedback mechanism, where its initial release stimulates production and release of further oxytocin. For example, when oxytocin is released during a contraction of the uterus at the start of childbirth, this stimulates production and release of more oxytocin and an increase in the intensity and frequency of contractions. This process compounds in intensity and frequency and continues until the triggering activity ceases. A similar process takes place during lactation and during sexual activity.
Oxytocin is derived by enzymatic splitting from the peptide precursor encoded by the human OXT gene. The deduced structure of the active nonapeptide is:
Cys – Tyr – Ile – Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2.
Etymology
The term "oxytocin" derives from the Greek "ὠκυτόκος" (ōkutókos), based on ὀξύς (oxús), meaning "sharp" or "swift", and τόκος (tókos), meaning "childbirth". The adjective form is "oxytocic", which refers to medicines which stimulate uterine contractions, to speed up the process of childbirth.
History
The uterine-contracting properties of the principle that would later be named oxytocin were discovered by British pharmacologist Henry Hallett Dale in 1906, and its milk ejection property was described by Ott and Scott in 1910 and by Schafer and Mackenzie in 1911.In the 1920s, oxytocin and vasopressin were isolated from pituitary tissue and given their current names.
Oxytocins molecular structure was determined in 1952. In the early 1950s, American biochemist Vincent du Vigneaud found that oxytocin is made up of nine amino acids, and he identified its amino acid sequence, the first polypeptide hormone to be sequenced. In 1953, du Vigneaud carried out the synthesis of oxytocin, the first polypeptide hormone to be synthesized. Du Vigneaud was awarded the Nobel Prize in 1955 for his work.Further work on different synthetic routes for oxytocin, as well as the preparation of analogues of the hormone (e.g. 4-deamido-oxytocin) was performed in the following decade by Iphigenia Photaki.
Biochemistry
Estrogen has been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.
Biosynthesis
Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone (CRH) and dynorphin, for example, that act locally. The magnocellular neurons that make oxytocin are adjacent to magnocellular neurons that make vasopressin, and are similar in many respects.
The oxytocin peptide is synthesized as an inactive precursor protein from the OXT gene. This precursor protein also includes the oxytocin carrier protein neurophysin I. The inactive precursor protein is progressively hydrolyzed into smaller fragments (one of which is neurophysin I) via a series of enzymes. The last hydrolysis that releases the active oxytocin nonapeptide is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM).The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner. Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.Oxytocin is known to be metabolized by the oxytocinase, leucyl/cystinyl aminopeptidase. Other oxytocinases are also known to exist. Amastatin, bestatin (ubenimex), leupeptin, and puromycin have been found to inhibit the enzymatic degradation of oxytocin, though they also inhibit the degradation of various other peptides, such as vasopressin, met-enkephalin, and dynorphin A.
Neural sources
In the hypothalamus, oxytocin is made in magnocellular neurosecretory cells of the supraoptic and paraventricular nuclei, and is stored in Herring bodies at the axon terminals in the posterior pituitary. It is then released into the blood from the posterior lobe (neurohypophysis) of the pituitary gland. These axons (likely, but dendrites have not been ruled out) have collaterals that innervate neurons in the nucleus accumbens, a brain structure where oxytocin receptors are expressed. The endocrine effects of hormonal oxytocin and the cognitive or behavioral effects of oxytocin neuropeptides are thought to be coordinated through its common release through these collaterals. Oxytocin is also produced by some neurons in the paraventricular nucleus that project to other parts of the brain and to the spinal cord. Depending on the species, oxytocin receptor-expressing cells are located in other areas, including the amygdala and bed nucleus of the stria terminalis.
In the pituitary gland, oxytocin is packaged in large, dense-core vesicles, where it is bound to neurophysin I as shown in the inset of the figure; neurophysin is a large peptide fragment of the larger precursor protein molecule from which oxytocin is derived by enzymatic cleavage.
Secretion of oxytocin from the neurosecretory nerve endings is regulated by the electrical activity of the oxytocin cells in the hypothalamus. These cells generate action potentials that propagate down axons to the nerve endings in the pituitary; the endings contain large numbers of oxytocin-containing vesicles, which are released by exocytosis when the nerve terminals are depolarised.
Non-neural sources
Endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels.Outside the brain, oxytocin-containing cells have been identified in several diverse tissues, including in females in the corpus luteum and the placenta; in males in the testicles interstitial cells of Leydig; and in both sexes in the retina, the adrenal medulla, the thymus and the pancreas. The finding of significant amounts of this classically "neurohypophysial" hormone outside the central nervous system raises many questions regarding its possible importance in these diverse tissues.
Male
The Leydig cells in some species have been shown to possess the biosynthetic machinery to manufacture testicular oxytocin de novo, to be specific, in rats (which can synthesize vitamin C endogenously), and in guinea pigs, which, like humans, require an exogenous source of vitamin C (ascorbate) in their diets.
Female
Oxytocin is synthesized by corpora lutea of several species, including ruminants and primates. Along with estrogen, it is involved in inducing the endometrial synthesis of prostaglandin F2α to cause regression of the corpus luteum.
Evolution
Virtually all vertebrates have an oxytocin-like nonapeptide hormone that supports reproductive functions and a vasopressin-like nonapeptide hormone involved in water regulation. The two genes are usually located close to each other (less than 15,000 bases apart) on the same chromosome, and are transcribed in opposite directions (however, in fugu, the homologs are further apart and transcribed in the same direction).
The two genes are believed to result from a gene duplication event; the ancestral gene is estimated to be about 500 million years old and is found in cyclostomata (modern members of the Agnatha).
Biological function
Oxytocin has peripheral (hormonal) actions, and also has actions in the brain. Its actions are mediated by specific oxytocin receptors. The oxytocin receptor is a G-protein-coupled receptor, OT-R, which requires magnesium and cholesterol and is expressed in myometrial cells. It belongs to the rhodopsin-type (class I) group of G-protein-coupled receptors.Studies have looked at oxytocins role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, in-group bias, situational lack of honesty, autism, and maternal behaviors. Oxytocin is believed to have a significant role in social learning. There are indicators that oxytocin may help to decrease noise in the brains auditory system, increase perception of social cues and support more targeted social behavior. It may also enhance reward responses. However, its effects may be influenced by context, such as the presence of familiar or unfamiliar individuals.
Physiological
The peripheral actions of oxytocin mainly reflect secretion from the pituitary gland. The behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland, or that are collaterals from them. Oxytocin receptors are expressed by neurons in many parts of the brain and spinal cord, including the amygdala, ventromedial hypothalamus, septum, nucleus accumbens, and brainstem, although the distribution differs markedly between species. Furthermore, the distribution of these receptors changes during development and has been observed to change after parturition in the montane vole.
Milk ejection reflex/Letdown reflex: in lactating (breastfeeding) mothers, oxytocin acts at the mammary glands, causing milk to be let down into lactiferous ducts, from where it can be excreted via the nipple. Suckling by the infant at the nipple is relayed by spinal nerves to the hypothalamus. The stimulation causes neurons that make oxytocin to fire action potentials in intermittent bursts; these bursts result in the secretion of pulses of oxytocin from the neurosecretory nerve terminals of the pituitary gland.
Uterine contraction: important for cervical dilation before birth, oxytocin causes contractions during the second and third stages of labor. Oxytocin release during breastfeeding causes mild but often painful contractions during the first few weeks of lactation. This also serves to assist the uterus in clotting the placental attachment point postpartum. However, in knockout mice lacking the oxytocin receptor, reproductive behavior and parturition are normal.
In male rats, oxytocin may induce erections. A burst of oxytocin is released during ejaculation in several species, including human males; its suggested function is to stimulate contractions of the reproductive tract, aiding sperm release.
Human sexual response: Oxytocin levels in plasma rise during sexual stimulation and orgasm. At least two uncontrolled studies have found increases in plasma oxytocin at orgasm – in both men and women. Plasma oxytocin levels are increased around the time of self-stimulated orgasm and are still higher than baseline when measured five minutes after self arousal. The authors of one of these studies speculated that oxytocins effects on muscle contractibility may facilitate sperm and egg transport.In a study measuring oxytocin serum levels in women before and after sexual stimulation, the author suggests it serves an important role in sexual arousal. This study found genital tract stimulation resulted in increased oxytocin immediately after orgasm. Another study reported increases of oxytocin during sexual arousal could be in response to nipple/areola, genital, and/or genital tract stimulation as confirmed in other mammals. Murphy et al. (1987), studying men, found that plasma oxytocin levels remain unchanged during sexual arousal, but that levels increase sharply after ejaculation, returning to baseline levels within 30 minutes. In contrast, vasopressin was increased during arousal but returned to baseline at the time of ejaculation. The study concludes that (in males) vasopressin is secreted during arousal, while oxytocin is only secreted after ejaculation. A more recent study of men found an increase in plasma oxytocin immediately after orgasm, but only in a portion of their sample that did not reach statistical significance. The authors noted these changes "may simply reflect contractile properties on reproductive tissue".Due to its similarity to vasopressin, it can reduce the excretion of urine slightly, and so it can be classified as an antidiuretic. In several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and, in humans, high doses can result in low sodium levels (hyponatremia).
Cardiac effects: oxytocin and oxytocin receptors are also found in the heart in some rodents, and the hormone may play a role in the embryonal development of the heart by promoting cardiomyocyte differentiation. However, the absence of either oxytocin or its receptor in knockout mice has not been reported to produce cardiac insufficiencies.
Modulation of hypothalamic-pituitary-adrenal axis activity: oxytocin, under certain circumstances, indirectly inhibits release of adrenocorticotropic hormone and cortisol and, in those situations, may be considered an antagonist of vasopressin.
Preparing fetal neurons for delivery (in rats): crossing the placenta, maternal oxytocin reaches the fetal brain and induces a switch in the action of neurotransmitter GABA from excitatory to inhibitory on fetal cortical neurons. This silences the fetal brain for the period of delivery and reduces its vulnerability to hypoxic damage.
Feeding: a 2012 paper suggested that oxytocin neurons in the para-ventricular hypothalamus in the brain may play a key role in suppressing appetite under normal conditions and that other hypothalamic neurons may trigger eating via inhibition of these oxytocin neurons. This population of oxytocin neurons is absent in Prader-Willi syndrome, a genetic disorder that leads to uncontrollable feeding and obesity, and may play a key role in its pathophysiology. Research on the oxytocin-related neuropeptide asterotocin in starfish also showed that in echinoderms, the chemical induces muscle relaxation, and in starfish specifically caused the organisms to evert their stomach and react as though feeding on prey, even when none were present.
Psychological
Autism: Oxytocin has been implicated in the etiology of autism, with one report suggesting autism is correlated to a mutation on the oxytocin receptor gene (OXTR). Studies involving Caucasian, Finnish and Chinese Han families provide support for the relationship of OXTR with autism. Autism may also be associated with an aberrant methylation of OXTR.
Protection of brain functions: Studies in rats have demonstrated that nasal application of oxytocin can alleviate impaired learning capabilities caused by restrained stress. The authors attributed this effect to an improved hippocampal response in Brain-Derived Neurotrophic Factor (BDNF) being observed. Accordingly, oxytocin has been shown to promote neural growth in the hippocampus in rats even during swim stress or glucocorticoid administration. In a mouse model of early onset of Alzheimers, the administration of oxytocin by a gel particularly designed to make the peptide accessible for the brain, the cognitive decline and hippocampal atrophy of these mice were delayed. Moreover, the amyloid β-protein deposit and nerve cell apoptosis were retarded. An observed inhibitory impact by oxytocin on the inflammatory activity of the microglia was proposed to be an important factor.
Bonding
In the prairie vole, oxytocin released into the brain of the female during sexual activity is important for forming a pair bond with her sexual partner. Vasopressin appears to have a similar effect in males. Oxytocin has a role in social behaviors in many species, so it likely also does in humans. In a 2003 study, both humans and dog oxytocin levels in the blood rose after a five to 24 minute petting session. This possibly plays a role in the emotional bonding between humans and dogs.
Maternal behavior: Female rats given oxytocin antagonists after giving birth do not exhibit typical maternal behavior. By contrast, virgin female sheep show maternal behavior toward foreign lambs upon cerebrospinal fluid infusion of oxytocin, which they would not do otherwise. Oxytocin is involved in the initiation of human maternal behavior, not its maintenance; for example, it is higher in mothers after they interact with unfamiliar children rather than their own.
Human ingroup bonding: Oxytocin can increase positive attitudes, such as bonding, toward individuals with similar characteristics, who then become classified as "in-group" members, whereas individuals who are dissimilar become classified as "out-group" members. Race can be used as an example of in-group and out-group tendencies because society often categorizes individuals into groups based on race (Caucasian, African American, Latino, etc.). One study that examined race and empathy found that participants receiving nasally administered oxytocin had stronger reactions to pictures of in-group members making pained faces than to pictures of out-group members with the same expression. Moreover, individuals of one race may be more inclined to help individuals of the same race than individuals of another race when they are experiencing pain. Oxytocin has also been implicated in lying when lying would prove beneficial to other in-group members. In a study where such a relationship was examined, it was found that when individuals were administered oxytocin, rates of dishonesty in the participants responses increased for their in-group members when a beneficial outcome for their group was expected. Both of these examples show the tendency of individuals to act in ways that benefit those considered to be members of their social group, or in-group.Oxytocin is not only correlated with the preferences of individuals to associate with members of their own group, but it is also evident during conflicts between members of different groups. During conflict, individuals receiving nasally administered oxytocin demonstrate more frequent defense-motivated responses toward in-group members than out-group members. Further, oxytocin was correlated with participant desire to protect vulnerable in-group members, despite that individuals attachment to the conflict. Similarly, it has been demonstrated that when oxytocin is administered, individuals alter their subjective preferences in order to align with in-group ideals over out-group ideals. These studies demonstrate that oxytocin is associated with intergroup dynamics. Further, oxytocin influences the responses of individuals in a particular group to those of another group. The in-group bias is evident in smaller groups; however, it can also be extended to groups as large as ones entire country leading toward a tendency of strong national zeal. A study done in the Netherlands showed that oxytocin increased the in-group favoritism of their nation while decreasing acceptance of members of other ethnicities and foreigners. People also show more affection for their countrys flag while remaining indifferent to other cultural objects when exposed to oxytocin. It has thus been hypothesized that this hormone may be a factor in xenophobic tendencies secondary to this effect. Thus, oxytocin appears to affect individuals at an international level where the in-group becomes a specific "home" country and the out-group grows to include all other countries.
Drugs
Drug interaction: According to several studies in animals, oxytocin inhibits the development of tolerance to various addictive drugs (opiates, cocaine, alcohol), and reduces withdrawal symptoms. MDMA (ecstasy) may increase feelings of love, empathy, and connection to others by stimulating oxytocin activity primarily via activation of serotonin 5-HT1A receptors, if initial studies in animals apply to humans. The anxiolytic drug buspirone may produce some of its effects via 5-HT1A receptor-induced oxytocin stimulation as well.
Addiction vulnerability: Concentrations of endogenous oxytocin can impact the effects of various drugs and ones susceptibility to substance use disorders, with higher concentrations associated with lower susceptibility. The status of the endogenous oxytocin system can enhance or reduce susceptibility to addiction through its bidirectional interaction with numerous systems, including the dopamine system, the hypothalamic–pituitary–adrenal axis and the immune system. Individual differences in the endogenous oxytocin system based on genetic predisposition, gender and environmental influences, may therefore affect addiction vulnerability. Oxytocin may be related to the place conditioning behaviors observed in habitual drug abusers.
Fear and anxiety
Oxytocin is typically remembered for the effect it has on prosocial behaviors, such as its role in facilitating trust and attachment between individuals. However, oxytocin has a more complex role than solely enhancing prosocial behaviors. There is consensus that oxytocin modulates fear and anxiety; that is, it does not directly elicit fear or anxiety. Two dominant theories explain the role of oxytocin in fear and anxiety. One theory states that oxytocin increases approach/avoidance to certain social stimuli and the second theory states that oxytocin increases the salience of certain social stimuli, causing the animal or human to pay closer attention to socially relevant stimuli.Nasally administered oxytocin has been reported to reduce fear, possibly by inhibiting the amygdala (which is thought to be responsible for fear responses). Indeed, studies in rodents have shown oxytocin can efficiently inhibit fear responses by activating an inhibitory circuit within the amygdala. Some researchers have argued oxytocin has a general enhancing effect on all social emotions, since intranasal administration of oxytocin also increases envy and Schadenfreude. Individuals who receive an intranasal dose of oxytocin identify facial expressions of disgust more quickly than individuals who do not receive oxytocin. Facial expressions of disgust are evolutionarily linked to the idea of contagion. Thus, oxytocin increases the salience of cues that imply contamination, which leads to a faster response because these cues are especially relevant for survival. In another study, after administration of oxytocin, individuals displayed an enhanced ability to recognize expressions of fear compared to the individuals who received the placebo. Oxytocin modulates fear responses by enhancing the maintenance of social memories. Rats that are genetically modified to have a surplus of oxytocin receptors display a greater fear response to a previously conditioned stressor. Oxytocin enhances the aversive social memory, leading the rat to display a greater fear response when the aversive stimulus is encountered again.
Mood and depression
Oxytocin produces antidepressant-like effects in animal models of depression, and a deficit of it may be involved in the pathophysiology of depression in humans. The antidepressant-like effects of oxytocin are not blocked by a selective antagonist of the oxytocin receptor, suggesting that these effects are not mediated by the oxytocin receptor. In accordance, unlike oxytocin, the selective non-peptide oxytocin receptor agonist WAY-267,464 does not produce antidepressant-like effects, at least in the tail suspension test. In contrast to WAY-267,464, carbetocin, a close analogue of oxytocin and peptide oxytocin receptor agonist, notably does produce antidepressant-like effects in animals. As such, the antidepressant-like effects of oxytocin may be mediated by modulation of a different target, perhaps the vasopressin V1A receptor where oxytocin is known to weakly bind as an agonist.Oxytocin mediates the antidepressant-like effects of sexual activity. A drug for sexual dysfunction, sildenafil enhances electrically evoked oxytocin release from the pituitary gland. In accordance, it may have promise as an antidepressant.
Sex differences
It has been shown that oxytocin differentially affects males and females. Females who are administered oxytocin are overall faster in responding to socially relevant stimuli than males who received oxytocin. Additionally, after the administration of oxytocin, females show increased amygdala activity in response to threatening scenes; however, males do not show increased amygdala activation. This phenomenon can be explained by looking at the role of gonadal hormones, specifically estrogen, which modulate the enhanced threat processing seen in females. Estrogen has been shown to stimulate the release of oxytocin from the hypothalamus and promote receptor binding in the amygdala.It has also been shown that testosterone directly suppresses oxytocin in mice. This has been hypothesized to have evolutionary significance. With oxytocin suppressed, activities such as hunting and attacking invaders would be less mentally difficult as oxytocin is strongly associated with empathy.
Social
Affecting generosity by increasing empathy during perspective taking: In a neuroeconomics experiment, intranasal oxytocin increased generosity in the Ultimatum Game by 80%, but had no effect in the Dictator Game that measures altruism. Perspective-taking is not required in the Dictator Game, but the researchers in this experiment explicitly induced perspective-taking in the Ultimatum Game by not identifying to participants into which role they would be placed. Serious methodological questions have arisen, however, with regard to the role of oxytocin in trust and generosity. Empathy in healthy males has been shown to be increased after intranasal oxytocin This is most likely due to the effect of oxytocin in enhancing eye gaze. There is some discussion about which aspect of empathy oxytocin might alter – for example, cognitive vs. emotional empathy. While studying wild chimpanzees, it was noted that after a chimpanzee shared food with a non-kin related chimpanzee, the subjects levels of oxytocin increased, as measured through their urine. In comparison to other cooperative activities between chimpanzees that were monitored including grooming, food sharing generated higher levels of oxytocin. This comparatively higher level of oxytocin after food sharing parallels the increased level of oxytocin in nursing mothers, sharing nutrients with their kin.
Trust is increased by oxytocin. Study found that with the oxytocin nasal spray, people place more trust to strangers in handling their money. Disclosure of emotional events is a sign of trust in humans. When recounting a negative event, humans who receive intranasal oxytocin share more emotional details and stories with more emotional significance. Humans also find faces more trustworthy after receiving intranasal oxytocin. In a study, participants who received intranasal oxytocin viewed photographs of human faces with neutral expressions and found them to be more trustworthy than those who did not receive oxytocin. This may be because oxytocin reduces the fear of social betrayal in humans. Even after experiencing social alienation by being excluded from a conversation, humans who received oxytocin scored higher in trust on the Revised NEO Personality Inventory. Moreover, in a risky investment game, experimental subjects given nasally administered oxytocin displayed "the highest level of trust" twice as often as the control group. Subjects who were told they were interacting with a computer showed no such reaction, leading to the conclusion that oxytocin was not merely affecting risk aversion. When there is a reason to be distrustful, such as experiencing betrayal, differing reactions are associated with oxytocin receptor gene (OXTR) differences. Those with the CT haplotype experience a stronger reaction, in the form of anger, to betrayal.
Romantic attachment: In some studies, high levels of plasma oxytocin have been correlated with romantic attachment. For example, if a couple is separated for a long period of time, anxiety can increase due to the lack of physical affection. Oxytocin may aid romantically attached couples by decreasing their feelings of anxiety when they are separated.
Group-serving dishonesty/deception: In a carefully controlled study exploring the biological roots of immoral behavior, oxytocin was shown to promote dishonesty when the outcome favored the group to which an individual belonged instead of just the individual.
Oxytocin affects social distance between adult males and females, and may be responsible at least |
Oxytocin | in part for romantic attraction and subsequent monogamous pair bonding. An oxytocin nasal spray caused men in a monogamous relationship, but not single men, to increase the distance between themselves and an attractive woman during a first encounter by 10 to 15 centimeters. The researchers suggested that oxytocin may help promote fidelity within monogamous relationships. For this reason, it is sometimes referred to as the "bonding hormone". There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders. Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behavior.
Social behavior and wound healing: Oxytocin is also thought to modulate inflammation by decreasing certain cytokines. Thus, the increased release in oxytocin following positive social interactions has the potential to improve wound healing. A study by Marazziti and colleagues used heterosexual couples to investigate this possibility. They found increases in plasma oxytocin following a social interaction were correlated with faster wound healing. They hypothesized this was due to oxytocin reducing inflammation, thus allowing the wound to heal more quickly. This study provides preliminary evidence that positive social interactions may directly influence aspects of health. According to a study published in 2014, silencing of oxytocin receptor interneurons in the medial prefrontal cortex (mPFC) of female mice resulted in loss of social interest in male mice during the sexually receptive phase of the estrous cycle. Oxytocin evokes feelings of contentment, reductions in anxiety, and feelings of calmness and security when in the company of the mate. This suggests oxytocin may be important for the inhibition of the brain regions associated with behavioral control, fear, and anxiety, thus allowing orgasm to occur. Research has also demonstrated that oxytocin can decrease anxiety and protect against stress, particularly in combination with social support. It is found, that endocannabinoid signaling mediates oxytocin-driven social reward. According to a study published in 2008, its results pointed to how a lack of oxytocin in mice saw a abnormalities in emotional behavior. Another study in conducted in 2014, saw similar results with a variation in the oxytocin receptor is connected with dopamine transporter and how levels of oxytocin are dependent on the levels of dopamine transporter levels. One study explored the effects of low levels of oxytocin and the other on possible explanation of what affects oxytocin receptors. As a lack of social skills and proper emotional behavior are common signs of Autism, low levels of oxytocin could become a new sign for individuals that fall into the Autism Spectrum.
Chemistry
Oxytocin is a peptide of nine amino acids (a nonapeptide) in the sequence cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amide (Cys – Tyr – Ile – Gln – Asn – Cys – Pro – Leu – Gly – NH2, or CYIQNCPLG-NH2); its C-terminus has been converted to a primary amide and a disulfide bridge joins the cysteine moieties. Oxytocin has a molecular mass of 1007 Da, and one international unit (IU) of oxytocin is the equivalent of 1.68 μg of pure peptide.While the structure of oxytocin is highly conserved in placental mammals, a novel structure of oxytocin was reported in 2011 in marmosets, tamarins, and other new world primates. Genomic sequencing of the gene for oxytocin revealed a single in-frame mutation (thymine for cytosine) which results in a single amino acid substitution at the 8-position (proline for leucine). Since this original Lee et al. paper, two other laboratories have confirmed Pro8-OT and documented additional oxytocin structural variants in this primate taxon. Vargas-Pinilla et al. sequenced the coding regions of the OXT gene in other genera in new world primates and identified the following variants in addition to Leu8- and Pro8-OT: Ala8-OT, Thr8-OT, and Val3/Pro8-OT. Ren et al. identified a variant further, Phe2-OT in howler monkeys.The biologically active form of oxytocin, commonly measured by RIA and/or HPLC techniques, is the oxidized octapeptide oxytocin disulfide, but oxytocin also exists as a reduced straight-chain (non-cyclic) dithiol nonapeptide called oxytoceine. It has been theorized that oxytoceine may act as a free radical scavenger, as donating an electron to a free radical allows oxytoceine to be re-oxidized to oxytocin via the dehydroascorbate / ascorbate redox couple.Recent advances in analytical instrumental techniques highlighted the importance of liquid chromatography (LC) coupled with mass spectrometry (MS) for measuring oxytocin levels in various samples derived from biological sources. Most of these studies optimized the oxytocin quantification in electrospray ionization (ESI) positive mode, using [M+H]+ as the parent ion at mass-to-charge ratio (m/z) 1007.4 and the fragment ions as diagnostic peaks at m/z 991.0, m/z 723.2 and m/z 504.2. These important ion selections paved the way for the development of current methods of oxytocin quantification using MS instrumentation.
The structure of oxytocin is very similar to that of vasopressin. Both are nonapeptides with a single disulfide bridge, differing only by two substitutions in the amino acid sequence (differences from oxytocin bolded for clarity): Cys – Tyr – Phe – Gln – Asn – Cys – Pro – Arg – Gly – NH2. Oxytocin and vasopressin were isolated and their total synthesis reported in 1954, work for which Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry with the citation: "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone."Oxytocin and vasopressin are the only known hormones released by the human posterior pituitary gland to act at a distance. However, oxytocin neurons make other peptides, including corticotropin-releasing hormone and dynorphin, for example, that act locally. The magnocellular neurosecretory cells that make oxytocin are adjacent to magnocellular neurosecretory cells that make vasopressin. These are large neuroendocrine neurons which are excitable and can generate action potentials.
In popular culture
"Oxytocin" is the name of the fifth song on Billie Eilishs second album Happier Than Ever.
In the novel The Fireman by Joe Hill, the hormone plays a role in neutralizing the danger posed by an infectious spore that causes a condition known as Dragonscale. If the spore enters an oxytocin-rich environment, it will enter a dormant state instead of causing its host to undergo spontaneous human combustion.
The formula for Oxytocin is displayed as written on the fingers of Nina Zilli and appears in the opening shot of her video for "Sola".
Jack (Steve Zahn), a character in the 2004 movie “Employee of the Month” explains how oxytocin performs in the female body at the 45m27s mark. A more detailed explanation on oxytocin begins at 44m40s.
See also
Oxytocin (medication)
References
Further reading
External links
Media related to Oxytocin at Wikimedia Commons |
Efmoroctocog alfa | Efmoroctocog alfa, sold under the brand name Elocta among others, is a medication for the treatment and prophylaxis of bleeding in people with hemophilia A. Efmoroctocog alfa is a recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc). It is produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line.It was approved for medical use in the United States in June 2014, and for use in the European Union in November 2015.
Medical uses
In the United States, efmoroctocog alfa (Eloctate) is indicated for adults and children with Hemophilia A for (1) on-demand treatment and control of bleeding episodes, (2) perioperative management, and (3) routine prophylaxis to prevent or reduce the frequency of bleeding episodes.In the European Union, efmoroctocog alfa (Elocta) is indicated for treatment and prophylaxis of bleeding in people with haemophilia A.
References
External links
"Efmoroctocog alfa". Drug Information Portal. U.S. National Library of Medicine. |
Rotavirus vaccine | Rotavirus vaccine is a vaccine used to protect against rotavirus infections, which are the leading cause of severe diarrhea among young children. The vaccines prevent 15–34% of severe diarrhea in the developing world and 37–96% of severe diarrhea in the developed world. The vaccines decrease the risk of death among young children due to diarrhea. Immunizing babies decreases rates of disease among older people and those who have not been immunized.The World Health Organization (WHO) recommends that rotavirus vaccine be included in national routine vaccinations programs, especially in areas where the disease is common. This should be done along with promoting breastfeeding, handwashing, clean water, and good sanitation. It is given by mouth and requires two or three doses. It should be given starting around six weeks of age.The vaccines are safe. This includes their use in people with HIV/AIDS. The vaccines are made from weakened rotavirus.The vaccine first became available in the United States in 2006. It is on the World Health Organizations List of Essential Medicines. As of 2013, there are two types of vaccine available globally, Rotarix and RotaTeq. Others are used in some countries.
Medical uses
Effectiveness
A 2009 review estimated that vaccination against rotavirus would prevent about 45% of deaths due to rotavirus gastroenteritis, or about 228,000 deaths annually worldwide. At US$5 per dose, the estimated cost per life saved was $3,015, $9,951 and $11,296 in low-, lower-middle-, and upper-middle-income countries, respectively.Safety and efficacy trials in Africa and Asia found that the vaccines dramatically reduced severe disease among infants in developing countries, where a majority of rotavirus-related deaths occur. A 2019 Cochrane review concluded that RV1, RV5, and Rotavac vaccines are safe and are effective at preventing diarrhea.Rotavirus vaccines are licensed in more than 100 countries, and more than 80 countries have introduced routine rotavirus vaccination. The incidence and severity of rotavirus infections has declined significantly in countries that have acted on the recommendation to introduce the rotavirus vaccine. In Mexico, which in 2006 was among the first countries in the world to introduce rotavirus vaccine, the diarrheal disease death rates from rotavirus dropped by more than 65% among children age two and under during the 2009 rotavirus season. In Nicaragua, which in 2006 became the first developing country to introduce the rotavirus vaccine, investigators recorded a substantial impact, with rotavirus vaccine preventing 60% of cases against severe rotavirus and cutting emergency room visits in half. In the United States, vaccination has reduced rotavirus-related hospitalizations by as much as 86% since 2006. In April 2016, the World Health Organization released statistics for the period of 2000–2013, which showed developing countries that have introduced rotavirus vaccines experienced significant decreases in deaths and hospitalizations from rotavirus diarrhea after introduction.Additionally, the vaccines may also prevent illness in non-vaccinated children by limiting exposure through the number of circulating infections. A 2014 review of available clinical trial data from countries routinely using rotavirus vaccines in their national immunization programs found that rotavirus vaccines have reduced rotavirus hospitalizations by 49–92% and all-cause diarrhea hospitalizations by 17–55%.
Schedule
The World Health Organization recommends the first dose of vaccine be given right after six weeks of age.
Types
Rotarix
Rotarix is a monovalent, human, live attenuated rotavirus vaccine containing one rotavirus strain of G1P[8] specificity.
Rotarix is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) when administered as a 2-dose series in infants and children. It was approved in Europe in 2006 and by the U.S. FDA in April 2008. It is administered by mouth.
RotaTeq
RotaTeq is a live, oral pentavalent vaccine that contains five rotavirus strains produced by reassortment. The rotavirus A parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid, VP7, proteins (serotypes G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein VP4 (type P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein VP4, (type P1A), from the human rotavirus parent strain and the outer capsid protein VP7 (serotype G6) from the bovine rotavirus parent strain. In February 2006, the U.S. Food and Drug Administration approved RotaTeq for use in the United States. In August 2006, Health Canada approved RotaTeq for use in Canada. Merck worked with a range of partners including governmental and non-governmental organisations to develop and implement mechanisms for providing access to this vaccine in the developing world, an effort which was slated to come to an end in 2020.
Rotavac
Rotavac was licensed for use in India in 2014, and is manufactured by Bharat Biotech International Limited. It is a live attenuated, monovalent vaccine containing a G9P[11] human strain isolated from an Indian child. It is given by mouth in a three-dose series, four weeks apart, beginning at six weeks of age up until eight months of age.
Rotavin-M1
Rotavin-M1 was licensed for use in Vietnam in 2007, and is manufactured by the Center for Research and Production of Vaccines. The vaccine contains a G1P[8] human rotavirus strain.
Lanzhou lamb
Lanzhou lamb rotavirus vaccine was licensed for use in China in 2000, and is manufactured by the Lanzhou Institute of Biological Products. It contains a G10P[12] lamb rotavirus strain.
Rotasiil
Rotasiil is a lyophilized pentavalent vaccine licensed for use in India in 2018. It contain human bovine reassortant strains of rotavirus serotypes G1, G2, G3, G4 and G9. This is worlds first thermostable vaccine which can be stored without refrigeration at or below 25 °C. Rotasiil is manufactured by the Serum Institute of India.
History
In 1998, a rotavirus vaccine (RotaShield, by Wyeth) was licensed for use in the United States. Clinical trials in the United States, Finland, and Venezuela had found it to be 80 to 100% effective at preventing severe diarrhea caused by rotavirus A, and researchers had detected no statistically significant serious adverse effects. The manufacturer of the vaccine, however, withdrew it from the market in 1999, after it was discovered that the vaccine may have contributed to an increased risk for intussusception, or bowel obstruction, in one of every 12,000 vaccinated infants. There then followed eight years of delay until rival manufacturers were able to introduce new vaccines that were shown to be more safe and effective in children: Rotarix by GlaxoSmithKline and RotaTeq by Merck. Both are taken orally and contain disabled live virus.The World Health Organization recommends that rotavirus vaccine be included in all national immunization schedules because the risk of intussusception following rotavirus vaccination remains very low compared with the benefits of preventing the impact of severe and deadly diarrhea.
Society and culture
More than 80 countries have introduced routine rotavirus vaccination, almost half with the support of Gavi, the Vaccine Alliance. In order to make rotavirus vaccines available, accessible, and affordable in all countries—particularly low- and middle-income countries in Africa and Asia where the majority of rotavirus deaths occur—international non-governmental organization PATH, the WHO, the U.S. Centers for Disease Control and Prevention (CDC), and Gavi have partnered with research institutions and governments to generate and disseminate evidence, lower prices, and accelerate introduction. These and other organizations continue to work to improve coverage and public health impact of rotavirus vaccination today.
Temporary suspension in the US
On March 22, 2010, the detection of DNA from porcine circovirus types 1 and 2 within RotaTeq and Rotarix prompted the FDA to suspend the use of rotavirus vaccines while conducting an investigation the finding of DNA from porcine circovirus-1 (PCV1) in the vaccine in collaboration with the 12 members of the Vaccines and Related Biological Products Advisory Committee (VRBPAC). On May 6, 2010, the FDA announced its decision to revoke the suspension, stating that porcine circovirus types 1 and 2 pose no safety risks in humans and concluded that health risks involved did not offset the benefits of the vaccination. In May 2010 the suspension of the Rotarix vaccine was lifted.
Research
Doctors Without Borders (MSF) developed a heat-stable version named BRV-PV. Phase 3 of the clinical trials were completed in Niger on December 31, 2020.The vaccine has been associated with lower rates of type 1 diabetes.
References
Further reading
Cortese MM, Parashar UD (February 2009). "Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP)" (PDF). MMWR Recomm Rep. 58 (RR-2): 1–25. PMID 19194371.
External links
"Rotavirus Vaccine Information Statement". U.S. Centers for Disease Control and Prevention (CDC). 2019-10-25.
Rotavirus, Vaccine Resource Library
Rotavirus ROTA Council
Rotavirus Vaccines at the US National Library of Medicine Medical Subject Headings (MeSH) |
Chlorphenamine | Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken by mouth. The medication takes effect within two hours and lasts for about 4-6.Common side effects include sleepiness, restlessness, and weakness. Other side effects may include dry mouth and wheeziness. It is a first-generation antihistamine and works by blocking the H1 receptor.Chlorpheniramine was patented in 1948 and came into medical use in 1949. It is available as a generic medication and over the counter.
Medical uses
Combination products
Chlorphenamine is often combined with phenylpropanolamine to form an allergy medication with both antihistamine and decongestant properties, though phenylpropanolamine is no longer available in the US after studies showed it increased the risk of stroke in young women. Chlorphenamine remains available with no such risk.
Chlorphenamine may be combined with the opioid hydrocodone. Chlorphenamine/dihydrocodeine immediate-release syrups are also marketed. The antihistamine is helpful in cases where allergy or common cold is the reason for the cough; it is also a potentiator of opioids, allowing enhanced suppression of cough, analgesia, and other effects from a given quantity of the drug by itself. In various places in the world, cough and cold preparations containing codeine and chlorphenamine are available.In the drug Coricidin, chlorphenamine is combined with the cough suppressant dextromethorphan. In the drug Cêgripe, chlorphenamine is combined with the analgesic paracetamol.
Side effects
The adverse effects include drowsiness, dizziness, confusion, constipation, anxiety, nausea, blurred vision, restlessness, decreased coordination, dry mouth, shallow breathing, hallucinations, irritability, problems with memory or concentration, tinnitus and trouble urinating.
Chlorphenamine produces less sedation than other first-generation antihistamines.A large study on people 65 years old or older, linked the development of Alzheimers disease and other forms of dementia to the "higher cumulative" use of chlorphenamine and other first-generation antihistamines, due to their anticholinergic properties.
Pharmacology
Pharmacodynamics
Chlorphenamine acts primarily as a potent H1 antihistamine. It is specifically a potent inverse agonist of the histamine H1 receptor. The drug is also commonly described as possessing weak anticholinergic activity by acting as an antagonist of the muscarinic acetylcholine receptors. The dextrorotatory stereoisomer, dexchlorpheniramine, has been reported to possess Kd values of 15 nM for the H1 receptor and 1,300 nM for the muscarinic acetylcholine receptors in human brain tissue. The smaller the Kd value, the greater the binding affinity of the ligand for its target.
In addition to acting as an inverse agonist at the H1 receptor, chlorphenamine has been found to act as a serotonin reuptake inhibitor (Kd = 15.2 nM for the serotonin transporter). It has only weak affinity for the norepinephrine and dopamine transporters (Kd = 1,440 nM and 1,060 nM, respectively). A similar antihistamine, brompheniramine, led to the discovery of the selective serotonin reuptake inhibitor (SSRI) zimelidine.A study found that dexchlorphenamine had Ki values for the human cloned H1 receptor of 2.67 to 4.81 nM while levchlorphenamine had Ki values of 211 to 361 nM for this receptor, indicating that dexchlorphenamine is the active enantiomer. Another study found that dexchlorphenamine had a Ki value of 20 to 30 μM for the muscarinic acetylcholine receptor using rat brain tissue while levchlorphenamine had a Ki value of 40 to 50 μM for this receptor, indicating that both enantiomers have very low affinity for it.
Pharmacokinetics
The elimination half-life of chlorphenamine has variously ranged between 13.9 and 43.4 hours in adults following a single dose in clinical studies.
Chemistry
Chlorphenamine is an alkylamine and is a part of a series of antihistamines including pheniramine (Naphcon) and its halogenated derivatives including fluorpheniramine, dexchlorphenamine (Polaramine), brompheniramine (Dimetapp), dexbrompheniramine (Drixoral), deschlorpheniramine, and iodopheniramine. The halogenated alkylamine antihistamines all exhibit optical isomerism, and chlorphenamine in the indicated products is racemic chlorphenamine maleate, whereas dexchlorphenamine is the dextrorotary stereoisomer.
Synthesis
There are several patented methods for the synthesis of chlorphenamine. In one example, 4-chlorophenylacetonitrile is reacted with 2-chloropyridine in the presence of sodium amide to form 4-chlorophenyl(2-pyridyl)acetonitrile. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives γ-(4-chlorphenyl)-γ-cyano-N,N-dimethyl-2-pyridinepropanamine, the hydrolysis and decarboxylation of which lead to chlorphenamine.
A second method boom starts from pyridine, which undergoes alkylation by 4-chlorophenylacetonitrile, giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.
Society and culture
Names
Chlorphenamine is the INN while chlorpheniramine is the USAN and former BAN.
Brand names have included Demazin, Allerest 12 Hour, Codral Nighttime, Chlornade, Contac 12 Hour, Exchange Select Allergy Multi-Symptom, A. R. M. Allergy Relief, Ordrine, Ornade Spansules, Piriton, Teldrin, Triaminic, and Tylenol Cold/Allergy.
== References == |
Scopolamine | Scopolamine, also known as hyoscine, or Devils Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion sickness and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva. When used by injection, effects begin after about 20 minutes and last for up to 8 hours. It may also be used orally and as a transdermal patch.Common side effects include sleepiness, blurred vision, dilated pupils, and dry mouth. It is not recommended in people with angle-closure glaucoma or bowel obstruction. Whether its use during pregnancy is safe remains unclear, and use during breastfeeding is still cautioned by health professionals and manufacturers of the drug. Scopolamine is in the antimuscarinic family of drugs and works by blocking some of the effects of acetylcholine within the nervous system.Scopolamine was first written about in 1881 and started to be used for anesthesia around 1900. Around this time it was first proposed for and then subsequently used for years to induce amnesia and synergistic pain relief during childbirth by administering a combination of both scopolamine and morphine. These alkaloids when used in combination gave rise to a synergistic state called "twilight sleep". Scopolamine is also the main active component produced by certain plants of the nightshade family, which historically have been used as psychoactive drugs (known as deliriants) due to their antimuscarinic-induced hallucinogenic effects. The name "scopolamine" is derived from one type of nightshade known as Scopolia, while the name "hyoscine" is derived from another type known as Hyoscyamus niger. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Scopolamine has a number of uses in medicine where it is used in low doses to treat:
Postoperative nausea and vomiting.
Motion sickness, including sea sickness, leading to its use by scuba divers (where it is often applied as a transdermal patch behind the ear)
Gastrointestinal spasms
Renal or biliary spasms
Aid in gastrointestinal radiology and endoscopy
Irritable bowel syndrome
Clozapine-induced drooling
Bowel colic
Eye inflammationIt is sometimes used as a premedication, (especially to reduce respiratory tract secretions) in surgery, most commonly by injection.
Breastfeeding
Scopolamine enters breast milk by secretion. Although no human studies exist to document the safety of scopolamine while nursing, the manufacturer recommends that caution be taken if scopolamine is administered to a breastfeeding woman.
Elderly
The likelihood of experiencing adverse effects from scopolamine is increased in the elderly relative to younger people. This phenomenon is especially true for older people who are also on several other medications. Scopolamine use should be avoided in this age group because of these potent anticholinergic adverse effects, which have also been linked to an increased risk for dementia.
Adverse effects
Adverse effect incidence:Uncommon (0.1–1% incidence) adverse effects include:
Dry mouth
Anhidrosis (reduced ability to sweat to cool off)
Tachycardia (usually occurs at higher doses and is succeeded by bradycardia)
Bradycardia
Urticaria (hives)
Pruritus (itching)Rare (<0.1% incidence) adverse effects include:
Constipation
Urinary retention
Hallucinations
Agitation
Confusion
Restlessness
SeizuresUnknown frequency adverse effects include:
Anaphylactic shock or reactions
Dyspnea (shortness of breath)
Rash
Erythema
Other hypersensitivity reactions
Blurred vision
Mydriasis (dilated pupils)
Drowsiness
Dizziness
Somnolence
Overdose
Physostigmine, a cholinergic drug that readily crosses the blood-brain barrier, has been used as an antidote to treat the central nervous system depression symptoms of a scopolamine overdose. Other than this supportive treatment, gastric lavage and induced emesis (vomiting) are usually recommended as treatments for oral overdoses. The symptoms of overdose include:
Tachycardia
Arrhythmia
Blurred vision
Photophobia
Urinary retention
Drowsiness or paradoxical reaction, which can present with hallucinations
Cheyne-Stokes respiration
Dry mouth
Skin reddening
Inhibition of gastrointestinal motility
Interactions
Due to interactions with metabolism of other drugs, scopolamine can cause significant unwanted side effects or unpredictable synergies when taken with other medications or compounds. Specific attention should be paid to other medications in the same pharmacologic class as scopolamine, also known as anticholinergics. These additional compounds could also potentially interact with the metabolism of scopolamine: receptor-binding analgesic/pain medication such as gabapentinoids or opioids, ethanol, cannabinoids, zolpidem, thiazide diuretics, nicotine, benzodiazepines, buprenorphine, and especially anticholinergic drugs such as tiotropium, diphenhydramine, dimenhydrinate, etc.
Route of administration
Scopolamine can be taken by mouth, subcutaneously, in the eye, and intravenously, as well as via a transdermal patch.
Pharmacokinetic
Scopolamine undergoes first-pass metabolism and about 2.6% is excreted unchanged in urine. Grapefruit juice decreases metabolism of scopolamine consequently increasing plasma concentration.
Pharmacodynamics
Scopolamine is a nonspecific muscarinic antagonist at all four muscarinic acetylcholine receptors (M1, M2, M3, and M4).,
Biosynthesis in plants
Scopolamine is among the secondary metabolites of plants from Solanaceae (nightshade) family of plants, such as henbane (Hyoscyamus niger), jimson weed (Datura), angels trumpets (Brugmansia), deadly nightshade (Belladonna), mandrake (Mandragora officinarum), and corkwood (Duboisia).
The biosynthesis of scopolamine begins with the decarboxylation of L-ornithine to putrescine by ornithine decarboxylase. Putrescine is methylated to N-methylputrescine by putrescine N-methyltransferase.A putrescine oxidase that specifically recognizes methylated putrescine catalyzes the deamination of this compound to 4-methylaminobutanal, which then undergoes a spontaneous ring formation to N-methyl-pyrrolium cation. In the next step, the pyrrolium cation condenses with acetoacetic acid yielding hygrine. No enzymatic activity could be demonstrated to catalyze this reaction. Hygrine further rearranges to tropinone.Subsequently, tropinone reductase I converts tropinone to tropine, which condenses with phenylalanine-derived phenyllactate to littorine. A cytochrome P450 classified as Cyp80F1 oxidizes and rearranges littorine to hyoscyamine aldehyde. In the final step, hyoscyamine undergoes epoxidation catalyzed by 6beta-hydroxyhyoscyamine epoxidase yielding scopolamine.
History
One of the earlier alkaloids isolated from plant sources, scopolamine has been in use in its purified forms (such as various salts, including hydrochloride, hydrobromide, hydroiodide, and sulfate), since its isolation by the German scientist Albert Ladenburg in 1880, and as various preparations from its plant-based form since antiquity and perhaps prehistoric times. Following the description of the structure and activity of scopolamine by Ladenburg, the search for synthetic analogues, and methods for total synthesis, of scopolamine and atropine in the 1930s and 1940s resulted in the discovery of diphenhydramine, an early antihistamine and the prototype of its chemical subclass of these drugs, and pethidine, the first fully synthetic opioid analgesic, known as Dolantin and Demerol amongst many other trade names.In 1899, a Dr. Schneiderlin recommended the use of scopolamine and morphine for surgical anaesthesia, and it started to be used sporadically for that purpose. The use of this combination in obstetric anesthesiology was first proposed by Richard von Steinbuchel in 1902 and was picked up and further developed by Carl Gauss in Freiburg, Germany, starting in 1903. The method came to be known as Dämmerschlaf ("twilight sleep") or the "Freiburg method". It spread rather slowly, and different clinics experimented with different dosages and ingredients; in 1915, the Canadian Medical Association Journal reported, "the method [was] really still in a state of development". It remained widely used in the US until the 1960s, when growing chemophobia and a desire for more natural childbirth led to its abandonment.
Society and culture
Names
Hyoscine hydrobromide is the international nonproprietary name, and scopolamine hydrobromide is the United States Adopted Name. Other names include levo-duboisine, devils breath, and burundanga.
Australian bush medicine
A bush medicine developed by Aboriginal peoples of the eastern states of Australia from the soft corkwood tree (Duboisia myoporoides) was used by the Allies in World War II to stop soldiers from getting seasick when they sailed across the English Channel on their way to France during the Invasion of Normandy. Later, the same substance was found to be usable in the production of scopolamine and hyoscyamine, which are used in eye surgery, and a multimillion dollar industry was built in Queensland based on this substance.
Recreational and religious use
While it has been occasionally used recreationally for its hallucinogenic properties, the experiences are often unpleasant, mentally and physically. It is also physically dangerous and officially classified as a deliriant drug, so repeated recreational use is rare. In June 2008, more than 20 people were hospitalized with psychosis in Norway after ingesting counterfeit rohypnol tablets containing scopolamine. In January 2018, 9 individuals were hospitalized in Perth, Western Australia, after reportedly ingesting scopolamine. However, the alkaloid scopolamine, when taken recreationally for its psychoactive effect is usually taken in the form of preparations from plants of the genera Datura or Brugmansia, often by adolescents or young adults in order to achieve hallucinations and an altered state of consciousness induced by muscarinic antagonism. In circumstances such as these, the intoxication is usually built on a synergistic, but even more toxic mixture of the additional alkaloids in the plants which includes atropine and hyoscyamine.
Historically, the various plants that produce scopolamine have been used psychoactively for spiritual and magical purposes. When entheogenic preparations of these plants were used, scopolamine was considered to be the main psychoactive compound and was largely responsible for the hallucinogenic effects, particularly when the preparation was made into a topical ointment (most notably flying ointment). Scopolamine is reported to be the only active alkaloid within these plants that can effectively be absorbed through the skin to cause effects. Different recipes for these ointments were explored in European witchcraft at least as far back as the Early Modern period and included multiple ingredients to help with the transdermal absorption of scopolamine (such as animal fat), as well as other possible ingredients to counteract its noxious and dysphoric effects.In Christianity, although not explicitly designated for ritualistic or spiritual use; in the Bible there are multiple mentions of Mandrake which is a psychoactive and hallucinogenic plant root that contains scopolamine. It was associated with fertility power and (sexual) desire where it was yearned for by Rachel, who apparently was "barren" (infertile) but trying to conceive.
Interrogation
The effects of scopolamine were studied for use as a truth serum in interrogations in the early 20th century, but because of the side effects, investigations were dropped. In 2009, the Czechoslovak state security secret police were proven to have used scopolamine at least three times to obtain confessions from alleged antistate dissidents.
Crime
A travel advisory published by the US Overseas Security Advisory Council (OSAC) in 2012 stated: One common and particularly dangerous method that criminals use in order to rob a victim is through the use of drugs. The most common [in Colombia] has been scopolamine. Unofficial estimates put the number of annual scopolamine incidents in Colombia at approximately 50,000. Scopolamine can render a victim unconscious for 24 hours or more. In large doses, it can cause respiratory failure and death. It is most often administered in liquid or powder form in foods and beverages. The majority of these incidents occur in night clubs and bars, and usually men, perceived to be wealthy, are targeted by young, attractive women. It is recommended that, to avoid becoming a victim of scopolamine, a person should never accept food or beverages offered by strangers or new acquaintances, nor leave food or beverages unattended in their presence. Victims of scopolamine or other drugs should seek immediate medical attention.
Between 1998 and 2004, 13% of emergency-room admissions for "poisoning with criminal intentions" in a clinic of Bogotá, Colombia, have been attributed to scopolamine, and 44% to benzodiazepines. Most commonly, the person has been poisoned by a robber who gave the victim a scopolamine-laced beverage, in the hope that the victim would become unconscious or unable to effectively resist the robbery.Beside robberies, it is also allegedly involved in express kidnappings and sexual assault. The Hospital Clínic in Barcelona introduced a protocol in 2008 to help medical workers identify cases, while Madrid hospitals adopted a similar working document in February 2015. Hospital Clínic has found little scientific evidence to support this use and relies on the victims stories to reach any conclusion. Although poisoning by scopolamine appears quite often in the media as an aid for raping, kidnapping, killing, or robbery, the effects of this drug and the way it is applied by criminals (transdermal injection, on playing cards and papers, etc.) are often exaggerated, especially skin exposure, as the dose that can be absorbed by the skin is too low to have any effect. Scopolamine transdermal patches must be used for hours to days. There are certain other aspects of the usage of scopolamine in crimes. Powdered scopolamine is referred to as "devils breath". In popular media and television, it is portrayed as a method to brainwash or control people into being defrauded by their attackers; There is debate whether these claims are true. It is not verified if the powdered form is capable of inducing a suggestive state. The danger is real enough that in addition of Overseas Security Advisory Council (OSAC) in 2012, the US Department of State, as well as the Government of Canada published Travel Advisory too, issued advisory warning travelers about the possibility of targeting. Criminals using Devil’s Breath often use attractive, young women to target men that they believe are wealthy. Nevertheless, the drug is known to produce loss of memory following exposure and sleepiness, similar to the effect of benzodiazepines or alcohol poisoning.
Research
Scopolamine is used as a research tool to study memory encoding. Initially, in human trials, relatively low doses of the muscarinic receptor antagonist scopolamine were found to induce temporary cognitive defects. Since then, scopolamine has become a standard drug for experimentally inducing cognitive defects in animals. Results in primates suggest that acetylcholine is involved in the encoding of new information into long-term memory.Scopolamine produces detrimental effects on short-term memory, memory acquisition, learning, visual recognition memory, visuospatial praxis, visuospatial memory, visuoperceptual function, verbal recall, and psychomotor speed. It does not seem to impair recognition and memory retrieval, though. Acetylcholine projections in hippocampal neurons, which are vital in mediating long-term potentiation, are inhibited by scopolamine. Scopolamine also inhibits cholinergic-mediated glutamate release in hippocampal neurons, which assist in depolarization, potentiation of action potential, and synaptic suppression. Scopolamines effects on acetylcholine and glutamate release in the hippocampus favor retrieval-dominant cognitive functioning. Scopolamine has been used to model the defects in cholinergic function for models of Alzheimers, dementia, fragile X syndrome, and Down syndrome.Scopolamine has also been investigated as a rapid-onset antidepressant, with a number of small studies finding positive results.NASA agreed to develop a nasal administration method. With a precise dosage, the NASA spray formulation has been shown to work faster and more reliably than the oral form to treat motion sickness.
References
External links
Media related to Scopolamine at Wikimedia Commons
"Scopolamine". Drug Information Portal. U.S. National Library of Medicine. |
Tylenol | Tylenol may refer to:
Paracetamol (acetaminophen), a medication used to treat pain and fever
Tylenol (brand), an American brand of drugs containing paracetamol |
Lustra | Lustra may refer to:
Lustrum (plural "Lustra"), a period of five years.
Lustra, poetry, by Ezra Pound.
Lustra, Campania, a commune in the province of Salerno (Campania, Italy).
Lustra (album), a 1997 album by British band Echobelly.
Lustra (band), a pop punk band best known for the song "Scotty Doesnt Know" in the movie EuroTrip |
Oxytocin (medication) | Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labor, increase the speed of labor, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.Oxytocin is also available in intranasal spray form for psychiatric, endocrine and weight management use as a supplement. Intranasal oxytocin works on a different pathway than injected oxytocin, primarily along the olfactory nerve crossing the brain blood barrier to the olfactory lobe in the brain, where dense magnocellular oxytocin neurons receive the dose application.
The use of synthetic oxytocin as an injectable medication for inducing childbirth can result in excessive contraction of the uterus that can risk the health of the baby. Common side effects in the mother include nausea and a slow heart rate. Serious side effects include rupture of the uterus and with excessive dose, water intoxication. Allergic reactions including anaphylaxis may also occur.The natural occurrence of oxytocin was discovered in 1906. It is on the World Health Organizations List of Essential Medicines.
Medical uses
An intravenous infusion of oxytocin is used to induce labor and to support labor in case of slow childbirth if the oxytocin challenge test fails. Whether a high dose is better than a standard dose for labor induction is unclear. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release.
The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors. It is registered in many countries for use in suppressing premature labor between 24 and 33 weeks of gestation. It has fewer side effects than drugs previously used for this purpose (such as ritodrine, salbutamol and terbutaline).Oxytocin has not been found to be useful for improving breastfeeding success.
Contraindications
Oxytocin injection (synthetic) is contraindicated in any of these conditions:
Substantial cephalopelvic disproportion
Unfavorable fetal position or presentation (e.g., transverse lies) undeliverable without conversion before delivery
Obstetric emergencies where maternal or fetal risk-to-benefit ratio favors surgery
Fetal distress when delivery is not imminent
Umbilical cord prolapse
Uterine activity fails to progress adequately
Hyperactive or hypertonic uterus
Vaginal delivery is contraindicated (e.g., invasive cervical carcinoma, active genital herpes infection, total placenta previa, vasa previa, cord presentation or prolapse)
Uterine or cervical scarring from previous cesarean section or major cervical or uterine (e.g., transfundal) surgery
Unengaged fetal head
History of hypersensitivity to oxytocin or any ingredient in the formulation
Side effects
Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon. These maternal events have been reported:
Subarachnoid hemorrhage
Increased blood pressure
Cardiac arrhythmia including increased or decreased heart rate, and premature ventricular contraction
Impaired uterine blood flow
Pelvic hematoma
Afibrinogenemia
Anaphylaxis
Nausea and vomiting
Increase fetal blood flowExcessive dosage or long-term administration (over a period of 24 hours or longer) has been known to result in tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal.
Oxytocin was added to the Institute for Safe Medication Practicess list of High Alert Medications in Acute Care Settings in 2012. The list includes medications that have a high risk for harm if administered incorrectly.During pregnancy, increased uterine motility has led to decreased heart rate, cardiac arrhythmia, seizures, brain damage, and death in the fetus or neonate.Use is linked to an increased risk of postpartum depression in the mother.Certain learning and memory functions are impaired by centrally administered oxytocin. Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks. However, oxytocin does seem to facilitate learning and memory specifically for social information. Healthy males administered intranasal oxytocin show improved memory for human faces, in particular happy faces.
Pharmacokinetics
Routes of administration
One IU of oxytocin is the equivalent of about 2 μg or mcg of pure peptide.
Injection: Clinical doses of oxytocin are given by injection either into a muscle or into a vein to cause contraction of the uterus. Very small amounts (< 1%) do appear to enter the central nervous system in humans when peripherally administered. The compound has a half-life of typically about 3 minutes in the blood when given intravenously. Intravenous administration requires 40 minutes to reach a steady-state concentration and achieve maximum uterine contraction response.
Buccal: Oxytocin was delivered in buccal tablets, but this is not common practice any more.
Under the tongue: Oxytocin is poorly absorbed sublingually.
Nasal administration: Oxytocin is effectively distributed to the brain when administered intranasally via a nasal spray, after which it reliably crosses the blood–brain barrier and exhibits psychoactive effects in humans. No serious adverse effects with short-term application of oxytocin with 18~40 IU (36–80 mcg) have been recorded. Intranasal oxytocin has a central duration of at least 2.25 hours and as long as 4 hours.
Oral: Oxytocin is destroyed in the gastrointestinal tract, so it is not active orally.
History
Oxytocins uterine-contracting properties were discovered by British pharmacologist Henry Hallett Dale in 1906. Oxytocins milk ejection property was described by Ott and Scott in 1910 and by Schafer and Mackenzie in 1911.Oxytocin was the first polypeptide hormone to be sequenced or synthesized. Du Vigneaud was awarded the Nobel Prize in 1955 for his work.
Etymology
The word oxytocin was coined from the term oxytocic. Greek ὀξύς, oxys, and τόκος, tokos, meaning "quick birth".
Society and culture
Counterfeits
In African countries, some oxytocin products were found to be counterfeit medications.
Other uses
The trust-inducing property of oxytocin might help those with social anxiety and depression, anxiety, fear, and social dysfunctions, such as generalized anxiety disorder, post-traumatic stress disorder, and social anxiety disorder, as well as autism and schizophrenia, among others. However, in one meta-analysis only autism spectrum disorder showed a significant combined effect size.People using oxytocin show improved recognition for positive social cues over threatening social cues and improved recognition of fear.
Autism: Oxytocin may play a role in autism and may be an effective treatment for autisms repetitive and affiliative behaviors.
Relationship counseling: The use of oxytocin in relationship counseling for well-being has been suggested.
See also
Attachment theory
List of investigational anxiolytics
List of investigational sexual dysfunction drugs
== References == |
Rosiglitazone | Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis in 2007 that linked the drugs use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drugs patent expired in 2012.It was patented in 1987 and approved for medical use in 1999. Despite rosiglitazones effectiveness at decreasing blood sugar in type 2 diabetes mellitus, its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death. Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK; as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.
Some reviewers recommended rosiglitazone be taken off the market, but an FDA panel disagreed, and it remains available in the U.S. From November 2011 until November 2013, the federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies. In 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of a 2009 trial which failed to show increased heart attack risk.In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks. It was withdrawn from the market in the UK, Spain and India in 2010, and in New Zealand and South Africa in 2011.
Medical uses
Rosiglitazone was approved for glycemic control in people with type 2 diabetes, as measured by glycated haemoglobin A1c (HbA1c) as a surrogate endpoint, similar to that of other oral antidiabetic drugs. The controversy over adverse effects has dramatically reduced the use of rosiglitazone.Published studies did not provide evidence that outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by rosiglitazone.
Adverse effects
Heart failure
One of the safety concerns identified before approval was fluid retention. Moreover, the combination of rosiglitazone with insulin resulted in a higher rate of congestive heart failure. In Europe there were contraindications for use in heart failure and combination with insulin.A meta analysis of all trials from 2010 and 2019 confirmed a higher risk of heart failure and a double risk when rosiglitazone was administered as add-on therapy to insulin. Two meta-analyses of real life cohort studies found a higher risk of heart failure compared to pioglitazone. There were 649 excess cases of heart failure every 100,000 patients who received rosiglitazone rather than pioglitazone.
Heart attacks
The relative risk of ischemic cardiac events seen in pre-approval trials of rosiglitazone was similar to that of comparable drugs, but there was increased LDL cholesterol, LDL/HDL cholesterol ratio, triglycerides and weight.In 2005, at the insistence of the World Health Organization, GSK performed a meta-analysis of all 37 trials involving use of rosiglitazone, finding a hazard ratio of 1.29 (0.99 to 1.89).
In 2006 the GSK updated the analysis, now including 42 trials and showing a hazard ratio of 1.31 (1.01 to 1.70). A large observational study comparing patients treated with rosiglitizone with patients treated with other diabetes therapies was performed at the same time and found a relative risk of 0.93 (95% C.I. 0.8 to 1.1) for those treated with rosiglitazone. The information was passed to the FDA and posted on the company website, but not otherwise published. GSK provided these analyses to the FDA, but neither the company nor the FDA warned prescribers or patients of the hazard. According to the FDA, the Agency did not issue a safety bulletin because the results of the meta analysis conflicted with those of the observational study and with the results of the ADOPT trial.A meta-analysis in May 2007 reported the use of rosiglitazone was associated with a 1.4 fold increased risk of heart attack and a numerically higher (but non-significant) increase in risk of death from all cardiovascular diseases against control. It contained 42 trials of which 27 were unpublished. Another meta analysis of 4 trials with follow-up longer than 1 year found similar results. Nissens meta analysis was criticized in a 2007 article by George Diamond et al. in the Annals of Internal Medicine. The authors concluded that Nissens analysis had excluded trials with important data on the cardiovascular profile of rosiglitazone, had inappropriately combined trials of greatly differing design, and had inappropriately excluded trials with no cardiovascular events. The authors concluded that no firm conclusion could be drawn regarding whether rosiglitazone increased or decreased cardiovascular risk. Investigators from the Cochrane Collaboration published a meta-analysis of their own on the use of rosiglitazone in Type II diabetes, concluding there was not sufficient evidence to show any health benefit for rosiglitazone. Noting the recent publication by Nissen, they repeated their meta analysis including only the trials included in the Nissen study that dealt with Type II diabetics. (The Nissen study included some trials in people with other disorders.) They did not find a statistically significant increase in cardiovascular events, but noted that all of the cardiovascular endpoints they analyzed showed a non-significant trend toward worse outcomes in the rosiglitazone arms.In July 2007 the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. FDA scientist Joy Mele presented a meta analysis examining the cardiovascular risk of rosiglitazone in completed clinical trials. The study found an overall 1.4x increase in risk of cardiovascular ischemic events relative to the control arms. The results were heterogenous, with clear evidence of increased risk relative to placebo but not relative to other diabetes treatments and higher risk associated with combinations of rosiglitazone with insulin or metformin. Based on the 1.4x increased risk relative to control groups, FDA scientist David Graham presented an analysis suggesting that rosiglitazone had caused 83,000 excess heart attacks between 1999 and 2007.: 4 The advisory panel voted 20 : 3 that the evidence available indicated that rosiglitazone increased the risk of cardiovascular events and 22 : 1 that the overall risk:benefit ratio of rosiglitazone justified its continued marketing in the United States. The FDA placed restrictions on the drug, including adding a boxed warning about heart attacks, but did not withdraw it.In 2000 a study to address the concerns regarding cardiovascular safety was requested by the European Medicines Agency (EMA). GSK agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed that rosiglitazone was non-inferior to treatment with metformin or a sulfonylurea with respect to the rate of cardiovascular events and cardiovascular death. European regulators concluded that due in part to design limitations, the results neither proved nor eliminated concerns of excess cardiovascular risk.In February 2010, the FDAs associate director of drug safety, recommended rosiglitazone be taken off the market. In June 2010, they published a retrospective study comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States and concluded rosiglitazone was associated with "an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older". The number needed to harm with roziglitazone was sixty. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
Two meta analyses released in 2010, one incorporating 56 trials and a second incorporating 164 trials reached conflicting conclusions. Nissen et al. found again an increased risk for heart infarction against control, but no increased risk for cardiovascular death. Mannucci et al. found no statistically significant increase in cardiac events but a significant increase in heart failure. A 2011 drug class review found an increased risk of cardiovascular adverse events.A meta-analysis of 16 observational studies released in March, 2011, compared rosiglitazone to pioglitazone, finding support for greater cardiovascular safety for pioglitazone. The meta-analysis involved 810 000 patients taking rosiglitazone or pioglitazone. The study suggests 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone. This was confirmed by another meta-analysis involving 945 286 patients in 8 retrospective cohort studies, most in the US.In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.
Death
There was no difference in all cause and vascular death in a meta-analysis of 4 trials against controls. Two meta-analyses of cohort studies found excess deaths against pioglitazone.
Stroke
An retrospective observational study performed using Medicare data found that patients treated with rosiglitazone had a 27% higher risk of stroke compared to those treated with pioglitazone.
Bone fractures
GlaxoSmithKline reported a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide.
The information was based on data from the ADOPT trial The same increase has been found with pioglitazone (Actos), another thiazolidinedione.
A meta-analysis of 10 RCTs, involving 13,715 patients and including both rosiglitazone- and pioglitazone-treated patients, showed an overall 45% increased risk of fracture with thiazolidone use compared with placebo or active comparator. It doubled the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.
Hypoglycaemia
The risk of hypoglycaemia is reduced with thiazolidinediones when compared with sulfonylureas; the risk is similar to the risk with metformin (high strength of evidence).
Weight gain
Both thiazolidinediones cause a similar degree of weight gain to that caused by sulfonylureas (moderate strength of evidence).
Eye damage
Both rosiglitazone and pioglitazone have been suspected of causing macular edema, which damages the retina of the eye and causes partial blindness. Blindness is also a possible effect of diabetes, which rosiglitazone is intended to treat. One report documented several occurrences and recommended discontinuation at the first sign of vision problems. A retrospective cohort study showed an association between the use of thiazolidinediones and the incidence of diabetic macular edema (DME). Both use was associated with a 2,3 higher risk at 1 year and at 10 year follow-up, rising to 3 if associated with insulin.
Hepatotoxicity
Moderate to severe acute hepatitis has occurred in several adults who had been taking the drug at the recommended dose for two to four weeks. Plasma rosiglitazone concentrations may be increased in people with existing liver problems.
Contraindications
Both rosiglitazone and pioglitazone are contraindicated in people with NYHA Class III and IV heart failure. They are not recommended for use in heart failure.In Europe rosiglitazone was contraindicated for heart failure or history of heart failure with regard to all NYHA stages, for combined use with insulin and for acute coronary syndrome. The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.
Pharmacology
Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs). PPARs are transcription factors that reside in the nucleus and become activated by ligands such as thiazolidinediones. Thiazolidinediones enter the cell, bind to the nuclear receptors, and alter the expression of genes. The several PPARs include PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to PPARγ.
PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.
Rosiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. Nuclear factor kappa-B (NF-κB), a signaling molecule, stimulates the inflammatory pathways. NF-κB inhibitor (IκB) downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.
History
Rosiglitazone was approved by the US FDA in 1999 and by the EMA in 2000; the EMA however required two postmarketing studies on longterm adverse effects, one for chronic heart failure and the other for cardiovascular effects.
Society and culture
Sales
US sales of the drug were of $2.2 billion in 2006. Sales in 2Q 2007 down 22% compared to 2006. 4Q 2007 sales down to $252 million.Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.
Lawsuits
According to analysts from UBS, 13,000 suits had been filed by March 2010. Included among those suing: Santa Clara County, California, which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for "triple damages".
In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits. In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007. The settlement stems from claims made by four employees of GlaxoSmithKline, including a former senior marketing development manager for the company and a regional vice president, who tipped off the government about a range of improper practices from the late 1990s to the mid-2000s.
United States investigations
GlaxoSmithKline was being investigated by the FDA and the US Congress regarding Avandia.
Senators Democrat Max Baucus and Republican Charles Grassley filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report noted the drug caused 500 avoidable heart attacks a month, and Glaxo officials sought to intimidate doctors who criticized the drug. It also said GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.The Senate Finance Committee, in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alleged by the committee that the company initiated a "ghostwriting campaign", whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals. GSK defended itself by presenting data that its own tests found Avandia to be safe, although an FDA staff report showed the conclusions were flawed.On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. Twelve members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and three voted to keep it on the market with the current warning label. The panel has come to some controversy, however; on July 20, 2010, one of the panelists was discovered to have been a paid speaker for GlaxoSmithKline, arousing questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels.In 2011 the FDA has decided on revising its prescribing information and medication guides for all rosilitazone containing medicines. The US label for rosiglitazone (Avandia, GlaxoSmithKline) and all rosiglitazone-containing medications (Avandamet and Avandaryl) now include the additional safety information and restrictions. The revised labels restrict use to patients already taking a rosiglitazone-containing medicine or to new patients who are unable to achieve adequate glycemic control on other diabetes medications and to those, who in consultation with their healthcare provider, have decided not to take Actos (pioglitazone) or other pioglitazone-containing medicines for medical reasons.In June 2013 an FDA Advisory Committee reviewed all available data, including a re-adjudicated RECORD trial, found no evidence of increased cardiovascular risk with Avandia, and voted to remove the restrictions on Avandia marketing in the United States. In November 2013, the US FDA removed these marketing restrictions on the product. Under the FDAs instruction, Avandias maker, GlaxoSmithKline, had funded the Duke Clinical Research Institute to re-analyze the raw data from the study. At the 2010 panel, three panelists voted that the existing warnings were good enough; two were back in 2013. Seven voted to make those warnings more onerous, and five of them returned. But of the 10 who voted to restrict Avandias use, only four returned. And of the 12 who voted in 2010 to withdraw Avandia from the market, only three came back.
European investigations
In 2000 a study to address the concerns regarding cardiovascular safety was requested by the EMA, and the makers agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed non-inferiority with regard to cardiovascular events and cardiovascular death when the treatment with rosiglitazone was compared with metformin or a sulfonylurea. For myocardial infarction, there was a non-statistically significant increase in risk. In their assessment, the European regulators acknowledged weaknesses of the study, such as an unexpectedly low rate of cardiovascular events and the open-label design, which may lead to reporting bias. They found that the results were inconclusive. The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.According to a probe by the British Medical Journal in September 2010, the United Kingdoms Commission on Human Medicines recommended to the Medicines and Healthcare Products Regulatory Agency (MHRA) back in July 2010, to withdraw Avandia sale because its "risks outweigh its benefits". Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.
New Zealand
Rosiglitazone was withdrawn from the New Zealand market April 2011 because Medsafe concluded the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits.
South Africa
A notice issued by the Medicines Control Council of South Africa on July 5, 2011, stated that it had resolved on July 3, 2011, to withdraw all rosiglitazone-containing medicines from the South African market due to safety risks. It disallowed all new prescriptions of Avandia.
Controversy and response
Following the reports in 2007 that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. A 2010 article in Time uses the Avandia case as evidence of a broken FDA regulatory system that "may prove criminal as well as fatal". It details the disclosure failures, adding, "Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public." It reports, "the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandias heart risks", according to deputy FDA commissioner Dr. Joshua Sharfstein. GSK threatened academics who reported adverse research results, and received multiple warning letters from the FDA for deceptive marketing and failure to report clinical data. The maker of the drug, GlaxoSmithKline, has dealt with serious backlash against the company for the drugs controversy. Sales on the drug dropped significantly after the story first broke in 2007, dropping from $2.5 billion in 2006 to less than $408 million in 2009 in the US.In response to the rise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE, in 2010. The FDA also halted the TIDE study in the United States.Three doctors groups, the Endocrine Society, the American Diabetes Association and the American Association of Clinical Endocrinologists, urged patients to continue to take the drug as it would be much worse to stop all treatment, despite any associated risk, but that patients could consult their doctors and begin a switch to a different drug if they or their doctors find concern. The American Heart Association said in a statement in June 2010: " ...the reports deserves serious consideration, and patients with diabetes who are 65 years of age or older and being treated with rosiglitazone should discuss the findings with their prescribing physician....".
"For patients with diabetes, the most serious consequences are heart disease and stroke, and the risk of suffering from them is significantly increased when diabetes is present. As in most situations, patients should not change or stop medications without consulting their healthcare provider."As a result of the Avandia Affair, FDA required that cardiac safety be demonstrated for new drugs to treat type 2 diabetes. This process is described by Dr Robert Misbin in INSULIN-History from an FDA Insider, published June 1, 2020 on Amazon. Dr Misbin was the first FDA reviewer for rosiglitazone (Avandia) and cautioned about its potential to increase the risk of cardiovascular disease.
Research
Rosiglitazone was thought to be able to benefit patients with Alzheimers disease who do not express the ApoE4 allele, but the phase III trial designed to test this showed that rosiglitazone was ineffective in all patients, including ApoE4-negative patients.Rosiglitazone may also treat mild to moderate ulcerative colitis, due to its anti-inflammatory properties as a PPAR ligand.
Synthesis
References
External links
MedlinePlus article
Medscape
U.S. National Library of Medicine: Drug Information Portal – Rosiglitazone |
Sargramostim | Sargramostim (tradename Leukine) is a recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) that functions as an immunostimulator.
Medical uses
Sargramostim is primarily used for myeloid reconstitution after autologous or allogeneic bone marrow transplantation. It is also used to treat neutropenia induced by chemotherapy during the treatment of acute myeloid leukemia. It also used as a medical countermeasure for treating people who have been exposed to sufficient radiation to suppress bone marrow myelogenesis.It is administered via intravenous infusion.
Contraindications
Sargramostim should not be used in people with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product and for concomitant use with chemotherapy and radiotherapy.There is a formulation with benzyl alcohol, which is toxic to babies; other formulations should be used. Sargramostim has not been tested in pregnant women but appears to be toxic to fetuses. There is no data as to whether sargramostim is expressed in breast milk.
Adverse effects
Some people have experienced anaphylaxis when given the drug; and infusion reactions have occurred as well, including edema, capillary leak syndrome, a build up of fluid around the lungs and around the heart. Irregular heart rhythms have occurred, especially in people with a history of that problem. It suppresses some white blood cells, and may promote tumor growth.
Pharmacology
Sargramostim is a version of GM-CSF, which has a normal role in human biology, causing progenitor cells to differentiate into neutrophils, monocytes, macrophages, and, myeloid-derived dendritic cells; it can also activate mature granulocytes and macrophages, and can contribute to the differentiation of megakaryocytic progenitors and erythroid progenitor cells.
Chemistry
Sargramostim is a recombinant version of GM-CSF, which is a glycoprotein made of 127 amino acids; sargramostim is mixture of three versions of GM-CSF that have molecular weights of 19,500, 16,800 and 15,500 Daltons. It is manufactured in yeast.
History
The sequence of human GM-CSF was first identified in 1985 and soon three recominbant human GM-CSFs were produced, one in bacteria, one in mammalian cells, and one in yeast; Immunex developed GM-CSF manufactured in yeast into Leukine. Clinical trials of sargramostim were initiated in 1987; in that same year it was administered to six people as part of a compassionate-use protocol for the victims of cesium irradiation from the Goiânia accident.It was approved by the FDA in March 1991 under the trade name Leukine for acceleration of white blood cell recovery following autologous bone marrow transplantation in patients with non-Hodgkins lymphoma, acute lymphocytic leukemia, or Hodgkins disease. In November 1996, the FDA also approved sargramostim for treatment of fungal infections and replenishment of white blood cells following chemotherapy. A liquid formulation was approved in 1995. Immunex was acquired by Amgen in 2002. As part of the acquisition, Leukine was spun off to Berlex, which became Bayer HealthCare in 2007.In January 2008, Bayer informed healthcare professionals of the market withdrawal of the current liquid formulation of sargramostim. The liquid formulation was withdrawn because of an upward trend in spontaneous reports of adverse reactions, including syncope (fainting), which are temporally correlated with a change that was made to the formulation around April 2007 to include edetate disodium (EDTA). The upward trend in adverse reaction reporting rates had not been observed with the use of lyophilized sargramostim. The original liquid formulation without EDTA was returned to the market in the US in May 2008.In 2009, Genzyme acquired the rights to Leukine from Bayer, including the manufacturing facility in the Seattle area.In March 2018 the label was extended to use as a countermeasure for acute radiation syndrome.
== References == |
Ponatinib | Ponatinib (trade name Iclusig eye-KLOO-sig, previously AP24534) is an oral drug developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor. Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.The United States Food and Drug Administration approved the drug as a candidate in December 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels". This suspension was partially lifted on Dec. 20, 2013 with ponatinib being issued revised prescribing information, a new "Black Box Warning" and a "Risk Evaluation and Mitigation Strategy" in place to better evaluate the risks and benefits of using the drug.
In the US it can cost $138,000 a year, which has been criticized.
Approvals and indications
Ponatinib was approved by the US FDA on December 14, 2012, for patients with resistant or intolerant CML and Ph+ ALL, based on results of the PACE phase II trial reported days earlier at the annual ASH meeting. Because the approval was under the FDA Accelerated Approval program the applicant was required to carry out additional studies. Based on these additional studies, the FDA granted in 2016 full approval and updated the label to include patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia for whom no other tyrosine kinase inhibitor therapy is indicated. Approval was also granted for T315I-positive and T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia.
Adverse effects
The United States Food and Drug Administration issued a partial clinical hold on new trial enrollment for ponatinib on October 9, 2013, due to an increased number of blood clots observed in patients taking the drug. The EPIC trial was later canceled on October 18. Subsequent studies of 449 patients treated during 4 years with ponatinib for chronic phase chronic myelogenous leukemia found the following adverse reactions. 150 Patients experienced cardiac vascular (21% of patients), peripheral vascular (12%), and cerebrovascular (9%) arterial occlusive events. Venous thromboembolic events occurred in 6% of patients. The most common all-grade adverse events included hypertension (69%), rash (63%), abdominal pain (48%), fatigue (47%), headache (43%), arterial ischemia (42%), dry skin (42%), constipation (41%), arthralgia (32%), nausea (28%), pyrexia (26%), peripheral neuropathy (24%), myalgia (24%), pain in extremity (23%), back pain (21%), and diarrhea (20%). In addition, there have been reported cases of the posterior reversible encephalopathy syndrome. Recently, an analogue of ponatinib was developed that retained anti-tumor efficacy but had reduced cardiovascular toxicity in experimental models.
Clinical trials
In 2010 ARIAD announced result from a Phase I study of ponatinib in patients with resistant and refractory chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). The study demonstrated that in chronic-phase CML patients treated with ponatinib, 66 percent of patients in the trial achieved a major cytogenetic response, including 100 percent of patients who also had a T315I mutation.The PACE (Ponatinib Ph+ ALL and CML Evaluation) pivotal phase II trial started enrolling patients in September 2010 and is designed to provide definitive clinical data for regulatory approval in this setting. Good results were reported in December 2012.The EPIC (Evaluation of Ponatinib versus Imatinib in CML) phase-III trial began in June 2012 and was halted on October 18, 2013.
Mechanism of action
The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL. CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases such as accelerated or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. Because both of these diseases express the BCR-ABL protein, this would render them potentially susceptible to treatment with ponatinib. BCR-ABL is detected in 95% of patients with CML.Patients with CML currently receive front line therapies nilotinib and/or dasatinib though 22−33% of patients discontinue therapy by two years due to adverse events, treatment failure and other causes.
Discovery and origin
Ponatinib was designed using ARIADs computational and structure-based drug design platform to inhibit the enzymatic activity of BCR-ABL with very high potency and broad specificity. Ponatinib was intended to target not only native BCR-ABL, but also its isoforms that carry mutations that confer resistance to treatment with existing tyrosine kinase inhibitors, including especially the T315I mutation for which no effective therapy exists.The road to discovery is linked to AP23464, one of the first of Ariads ATP competitive dual Src/Abl inhibitors. AP23464 was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. The substance potently inhibits Src and Bcr-Abl kinases including many common imatinib-resistant Bcr-Abl mutations. AP23464 does not inhibit the T315I mutation, however, whereas ponatinib does.
Cost, coverage and availability
[US] Oncologists have complained that many patients cannot afford the "astronomical" cost of $138,000 a year, which makes it one of the most expensive drugs in medicine, and [in their view] far more expensive than what is needed to pay the development costs.In 2015 ponatinib is available in England for the treatment of CML (chronic phase, accelerated phase or blast phase) and Ph+ ALL in patients with documented T315I mutation under the Cancer Drugs Fund, and has not been appraised by the National Institute for Health and Care Excellence (NICE), who noted the small expected patient population. NICE estimated that ponatinib would cost approximately £61,000 per year, but the price paid under the Cancer Drugs Fund is confidential and may be different.
See also
Bcr-Abl tyrosine-kinase inhibitor, especially the sections on Ponatinib development
and binding
References
External links
"Ponatinib". Drug Information Portal. U.S. National Library of Medicine. |
Tipranavir | Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name Aptivus AP-tiv-əs. It is administered with ritonavir in combination therapy to treat HIV infection.
Tipranavir has the ability to inhibit the replication of viruses that are resistant to other protease inhibitors and it recommended for patients who are resistant to other treatments. Resistance to tipranavir itself seems to require multiple mutations. Tipranavir was approved by the Food and Drug Administration (FDA) on June 22, 2005, and was approved for pediatric use on June 24, 2008.Tipranavir should only be taken in combination with ritonavir and other antiretroviral drugs, and is not approved for treatment-naïve patients. Like lopinavir and atazanavir, it is very potent and is effective in salvage therapy for patients with drug resistance. However, side effects of tipranavir may be more severe than those of other antiretrovirals. Some side effects include intracranial hemorrhage, hepatitis, hepatic decompensation, hyperglycemia and diabetes mellitus. The drug has also been shown to cause increases in total cholesterol and triglycerides.Aptivus labeling has a black box warning regarding hepatotoxicity and intracranial hemorrhage.
References
External links
"Tipranavir". Drug Information Portal. U.S. National Library of Medicine. |
Provera | Provera is an Italian surname. Notable people with the surname include:
Giovanni Marchese di Provera (c.1736–1804), Italian general
Marco Tronchetti Provera (born 1948), Italian businessman
See also
Medroxyprogesterone acetate, sold under the brand name Depo-Provera |
Desipramine | Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.
Medical uses
Desipramine is primarily used for the treatment of depression. It may also be useful to treat symptoms of attention-deficit hyperactivity disorder (ADHD). Evidence of benefit is only in the short term, and with concerns of side effects its overall usefulness is not clear. Desipramine at very low doses is also used to help reduce the pain associated with functional dyspepsia. It has also been tried, albeit with little evidence of effectiveness, in the treatment of cocaine dependence. Evidence for usefulness in neuropathic pain is also poor.
Side effects
Desipramine tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive or memory impairments.
Overdose
Desipramine is particularly toxic in cases of overdose, compared to other antidepressants. Any overdose or suspected overdose of desipramine is considered to be a medical emergency and can result in death without prompt medical intervention.
Pharmacology
Pharmacodynamics
Desipramine is a very potent and relatively selective norepinephrine reuptake inhibitor (NRI), which is thought to enhance noradrenergic neurotransmission. Based on one study, it has the highest affinity for the norepinephrine transporter (NET) of any other TCA, and is said to be the most noradrenergic and the most selective for the NET of the TCAs. The observed effectiveness of desipramine in the treatment of ADHD was the basis for the development of the selective NRI atomoxetine and its use in ADHD.Desipramine has the weakest antihistamine and anticholinergic effects of the TCAs. It tends to be slightly activating/stimulating rather than sedating, unlike most others TCAs. Whereas other TCAs are useful for treating insomnia, desipramine can cause insomnia as a side effect due to its activating properties. The drug is also not associated with weight gain, in contrast to many other TCAs. Secondary amine TCAs like desipramine and nortriptyline have a lower risk of orthostatic hypotension than other TCAs, although desipramine can still cause moderate orthostatic hypotension.
Pharmacokinetics
Desipramine is the major metabolite of imipramine and lofepramine.
Chemistry
Desipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzazepine TCAs include imipramine (N-methyldesipramine), clomipramine, trimipramine, and lofepramine (N-(4-chlorobenzoylmethyl)desipramine). Desipramine is a secondary amine TCA, with its N-methylated parent imipramine being a tertiary amine. Other secondary amine TCAs include nortriptyline and protriptyline. The chemical name of desipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C18H22N2 with a molecular weight of 266.381 g/mol. The drug is used commercially mostly as the hydrochloride salt; the dibudinate salt is or has been used for intramuscular injection in Argentina (brand name Nebril) and the free base form is not used. The CAS Registry Number of the free base is 50-47-5, of the hydrochloride is 58-28-6, and of the dibudinate is 62265-06-9.
History
Desipramine was developed by Geigy. It first appeared in the literature in 1959 and was patented in 1962. The drug was first introduced for the treatment of depression in 1963 or 1964.
Society and culture
Generic names
Desipramine is the generic name of the drug and its INN and BAN, while desipramine hydrochloride is its USAN, USP, BAN, and JAN. Its generic name in French and its DCF are désipramine, in Spanish and Italian and its DCIT are desipramina, in German is desipramin, and in Latin is desipraminum.
Brand names
Desipramine is or has been marketed throughout the world under a variety of brand names, including Irene, Nebril, Norpramin, Pertofran, Pertofrane, Pertrofran, and Petylyl among others.
References
External links
Desipramine - MedlinePlus |
Quinapril | Quinapril, sold under the brand name Accupril among others, is a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.Common side effects include headaches, dizziness, feeling tired, and cough. Serious side effects may include liver problems, low blood pressure, angioedema, kidney problems, and high blood potassium. Use in pregnancy and breastfeeding is not recommended. It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.Quinapril was patented in 1980 and came into medical use in 1989. It is available as a generic medication. In 2019, it was the 294th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Medical uses
Quinapril is indicated for the treatment of high blood pressure (hypertension) and as adjunctive therapy in the management of heart failure. It may be used for the treatment of hypertension by itself or in combination with thiazide diuretics, and with diuretics and digoxin for heart failure.
Contraindications
Pregnancy
Impaired renal and liver function
Patients with a history of angioedema related to previous treatment with an ACE inhibitor
Hypersensitivity to quinapril
Side effects
Side effects of quinapril include dizziness, cough, vomiting, upset stomach, angioedema, and fatigue.
Mechanism of action
Quinapril inhibits angiotensin converting enzyme, an enzyme which catalyses the formation of angiotensin II from its precursor, angiotensin I. Angiotensin II is a powerful vasoconstrictor and increases blood pressure through a variety of mechanisms. Due to reduced angiotensin production, plasma concentrations of aldosterone are also reduced, resulting in increased excretion of sodium in the urine and increased concentrations of potassium in the blood.
Partial Recall
In April of 2022, Pfizer voluntarily recalled five batches of the drug because of the presence of a nitrosamine, NNitroso-quinapril. Testing found that the amount of nitrosamines was above the acceptable daily intake level (all humans are exposed to nitrosamines up to a certain daily level by cured and grilled meats, water, dairy products, and vegetables) set by the U.S.s Food and Drug Administration (FDA). Though long-term ingestion of NNitroso-quinapril potentially might cause cancer in some individuals, there is not believed to be an imminent risk of harm.
References
External links
"Quinapril hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Propofol | Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. It is also used for status epilepticus if other medications have not worked. It is given by injection into a vein, and the maximum effect takes about two minutes to occur and typically lasts five to ten minutes. Propofol is also used for medical assistance in dying in Canada.The medication appears to be safe for use during pregnancy but has not been well studied for use in this case. It is not recommended for use during a cesarean section. It is not a pain medication, so opioids such as morphine may also be used; however, whether or not they are always needed is not clear. Propofol is believed to work at least partly via a receptor for GABA.Propofol was discovered in 1977 and approved for use in the United States in 1989. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It has been referred to as milk of amnesia (a play on "milk of magnesia"), because of the milk-like appearance of the intravenous preparation, and because of its tendency to suppress memory recall. Propofol is also used in veterinary medicine for anesthesia.
Medical uses
Anesthesia
To induce general anesthesia, propofol is the drug used almost exclusively, having largely replaced sodium thiopental. It can also be administered as part of an anesthesia maintenance technique called total intravenous anesthesia, using either manually programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion (TCI). Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit. In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost. Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length. One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is because studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation. Propofol has also been suggested as a sleep aid in critically ill adults in the ICU; however, the effectiveness of this medicine at replicating the mental and physical aspects of sleep for people in the ICU is not clear.Propofol can be run through a peripheral IV or central line. Propofol is frequently paired with fentanyl (for pain relief) in intubated and sedated people. The two drugs are compatible in IV form.
Procedural sedation
Propofol is safe and effective for gastrointestinal endoscopy procedures. Its use in these settings results in a faster recovery compared to midazolam. It can also be combined with opioids or benzodiazepines. Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI. It is also often used in combination with ketamine with minimal side effects.
Assisted death in Canada
A lethal dose of propofol is used for medical assistance in dying in Canada to quickly induce deep coma and death, but rocuronium is always given—even when patient dies as a result of propofol injection. Delivery order of IV medication is as follows:Step 1: Midazolam 10–20 mg given as 2−4ml of 5 mg/ml preparation for pre-anesthesia, induces sleep in 1−2 minutes.
Step 2: Lidocaine 40 mg given as 4ml of 1% preparation to reduce possible burning in peripheral vein caused by propofol. Pause to allow effect.
Step 3: Propofol 1000 mg given as 100ml of 10 mg/ml preparation. Loss of consciousness occurs within 10 seconds and coma occurs in 1–2 minutes. Death may result from the propofol but rocuronium is still given.
Step 4: Rocuronium 200 mg given as 20ml of 10 mg/ml preparation to induce respiratory arrest. Cardiac arrest subsequently follows about 5 minutes later due to hypoxia.
COVID-19
In March 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Propofol‐Lipuro 1% to maintain sedation via continuous infusion in people older than sixteen with suspected or confirmed COVID-19 who require mechanical ventilation in an intensive care unit ICU setting. In the circumstances of this public health emergency, it would not be feasible to require healthcare providers to seek to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% only to be used for patients with suspected or confirmed COVID-19; therefore, this authorization does not limit use to such patients.
Other uses
Executions
The US state of Missouri added propofol to its execution protocol in April 2012. However, Governor Jay Nixon halted the first execution by the administration of a lethal dose of propofol in October 2013 following threats from the European Union to limit the drugs export if it were used for that purpose. The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States.
Recreational use
Recreational use of the drug via self-administration has been reported but is relatively rare due to its potency and the level of monitoring required for safe use — critically, a steep dose-response curve makes recreational use of propofol very dangerous, and deaths from self-administration continue to be reported. The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug. It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling. Long-term use has been reported to result in addiction.Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroners conclusion that music icon Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on 25 June 2009. According to a 22 July 2009 search warrant affidavit unsealed by the district court of Harris County, Texas, Jacksons physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before Jacksons death. Even so, as of 2016, propofol was not on a US Drug Enforcement Administration schedule.
Side effects
One of propofols most common side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1, found on sensory nerves and can be mitigated by pretreatment with lidocaine. Less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show considerable variability in their response to propofol, at times showing profound sedation with small doses[1].
Additional side effects include low blood pressure related to vasodilation, transient apnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents. Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity. This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics.Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation. There are also reports that it may cause green discolouration of the urine.Although propofol is heavily used in the adult ICU setting, the side effects associated with propofol seem to be of greater concern in children. In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning.As a respiratory depressant, propofol frequently produces apnea. The persistence of apnea can depend on factors such as premedication, dose administered, and rate of administration, and may sometimes persist for longer than 60 seconds. Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rate, minute volume, tidal volume, mean inspiratory flow rate, and functional residual capacity.Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration. In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.A more serious but rare side effect is dystonia. Mild myoclonic movements are common, as with other intravenous hypnotic agents. Propofol appears to be safe for use in porphyria, and has not been known to trigger malignant hyperpyrexia.Propofol is also reported to induce priapism in some individuals, and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.Rare side effects include:
Anxiety.
changes in vision.
cloudy urine.
coughing up blood.
delirium or hallucinations.
difficult urination.
difficulty swallowing.
dry eyes, mouth, nose, or throat.As with any other general anesthetic agent, propofol should be administered only where appropriately trained staff and facilities for monitoring are available, as well as proper airway management, a supply of supplemental oxygen, artificial ventilation, and cardiovascular resuscitation.Because of its lipid base, some hospital facilities require the IV tubing (of continuous propofol infusions) to be changed after 12 hours. This is a preventive measure against microbial growth and infection.
Propofol infusion syndrome
A rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes in combination with catecholamines and/or corticosteroids.
Interactions
The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.
Pharmacology
Pharmacodynamics
Propofol has been proposed as having several mechanisms of action, both through potentiation of GABAA receptor activity and therefore acting as a GABAA receptor positive allosteric modulator, thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well. Propofol analogs have been shown to also act as sodium channel blockers. Some research has also suggested that the endocannabinoid system may contribute significantly to propofols anesthetic action and to its unique properties. An EEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brains information integration capacity.
Pharmacokinetics
Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver.
The half-life of elimination of propofol has been estimated to be between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Propofol is versatile; the drug can be given for short or prolonged sedation, as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects have led to its widespread use for sedation and anesthesia.
History
John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI) spent 13 years developing propofol, an effort which led to the awarding to him of the prestigious 2018 Lasker Award for clinical research. Propofol was originally developed as ICI 35868. It was chosen for development after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols.First identified as a drug candidate in 1973, clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan. The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents. Propofol emulsion is a highly opaque white fluid due to the scattering of light from the tiny (about 150-nm) oil droplets it contains: Tyndall Effect.
Developments
A water-soluble prodrug form, fospropofol, has been developed and tested with positive results. Fospropofol is rapidly broken down by the enzyme alkaline phosphatase to form propofol. Marketed as Lusedra, this formulation may not produce the pain at injection site that often occurs with the conventional form of the drug. The U.S. Food and Drug Administration (FDA) approved the product in 2008.
However fospropofol is a Schedule IV controlled substance with the DEA ACSCN of 2138 in the United States unlike propofol.By incorporation of an azobenzene unit, a photoswitchable version of propofol (AP2) was developed in 2012, that allows for optical control of GABAA receptors with light. In 2013, a propofol binding site on mammalian GABAA receptors has been identified by photolabeling using a diazirine derivative. Additionally, it was shown that the hyaluronan polymer present in the synovia can be protected from free-radical depolymerization by propofol.
References
External links
"Propofol". Drug Information Portal. U.S. National Library of Medicine.
GB patent 1472793, John B Glen & Roger James, "Pharmaceutical Compositions", published 1977-05-04, assigned to Imperial Chemical Industries Ltd |
Mitotane | Mitotane, sold under the brand name Lysodren, is a steroidogenesis inhibitor and cytostatic antineoplastic medication which is used in the treatment of adrenocortical carcinoma and Cushings syndrome. It is a derivative of the early insecticide DDT and an isomer of p,p-DDD (4,4-dichlorodiphenyldichloroethane) and is also known as 2,4-(dichlorodiphenyl)-2,2-dichloroethane (o,p-DDD).
Medical uses
Mitotane has been produced by Bristol Myers Squibb but it is marketed as an orphan drug for adrenocortical carcinoma due to the small number of patients in need of it. Its main use is in those patients who have persistent disease despite surgical resection, those who are not surgical candidates, or those who have metastatic disease. In a 2007 retrospective study of 177 patients from 1985 to 2005 showed a significant increase in the recurrence-free interval after radical surgery followed by mitotane when compared to surgery alone. The drug is also sometimes used in the treatment of Cushings syndrome.
Side effects
The use of mitotane is unfortunately limited by side effects, which, as reported by Schteinberg et al., include anorexia and nausea (88%), diarrhea (38%), vomiting (23%), decreased memory and ability to concentrate (50%), rash (23%), gynecomastia (50%), arthralgia (19%), and leukopenia (7%).
Pharmacology
Pharmacodynamics
Mitotane is an inhibitor of the adrenal cortex. It acts as an inhibitor of cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), and also of 11β-hydroxylase (CYP11B1), 18-hydroxylase (aldosterone synthase, CYP11B2), and 3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent. In addition, mitotane has direct and selective cytotoxic effects on the adrenal cortex, via an unknown mechanism, and thereby induces permanent adrenal atrophy similarly to DDD.
Chemistry
Analogues of mitotane include aminoglutethimide, amphenone B, and metyrapone.
History
Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma.
Society and culture
Generic names
Mitotane is the generic name of the drug and its INN, USAN, BAN, and JAN.
Brand names
Mitotane has been sold under the brand name Lysodren.
Veterinary use
Mitotane is also used to treat Cushings disease (pituitary-dependent Cushings syndrome) in dogs. The medication is used in the controlled destruction of adrenal tissue, leading to a decrease in cortisol production.
References
External links
V. P. Komissarenko; I. S. Chelnakova; A. S. Mikosha (1978). "Effect of o,p-dichlorodiphenyldichloroethane and perthane in vitro on glutathione reductase activity in the adrenals of dogs and guinea pigs". Bulletin of Experimental Biology and Medicine. 85 (2): 152–154. doi:10.1007/BF00800110. S2CID 23181221.
Government of Canada: Benzene, 1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)ethyl]- (Mitotane)
Environment Canada & Health Canada: RISK MANAGEMENT SCOPE for Benzene, 1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)ethyl]- (Mitotane), 2013 |
Clarithromycin | Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others. Clarithromycin can be taken by mouth as a pill or liquid.Common side effects include nausea, vomiting, headaches, and diarrhea. Severe allergic reactions are rare. Liver problems have been reported. It may cause harm if taken during pregnancy. It is in the macrolide class and works by slowing down bacterial protein synthesis.Clarithromycin was developed in 1980 and approved for medical use in 1990. It is on the World Health Organizations List of Essential Medicines. Clarithromycin is available as a generic medication. It is made from erythromycin and is chemically known as 6-O-methylerythromycin.
Medical uses
Clarithromycin is primarily used to treat a number of bacterial infections including pneumonia, Helicobacter pylori, and as an alternative to penicillin in strep throat. Other uses include cat scratch disease and other infections due to bartonella, cryptosporidiosis, as a second line agent in Lyme disease and toxoplasmosis. It may also be used to prevent bacterial endocarditis in those who cannot take penicillin. It is effective against upper and lower respiratory tract infections, skin and soft tissue infections and helicobacter pylori infections associated with duodenal ulcers.
Spectrum of bacterial susceptibility
Aerobic Gram-positive bacteria
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenesAerobic Gram-negative bacteria
Haemophilus parainfluenzae
Haemophilus influenzae
Moraxella catarrhalisHelicobacter
Helicobacter pyloriMycobacteria
Mycobacterium avium complex consisting of:
Mycobacterium avium avium
Mycobacterium intracellulareOther bacteria
Chlamydia pneumoniae
Mycoplasma pneumoniaeSafety and effectiveness of clarithromycin in treating clinical infections due to the following bacteria have not been established in adequate and well-controlled clinical trials:Aerobic Gram-positive bacteria
Streptococcus agalactiae
Streptococcus (Groups C, F, G)
Viridans group streptococciAerobic Gram-negative bacteria
Bordetella pertussis
Legionella pneumophila
Pasteurella multocidaAnaerobic Gram-positive bacteria
Clostridium perfringens
Peptococcus Niger
Cutibacterium acnesAnaerobic Gram-negative bacteria
Prevotella melaninogenica (formerly Bacteroides melaninogenicus)
Contraindications
Clarithromycin should not be taken by people who are allergic to other macrolides or inactive ingredients in the tablets, including microcrystalline cellulose, croscarmelose sodium, magnesium stearate, and povidone
Clarithromycin should not be used by people with a history of cholestatic jaundice and/or liver dysfunction associated with prior clarithromycin use.
Clarithromycin should not be used in the setting of hypokalaemia (low blood potassium)
Use of clarithromycin with the following medications: cisapride, pimozide, astemizole, terfenadine, ergotamine, ticagrelor, ranolazine or dihydroergotamine is not recommended.
It should not be used with colchicine in people with kidney or liver impairment.
Concomitant use with cholesterol medications such as lovastatin or simvastatin.
Hypersensitivity to clarithromycin or any component of the product, erythromycin, or any macrolide antibiotics.
QT prolongation or ventricular cardiac arrhythmias, including torsade de pointes.
Side effects
The most common side effects are gastrointestinal: diarrhea (3%), nausea (3%), abdominal pain (3%), and vomiting (6%). It also can cause headaches, insomnia, and abnormal liver function tests. Allergic reactions include rashes and anaphylaxis. Less common side effects (<1%) include extreme irritability, hallucinations (auditory and visual), dizziness/motion sickness, and alteration in senses of smell and taste, including a metallic taste. Dry mouth, panic attacks, and nightmares have also been reported, albeit less frequently.
Cardiac
In February 2018, the FDA issued a Safety Communication warning with respect to an increased risk for heart problems or death with the use of clarithromycin, and has recommended that alternative antibiotics be considered in those with heart disease.Clarithromycin can lead to a prolonged QT interval. In patients with long QT syndrome, cardiac disease, or patients taking other QT-prolonging medications, this can increase risk for life-threatening arrhythmias.In one trial, the use of short-term clarithromycin treatment was correlated with an increased incidence of deaths classified as sudden cardiac deaths in stable coronary heart disease patients not using statins. Some case reports suspect it of causing liver disease.
Liver and kidney
Clarithromycin has been known to cause jaundice, cirrhosis, and kidney problems, including kidney failure.
Central nervous system
Common adverse effects of clarithromycin in the central nervous system include dizziness, headaches. Rarely, it can cause ototoxicity, delirium and mania.
Infection
A risk of oral candidiasis and vaginal candidiasis, due to the elimination of the yeasts natural bacterial competitors by the antibiotic, has also been noted.
Pregnancy and breastfeeding
Clarithromycin should not be used in pregnant women except in situations where no alternative therapy is appropriate. Clarithromycin can cause potential hazard to the fetus hence should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. For lactating mothers it is not known whether clarithromycin is excreted in human milk.
Interactions
Clarithromycin inhibits a liver enzyme, CYP3A4, involved in the metabolism of many other commonly prescribed drugs. Taking clarithromycin with other medications that are metabolized by CYP3A4 may lead to unexpected increases or decreases in drug levels.
A few of the common interactions are listed below.
Colchicine
Clarithromycin has been observed to have a dangerous interaction with colchicine as the result of inhibition of CYP3A4 metabolism and P-glycoprotein transport. Combining these two drugs may lead to fatal colchicine toxicity, particularly in people with chronic kidney disease.
Statins
Taking clarithromycin concurrently with certain statins (a class of drugs used to reduce blood serum cholesterol levels) increases the risk of side effects, such as muscle aches and muscle break down (rhabdomyolysis).
Calcium channel blockers
Concurrent therapy with calcium channel blocker may increase risk of low blood pressure, kidney failure, and death, compared to pairing calcium channel blockers with azithromycin, a drug similar to clarithromycin but without CYP3A4 inhibition. Administration of clarithromycin in combination with verapamil have been observed to cause low blood pressure, low heart rate, and lactic acidosis.
Carbamazepine
Clarithromycin may double the level of carbamazepine in the body by reducing its clearance, which may lead to toxic symptoms of carbamazepine, such as double vision, loss of voluntary body movement, and nausea, as well as hyponatremia.
HIV medications
Depending on the combination of medications, clarithromycin therapy could be contraindicated, require changing doses of some medications, or be acceptable without dose adjustments. For example, clarithromycin may lead to decreased zidovudine concentrations.
Mechanism of action
Clarithromycin prevents bacteria from multiplying by acting as a protein synthesis inhibitor. It binds to 23S rRNA, a component of the 50S subunit of the bacterial ribosome, thus inhibiting the translation of peptides.
Pharmacokinetics
Unlike erythromycin, clarithromycin is acid-stable, so can be taken orally without having to be protected from gastric acids. It is readily absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, clarithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of clarithromycin are released; its concentration in the tissues can be over 10 times higher than in plasma. Highest concentrations are found in liver, lung tissue, and stool.
Metabolism
Clarithromycin has a fairly rapid first-pass metabolism in the liver. Its major metabolites include an inactive metabolite, N-desmethylclarithromycin, and an active metabolite, 14-(R)-hydroxyclarithromycin. Compared to clarithromycin, 14-(R)-hydroxyclarithromycin is less potent against mycobacterial tuberculosis and the Mycobacterium avium complex. Clarithromycin (20%-40%) and its active metabolite (10%-15%) are excreted in urine. Of all the drugs in its class, clarithromycin has the best bioavailability at 50%, which makes it amenable to oral administration.
Its elimination half-life is about 3 to 4 hours with 250 mg administered every 12 h, but increased to 5 to 7 h with 500 mg administered every 8 to 12 h. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.
History
Clarithromycin was invented by researchers at the Japanese drug company Taisho Pharmaceutical in 1980. The product emerged through efforts to develop a version of the antibiotic erythromycin that did not experience acid instability in the digestive tract, causing side effects, such as nausea and stomachache. Taisho filed for patent protection for the drug around 1980 and subsequently introduced a branded version of its drug, called Clarith, to the Japanese market in 1991. In 1985, Taisho partnered with the American company Abbott Laboratories for the international rights, and Abbott also gained FDA approval for Biaxin in October 1991. The drug went generic in Europe in 2004 and in the US in mid-2005.
Society and culture
Available forms
Clarithromycin is available as a generic medication. In the United States, clarithromycin is available as immediate-release tablets, extended-release tablets, and granules for oral suspension.
Brand names
Clarithromycin is available under several brand names in many different countries, including Biaxin, Crixan, Claritron, Clarihexal, Clacid, Claritt, Clacee, Clarac, Clariwin, Claripen, Clarem, Claridar, Cloff, Fromilid, Infex, Kalixocin, Karicin, Klaricid, Klaridex, Klacid, Klaram, Klabax, Klerimed, MegaKlar, Monoclar, Resclar, Rithmo, Truclar, Vikrol and Zeclar.
Manufacturers
In the UK the drug product is manufactured in generic form by a number of manufacturers including Somex Pharma, Ranbaxy, Aptil and Sandoz.
References
External links
"Clarithromycin". Drug Information Portal. U.S. National Library of Medicine.
US patent 4331803, Watanabe Y, Morimoto S, Omura S, "Novel erythromycin compounds", issued 1981-05-19, assigned to Taisho Pharmaceutical
"FDA review finds additional data supports the potential for increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease" (PDF). FDA Drug Safety Communication. |
Dextran | Dextran is a complex branched glucan (polysaccharide derived from the condensation of glucose), originally derived from wine. IUPAC defines dextrans as "Branched poly-α-d-glucosides of microbial origin having glycosidic bonds predominantly C-1 → C-6". Dextran chains are of varying lengths (from 3 to 2000 kilodaltons).
The polymer main chain consists of α-1,6 glycosidic linkages between glucose monomers, with branches from α-1,3 linkages. This characteristic branching distinguishes a dextran from a dextrin, which is a straight chain glucose polymer tethered by α-1,4 or α-1,6 linkages.
Occurrence
Dextran was discovered by Louis Pasteur as a microbial product in wine, but mass production was only possible after the development by Allene Jeanes of a process using bacteria. Dental plaque is rich in dextrans. Dextran is a complicating contaminant in the refining of sugar because it elevates the viscosity of sucrose solutions and fouls plumbing.Dextran is now produced from sucrose by certain lactic acid bacteria of the family lactobacillus. Species include Leuconostoc mesenteroides and Streptococcus mutans. The structure of dextran produced depends not only on the family and species of the bacterium but on the strain. They are separated by fractional precipitation from protein-free extracts using ethanol. Some bacteria coproduce fructans, which can complicate isolation of the dextrans.
Uses
Dextran 70 is on the WHO Model List of Essential Medicines, the most important medications needed in a health system.Medicinally it is used as an antithrombotic (antiplatelet), to reduce blood viscosity, and as a volume expander in hypovolaemia.
Microsurgery
These agents are used commonly by microsurgeons to decrease vascular thrombosis. The antithrombotic effect of dextran is mediated through its binding of erythrocytes, platelets, and vascular endothelium, increasing their electronegativity and thus reducing erythrocyte aggregation and platelet adhesiveness. Dextrans also reduce factor VIII-Ag Von Willebrand factor, thereby decreasing platelet function. Clots formed after administration of dextrans are more easily lysed due to an altered thrombus structure (more evenly distributed platelets with coarser fibrin). By inhibiting α-2 antiplasmin, dextran serves as a plasminogen activator, so possesses thrombolytic features.
Outside of these features, larger dextrans, which do not pass out of the vessels, are potent osmotic agents, thus have been used urgently to treat hypovolemia. The hemodilution caused by volume expansion with dextran use improves blood flow, thus further improving patency of microanastomoses and reducing thrombosis. Still, no difference has been detected in antithrombotic effectiveness in comparison of intra-arterial and intravenous administration of dextran.
Dextrans are available in multiple molecular weights ranging from 3 kDa to 2 MDa. The larger dextrans (>60,000 Da) are excreted poorly from the kidney, so remain in the blood for as long as weeks until they are metabolized. Consequently, they have prolonged antithrombotic and colloidal effects. In this family, dextran-40 (MW: 40,000 Da), has been the most popular member for anticoagulation therapy. Close to 70% of dextran-40 is excreted in urine within the first 24 hours after intravenous infusion, while the remaining 30% are retained for several more days.
Other medical uses
Dextran is used in some eye drops as a lubricant. and in certain intravenous fluids to solubilize other factors, such as iron (in a solution known as Iron Dextran).
Intravenous solutions with dextran function both as volume expanders and means of parenteral nutrition. Such a solution provides an osmotically neutral fluid that once in the body is digested by cells into glucose and free water. It is occasionally used to replace lost blood in emergency situations, when replacement blood is not available, but must be used with caution as it does not provide necessary electrolytes and can cause hyponatremia or other electrolyte disturbances.
Dextran also increases blood sugar levels.
Dextran can be used in an ATPS for PEGylation
Laboratory uses
Dextran is used in the osmotic stress technique for applying osmotic pressure to biological molecules.
It is also used in some size-exclusion chromatography matrices; an example is Sephadex.
Dextran has also been used in bead form to aid in bioreactor applications.
Dextran has been used as an immobilization agent in biosensors.
Dextran preferentially binds to early endosomes; fluorescent-labelled dextran can be used to visualize these endosomes under a microscope.
Dextran can be used as a stabilizing coating to protect metal nanoparticles from oxidation and improve biocompatibility.
Dextran coupled with a fluorescent molecule such as fluorescein isothiocyanate can be used to create concentration gradients of diffusible molecules for imaging and allow subsequent characterization of gradient slope.
Solutions of fluorescently-labelled dextran can be perfused through engineered vessels to analyze vascular permeability
Dextran is used to make microcarriers for industrial cell culture
Orally-administered dextran sodium sulphate is used to induce colitis in animal models of inflammatory bowel disease.
Side effects
Although relatively few side effects are associated with dextran use, these side effects can be very serious. These include anaphylaxis, volume overload, pulmonary edema, cerebral edema, or platelet dysfunction.
An uncommon but significant complication of dextran osmotic effect is acute kidney injury. The pathogenesis of this kidney failure is the subject of many debates with direct toxic effect on tubules and glomerulus versus intraluminal hyperviscosity being some of the proposed mechanisms. Patients with history of diabetes mellitus, chronic kidney disease, or vascular disorders are most at risk. Brooks and others recommend the avoidance of dextran therapy in patients with chronic kidney disease.
Research
Efforts have been made to develop modified dextran polymers. One of these has acetal modified hydroxyl groups. It is insoluble in water, but soluble in organic solvents. This allows it to be processed in the same manner as many polyesters, like poly(lactic-co-glycolic acid), through processes like solvent evaporation and emulsion. Acetalated dextran is structurally different from acetylated dextran. As of 2017 several uses for drug delivery had been explored in vitro and a few had been tested in animal models.
See also
Pentoxifylline
References
External links
Resource on dextran properties and structure of dextran polymers
Dextrans at the US National Library of Medicine Medical Subject Headings (MeSH) |
Tropical cyclone | A tropical cyclone is a rapidly rotating storm system characterized by a low-pressure center, a closed low-level atmospheric circulation, strong winds, and a spiral arrangement of thunderstorms that produce heavy rain and squalls. Depending on its location and strength, a tropical cyclone is referred to by different names, including hurricane (), typhoon (), tropical storm, cyclonic storm, tropical depression, or simply cyclone. A hurricane is a strong tropical cyclone that occurs in the Atlantic Ocean or northeastern Pacific Ocean, and a typhoon occurs in the northwestern Pacific Ocean. In the Indian Ocean, south Pacific, or (rarely) South Atlantic, comparable storms are referred to simply as "tropical cyclones", and such storms in the Indian Ocean can also be called "severe cyclonic storms".
"Tropical" refers to the geographical origin of these systems, which form almost exclusively over tropical seas. "Cyclone" refers to their winds moving in a circle, whirling round their central clear eye, with their surface winds blowing counterclockwise in the Northern Hemisphere and clockwise in the Southern Hemisphere. The opposite direction of circulation is due to the Coriolis effect. Tropical cyclones typically form over large bodies of relatively warm water. They derive their energy through the evaporation of water from the ocean surface, which ultimately condenses into clouds and rain when moist air rises and cools to saturation. This energy source differs from that of mid-latitude cyclonic storms, such as noreasters and European windstorms, which are powered primarily by horizontal temperature contrasts. Tropical cyclones are typically between 100 and 2,000 km (62 and 1,243 mi) in diameter. Every year tropical cyclones impact various regions of the globe including the Gulf Coast of North America, Australia, India, and Bangladesh.
The strong rotating winds of a tropical cyclone are a result of the conservation of angular momentum imparted by the Earths rotation as air flows inwards toward the axis of rotation. As a result, they rarely form within 5° of the equator. Tropical cyclones are very rare in the South Atlantic (although occasional examples do occur) due to consistently strong wind shear and a weak Intertropical Convergence Zone. Conversely, the African easterly jet and areas of atmospheric instability give rise to cyclones in the Atlantic Ocean and Caribbean Sea, while cyclones near Australia owe their genesis to the Asian monsoon and Western Pacific Warm Pool.
The primary energy source for these storms is warm ocean waters. These storms are therefore typically strongest when over or near water, and they weaken quite rapidly over land. This causes coastal regions to be particularly vulnerable to tropical cyclones, compared to inland regions. Coastal damage may be caused by strong winds and rain, high waves (due to winds), storm surges (due to wind and severe pressure changes), and the potential of spawning tornadoes. Tropical cyclones draw in air from a large area and concentrate the water content of that air (from atmospheric moisture and moisture evaporated from water) into precipitation over a much smaller area. This replenishing of moisture-bearing air after rain may cause multi-hour or multi-day extremely heavy rain up to 40 km (25 mi) from the coastline, far beyond the amount of water that the local atmosphere holds at any one time. This in turn can lead to river flooding, overland flooding, and a general overwhelming of local water control structures across a large area. Although their effects on human populations can be devastating, tropical cyclones may play a role in relieving drought conditions, though this claim is disputed. They also carry heat and energy away from the tropics and transport it towards temperate latitudes, which plays an important role in regulating global climate.
Background
A tropical cyclone is the generic term for a warm-cored, non-frontal synoptic-scale low-pressure system over tropical or subtropical waters around the world. The systems generally have a well-defined center which is surrounded by deep atmospheric convection and a closed wind circulation at the surface.Historically, tropical cyclones have occurred around the world for thousands of years, with one of the earliest tropical cyclones on record estimated to have occurred in Western Australia in around 4000 BC. However, before satellite imagery became available during the 20th century, many of these systems went undetected unless it impacted land or a ship encountered it by chance.These days, on average around 80 to 90 named tropical cyclones form each year around the world, over half of which develop hurricane-force winds of 65 kn (120 km/h; 75 mph) or more. Around the world, a tropical cyclone is generally deemed to have formed once mean surface winds in excess of 35 kn (65 km/h; 40 mph) are observed. It is assumed at this stage that a tropical cyclone has become self-sustaining and can continue to intensify without any help from its environment.A study review article published in 2021 in Nature Geoscience concluded that the geographic range of tropical cyclones will probably expand poleward in response to climate warming of the Hadley circulation.
Intensity
Tropical cyclone intensity is based on wind speeds and pressure; relationships between winds and pressure are often utilized in determining the intensity of a storm. Tropical cyclone scales such as the Saffir-Simpson Hurricane Wind Scale and Australias scale (Bureau of Meteorology) only use wind speed for determining the category of a storm. The most intense storm on record is Typhoon Tip in the northwestern Pacific Ocean in 1979, which reached a minimum pressure of 870 hPa (26 inHg) and maximum sustained wind speeds of 165 kn (85 m/s; 306 km/h; 190 mph). The highest maximum sustained wind speed ever recorded was 185 kn (95 m/s; 343 km/h; 213 mph) in Hurricane Patricia in 2015—the most intense cyclone ever recorded in the Western Hemisphere.
Factors that influence intensity
Warm sea surface temperatures are required in order for tropical cyclones to form and strengthen. The commonly-accepted minimum temperature range for this to occur is 26–27 °C (79–81 °F), however, multiple studies have proposed a lower minimum of 25.5 °C (77.9 °F). Higher sea surface temperatures result in faster intensification rates and sometimes even rapid intensification. High ocean heat content, also known as Tropical Cyclone Heat Potential, allows storms to achieve a higher intensity. Most tropical cyclones that experience rapid intensification are traversing regions of high ocean heat content rather than lower values. High ocean heat content values can help to offset the oceanic cooling caused by the passage of a tropical cyclone, limiting the effect this cooling has on the storm. Faster-moving systems are able to intensify to higher intensities with lower ocean heat content values. Slower-moving systems require higher values of ocean heat content to achieve the same intensity.The passage of a tropical cyclone over the ocean causes the upper layers of the ocean to cool substantially, a process known as upwelling, which can negatively influence subsequent cyclone development. This cooling is primarily caused by wind-driven mixing of cold water from deeper in the ocean with the warm surface waters. This effect results in a negative feedback process that can inhibit further development or lead to weakening. Additional cooling may come in the form of cold water from falling raindrops (this is because the atmosphere is cooler at higher altitudes). Cloud cover may also play a role in cooling the ocean, by shielding the ocean surface from direct sunlight before and slightly after the storm passage. All these effects can combine to produce a dramatic drop in sea surface temperature over a large area in just a few days. Conversely, the mixing of the sea can result in heat being inserted in deeper waters, with potential effects on global climate.Vertical wind shear negatively impacts tropical cyclone intensification by displacing moisture and heat from a systems center. Low levels of vertical wind shear are most optimal for strengthening, while stronger wind shear induces weakening. Dry air entraining into a tropical cyclones core has a negative effect on its development and intensity by diminishing atmospheric convection and introducing asymmetries in the storms structure. Symmetric, strong outflow leads to a faster rate of intensification than observed in other systems by mitigating local wind shear. Weakening outflow is associated with the weakening of rainbands within a tropical cyclone.The size of tropical cyclones plays a role in how quickly they intensify. Smaller tropical cyclones are more prone to rapid intensification than larger ones. The Fujiwhara effect, which involves interaction between two tropical cyclones, can weaken and ultimately result in the dissipation of the weaker of two tropical cyclones by reducing the organization of the systems convection and imparting horizontal wind shear. Tropical cyclones typically weaken while situated over a landmass because conditions are often unfavorable as a result of the lack of oceanic forcing. The Brown ocean effect can allow a tropical cyclone to maintain or increase its intensity following landfall, in cases where there has been copious rainfall, through the release of latent heat from the saturated soil. Orographic lift can cause an significant increase in the intensity of the convection of a tropical cyclone when its eye moves over a mountain, breaking the capped boundary layer that had been restraining it. Jet streams can both enhance and inhibit tropical cyclone intensity by influencing the storms outflow as well as vertical wind shear.
Formation
Tropical cyclones tend to develop during the summer, but have been noted in nearly every month in most tropical cyclone basins. Tropical cyclones on either side of the Equator generally have their origins in the Intertropical Convergence Zone, where winds blow from either the northeast or southeast. Within this broad area of low-pressure, air is heated over the warm tropical ocean and rises in discrete parcels, which causes thundery showers to form. These showers dissipate quite quickly; however, they can group together into large clusters of thunderstorms. This creates a flow of warm, moist, rapidly rising air, which starts to rotate cyclonically as it interacts with the rotation of the earth.Several factors are required for these thunderstorms to develop further, including sea surface temperatures of around 27 °C (81 °F) and low vertical wind shear surrounding the system, atmospheric instability, high humidity in the lower to middle levels of the troposphere, enough Coriolis force to develop a low-pressure center, a pre-existing low-level focus or disturbance,
There is a limit on tropical cyclone intensity which is strongly related to the water temperatures along its path. and upper-level divergence.
An average of 86 tropical cyclones of tropical storm intensity form annually worldwide. Of those, 47 reach strength higher than 119 km/h (74 mph), and 20 become intense tropical cyclones (at least Category 3 intensity on the Saffir–Simpson scale).Climate cycles such as ENSO and the Madden–Julian oscillation modulate the timing and frequency of tropical cyclone development. Rossby waves can aid in the formation of a new tropical cyclone by disseminating the energy of an existing, mature storm. Kelvin waves can contribute to tropical cyclone formation by regulating the development of the westerlies. Cyclone formation is usually reduced 3 days prior to the waves crest and increased during the 3 days after.
Rapid intensification
On occasion, tropical cyclones may undergo a process known as rapid intensification, a period in which the maximum sustained winds of a tropical cyclone increase by 30 kn (56 km/h; 35 mph) or more within 24 hours. Similarly, rapid deepening in tropical cyclones is defined as a minimum sea surface pressure decrease of 1.75 hPa (0.052 inHg) per hour or 42 hPa (1.2 inHg) within a 24-hour period; explosive deepening occurs when the surface pressure decreases by 2.5 hPa (0.074 inHg) per hour for at least 12 hours or 5 hPa (0.15 inHg) per hour for at least 6 hours. For rapid intensification to occur, several conditions must be in place. Water temperatures must be extremely high (near or above 30 °C (86 °F)), and water of this temperature must be sufficiently deep such that waves do not upwell cooler waters to the surface. On the other hand, Tropical Cyclone Heat Potential is one of such non-conventional subsurface oceanographic parameters influencing the cyclone intensity. Wind shear must be low; when wind shear is high, the convection and circulation in the cyclone will be disrupted. Usually, an anticyclone in the upper layers of the troposphere above the storm must be present as well—for extremely low surface pressures to develop, air must be rising very rapidly in the eyewall of the storm, and an upper-level anticyclone helps channel this air away from the cyclone efficiently. However, some cyclones such as Hurricane Epsilon have rapidly intensified despite relatively unfavorable conditions.
Dissipation
There are a number of ways a tropical cyclone can weaken, dissipate, or lose its tropical characteristics. These include making landfall, moving over cooler water, encountering dry air, or interacting with other weather systems; however, once a system has dissipated or lost its tropical characteristics, its remnants could regenerate a tropical cyclone if environmental conditions become favorable.A tropical cyclone can dissipate when it moves over waters significantly cooler than 26.5 °C (79.7 °F). This will deprive the storm of such tropical characteristics as a warm core with thunderstorms near the center, so that it becomes a remnant low-pressure area. Remnant systems may persist for several days before losing their identity. This dissipation mechanism is most common in the eastern North Pacific. Weakening or dissipation can also occur if a storm experiences vertical wind shear which causes the convection and heat engine to move away from the center; this normally ceases the development of a tropical cyclone. In addition, its interaction with the main belt of the Westerlies, by means of merging with a nearby frontal zone, can cause tropical cyclones to evolve into extratropical cyclones. This transition can take 1–3 days.Should a tropical cyclone make landfall or pass over an island, its circulation could start to break down, especially if it encounters mountainous terrain. When a system makes landfall on a large landmass, it is cut off from its supply of warm moist maritime air and starts to draw in dry continental air. This, combined with the increased friction over land areas, leads to the weakening and dissipation of the tropical cyclone. Over a mountainous terrain, a system can quickly weaken; however, over flat areas, it may endure for two to three days before circulation breaks down and dissipates.Over the years, there have been a number of techniques considered to try to artificially modify tropical cyclones. These techniques have included using nuclear weapons, cooling the ocean with icebergs, blowing the storm away from land with giant fans, and seeding selected storms with dry ice or silver iodide. These techniques, however, fail to appreciate the duration, intensity, power or size of tropical cyclones.
Methods for assessing intensity
A variety of methods or techniques, including surface, satellite, and aerial, are utilized to assess the intensity of a tropical cyclone. Reconnaissance aircraft fly around and through tropical cyclones, outfitted with specialized instruments, to collect information that can be used to ascertain the winds and pressure of a system. Tropical cyclones possess winds of different speeds at different heights. Winds recorded at flight level can be converted to find the wind speeds at the surface. Surface observations, such as ship reports, land stations, mesonets, coastal stations, and buoys, can provide information on a tropical cyclones intensity or the direction it is traveling. Wind-pressure relationships (WPRs) are used as a way to determine the pressure of a storm based on its wind speed. Several different methods and equations have been proposed to calculate WPRs. Tropical cyclones agencies each use their own, fixed WPR, which can result in inaccuracies between agencies that are issuing estimates on the same system. The ASCAT is a scatterometer used by the MetOp satellites to map the wind field vectors of tropical cyclones. The SMAP uses an L-band radiometer channel to determine the wind speeds of tropical cyclones at the ocean surface, and has been shown to be reliable at higher intensities and under heavy rainfall conditions, unlike scatterometer-based and other radiometer-based instruments.The Dvorak technique plays a large role in both the classification of a tropical cyclone and the determination of its intensity. Used in warning centers, the method was developed by Vernon Dvorak in the 1970s, and uses both visible and infrared satellite imagery in the assessment of tropical cyclone intensity. The Dvorak technique utilizes a scale of "T-numbers", scaling in increments of ½ from T1.0 to T8.0. Each T-number has an intensity assigned to it, with larger T-numbers indicating a stronger system. Tropical cyclones are assessed by forecasters according to an array of patterns, including curved banding features, shear, central dense overcast, and eye, in order to determine the T-number and thus assess the intensity of the storm. The Cooperative Institute for Meteorological Satellite Studies works to develop and improve automated satellite methods, such as the Advanced Dvorak Technique (ADT) and SATCON. The ADT, used by a large number of forecasting centers, utilizes infrared geostationary satellite imagery and an algorithm based upon the Dvorak technique to assess the intensity of tropical cyclones. The ADT has a number of differences from the conventional Dvorak technique, including changes to intensity constraint rules and the usage of microwave imagery to base a systems intensity upon its internal structure, which prevents the intensity from leveling off before an eye emerges in infrared imagery. The SATCON weights estimates from various satellite-based systems and microwave sounders, accounting for the strengths and flaws in each individual estimate, to produce a consensus estimate of a tropical cyclones intensity which can be more reliable than the Dvorak technique at times.
Intensity metrics
Multiple intensity metrics are utilized, including accumulated cyclone energy (ACE), the Hurricane Surge Index, the Hurricane Severity Index, the Power Dissipation Index (PDI), and integrated kinetic energy (IKE). ACE is a metric of the total energy a system has exerted over its lifespan. ACE is calculated by summing the squares of a cyclones sustained wind speed, every six hours as long as the system is at or above tropical storm intensity and either tropical or subtropical. The calculation of the PDI is similar in nature to ACE, with the major difference being that wind speeds are cubed rather than squared. The Hurricane Surge Index is a metric of the potential damage a storm may inflict via storm surge. It is calculated by squaring the dividend of the storms wind speed and a climatological value (33 metres per second (74 mph)), and then multiplying that quantity by the dividend of the radius of hurricane-force winds and its climatological value (96.6 kilometres (60.0 mi)). This can be represented in equation form as:
(
v
33
m
/
s
)
2
×
(
r
96.6
k
m
)
{\displaystyle \left({\frac {v}{33m/s}}\right)^{2}\times \left({\frac {r}{96.6km}}\right)\,}
where v is the storms wind speed and r is the radius of hurricane-force winds. The Hurricane Severity Index is a scale that can assign up to 50 points to a system; up to 25 points come from intensity, while the other 25 come from the size of the storms wind field. The IKE model measures the destructive capability of a tropical cyclone via winds, waves, and surge. It is calculated as:
∫
V
o
l
1
2
p
u
2
d
v
{\displaystyle \int _{Vol}{\frac {1}{2}}pu^{2}d_{v}\,}
where p is the density of air, u is a sustained surface wind speed value, and dv is the volume element.
Classification and naming
Intensity classifications
Around the world, tropical cyclones are classified in different ways, based on the location (tropical cyclone basins), the structure of the system and its intensity. For example, within the Northern Atlantic and Eastern Pacific basins, a tropical cyclone with wind speeds of over 65 kn (120 km/h; 75 mph) is called a hurricane, while it is called a typhoon or a severe cyclonic storm within the Western Pacific or North Indian Oceans. Within the Southern Hemisphere, it is either called a hurricane, tropical cyclone or a severe tropical cyclone, depending on if it is located within the South Atlantic, South-West Indian Ocean, Australian region or the South Pacific Ocean.
Naming
The practice of using names to identify tropical cyclones goes back many years, with systems named after places or things they hit before the formal start of naming. The system currently used provides positive identification of severe weather systems in a brief form, that is readily understood and recognized by the public. The credit for the first usage of personal names for weather systems is generally given to the Queensland Government Meteorologist Clement Wragge who named systems between 1887 and 1907. This system of naming weather systems subsequently fell into disuse for several years after Wragge retired, until it was revived in the latter part of World War II for the Western Pacific. Formal naming schemes have subsequently been introduced for the North and South Atlantic, Eastern, Central, Western and Southern Pacific basins as well as the Australian region and Indian Ocean.At present, tropical cyclones are officially named by one of twelve meteorological services and retain their names throughout their lifetimes to provide ease of communication between forecasters and the general public regarding forecasts, watches, and warnings. Since the systems can last a week or longer and more than one can be occurring in the same basin at the same time, the names are thought to reduce the confusion about what storm is being described. Names are assigned in order from predetermined lists with one, three, or ten-minute sustained wind speeds of more than 65 km/h (40 mph) depending on which basin it originates. However, standards vary from basin to basin with some tropical depressions named in the Western Pacific, while tropical cyclones have to have a significant amount of gale-force winds occurring around the center before they are named within the Southern Hemisphere. The names of significant tropical cyclones in the North Atlantic Ocean, Pacific Ocean, and Australian region are retired from the naming lists and replaced with another name. Tropical cyclones that develop around the world are assigned an identification code consisting of a two-digit number and suffix letter by the warning centers that monitor them.
Structure
Eye and center
At the center of a mature tropical cyclone, air sinks rather than rises. For a sufficiently strong storm, air may sink over a layer deep enough to suppress cloud formation, thereby creating a clear "eye". Weather in the eye is normally calm and free of convective clouds, although the sea may be extremely violent. The eye is normally circular and is typically 30–65 km (19–40 mi) in diameter, though eyes as small as 3 km (1.9 mi) and as large as 370 km (230 mi) have been observed.The cloudy outer edge of the eye is called the "eyewall". The eyewall typically expands outward with height, resembling an arena football stadium; this phenomenon is sometimes referred to as the "stadium effect". The eyewall is where the greatest wind speeds are found, air rises most rapidly, clouds reach their highest altitude, and precipitation is the heaviest. The heaviest wind damage occurs where a tropical cyclones eyewall passes over land.In a weaker storm, the eye may be obscured by the central dense overcast, which is the upper-level cirrus shield that is associated with a concentrated area of strong thunderstorm activity near the center of a tropical cyclone.The eyewall may vary over time in the form of eyewall replacement cycles, particularly in intense tropical cyclones. Outer rainbands can organize into an outer ring of thunderstorms that slowly moves inward, which is believed to rob the primary eyewall of moisture and angular momentum. When the primary eyewall weakens, the tropical cyclone weakens temporarily. The outer eyewall eventually replaces the primary one at the end of the cycle, at which time the storm may return to its original intensity.
Size
There are a variety of metrics commonly used to measure storm size. The most common metrics include the radius of maximum wind, the radius of 34-knot (17 m/s; 63 km/h; 39 mph) wind (i.e. gale force), the radius of outermost closed isobar (ROCI), and the radius of vanishing wind. An additional metric is the radius at which the cyclones relative vorticity field decreases to 1×10−5 s−1.
On Earth, tropical cyclones span a large range of sizes, from 100–2,000 km (62–1,243 mi) as measured by the radius of vanishing wind. They are largest on average in the northwest Pacific Ocean basin and smallest in the northeastern Pacific Ocean basin. If the radius of outermost closed isobar is less than two degrees of latitude (222 km (138 mi)), then the cyclone is "very small" or a "midget". A radius of 3–6 latitude degrees (333–670 km (207–416 mi)) is considered "average sized". "Very large" tropical cyclones have a radius of greater than 8 degrees (888 km (552 mi)). Observations indicate that size is only weakly correlated to variables such as storm intensity (i.e. maximum wind speed), radius of maximum wind, latitude, and maximum potential intensity. Typhoon Tip is the largest cyclone on record, with tropical storm-force winds 2,170 km (1,350 mi) in diameter. The smallest storm on record is Tropical Storm Marco (2008), which generated tropical storm-force winds only 37 km (23 mi) in diameter.
Movement
The movement of a tropical cyclone (i.e. its "track") is typically approximated as the sum of two terms: "steering" by the background environmental wind and "beta drift". Some tropical cyclones can move across large distances, such as Hurricane John, the longest-lasting tropical cyclone on record, which traveled 13,280 km (8,250 mi), the longest track of any Northern Hemisphere tropical cyclone, over its 31-day lifespan in 1994.
Environmental steering
Environmental steering is the primary influence on the motion of tropical cyclones. It represents the movement of the storm due to prevailing winds and other wider environmental conditions, similar to "leaves carried along by a stream".Physically, the winds, or flow field, in the vicinity of a tropical cyclone may be treated as having two parts: the flow associated with the storm itself, and the large-scale background flow of the environment. Tropical cyclones can be treated as local maxima of vorticity suspended within the large-scale background flow of the environment. In this way, tropical cyclone motion may be represented to first-order as advection of the storm by the local environmental flow. This environmental flow is termed the "steering flow" and is the dominant influence on tropical cyclone motion. The strength and direction of the steering flow can be approximated as a vertical integration of the winds blowing horizontally in the cyclones vicinity, weighted by the altitude at which those winds are occurring. Because winds can vary with height, determining the steering flow precisely can be difficult.
The pressure altitude at which the background winds are most correlated with a tropical cyclones motion is known as the "steering level". The motion of stronger tropical cyclones is more correlated with the background flow averaged across a thicker portion of troposphere compared to weaker tropical cyclones whose motion is more correlated with the background flow averaged across a narrower extent of the lower troposphere. When wind shear and latent heat release is present, tropical cyclones tend to move towards regions where potential vorticity is increasing most quickly.Climatologically, tropical cyclones are steered primarily westward by the east-to-west trade winds on the equatorial side of the subtropical ridge—a persistent high-pressure area over the worlds subtropical oceans. In the tropical North Atlantic and Northeast Pacific oceans, the trade winds steer tropical easterly waves westward from the African coast toward the Caribbean Sea, North America, and |
Tropical cyclone | ultimately into the central Pacific Ocean before the waves dampen out. These waves are the precursors to many tropical cyclones within this region. In contrast, in the Indian Ocean and Western Pacific in both hemispheres, tropical cyclogenesis is influenced less by tropical easterly waves and more by the seasonal movement of the Intertropical Convergence Zone and the monsoon trough. Other weather systems such as mid-latitude troughs and broad monsoon gyres can also influence tropical cyclone motion by modifying the steering flow.
Beta drift
In addition to environmental steering, a tropical cyclone will tend to drift poleward and westward, a motion known as "beta drift". This motion is due to the superposition of a vortex, such as a tropical cyclone, onto an environment in which the Coriolis force varies with latitude, such as on a sphere or beta plane. The magnitude of the component of tropical cyclone motion associated with the beta drift ranges between 1–3 m/s (3.6–10.8 km/h; 2.2–6.7 mph) and tends to be larger for more intense tropical cyclones and at higher latitudes. It is induced indirectly by the storm itself as a result of feedback between the cyclonic flow of the storm and its environment.Physically, the cyclonic circulation of the storm advects environmental air poleward east of center and equatorial west of center. Because air must conserve its angular momentum, this flow configuration induces a cyclonic gyre equatorward and westward of the storm center and an anticyclonic gyre poleward and eastward of the storm center. The combined flow of these gyres acts to advect the storm slowly poleward and westward. This effect occurs even if there is zero environmental flow. Due to a direct dependence of the beta drift on angular momentum, the size of a tropical cyclone can impact the influence of beta drift on its motion; beta drift imparts a greater influence on the movement of larger tropical cyclones than that of smaller ones.
Multiple storm interaction
A third component of motion that occurs relatively infrequently involves the interaction of multiple tropical cyclones. When two cyclones approach one another, their centers will begin orbiting cyclonically about a point between the two systems. Depending on their separation distance and strength, the two vortices may simply orbit around one another, or else may spiral into the center point and merge. When the two vortices are of unequal size, the larger vortex will tend to dominate the interaction, and the smaller vortex will orbit around it. This phenomenon is called the Fujiwhara effect, after Sakuhei Fujiwhara.
Interaction with the mid-latitude westerlies
Though a tropical cyclone typically moves from east to west in the tropics, its track may shift poleward and eastward either as it moves west of the subtropical ridge axis or else if it interacts with the mid-latitude flow, such as the jet stream or an extratropical cyclone. This motion, termed "recurvature", commonly occurs near the western edge of the major ocean basins, where the jet stream typically has a poleward component and extratropical cyclones are common. An example of tropical cyclone recurvature was Typhoon Ioke in 2006.
Formation regions and warning centers
The majority of tropical cyclones each year form in one of seven tropical cyclone basins, which are monitored by a variety of meteorological services and warning centres. Ten of these warning centres worldwide are designated as either a Regional Specialized Meteorological Centre or a Tropical Cyclone Warning Centre by the World Meteorological Organisations (WMO) tropical cyclone programme. These warning centres issue advisories which provide basic information and cover a systems present, forecast position, movement and intensity, in their designated areas of responsibility. Meteorological services around the world are generally responsible for issuing warnings for their own country, however, there are exceptions, as the United States National Hurricane Center and Fiji Meteorological Service issue alerts, watches and warnings for various island nations in their areas of responsibility. The United States Joint Typhoon Warning Center and Fleet Weather Center also publicly issue warnings, about tropical cyclones on behalf of the United States Government. The Brazilian Navy Hydrographic Center names South Atlantic tropical cyclones, however the South Atlantic is not a major basin, and not an official basin according to the WMO.
Preparations
Ahead of the formal season starting, people are urged to prepare for the effects of a tropical cyclone by politicians and weather forecasters, amongst others. They prepare by determining their risk to the different types of weather, tropical cyclones cause, checking their insurance coverage and emergency supplies, as well as determining where to evacuate to if needed. When a tropical cyclone develops and is forecast to impact land, each member nation of the World Meteorological Organization issues various watches and warnings to cover the expected impacts. However, there are some exceptions with the United States National Hurricane Center and Fiji Meteorological Service responsible for issuing or recommending warnings for other nations in their area of responsibility.: 2–4
Impacts
Natural phenomena caused or worsened by tropical cyclones
Tropical cyclones out at sea cause large waves, heavy rain, floods and high winds, disrupting international shipping and, at times, causing shipwrecks. Tropical cyclones stir up water, leaving a cool wake behind them, which causes the region to be less favorable for subsequent tropical cyclones. On land, strong winds can damage or destroy vehicles, buildings, bridges, and other outside objects, turning loose debris into deadly flying projectiles. The storm surge, or the increase in sea level due to the cyclone, is typically the worst effect from landfalling tropical cyclones, historically resulting in 90% of tropical cyclone deaths. Cyclone Mahina produced the highest storm surge on record, 13 m (43 ft), at Bathurst Bay, Queensland, Australia, in March 1899. Other ocean-based hazards that tropical cyclones produce are rip currents and undertow. These hazards can occur hundreds of kilometers (hundreds of miles) away from the center of a cyclone, even if other weather conditions are favorable.
The broad rotation of a landfalling tropical cyclone, and vertical wind shear at its periphery, spawns tornadoes. Tornadoes can also be spawned as a result of eyewall mesovortices, which persist until landfall. Hurricane Ivan produced 120 tornadoes, more than any other tropical cyclone. Lightning activity is produced within tropical cyclones; this activity is more intense within stronger storms and closer to and within the storms eyewall. Tropical cyclones can increase the amount of snowfall a region experiences by delivering additional moisture. Wildfires can be worsened when a nearby storm fans their flames with its strong winds.
Impact on property and human life
Tropical cyclones regularly affect the coastlines of most of Earths major bodies of water along the Atlantic, Pacific, and Indian oceans. Tropical cyclones have caused significant destruction and loss of human life, resulting in about 2 million deaths since the 19th century. Large areas of standing water caused by flooding lead to infection, as well as contributing to mosquito-borne illnesses. Crowded evacuees in shelters increase the risk of disease propagation. Tropical cyclones significantly interrupt infrastructure, leading to power outages, bridge and road destruction, and the hampering of reconstruction efforts. Winds and water from storms can damage or destroy homes, buildings, and other manmade structures. Tropical cyclones destroy agriculture, kill livestock, and prevent access to marketplaces for both buyers and sellers; both of these result in financial losses. Powerful cyclones that make landfall – moving from the ocean to over land – are some of the most impactful, although that is not always the case. An average of 86 tropical cyclones of tropical storm intensity form annually worldwide, with 47 reaching hurricane or typhoon strength, and 20 becoming intense tropical cyclones, super typhoons, or major hurricanes (at least of Category 3 intensity).In Africa, tropical cyclones can originate from tropical waves generated over the Sahara Desert, or otherwise strike the Horn of Africa and Southern Africa. Cyclone Idai in March 2019 hit central Mozambique, becoming the deadliest tropical cyclone on record in Africa, with 1,302 fatalities, and damage estimated at US$2.2 billion. Réunion island, located east of Southern Africa, experiences some of the wettest tropical cyclones on record. In January 1980, Cyclone Hyacinthe produced 6,083 mm (239.5 in) of rain over 15 days, which was the largest rain total recorded from a tropical cyclone on record. In Asia, tropical cyclones from the Indian and Pacific oceans regularly affect some of the most populated countries on Earth. In 1970, a cyclone struck Bangladesh, then known as East Pakistan, producing a 6.1 m (20 ft) storm surge that killed at least 300,000 people; this made it the deadliest tropical cyclone on record. In October 2019, Typhoon Hagibis struck the Japanese island of Honshu and inflicted US$15 billion in damage, making it the costliest storm on record in Japan. The islands that comprise Oceania, from Australia to French Polynesia, are routinely affected by tropical cyclones. In Indonesia, a cyclone struck the island of Flores in April 1973, killing 1,653 people, making it the deadliest tropical cyclone recorded in the Southern Hemisphere.Atlantic and Pacific hurricanes regularly affect North America. In the United States, hurricanes Katrina in 2005 and Harvey in 2017 are the countrys costliest ever natural disasters, with monetary damage estimated at US$125 billion. Katrina struck Louisiana and largely destroyed the city of New Orleans, while Harvey caused significant flooding in southeastern Texas after it dropped 60.58 in (1,539 mm) of rainfall; this was the highest rainfall total on record in the country. Europe is rarely affected by tropical cyclones; however, the continent regularly encounters storms after they transitioned into extratropical cyclones. Only one tropical depression – Vince in 2005 – struck Spain, and only one subtropical cyclone – Subtropical Storm Alpha in 2020 – struck Portugal. Occasionally, there are tropical-like cyclones in the Mediterranean Sea. The northern portion of South America experiences occasional tropical cyclones, with 173 fatalities from Tropical Storm Bret in August 1993. The South Atlantic Ocean is generally inhospitable to the formation of a tropical storm. However, in March 2004, Hurricane Catarina struck southeastern Brazil as the first hurricane on record in the South Atlantic Ocean.
Environmental impact
Although cyclones take an enormous toll in lives and personal property, they may be important factors in the precipitation regimes of places they impact, as they may bring much-needed precipitation to otherwise dry regions. Their precipitation may also alleviate drought conditions by restoring soil moisture, though one study focused on the Southeastern United States suggested tropical cyclones did not offer significant drought recovery. Tropical cyclones also help maintain the global heat balance by moving warm, moist tropical air to the middle latitudes and polar regions, and by regulating the thermohaline circulation through upwelling. The storm surge and winds of hurricanes may be destructive to human-made structures, but they also stir up the waters of coastal estuaries, which are typically important fish breeding locales. Ecosystems, such as saltmarshes and Mangrove forests, can be severely damaged or destroyed by tropical cyclones, which erode land and destroy vegetation. Tropical cyclones can cause harmful algae blooms to form in bodies of water by increasing the amount of nutrients available. Insect populations can decrease in both quantity and diversity after the passage of storms. Strong winds associated with tropical cyclones and their remnants are capable of felling thousands of trees, causing damage to forests.When hurricanes surge upon shore from the ocean, salt is introduced to many freshwater areas and raises the salinity levels too high for some habitats to withstand. Some are able to cope with the salt and recycle it back into the ocean, but others can not release the extra surface water quickly enough or do not have a large enough freshwater source to replace it. Because of this, some species of plants and vegetation die due to the excess salt. In addition, hurricanes can carry toxins and acids onshore when they make landfall. The floodwater can pick up the toxins from different spills and contaminate the land that it passes over. These toxins are harmful to the people and animals in the area, as well as the environment around them. Tropical cyclones can cause oil spills by damaging or destroying pipelines and storage facilities. Similarly, chemical spills have been reported when chemical and processing facilities were damaged. Waterways have become contaminated with toxic levels of metals such as nickel, chromium, and mercury during tropical cyclones.Tropical cyclones can have an extensive effect on geography, such as creating or destroying land. Cyclone Bebe increased the size of Tuvalu island, Funafuti Atoll, by nearly 20%. Hurricane Walaka destroyed the small East Island in 2018, which destroyed the habitat for the endangered Hawaiian monk seal, as well as, threatened sea turtles and seabirds. Landslides frequently occur during tropical cyclones and can vastly alter landscapes; some storms are capable of causing hundreds to tens of thousands of landslides. Storms can erode coastlines over an extensive area and transport the sediment to other locations.
Response
Hurricane response is the disaster response after a hurricane. Activities performed by hurricane responders include assessment, restoration, and demolition of buildings; removal of debris and waste; repairs to land-based and maritime infrastructure; and public health services including search and rescue operations. Hurricane response requires coordination between federal, tribal, state, local, and private entities. According to the National Voluntary Organizations Active in Disaster, potential response volunteers should affiliate with established organizations and should not self-deploy, so that proper training and support can be provided to mitigate the danger and stress of response work.Hurricane responders face many hazards. Hurricane responders may be exposed to chemical and biological contaminants including stored chemicals, sewage, human remains, and mold growth encouraged by flooding, as well as asbestos and lead that may be present in older buildings. Common injuries arise from falls from heights, such as from a ladder or from level surfaces; from electrocution in flooded areas, including from backfeed from portable generators; or from motor vehicle accidents. Long and irregular shifts may lead to sleep deprivation and fatigue, increasing the risk of injuries, and workers may experience mental stress associated with a traumatic incident. Additionally, heat stress is a concern as workers are often exposed to hot and humid temperatures, wear protective clothing and equipment, and have physically difficult tasks.
Climatology
Tropical cyclones have occurred around the world for millennia. Reanalyses and research are being undertaken to extend the historical record, through the usage of proxy data such as overwash deposits, beach ridges and historical documents such as diaries. Major tropical cyclones leave traces in overwash records and shell layers in some coastal areas, which have been used to gain insight into hurricane activity over the past thousands of years. Sediment records in Western Australia suggest an intense tropical cyclone in the 4th millennium BC. Proxy records based on paleotempestological research have revealed that major hurricane activity along the Gulf of Mexico coast varies on timescales of centuries to millennia. In the year 957, a powerful typhoon struck southern China, killing around 10,000 people due to flooding. The Spanish colonization of Mexico described "tempestades" in 1730, although the official record for Pacific hurricanes only dates to 1949. In the south-west Indian Ocean, the tropical cyclone record goes back to 1848. In 2003, the Atlantic hurricane reanalysis project examined and analyzed the historical record of tropical cyclones in the Atlantic back to 1851, extending the existing database from 1886.Before satellite imagery became available during the 20th century, many of these systems went undetected unless it impacted land or a ship encountered it by chance. Often in part because of the threat of hurricanes, many coastal regions had sparse population between major ports until the advent of automobile tourism; therefore, the most severe portions of hurricanes striking the coast may have gone unmeasured in some instances. The combined effects of ship destruction and remote landfall severely limit the number of intense hurricanes in the official record before the era of hurricane reconnaissance aircraft and satellite meteorology. Although the record shows a distinct increase in the number and strength of intense hurricanes, therefore, experts regard the early data as suspect. The ability of climatologists to make a long-term analysis of tropical cyclones is limited by the amount of reliable historical data. During the 1940s, routine aircraft reconnaissance started in both the Atlantic and Western Pacific basin during the mid-1940s, which provided ground truth data, however, early flights were only made once or twice a day. Polar-orbiting weather satellites were first launched by the United States National Aeronautics and Space Administration in 1960 but were not declared operational until 1965. However, it took several years for some of the warning centres to take advantage of this new viewing platform and develop the expertise to associate satellite signatures with storm position and intensity.Each year on average, around 80 to 90 named tropical cyclones form around the world, of which over half develop hurricane-force winds of 65 kn (120 km/h; 75 mph) or more. Worldwide, tropical cyclone activity peaks in late summer, when the difference between temperatures aloft and sea surface temperatures is the greatest. However, each particular basin has its own seasonal patterns. On a worldwide scale, May is the least active month, while September is the most active month. November is the only month in which all the tropical cyclone basins are in season. In the Northern Atlantic Ocean, a distinct cyclone season occurs from June 1 to November 30, sharply peaking from late August through September. The statistical peak of the Atlantic hurricane season is September 10. The Northeast Pacific Ocean has a broader period of activity, but in a similar time frame to the Atlantic. The Northwest Pacific sees tropical cyclones year-round, with a minimum in February and March and a peak in early September. In the North Indian basin, storms are most common from April to December, with peaks in May and November. In the Southern Hemisphere, the tropical cyclone year begins on July 1 and runs all year-round encompassing the tropical cyclone seasons, which run from November 1 until the end of April, with peaks in mid-February to early March.Of various modes of variability in the climate system, El Niño–Southern Oscillation has the largest impact on tropical cyclone activity. Most tropical cyclones form on the side of the subtropical ridge closer to the equator, then move poleward past the ridge axis before recurving into the main belt of the Westerlies. When the subtropical ridge position shifts due to El Niño, so will the preferred tropical cyclone tracks. Areas west of Japan and Korea tend to experience much fewer September–November tropical cyclone impacts during El Niño and neutral years. During La Niña years, the formation of tropical cyclones, along with the subtropical ridge position, shifts westward across the western Pacific Ocean, which increases the landfall threat to China and much greater intensity in the Philippines. The Atlantic Ocean experiences depressed activity due to increased vertical wind shear across the region during El Niño years. Tropical cyclones are further influenced by the Atlantic Meridional Mode, the Quasi-biennial oscillation and the Madden–Julian oscillation.
Influence of climate change
Climate change can affect tropical cyclones in a variety of ways: an intensification of rainfall and wind speed, a decrease in overall frequency, an increase in the frequency of very intense storms and a poleward extension of where the cyclones reach maximum intensity are among the possible consequences of human-induced climate change. Tropical cyclones use warm, moist air as their fuel. As climate change is warming ocean temperatures, there is potentially more of this fuel available. Between 1979 and 2017, there was a global increase in the proportion of tropical cyclones of Category 3 and higher on the Saffir–Simpson scale. The trend was most clear in the North Atlantic and in the Southern Indian Ocean. In the North Pacific, tropical cyclones have been moving poleward into colder waters and there was no increase in intensity over this period. With 2 °C (3.6 °F) warming, a greater percentage (+13%) of tropical cyclones are expected to reach Category 4 and 5 strength. A 2019 study indicates that climate change has been driving the observed trend of rapid intensification of tropical cyclones in the Atlantic basin. Rapidly intensifying cyclones are hard to forecast and therefore pose additional risk to coastal communities.Warmer air can hold more water vapor: the theoretical maximum water vapor content is given by the Clausius–Clapeyron relation, which yields ≈7% increase in water vapor in the atmosphere per 1 °C (1.8 °F) warming. All models that were assessed in a 2019 review paper show a future increase of rainfall rates. Additional sea level rise will increase storm surge levels. It is plausible that extreme wind waves see an increase as a consequence of changes in tropical cyclones, further exacerbating storm surge dangers to coastal communities. The compounding effects from floods, storm surge, and terrestrial flooding (rivers) are projected to increase due to global warming.There is currently no consensus on how climate change will affect the overall frequency of tropical cyclones. A majority of climate models show a decreased frequency in future projections. For instance, a 2020 paper comparing nine high-resolution climate models found robust decreases in frequency in the Southern Indian Ocean and the Southern Hemisphere more generally, while finding mixed signals for Northern Hemisphere tropical cyclones. Observations have shown little change in the overall frequency of tropical cyclones worldwide, with increased frequency in the North Atlantic and central Pacific, and significant decreases in the southern Indian Ocean and western North Pacific. There has been a poleward expansion of the latitude at which the maximum intensity of tropical cyclones occurs, which may be associated with climate change. In the North Pacific, there may also have been an eastward expansion. Between 1949 and 2016, there was a slowdown in tropical cyclone translation speeds. It is unclear still to what extent this can be attributed to climate change: climate models do not all show this feature.
Observation and forecasting
Observation
Intense tropical cyclones pose a particular observation challenge, as they are a dangerous oceanic phenomenon, and weather stations, being relatively sparse, are rarely available on the site of the storm itself. In general, surface observations are available only if the storm is passing over an island or a coastal area, or if there is a nearby ship. Real-time measurements are usually taken in the periphery of the cyclone, where conditions are less catastrophic and its true strength cannot be evaluated. For this reason, there are teams of meteorologists that move into the path of tropical cyclones to help evaluate their strength at the point of landfall.Tropical cyclones are tracked by weather satellites capturing visible and infrared images from space, usually at half-hour to quarter-hour intervals. As a storm approaches land, it can be observed by land-based Doppler weather radar. Radar plays a crucial role around landfall by showing a storms location and intensity every several minutes. Other satellites provide information from the perturbations of GPS signals, providing thousands of snapshots per day and capturing atmospheric temperature, pressure, and moisture content.In situ measurements, in real-time, can be taken by sending specially equipped reconnaissance flights into the cyclone. In the Atlantic basin, these flights are regularly flown by United States government hurricane hunters. These aircraft fly directly into the cyclone and take direct and remote-sensing measurements. The aircraft also launch GPS dropsondes inside the cyclone. These sondes measure temperature, humidity, pressure, and especially winds between flight level and the oceans surface. A new era in hurricane observation began when a remotely piloted Aerosonde, a small drone aircraft, was flown through Tropical Storm Ophelia as it passed Virginias eastern shore during the 2005 hurricane season. A similar mission was also completed successfully in the western Pacific Ocean.
Forecasting
High-speed computers and sophisticated simulation software allow forecasters to produce computer models that predict tropical cyclone tracks based on the future position and strength of high- and low-pressure systems. Combining forecast models with increased understanding of the forces that act on tropical cyclones, as well as with a wealth of data from Earth-orbiting satellites and other sensors, scientists have increased the accuracy of track forecasts over recent decades. However, scientists are not as skillful at predicting the intensity of tropical cyclones. The lack of improvement in intensity forecasting is attributed to the complexity of tropical systems and an incomplete understanding of factors that affect their development. New tropical cyclone position and forecast information is available at least every six hours from the various warning centers.
Geopotential height
In meteorology, geopotential heights are used when creating forecasts and analyzing pressure systems. Geopotential heights represent the estimate of the real height of a pressure system above the average sea level. Geopotential heights for weather are divided up into several levels. The lowest geopotential height level is 850 hPa (25.10 inHg), which represents the lowest 1,500 m (5,000 ft) of the atmosphere. The moisture content, gained by using either the relative humidity or the precipitable water value, is used in creating forecasts for precipitation. The next level, 700 hPa (20.67 inHg), is at a height of 2,300–3,200 m (7,700–10,500 ft); 700 hPa is regarded as the highest point in the lower atmosphere. At this layer, both vertical movement and moisture levels are used to locate and create forecasts for precipitation. The middle level of the atmosphere is at 500 hPa (14.76 inHg) or a height of 4,900–6,100 m (16,000–20,000 ft). The 500 hPa level is used for measuring atmospheric vorticity, commonly known as the spin of air. The relative humidity is also analyzed at this height in order to establish where precipitation is likely to materialize. The next level occurs at 300 hPa (8.859 inHg) or a height of 8,200–9,800 m (27,000–32,000 ft). The top-most level is located at 200 hPa (5.906 inHg), which corresponds to a height of 11,000–12,000 m (35,000–41,000 ft). Both the 200 and 300 hPa levels are mainly utilized to locate the jet stream.
Related cyclone types
In addition to tropical cyclones, there are two other classes of cyclones within the spectrum of cyclone types. These kinds of cyclones, known as extratropical cyclones and subtropical cyclones, can be stages a tropical cyclone passes through during its formation or dissipation. An extratropical cyclone is a storm that derives energy from horizontal temperature differences, which are typical in higher latitudes. A tropical cyclone can become extratropical as it moves toward higher latitudes if its energy source changes from heat released by condensation to differences in temperature between air masses; although not as frequently, an extratropical cyclone can transform into a subtropical storm, and from there into a tropical cyclone. From space, extratropical storms have a characteristic "comma-shaped" cloud pattern. Extratropical cyclones can also be dangerous when their low-pressure centers cause powerful winds and high seas.A subtropical cyclone is a weather system that has some characteristics of a tropical cyclone and some characteristics of an extratropical cyclone. They can form in a wide band of latitudes, from the equator to 50°. Although subtropical storms rarely have hurricane-force winds, they may become tropical in nature as their cores warm.
See also
Tropical cyclones in 2022
2022 Atlantic hurricane season
2022 Pacific hurricane season
2022 Pacific typhoon season
2022 North Indian Ocean cyclone season
2022–23 South-West Indian Ocean cyclone season
2022–23 Australian region cyclone season
2022–23 South Pacific cyclone season
References
External links
United States National Hurricane Center – North Atlantic, Eastern Pacific
United States Central Pacific Hurricane Center – Central Pacific
Japan Meteorological Agency – Western Pacific
India Meteorological Department – Indian Ocean
Météo-France – La Reunion – South Indian Ocean from 30°E to 90°E
Indonesian Meteorological Department – South Indian Ocean from 90°E to 125°E, north of 10°S
Australian Bureau of Meteorology – South Indian Ocean and South Pacific Ocean from 90°E to 160°E |
Tropical cyclone |
Papua New Guinea National Weather Service – South Pacific east of 160°E, north of 10°S
Fiji Meteorological Service – South Pacific west of 160°E, north of 25° S
MetService New Zealand – South Pacific west of 160°E, south of 25°S |
Amisulpride | Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic). It is also used to treat dysthymia.It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.Amisulpride is believed to work by blocking, or antagonizing, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorized to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available. It is marketed in all English-speaking countries except for Canada. A New York City based company, LB Pharmaceuticals, has announced the ongoing development of LB-102, also known as N-methyl amisulpride, an antipsychotic specifically targeting the United States. A poster presentation at European Neuropsychopharmacology seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.
Medical uses
Schizophrenia
Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia, amisulpride augmentation, similarly to sulpiride augmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia. Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.
Postoperative nausea and vomiting
Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.
Contraindications
Amisulprides use is contraindicated in the following disease states
Pheochromocytoma
Concomitant prolactin-dependent tumours e.g. prolactinoma, breast cancer
Movement disorders (e.g. Parkinsons disease and dementia with Lewy bodies)
Lactation
Children before the onset of pubertyNeither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.
Adverse effects
Very Common (≥10% incidence)Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism).Common (≥1%, <10% incidence)
Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.)
Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine)
Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as- constipation
- dry mouth
- disorder of accommodation
- Blurred vision
Rare (<1% incidence)
Blood dyscrasias such as leucopenia, neutropenia and agranulocytosis
QT interval prolongation (in a recent meta-analysis of the safety and efficacy of 15 antipsychotic drugs amisulpride was found to have the 2nd highest effect size for causing QT interval prolongation)Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2 receptors including those in the anterior pituitary.
Somnolence.
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Overdose
Torsades de pointes is common in overdose. Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).
Interactions
Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.), reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.
Pharmacology
Pharmacodynamics
Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.Amisulpride and its relatives sulpiride, levosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM). Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterize the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice. The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride. These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist. The clinical implications of this, if any, are unclear. In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.Amisulpride shows stereoselectivity in its actions. Aramisulpride ((R)-amisulpride) has higher affinity for the 5-HT7 receptor (Ki = 47 nM vs. 1,900 nM) while esamisulpride ((S)-amisulpride) has higher affinity for the D2 receptor (4.0 nM vs. 140 nM). An 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) which provides more balanced 5-HT7 and D2 receptor antagonism than racemic amisulpride (50:50 ratio of enantiomers) is under development for the treatment of bipolar depression.
Society and culture
Brand names
Brand names include: Amazeo, Amipride (AU), Amival, Solian (AU, IE, RU, UK, ZA), Soltus, Sulpitac (IN), Sulprix (AU), Midora (RO) and Socian (BR).
Availability
Amisulpride was not approved by the Food and Drug Administration for use in the United States until February 2020, but it is used in Europe, Israel, Mexico, India, New Zealand and Australia to treat psychosis and schizophrenia.An IV formulation of Amisulpride was approved for the treatment of postoperative nausea and vomiting ("PONV") in the United States in February 2020.
History
The U.S. Food and Drug Administration (FDA) approved amisulpride based on evidence from four clinical trials of 2323 subjects undergoing surgery or experiencing nausea and vomiting after the surgery. The trials were conducted at 80 sites in the United States, Canada and Europe.Two trials (Trials 1 and 2) enrolled subjects scheduled to have surgery. Subjects were randomly assigned to receive either amisulpride or a placebo drug at the beginning of general anesthesia. In Trial 1, subjects received amisulpride or placebo alone, and in Trial 2, they received amisulpride or placebo in combination with one medication approved for prevention of nausea and vomiting. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the surgery. The results then compared amisulpride to placebo.The other two trials (Trials 3 and 4) enrolled subjects who were experiencing nausea and vomiting after surgery. In Trial 3, subjects did not receive any medication to prevent nausea and vomiting before surgery and in Trial 4 they received the medication, but the treatment did not work. In both trials, subjects were randomly assigned to receive either amisulpride or placebo. Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the treatment. The trial compared amisulpride to placebo.
References
External links
"Amisulpride". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT01991860 for "US Phase III Study of APD421 in PONV" at ClinicalTrials.gov
Clinical trial number NCT02337062 for "Phase IIIb Study of APD421 in Combination as PONV Prophylaxis" at ClinicalTrials.gov |
Laudanum | Laudanum is a tincture of opium containing approximately 10% powdered opium by weight (the equivalent of 1% morphine). Laudanum is prepared by dissolving extracts from the opium poppy (Papaver somniferum Linnaeus) in alcohol (ethanol).
Reddish-brown in color and extremely bitter, laudanum contains several opium alkaloids, including morphine and codeine. Laudanum was historically used to treat a variety of conditions, but its principal use was as a pain medication and cough suppressant. Until the early 20th century, laudanum was sold without a prescription and was a constituent of many patent medicines. Today, laudanum is recognized as addictive and is strictly regulated and controlled as such throughout most of the world. The United States Controlled Substances Act, for one example, lists it on Schedule II, the second strictest category.
Laudanum is known as a "whole opium" preparation since it historically contained all the alkaloids found in the opium poppy, which are extracted from the dried latex of ripe seed pods (Papaver somniferum L., succus siccum). Today, however, the drug is often processed to remove all or most of the noscapine (also called narcotine) present as this is a strong emetic and does not add appreciably to the analgesic or antipropulsive properties of opium; the resulting solution is called Denarcotized Tincture of Opium or Deodorized Tincture of Opium (DTO).
Laudanum remains available by prescription in the United States (under the generic name "opium tincture") and in the European Union and United Kingdom (under the trade name Dropizol), although today the drugs therapeutic indication is generally limited to controlling diarrhea when other medications have failed.
The terms laudanum and tincture of opium are generally interchangeable, but in contemporary medical practice, the latter is used almost exclusively.
History
Paracelsuss laudanum
Paracelsus, a 16th-century Swiss alchemist, experimented with various opium concoctions, and recommended opium for reducing pain. One of his preparations, a pill which he extolled as his "archanum" or "laudanum", may have contained opium. Paracelsus laudanum was strikingly different from the standard laudanum of the 17th century and beyond, containing crushed pearls, musk, amber, and other substances.
British laudanum
One researcher has documented that "Laudanum, as listed in the London Pharmacopoeia (1618), was a pill made from opium, saffron, castor, ambergris, musk and nutmeg".: 45
Sydenhams laudanum
In the 1660s English physician Thomas Sydenham (1624–1689) popularized a proprietary opium tincture that he also named laudanum, although it differed substantially from the laudanum of Paracelsus. In 1676 Sydenham published a seminal work, Medical Observations Concerning the History and Cure of Acute Diseases, in which he promoted his brand of opium tincture, and advocated its use for a range of medical conditions.
18th century laudanum
By the 18th century, the medicinal properties of opium and laudanum were well known, and the term "laudanum" came to refer to any combination of opium and alcohol.
In the eighteenth century several physicians published work about it, including John Jones, who wrote The Mysteries of Opium Revealed (1700), which was described by one commentator as "extraordinary and perfectly unintelligible." The Scottish physician John Brown, creator of the Brunonian system of medicine, recommended opium for what he termed asthenic conditions, but his system was discredited by the time of his death. The most influential work was by George Young, who published a comprehensive medical text entitled Treatise on Opium (1753). Young, an Edinburgh surgeon and physician, wrote this to counter an essay on opium by his contemporary Charles Alston, professor of botany and materia medica at Edinburgh who had recommended the use of opium for a wide variety of conditions. Young countered this by emphasising the risks...that I may prevent such mischief as I can, I here give it as my sincere opinion... that opium is a poison by which great numbers are daily destroyed. Young gives a comprehensive account of the indications for the drug including its complications. He is critical about writers whose knowledge of the drug is based on chemical or animal experiments rather than clinical practice. The treatise is a detailed, balanced and valuable guide to prevailing knowledge and practice. As it gained popularity, opium, and after 1820, morphine, was mixed with a wide variety of agents, drugs and chemicals including mercury, hashish, cayenne pepper, ether, chloroform, belladonna, whiskey, wine and brandy.": 104
As one researcher has noted: "To understand the popularity of a medicine that eased—even if only temporarily—coughing, diarrhoea and pain, one only has to consider the living conditions at the time". In the 1850s, "cholera and dysentery regularly ripped through communities, its victims often dying from debilitating diarrhoea", and dropsy, consumption, ague and rheumatism were all too common.: 44–49 An 1869 article in Scientific American describes a farmer growing and harvesting poppy in Indian Springs, Georgia, and subsequently selling the raw material to a local pharmacist who prepared laudanum.
19th century laudanum
By the 19th century, laudanum was used in many patent medicines to "relieve pain... to produce sleep... to allay irritation... to check excessive secretions... to support the system... [and] as a soporific". The limited pharmacopoeia of the day meant that opium derivatives were among the most effective of available treatments, so laudanum was widely prescribed for ailments from colds to meningitis to cardiac diseases, in both adults and children. Laudanum was used during the yellow fever epidemic.
Innumerable Victorian women were prescribed the drug for relief of menstrual cramps and vague aches. Nurses also spoon-fed laudanum to infants. The Romantic and Victorian eras were marked by the widespread use of laudanum in Europe and the United States. Mary Todd Lincoln, for example, the wife of the US president Abraham Lincoln, was a laudanum addict, as was the English poet Samuel Taylor Coleridge, who was famously interrupted in the middle of an opium-induced writing session of Kubla Khan by a "person from Porlock". Initially a working class drug, laudanum was cheaper than a bottle of gin or wine, because it was treated as a medication for legal purposes and not taxed as an alcoholic beverage.
Laudanum was used in home remedies and prescriptions, as well as a single medication. For example, a 1901 medical book published for home health use gave the following two "Simple Remedy Formulas" for "dysenterry" [sic]: (1) Thin boiled starch, 2 ounces; Laudanum, 20 drops; "Use as an injection [meaning as an enema] every six to twelve hours"; (2) Tincture rhubarb, 1 ounce; Laudanum 4 drachms; "Dose: One teaspoonful every three hours." In a section entitled "Professional Prescriptions" is a formula for "diarrhoea (acute)": Tincture opium, deodorized, 15 drops; Subnitrate of bismuth, 2 drachms; Simple syrup, 1⁄2 ounce; Chalk mixture, 11⁄2 ounces, "A teaspoonful every two or three hours to a child one year old." "Diarrhoea (chronic)": Aqueous extract of ergot, 20 grains; Extract of nux vomica, 5 grains; Extract of Opium, 10 grains, "Make 20 pills. Take one pill every three or four hours."
20th century laudanum
The early 20th century brought increased regulation of all manner of narcotics, including laudanum, as the addictive properties of opium became more widely understood, and "patent medicines came under fire, largely because of their mysterious compositions".: 126 In the US, the Food and Drug Act of 1906 required that certain specified drugs, including alcohol, cocaine, heroin, morphine, and cannabis, be accurately labeled with contents and dosage. Previously many drugs had been sold as patent medicines with secret ingredients or misleading labels. Cocaine, heroin, cannabis, and other such drugs continued to be legally available without prescription as long as they were labeled. It is estimated that sale of patent medicines containing opiates decreased by 33% after labeling was mandated. In 1906 in Britain and in 1908 in Canada "laws requiring disclosure of ingredients and limitation of narcotic content were instituted".: 126 The Harrison Narcotics Tax Act of 1914 restricted the manufacture and distribution of opiates, including laudanum, and coca derivatives in the US. This was followed by Frances Loi des stupéfiants in 1916, and Britains Dangerous Drugs Act in 1920.: 126 Laudanum was supplied to druggists and physicians in regular and concentrated versions. For example, in 1915, Frank S. Betz Co., a medical supply company in Hammond, Indiana, advertised Tincture of Opium, U.S.P., for $2.90 per lb., Tincture of Opium Camphorated, U.S.P, for 85 cents per lb., and Tincture of Opium Deodorized, for $2.85 per lb. Four versions of opium as a fluid extract were also offered: (1) Opium, Concentrated (assayed) "For making Tincture Opii (Laudanum) U.S.P. Four times the strength of the regular U.S.P." tincture, for $9.35 per pint; (2) Opium, Camphorated Conc. "1 oz. making 8 ozs. Tr. Opii Camphorated U.S.P (Paregoric)" for $2.00 per pint; (3) Opium, Concentrated (Deodorized and Denarcotized) "Four times the strength of tincture, Used when Tinct. Opii U.S.P. is contraindicated" for $9.50 per pint, and (4) Opium (Aqueous), U.S.P., 1890, "Tr. (assayed) Papaver Somniferum" for $2.25 per pint.In 1929–30, Parke, Davis & Co., a major US drug manufacturer based in Detroit, Michigan, sold "Opium, U.S.P. (Laudanum)", as Tincture No. 23, for $10.80 per pint (16 fluid ounces), and "Opium Camphorated, U.S.P. (Paregoric)", as Tincture No. 20, for $2.20 per pint. Concentrated versions were available. "Opium Camphorated, for U.S.P. Tincture: Liquid No. 338" was "exactly 8 times the strength of Tincture Opium Camphorated (Paregoric) [italics in original], U.S.P., "designed for preparing the tincture by direct dilution," and cost $7 per pint. Similarly, at a cost of $36 per pint, "Opium Concentrated, for U.S.P. Tincture: Liquid No. 336", was "four times the strength of the official tincture", and "designed for the extemporaneous preparation of the tincture". The catalog also noted: "For quarter-pint bottles add 80c. per pint to the price given for pints."
Toward the middle 20th century, the use of opiates was generally limited to the treatment of pain, and opium was no longer a medically accepted "cure-all". Further, the pharmaceutical industry began synthesizing various opioids, such as propoxyphene, oxymorphone and oxycodone. These synthetic opioids, along with codeine and morphine were preferable to laudanum since a single opioid could be prescribed for different types of pain rather than the "cocktail" of laudanum, which contains nearly all of the opium alkaloids. Consequently, laudanum became mostly obsolete as an analgesic, since its principal ingredient is morphine, which can be prescribed by itself to treat pain. Until now, there has been no medical consensus on which of the two (laudanum or morphine alone) is the better choice for treating pain.
In 1970, the US adopted the Uniform Controlled Substances Act, which regulated opium tincture (Laudanum) as a Schedule II substance (currently DEA #9630), placing even tighter controls on the drug.
By the late 20th century, laudanums use was almost exclusively confined to treating severe diarrhea.
21st century laudanum
The current prescribing information for laudanum in the US states that opium tinctures sole indication is as an anti-diarrheal, although the drug is occasionally prescribed off-label for treating pain and neonatal withdrawal syndrome.
Historical varieties
Several historical varieties of laudanum exist, including Paracelsus laudanum, Sydenhams Laudanum (also known as tinctura opii crocata), benzoic laudanum (tinctura opii benzoica), and deodorized tincture of opium (the most common contemporary formulation), among others. Depending on the version, additional amounts of the substances and additional active ingredients (e.g. saffron, sugar, eugenol) are added, modifying its effects (e.g., amount of sedation, or antitussive properties).
There is probably no single reference that lists all the pharmaceutical variations of laudanum that were created and used in different countries during centuries since it was initially formulated. The reasons are that in addition to official variations described in pharmacopeias, pharmacists and drug manufacturers were free to alter such formulas. The alcohol content of Laudanum probably varied substantially; on the labels of turn-of-the-century bottles of Laudanum, alcoholic content is stated as 48%. In contrast, the current version of Laudanum contains about 18% alcohol.
The four variations of laudanum listed here were used in the United States during the late 19th century. The first, from an 1870 publication, is "Best Turkey opium 1 oz., slice, and pour upon it boiling water 1 gill, and work it in a bowl or mortar until it is dissolved; then pour it into the bottle, and with alcohol of 70 percent proof 1⁄2 pt., rinse the dish, adding the alcohol to the preparation, shaking well, and in 24 hours it will be ready for use. Dose—From 10 to 30 drops for adults, according to the strength of the patient, or severity of the pain. Thirty drops of this laudanum will be equal to one grain of opium. And this is a much better way to prepare it than putting the opium into alcohol, or any other spirits alone, for in that case much of the opium does not dissolve." The remaining three formulas are copied from an 1890 publication of the day:
Sydenhams Laudanum: "According to the Paris Codex this is prepared as follows: opium, 2 ounces; saffron, 1 ounce; bruised cinnamon and bruised cloves, each 1 drachm; sherry wine, 1 pint. Mix and macerate for 15 days and filter. Twenty drops are equal to one grain of opium."
Rousseaus Laudanum: "Dissolve 12 ounces white honey in 3 pounds warm water, and set it aside in a warm place. When fermentation begins add to it a solution of 4 ounces selected opium in 12 ounces water. Let the mixture stand for a month at a temperature of 86° Fahr.; then strain, filter, and evaporate to 10 ounces; finally strain and add 41⁄2 ounces proof alcohol. Seven drops of this preparation contain about 1 grain of opium."
Tincture of Opium (Laudanum), U.S.P., attributed to the United States Pharmacoepia of 1863: "Macerate 21⁄2 ounces opium, in moderately fine powder in 1 pint water for 3 days, with frequent agitation. Add 1 pint alcohol, and macerate for 3 days longer. Percolate, and displace 2 pints tincture by adding dilute alcohol in the percolator."
Modern status
United Kingdom
Opium tincture remains in the British Pharmacopoeia, where it is referred to as Tincture of Opium, B.P., Laudanum, Thebaic Tincture or Tinctura Thebaica, and "adjusted to contain 1% w/v of anhydrous morphine." It is a Class A substance under the Misuse of Drugs Act of 1971. At least one manufacturer (Macfarlan Smith) still produces opium tincture in the UK as of 2011.
"Gees Linctus" is also available from most UK pharmacies, especially independent stores. This contains "Opium Tincture", at 0.083 mL, per 5 mL.
United States
Tincture of Opium is available by prescription in the United States. It is regulated as a Schedule II drug (No. 9639) under the Controlled Substances Act.
In the United States, opium tincture is marketed and distributed by several pharmaceutical firms, each producing a single formulation of the drug, which is deodorized. Each mL contains 10 mg of anhydrous morphine (the equivalent of 100 mg of powdered opium), other opium alkaloids (except noscapine), and ethanol, 19%. It is available packaged in bottles of four US fluid ounces (118 mL) and 16 US fluid ounces (1 US pt; 473 mL).
Tincture of Opium is known as one of many "unapproved drugs" regulated by the U.S. Food and Drug Administration (FDA); the marketing and distribution of opium tincture prevails today only because opium tincture was sold prior to the Federal Food, Drug & Cosmetic Act of 1938. Its "grandfathered" status protects opium tincture from being required to undergo strict FDA drug reviews and subsequent approval processes. However, the FDA closely monitors the labeling of opium tincture. Bottles of opium tincture are required by the FDA to bear a bright red "POISON" label given the potency of the drug and the potential for overdose (see discussion about confusion with Paregoric below). Additionally, in a warning letter to a manufacturer of opium tincture in late 2009, the FDA noted that "we found that your firm is manufacturing and distributing the prescription drug Opium Tincture USP (Deodorized – 10 mg/mL). Based on our information, there are no FDA-approved applications on file for this drug product."
Pharmacology
Opium tincture is useful as an analgesic and antidiarrheal. Opium enhances the tone in the long segments of the longitudinal muscle and inhibits propulsive contraction of circular and longitudinal muscles. The pharmacological effects of opium tincture are due principally to its morphine content. The quantity of the papaverine and codeine alkaloids in opium tincture is too small to have any demonstrable central nervous system effect.Most modern formulations of opium tincture do not contain the alkaloid narcotine (also known as noscapine), which has antitussive properties. Even modest doses of narcotine can induce profound nausea and vomiting. Since opium tincture is usually prescribed for its antidiarrheal and analgesic properties (rather than as an antitussive), opium tincture without narcotine is generally preferred. This "de-narcotized" or "deodorized" opium tincture is formulated using a petroleum distillate to remove the narcotine.Oral doses of opium tincture are rapidly absorbed in the gastrointestinal tract and metabolized in the liver. Peak plasma concentrations of the morphine content are reached in about one hour, and nearly 75% of the morphine content of the opium tincture is excreted in the urine within 48 hours after oral administration.
Medical uses
Diarrhea
Opium tincture is indicated for the treatment of severe fulminant (intense, prolific) diarrhea that does not respond to standard therapy (e.g., Imodium or Lomotil).
The usual starting dose is 0.3 mL to 0.6 mL (about six to 12 drops) in a glass of water or juice four times a day. Refractory cases (such as diarrhea resulting from the complications of HIV/AIDS) may require higher than normal dosing, for example, 1 to 2 mL every 3 hours, for a total daily dose of up to 16mL a day. In terminal diseases, there is no ceiling dose for opium tincture; the dose is increased slowly until diarrhea is controlled.
Neonatal abstinence syndrome
Opium tincture is used to treat neonatal opioid withdrawal syndrome (NOWS) when diluted 1:25 (one part opium tincture to 25 parts water). The recommended dose is 0.2 mL of the diluted solution under the tongue every three hours, which may be increased by 0.05 mL every three hours until no objective signs of withdrawal are observed. In no event, however, should the dose exceed 0.7 mL every three hours. The opium tincture is gradually tapered over a 3- to 5-week period, at which point the newborn should be completely free of withdrawal symptoms.
Hazards
Potency of laudanum
Opium tincture is one of the most potent oral formulations of morphine available by prescription. Accidental or deliberate overdose is common with opium tincture given the highly concentrated nature of the solution. Overdose and death may occur with a single oral dose of between 100 and 150 mg of morphine in a healthy adult who has no tolerance to opiates. This represents the equivalent of between two to three teaspoons (10–15 mL) of opium tincture. Suicide by laudanum was common in the mid-19th century. Prudent medical judgment necessitates toward dispensing very small quantities of opium tincture in small dropper bottles or in pre-filled syringes to reduce the risk of intentional or accidental overdose.
Danger of confusion with paregoric
In the United States, opium tincture contains 10 mg per mL of anhydrous morphine. By contrast, opium tinctures weaker cousin, paregoric, also confusingly known as "camphorated tincture of opium", is 1/25th the strength of opium tincture, containing only 0.4 mg of morphine per mL. A 25-fold morphine overdose may occur if opium tincture is used where paregoric is indicated. Opium tincture is almost always dosed in drops, or fractions of a mL, or less commonly, in minims, while paregoric is dosed in teaspoons or tablespoons. Thus, an order for opium tincture containing directions in teaspoons is almost certainly in error. To avoid this potentially fatal outcome, the term "camphorated tincture of opium" is avoided in place of paregoric since the former can easily be mistaken for opium tincture.In 2004, the FDA issued a "Patient Safety" news bulletin stating that "To help resolve the confusion [between opium tincture and paregoric], FDA will be working with the manufacturers of these two drugs to clarify the labeling on the containers and in the package inserts." Indeed, in 2005, labels for opium tincture began to include the concentration of morphine (10 mg/mL) in large text beneath the words "Opium Tincture". The FDA has also alerted pharmacists and other medical practitioners about the dangers of confusing these drugs, and has recommended that opium tincture not be stocked as a standard item (i.e., that it should not be "on the shelf"), that opium tincture be dispensed in oral syringes, and that pharmacy software alert the dispenser if unusually large doses of opium tincture appear to be indicated.Despite the FDAs efforts over the past few years, the confusion persists, sometimes with deadly results. The Institute for Safe Medication Practices recommends that opium tincture not be stocked at all in a pharmacys inventory, and that "It may be time to relegate opium tincture and paregoric to the museum of outmoded opioid therapy." Despite the risk of confusion, opium tincture, like many end-stage medications, is indispensable for intractable diarrhea for terminally ill patients, such as those with AIDS and cancer.
Misinterpretation of "DTO"
The abbreviation "DTO," traditionally used to refer to Deodorized Tincture of Opium, is sometimes also erroneously employed to abbreviate "diluted tincture of opium." Diluted tincture of opium, also known as Camphorated Tincture of Opium (Paregoric) is a 1:25 mixture of opium tincture to water prescribed to treat withdrawal symptoms in newborns whose mothers were using opioids while pregnant. The United States Pharmacopeia and FDA recommend that practitioners refrain from using DTO in prescriptions, given this potential for confusion. In cases where pharmacists have misinterpreted DTO, and given "deodorized tincture of opium" when "diluted tincture of opium" was meant, infants have received a massive 25-fold overdose of morphine, sometimes resulting in fatalities.
Side effects
Side effects of laudanum are generally the same as with morphine, and include euphoria, dysphoria, pruritus, sedation, constipation, reduced tidal volume, respiratory depression, as well as psychological dependence, physical dependence, miosis, and xerostomia. Overdose can result in severe respiratory depression or collapse and death. The ethanol component can also induce adverse effects at higher doses; the side effects are the same as with alcohol.
Long-term use of laudanum in nonterminal diseases is discouraged due to the possibility of drug tolerance and addiction. Long-term use can also lead to abnormal liver function tests; specifically, prolonged morphine use can increase ALT and AST blood serum levels.
Treatment for overdose
Life-threatening overdose of opium tincture owes to the preparations morphine content. Morphine produces a dose-dependent depressive effect on the respiratory system, which can lead to profound respiratory depression, hypoxia, coma and finally respiratory arrest and death. If overdose of opium tincture is suspected, rapid professional intervention is required. The primary concern is re-establishing a viable airway and institution of assisted or controlled ventilation if the patient is unable to breathe on their own. Other supportive measures such as the use of vasopressors and oxygen may be indicated to treat cardiac and/or pulmonary failure. Cardiac arrhythmias or arrest will require advanced life-saving measures.
Intravenous naloxone or nalmefene, quick-acting opioid antagonists, are the first-line treatment to reverse respiratory depression caused by an overdose of opium tincture. Gastric lavage may be of some use in certain cases.
In fiction
In Mary Shelleys novel Frankenstein (1818), Victor Frankenstein takes laud |
Laudanum | anum as his only means of sleeping and thus preserving his life while in recovery from months of fever and a series of horrible events.
In Charles Dickenss novel Oliver Twist (1837), Nancy gave William "Bill" Sikes laudanum to keep him asleep while she ran away to meet Rose Maylie.
In Uncle Toms Cabin (1852), an anti-slavery novel by Harriet Beecher Stowe, an enslaved woman named Cassy talks about how she killed her newborn by laudanum overdose to spare him from experiencing the horrors of slavery.
In the novel Silas Marner: The Weaver of Raveloe by George Eliot (Mary Ann Evans) (1861), Silas finds and adopts a two-year old girl who had wandered into his house. The girl had been abandoned while walking with her opium-addicted mother, Molly Farren, who had fallen asleep in the snow and died. Earlier in the novel, in Chapter 3, it is specified that she uses laudanum.... if Molly should take a drop too much laudanum some day, and make a widower of you.
Wilkie Collins novel The Moonstone (1868) features laudanum "as an essential ingredient of the plot." Collins based his description of the drugs effects on his own experiences with it.
A laudanum-addicted character also appeared in Wilkie Collins novel Armadale (1864–66).
Laudanum appears in Charles Baudelaires prose poem The Double Room, published in his collection Le Spleen de Paris in 1869.
Laudanum is portrayed as the surgical drug of choice for fifteenth-century physicians in Lawrence Schoonovers novel The Burnished Blade (1948), the plot of which deals in part with the smuggling of expensive raw opium into France from the Empire of Trebizond.
In William Faulkners novel Requiem for a Nun (1951), Compson, Doctor Peabody, and Ratcliffe give whiskey tainted with laudanum to a group of rowdy lynchers and a militia band that had joined together. Upon their falling asleep, they were gathered up and locked in jail while still unconscious.
Stephen Maturin, one of the main characters in Patrick OBrians Aubrey–Maturin series of novels (1969–2004) about the Napoleonic wars, is a sometime laudanum addict.
Laudanum is prescribed in Glendon Swarthouts novel The Shootist (1975) to the character J.B. Books, played by John Wayne in Don Siegels movie adaptation (1976).
In Philippa Gregorys novel Wideacre (1987), the main character Beatrice Lacey nearly becomes addicted to laudanum when her eventual husband Dr. John MacAndrew prescribes it to her after her mothers death.
In the adaptation Interview with the Vampire (1994), which was based on the 1976 novel with the same name, Claudia uses laudanum to try and dispose of Lestat: Under the pretext of making peace, she offers him some drunk noble-blood twins to feed on, when she actually had them overdosed with the said drug.
In the film Tombstone (1993), Mattie Earp (Dana Wheeler-Nicholson), Wyatt Earps wife is addicted to laudanum. At the beginning of the film at the train station after her husband introduces her to his brothers and sisters-in-law she states, "Well, Wyatt, I couldnt find a single store that had laudanum anywhere." Her sister-in-law Louisa Earp (Lisa Collins) later said " Matter, Honey? Did you say you needed some laudanum? [...] I have some right here," hands Mattie a bottle and says, "Just be careful, now. Its full of hop," to which Mattie replies, "Oh, dont worry. I just get headaches sometimes." Later in the bedroom she and Wyatt shares, Mattie drinking out of a bottle, shows the effects of laudanum, hiding the bottle as Wyatt enters the bedroom asking, "Is that the opium Lou gave you? Its a new bottle, isnt it? You better go easy on that stuff," with Mattie replying, "Wyatt, leave me alone..."
In the film From Hell (2001), Inspector Abberline is a user of laudanum, and Jack the Ripper also uses laudanum for making his victims sleepy.
In the TV series Deadwood, the town doctor recommends laudanum several times, bringing a bottle of it to a patient. Initially in the series, Alma Garrett is an addict to laudanum. Trixie is a former addict.
In Dan Simmonss novel Drood (2009) the narrator Wilkie Collins takes laudanum daily to alleviate a wide variety of pains as well as to induce sleep.
In the horror video-game Amnesia: The Dark Descent (2010), laudanum can be found at several places in the castle, and can be used to regain health.
In the role-playing video-game Darkest Dungeon (2016), laudanum is a provision that is used to cure Horror, a stress-over-time negative effect. The role of laudanum is revisited in Darkest Dungeon 2.
In the browser-based role-playing video game Fallen London, the main character can take laudanum to decrease Nightmares, a negative stat, at the cost of increasing Wounds, another negative stat.
In Eleanor Cattons novel The Luminaries (2013), and the subsequent TV adaptation (2020), many characters are addicted to laudanum and it is used to murder Crosbie Wells.
In Sara Collins novel The Confessions of Frannie Langton (2019), the titular character becomes addicted to laudanum.
In the film The Highwaymen (2019), Bonnie Parker (Emily Brobst) of Bonnie and Clyde fame is addicted to laudanum.
In the film Winchester (2018), Doctor Eric Price is addicted to laudanum due to his wifes suicide.
In the novel Anna Karenina by Leo Tolstoy, the eponymous character becomes addicted to laudanum before committing suicide by jumping under a train.
In the horror video-game Amnesia: Rebirth (2020), laudanum can be found scarcely, and can be used to decrease the player characters fear.
In the Netflix adaptation of Julia Quinns novels Bridgerton (2020), when Baron Featherington, the Featherington patriarch is ambushed by gambling bookies, a bottle of laudanum poison is shown on the table and later the family learns of his off-screen death, presumably murdered.
In the book series All the Wrong Questions (2012–15) by Daniel Handler, Who Could That Be at This Hour? (2012) Lemony Snickets tea had laudanum. Laudanum is mentioned and used throughout the series, mostly by The Inhuman society.
It plays a major role in the plot of James Clavells historical novel Gai-Jin.
In the Soldier Son Trilogy (2005–07) by Robin Hobb, Gernian soldiers are issued "gettys tonic", a standardized dose formulated of laudanum and rum, to fortify their minds against the terror and demoralization the Speck magic induces.In the original version othe miniseries Roots, upon Tobys arrival to Virginia and ready for sale, the slave doctor says hell give laudanum to the wild ones, brandy to the dull ones and "let the buyer beware"
In Outlander, Claire uses Laudanum in several episodes throughout the 18th century
See also
Confessions of an English Opium-Eater
Kendal Black Drop
Poppy tea
References
External links
Media related to Laudanum at Wikimedia Commons
Merck Prescribing Information for Laudanum/Opium Tincture. Includes detailed dosage information. |
Ampicillin/sulbactam | Ampicillin/sulbactam is a fixed-dose combination medication of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the brand name Unasyn, generic only outside the United States, is an intravenous antibiotic. The second, an oral form called sultamicillin, is marketed under the brand name Ampictam outside the United States. And generic only in the United States, ampicillin/sulbactam is used to treat infections caused by bacteria resistant to beta-lactam antibiotics. Sulbactam blocks the enzyme which breaks down ampicillin and thereby allows ampicillin to attack and kill the bacteria.
Medical uses
Ampicillin/sulbactam has a wide array of medical use for many different types of infectious disease. It is usually reserved as a second-line therapy in cases where bacteria have become beta-lactamase resistant, rendering traditional penicillin-derived antibiotics ineffective. It is effective against certain gram positive bacteria, gram-negative bacteria, and anaerobes.
Gram-positive bacteria: Staphylococcus aureus (beta-lactamase and non-beta-lactamase producing), Staphylococcus epidermidis (beta-lactamase and non-beta-lactamase producing), Staphylococcus saprophyticus (beta-lactamase and non-beta-lactamase producing), Streptococcus faecalis (Enterococcus), Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus viridans.
Gram-negative bacteria: Hemophilus influenzae (beta-lactamase and non-beta-lactamase producing), Moraxella (Branhamella) catarrhalis (beta-lactamase and non-beta-lactamase producing), Escherichia coli (beta-lactamase and non-beta-lactamase producing), Klebsiella species (all known species are beta-lactamase producing), Proteus mirabilis (beta-lactamase and non-beta-lactamase producing), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Morganella morganii, and Neisseria gonorrhoeae (beta-lactamase and non-beta-lactamase producing).
Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus species, Bacteroides species including B. fragilis.Gynecological Infections
Ampicillin/sulbactam can be used to treat gynecological infections caused by beta-lactamase producing strains of Escherichia coli, and Bacteroides (including B. fragilis).Bone and joint infections
Ampicillin/sulbactam can be used in the treatment of bone and joint infections caused by susceptible beta-lactamase producing bacteria.Intra-abdominal infections
Ampicillin/sulbactam can be used to treat intra-abdominal infections caused by beta-lactamase producing strains of Escherichia coli, Klebsiella (including K. pneumonia), Bacteroides fragilis, and Enterobacter.Skin and skin structure Infections
This medication can be used to treat skin and skin structure infections caused from beta-lactamase-producing strains of Staphylococcus aureus, Enterobacter, Escherichia coli, Klebsiella (including K. pneumoniae), Proteus mirabilis, Bacteroides fragilis, and Acinetobacter calcoaceticus. Examples of skin conditions treated with ampicillin-sulbactam are moderate to severe diabetic foot infections and type 1 Necrotizing fasciitis, commonly referred to as "flesh-eating bacteria".
Contraindications
Ampicillin/sulbactam is contraindicated in individuals who have a history of a penicillin allergy. Symptoms of allergic reactions may range from rash to potentially life-threatening conditions, such as anaphylaxis. Patients who have asthma, eczema, hives, or hay fever are more likely to develop undesirable reactions to any of the penicillins.
Adverse effects
Reported adverse events include both local and systemic reactions. Local adverse reactions are characterized by redness, tenderness, and soreness of the skin at the injection site. The most common local reaction is injection site pain. It has been reported to occur in 16% of patients receiving intramuscular injections, and 3% of patients receiving intravenous injections. Less frequently reported side effects include inflammation of veins (1.2%), sometimes associated with a blood clot (3%). The most commonly reported systemic reactions are diarrhea (3%) and rash (2%). Less frequent systemic reactions to ampicillin/sulbactam include chest pain, fatigue, seizure, headache, painful urination, urinary retention, intestinal gas, nausea, vomiting, itching, hairy tongue, tightness in throat, reddening of the skin, nose bleeding, and facial swelling. These are reported to occur in less than 1% of patients.
Pharmacology
Pharmacodynamics and pharmacokinetics
The addition of sulbactam to ampicillin enhances the effects of ampicillin. This increases the antimicrobial activity by 4- to 32-fold when compared to ampicillin alone. Ampicillin is a time-dependent antibiotic. Its bacterial killing is largely related to the time that drug concentrations in the body remain above the minimum inhibitory concentration (MIC). The duration of exposure will thus correspond to how much bacterial killing will occur. Various studies have shown that, for maximum bacterial killing, drug concentrations must be above the MIC for 50-60% of the time for the penicillin group of antibiotics. This means that longer durations of adequate concentrations are more likely to produce therapeutic success. However, when ampicillin is given in combination with sulbactam, regrowth of bacteria has been seen when sulbactam levels fall below certain concentrations. As with many other antibiotics, under-dosing of ampicillin/sulbactam may lead to resistance.Ampicillin/sulbactam has poor absorption when given orally. The two drugs have similar pharmacokinetic profiles that appear unchanged when given together. Ampicillin and sulbactam are both hydrophilic antibiotics and have a volume of distribution (Vd) similar to the volume of extra-cellular body water. The volume that the drug distributes throughout in healthy patients is approximately 0.2 liters per kilogram of body weight. Patients on hemodialysis, elderly patients, and pediatric patients have shown a slightly increased volume of distribution.
Using typical doses, ampicillin/sulbactam has been shown to reach desired levels to treat infections in the brain, lungs, and abdominal tissues.
Both agents have moderate protein binding, reported at 38% for sulbactam and 28% for ampicillin.15,16 The half-life of ampicillin is approximately 1 hour, when used alone or in combination with sulbactam; therefore it will be eliminated from a healthy person in around 5 hours. It is eliminated primarily by the urinary system, with 75% excreted unchanged in the urine. Only small amounts of each drug were found to be excreted in the bile. Ampicillin/sulbactam should be given with caution in infants less than a week old and premature neonates. This is due to the underdeveloped urinary system in these patients, which can cause a significantly increased half-life for both drugs.16 Based on its elimination, ampicillin/sulbactam is typically given every 6 to 8 hours. Slowed clearance of both drugs has been seen in the elderly, renal disease patients, and critically ill patients on renal replacement therapy. Reduced clearance has been seen in both pediatric and post-operative patients. Adjustments in dosing frequency may be required in these patients due to these changes.
Mechanism of action
Ampicillin/sulbactam is a combination of a β-lactam antibiotic and a β-lactamase inhibitor. Ampicillin works by binding to penicillin-binding proteins (PBPs) to inhibit bacterial cell wall synthesis. This causes disruption of the bacterial cell wall and leads to bacterial cell death. However, resistant pathogens may produce β-lactamase enzymes that can inactivate ampicillin through hydrolysis. This is prevented by the addition of sulbactam, which binds and inhibits the β-lactamase enzymes. It is also capable of binding to the PBP of Bacteroides fragilis and Acinetobacter spp., even when it is given alone. The activity of sulbactam against Acinetobacter spp. seen in in-vitro studies makes it distinctive compared to other β-lactamase inhibitors, such as tazobactam and clavulanic acid.
Chemistry
Ampicillin sodium is derived from the basic penicillin nucleus, 6-aminopenicillanic acid. Its chemical name is monosodium (2S, 5R, 6R)-6-[(R)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate. It has a molecular weight of 371.39 grams and its chemical formula is C16H18N3NaO4S.
Sulbactam sodium is also a derivative of 6-aminopenicillanic acid. Chemically, it is known as either sodium penicillinate sulfone or sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide. It has a molecular weight of 255.22 grams and its chemical formula is C8H10NNaO5S.
Ampicillin/sulbactam is also used when the cause of an infection is not known (empiric therapy), such as intra-abdominal infections, skin infections, pneumonia, and gynecologic infections. It is active against a wide range of bacterial groups, including Staphylococcus aureus, Enterobacteriaceae, and anaerobic bacteria. Importantly, it is not active against Pseudomonas aeruginosa and should not be used alone when infection with this organism is suspected or known.
History
The introduction and use of ampicillin alone started in 1961. The development and introduction of this drug allowed the use of targeted therapies against gram-negative bacteria. With the rise of beta-lactamase producing bacteria, ampicillin and the other penicillin-derivatives became ineffective to these resistant organisms. With the introduction of beta-lactamase inhibitors such as sulbactam, combined with ampicillin made beta-lactamase producing bacteria susceptible.
Formulation
Ampicillin-sulbactam only comes in a parenteral formulation to be either used as intravenous or intramuscular injections, and can be formulated for intravenous infusion. It is formulated in a 2:1 ratio of ampicillin:sulbactam. The commercial preparations available include:
1.5 grams (1 gram ampicillin and 0.5 gram sulbactam)→Brand names: Unasyn, Unasyn ADD-Vantage, Unasyn Piggyback
3 grams (2 grams ampicillin and 1 gram sulbactam)→Brand names: Unasyn, Unasyn ADD-Vantage, Unasyn Piggyback
15 grams (10 grams ampicillin and 5 grams sulbactam)→Brand name: Unasyn
Society and culture
Names
Unasyn (US)
Subacillin (Taiwan)
Unictam (Egypt)
Ultracillin (Egypt)
Fortibiotic
Sulbin (Egypt)
Novactam (Egypt)
Sulbacin (Kenya)
References
External links
"Ampicillin mixture with Sulbactam". Drug Information Portal. U.S. National Library of Medicine. |
Testosterone cypionate | Testosterone cypionate, sold under the brand name Depo-Testosterone among others, is an androgen and anabolic steroid (AAS) medication which is used mainly in the treatment of low testosterone levels in men. It is also used in hormone therapy for transgender men. It is given by injection into muscle or subcutaneously, once every one to four weeks, depending on clinical indication.Side effects of testosterone cypionate include symptoms of masculinization like acne, increased hair growth, voice changes, and increased sexual desire. The drug is a synthetic androgen and anabolic steroid and hence is an agonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has strong androgenic effects and moderate anabolic effects, which make it useful for producing masculinization and suitable for androgen replacement therapy. Testosterone cypionate is a testosterone ester and a long-lasting prodrug of testosterone in the body. Because of this, it is considered to be a natural and bioidentical form of testosterone.Testosterone cypionate was introduced for medical use in 1951. Along with testosterone enanthate, testosterone undecanoate, and testosterone propionate, it is one of the most commonly used testosterone esters. It is used mainly in the United States. In addition to its medical use, testosterone cypionate is used to improve physique and performance. The drug is a controlled substance in many countries and so non-medical use is generally illicit.
Medical uses
Testosterone cypionate is used primarily in androgen replacement therapy. It is currently FDA approved for the treatment of primary or hypogonadotropic hypogonadism (either congenital or acquired). Its safety in andropause (late-onset hypogonadism in men) has not yet been established. It is currently used off-label for breast cancer, breast disorders, delayed puberty in boys, oligospermia (low sperm count), hormone replacement therapy in transgender men, and osteoporosis.
Side effects
Side effects of testosterone cypionate include virilization among others. It can also create conditions for heart attack, enlargement of prostate gland, liver malfunction, issues related to coagulation, pulmonary embolism, and polycythemia.
Pharmacology
Pharmacodynamics
Testosterone cypionate is a prodrug of testosterone and is an androgen and anabolic–androgenic steroid (AAS). That is, it is an agonist of the androgen receptor (AR).
Pharmacokinetics
The pharmacokinetics of testosterone cypionate via depot intramuscular injection, including its elimination half-life and duration of action, are said to be extremely comparable to and hence essentially the same as those of testosterone enanthate. As such, testosterone cypionate and testosterone enanthate are considered to be "functionally interchangeable" as medications. For reference, testosterone enanthate has an elimination half-life of 4.5 days and a mean residence time of 8.5 days and requires frequent administration of approximately once per week. Large fluctuations in testosterone levels result with it, with levels initially being elevated and supraphysiological. The pharmacokinetics of testosterone cypionate have been studied and reported.
Chemistry
Testosterone cypionate, or testosterone 17β-cyclopentylpropionate, is a synthetic androstane steroid and a derivative of testosterone. It is an androgen ester; specifically, it is the C17β cyclopentylpropionate (cypionate) ester of testosterone.
History
Testosterone cypionate was first synthesized in 1951 and was introduced for medical use in the United States the same year under the brand name Depo-Testosterone.
Society and culture
Generic names
Testosterone cypionate is the generic name of the drug and its USP. The drug does not have an INN, USAN, or BAN. It has also been referred to as testosterone cipionate, as well as testosterone cyclopentylpropionate or testosterone cyclopentanepropionate.
Brand names
Testosterone cypionate is or has been marketed under a variety of brand names, including:
Andro Cyp
Andronaq LA
Andronate
Dep Andro
Dep Test
Deposteron
Depostomead
Depotest
Depo-Testosterone
Depovirin
Durandro
Duratest
Jectatest
Malogen CYP
Pertestis
Testa-C
Testadiate Depo
Testex Elmu Prolongatum
Testoject LA
Virilon
Availability
Testosterone cypionate is marketed in the United States. It is not widely available outside of the United States, though it has been marketed in Canada, Australia, Spain, Brazil, and South Africa.
Legal status
Testosterone cypionate, along with other AAS, is a schedule III controlled substance in the United States under the Controlled Substances Act and a schedule IV controlled substance in Canada under the Controlled Drugs and Substances Act.
== References == |
Prostaglandin E2 | Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and in newborn babies to keep the ductus arteriosus open. In babies it is used in those with congenital heart defects until surgery can be carried out. It is also used to manage gestational trophoblastic disease. It may be used within the vagina or by injection into a vein.PGE2 synthesis within the body begins with the activation of arachidonic acid (AA) by the enzyme phospholipase A2. Once activated, AA is oxygenated by cyclooxygenase (COX) enzymes to form prostaglandin endoperoxides. Specifically, prostaglandin G2 (PGG2) is modified by the peroxidase moiety of the COX enzyme to produce prostaglandin H2 (PGH2) which is then converted to PGE2.Common side effects of PGE2 include nausea, vomiting, diarrhea, fever, and excessive uterine contraction. In babies there may be decreased breathing and low blood pressure. Caution should be taken in people with asthma or glaucoma and it is not recommended in those who have had a prior C-section. It works by binding and activating the prostaglandin E2 receptor which results in the opening and softening of the cervix and dilation of blood vessels.Prostaglandin E2 was first synthesized in 1970 and approved for medical use by the FDA in the United States in 1977. It is on the World Health Organizations List of Essential Medicines. Prostaglandin E2 works as well as prostaglandin E1 in babies.
Physiological effects
Dinoprostone has important effects in labor by inducing softening of the cervix and causing uterine contraction, and also stimulates osteoblasts to release factors that stimulate bone resorption by osteoclasts.Natural prostaglandins, including PGE1 and PGE2, are important in the structure and function of the ductus arteriosus in fetuses and newborns. They allow the ductus arteriosus to remain open, providing the necessary connection between the pulmonary artery and descending aorta that allows the blood to bypass the fetuss underdeveloped lungs and be transported to the placenta for oxygenation. The ductus arteriosus normally begins to close upon birth due to an increase of PGE2 metabolism, but in newborns with congenital heart disease, prostaglandins can be used to keep the ductus arteriosus open longer than normal to sustain healthy oxygen saturation levels in the blood. Although PGE1 is more commonly used in this setting, there has been a report of oral PGE2 being used to treat ductus-dependent congenital heart diseases in newborns to delay surgical treatment until the pulmonary arteries grew. In addition, PGE2 was used in another report to dilate the ductus arteriosus in newborns with various cardiovascular defects to allow for better perfusion of the lungs and kidneys. On the other hand, the post-partal synthesis of PGE2 in newborns is considered one cause of patent ductus arteriosus.The aerosol form of PGE2 serves as a bronchodilator, but its use in this setting is limited by the fact that it also causes coughing.PGE2, similarly to PGE1, acts as a direct vasodilator by acting on smooth muscle to cause dilation of blood vessels. In addition, PGE2 inhibits platelet aggregation.PGE2 also suppresses T cell receptor signaling and proliferation, and may play a role in resolution of inflammation. In addition, PGE2 limits the immune response by preventing B-lymphocyte differentiation and their ability to present antigens.
Central and peripheral nervous systems effects
Prostaglandin E2 (PGE2) has a variety of functions within the central nervous system and peripheral nervous system. When PGE2 interacts with EP3 receptors, it increases body temperature, resulting in fever. PGE2 is also a predominant prostanoid that contributes to inflammation via enhancing edema and leukocyte infiltration from increased vascular permeability (allowing more blood flow into an inflamed area of the body) when acting on EP2 receptors. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) blocks the activity of COX-2, resulting in a decrease of PGE2 production. NSAIDs blocking COX-2 and decreasing the production of PGE2 remediates fever and inflammation.Additionally, PGE2 acting on EP1 and EP4 receptors are a component in feeling pain via inflammatory nociception. When PGE2 binds to EP1 and EP4 receptors, an increase in excitability via cation channels as well as inhibition of hyperpolarizing potassium (K+) channels, increase membrane excitability. As a result, this causes peripheral nerve endings to report painful stimuli.
Immunity
As mentioned previously, PGE2 contributes to the inflammation when bound to EP2 receptors. In terms of immunity, prostaglandins have the ability to regulate lymphocyte function. PGE2 affect T-lymphocyte formation by regulating apoptosis of immature thymocytes. In addition, it can suppress an immune response by inhibiting B lymphocytes from forming into antibody-secreting plasma cells. When this process is suppressed, it causes a decrease in a humoral antibody response because of the decrease in production of antibodies. PGE2 also has roles in inhibition of cytotoxic T-cell function, cell division of T-lymphocytes, and the development of TH1 lymphocytes.
Neurological effects
In response to physiologic and psychologic stress, prostaglandin E2 is involved in several inflammation and immunity pathways. As one of the most abundant prostaglandins in the body, Prostaglandin E2 is involved almost all typical inflammation markers such as redness, swelling, and pain. It regulates these responses through binding to G coupled protein prostaglandin E2 (PGE2) receptors (EP1, EP2, EP3, and EP4). The activation of these different EP receptors is dependent on the type of triggering stress stimuli and results in the corresponding stress response. Activation of EP1 via PGE2 results in the suppression of impulse behaviors in response to psychological stress. Prostaglandin E2 is involved in regulating illness induced memory impairment via activation of EP2. Prostaglandin E2 activation of EP3 results in regulation of illness induced fever. EP4 is functionally similar to EP2 and has also been shown in studies to have a role in hypothermia and anorexia. In addition to inflammatory effects, Prostaglandin E2 has been shown to have anti-inflammatory effects as well, due to its different actions on varying receptors.
Smooth muscle effects
Prostaglandin E2 (PGE2) serves a significant role in vascular smooth muscle tone regulation. It is a vasodilator produced by endothelial cells. It promotes vasodilation of smooth muscles by increasing the activity of cyclic adenosine monophosphate (cAMP) to decrease intracellular calcium levels via the IP and EP4 receptors. Conversely, Prostaglandin E2 can also induce vasoconstriction via activation of EP1 and EP3 receptors, which activates the Ca2+ pathway and decreased cAMP activity.Within the gastrointestinal tract, PGE2 activates smooth muscles to cause contractions on longitudinal muscle when acting on EP3 receptors. In contrast, PGE2 effects on respiratory smooth muscle result in relaxation.
Kidney effects
Prostaglandin E2 (PGE2), along with other prostaglandins, are synthesized within the cortex and medulla of the kidney. The role of renal COX-2-derived PGE2 within the kidney is to maintain renal blood flow and glomerular filtration rate (GFR) through localized vasodilation. COX-2-derived prostanoids work to increase medullary blood flow as well as inhibit sodium reabsorption within kidney tubules. PGE2 also assists the kidneys with systemic blood pressure control by modifying water and sodium excretion. In addition, it is also thought to activate EP4 or EP2 to increase renin release, resulting in an elevation of GFR and sodium retention to raise systemic blood pressure levels within the body.
Medical uses
Cervical ripening
In the setting of labor and delivery, cervical ripening (also known as cervical effacement) is a natural process that occurs before labor, in which the cervix becomes softer, thinner, and dilated, enabling the fetus to pass through the cervix. A ripe cervix is favorable prior to induction of labor, which is a common obstetric practice, and increases the chances for a successful induction. Pharmacological methods are sometimes required to induce cervical ripening that does not occur naturally. The natural ripening of the cervix is mediated by prostaglandins, thus a common pharmacological method is to use external prostaglandins such as PGE2, or dinoprostone. Results of a systematic review and meta-analysis of the literature found that outpatient cervical ripening with dinoprostone or single-balloon catheters did not increase the risk of cesarean deliveries.PGE2 achieves cervical ripening and softening by stimulating uterine contractions as well as directly acting on the collagenase present in the cervix to soften it. There are currently two formulations of PGE2 analog available for use in cervical ripening: Prepidil, a vaginal gel, and Cervidil, a vaginal insert. PGE2 is similar to oxytocin in terms of successful labor induction and the time from induction to delivery.
Termination of intrauterine pregnancy
Prostaglandin E2 (PGE2) is a common pharmacological method of termination of pregnancy, particularly in the second trimester or for missed abortion, which is a miscarriage in which the fetus did not evacuate the uterus. However, PGE2 is not feticidal, and only induces abortion by stimulating uterine contractions. It is recommended that 20 mg of dinoprostone vaginal suppository be administered every three to five hours to evacuate the uterus. The abortion should occur within 24 hours after the beginning of administration of dinoprostone; if it does not, dinoprostone should no longer be given and other interventions would be required, such as dilation and curettage.
Side effects
A common side effect of prostaglandin E2 is its effect on gastrointestinal smooth muscle resulting in nausea, vomiting and diarrhea. Other side effects include headache, shivering, and chills. The suppository form of prostaglandin E2 is associated with increased severity of these symptoms. Fever is also a common side effect with use of prostaglandin E2. Administration of prostaglandin E2 should be stopped if a person experiences side effects such as fever.The insert and gel forms have been shown to have minimal gastrointestinal effects, but are more associated with increase stimulation of the uterus as well as fetal distress. Uterine hyperstimulation is effectively treated by stopping use of prostaglandin E2. Other monitoring parameters include sustained uterine contractions and fetal distress. In babies there may be decreased breathing and low blood pressure. Care should be taken in people with asthma or glaucoma and it is not recommended in those who have had a prior C-section.
Mechanism of action
Prostaglandin E2 binds to G protein-coupled receptors (GPCRs) EP1, EP2, EP3, and EP4 to cause various downstream effects to cause direct contractions in the myometrium. In addition, PGE2 inhibits Na+ absorption within the Thick Ascending Limb (TAL) of the Loop of Henle and ADH-mediated water transport in collecting tubules. As a result, blockage of PGE2 synthesis with NSAIDs can limit the efficacy of loop diuretics.
Administration
Prostaglandin E2 (PGE2) should only be administered by, or under the direct supervision of, a physician and careful monitoring should be performed. PGE2 comes in many dosage forms with varying pharmacokinetic properties. For example PGE2 can come in a gel formulation that requires six hour dosing or it can come as a slow release dinoprostone pessary that does not need to be re-administered and can be taken out if necessary. In a quality improvement project done in UK, the switch from prostaglandin gel to the slow release dinoprostone pessary was able to lower cesarian section rates in women undergoing induction of labor in maternity care.For the vaginal insert (brand name Cervidil), the manufacturer recommends keeping the medication frozen until use since it does not need to be warmed to room temperature. Once the package is open, a water miscible lubricant may be used to insert the medication, using your finger place the device into the vagina and position the device transversely in the posterior vaginal fornix. The person receiving the drug should remain laying down for two hours after administration of the insert is complete. The manufacturer also recommends waiting 30 minutes after removal of insert before starting oxytocin.The vaginal gel (brand name Prostin E2, Canada) is administered through a prefilled syringe and the medication is placed in the posterior fornix of the vagina. After administration people should stay laying down for at least 30 minutes after they have received the drug.
Contraindications
Contraindications to a medication are any reasons to not use the drug. Prostaglandin E2 (PGE2) is used to induce labor and should not be used in people that are contraindicated to give birth vaginally or spontaneous labor. PGE2 should not be used in people with allergies to prostaglandins or any components in the drugs formulations. PGE2 should be stopped before other oxytocic agents like oxytocin are given.Dinoprostone as a vaginal suppository is contraindicated for women with acute pelvic inflammatory disease or active disease of the cardiovascular, respiratory, hepatic, or renal systems. Caution is required for people with a history of cervical malignancy, hypo- or hypertension, anemia, epilepsy, jaundice, asthma, or pulmonary diseases. The suppository formulation is also not indicated for viable fetus evacuation.Endocervical gel is contraindicated in those with who have a history of C-sections or major uterine surgery, if the fetus is in distress and delivery is not imminent, vaginal bleeding throughout the pregnancy that is unexplained, history of difficult labors and deliveries, have cephalopelvic disproportion, less than six previous term babies with nonvertex presentation, hyper or hypotonic uterine patterns.
Toxicity
When prostaglandin E2 (PGE2) is given in excess, hyper-stimulation of the uterus occurs and immediate discontinuation of the drug usually results in resolution of toxic effects. If symptoms continue a beta adrenergic drug (e.g. terbutaline) can be used.There are many different dosage forms of PGE2. The pharmacokinetic properties vary between dosage forms and should not be interchanged. A medication error was cited in the Institute for Safe Medication Practices where Prostin E2 was used in place of Cervidil. The hospital had run out of Cervidil which is a 10 mg endocervical insert and the provider decided to use half of a 20 mg Prostin E2 vaginal suppository. Cervidil delivers the drug at a constant rate and can be removed as necessary while Prostin E2 dissolves immediately and can not be removed. This error resulted in an emergency C-section since the fetuss heart rate dropped suddenly.
Pharmacokinetics
The synthetic PGE2 dinoprostone has a plasma half-life of approximately 2.5–5 minutes, after vaginal administration, with most metabolites being excreted in the urine.
History
Swedish physiologist Ulf von Euler and British physiologist M.W. Goldblatt, first discovered prostaglandins independently in 1935 as factors contained in human seminal fluid. Prostaglandins were noted for having blood pressure reducing effects and smooth muscle regulation effects. Prostaglandin E2 itself was identified in 1962 by Swedish biochemist Sune Bergström in the seminal fluid of sheep. The structure of prostaglandins is conserved in mammals, but it is also produced by marine organisms which allowed for more research into their biological roles. Prostaglandins were discovered to be products of arachidonic acid and with the ability to radio label arachidonic acid in the early 1960s, American chemist E.J. Corey was able to synthesize prostaglandin E2 in the lab in the 1970. This advancement paved the way for later studies that helped define the actions and response of prostaglandin E2. Prostaglandin E2 was approved for medical use in the United States in 1977 and it is on the World Health Organizations List of Essential Medicines. Prostaglandin E2 was approved by the FDA in 1977.
References
External links
"Dinoprostone". Drug Information Portal. U.S. National Library of Medicine. |
Sucralfate | Sucralfate, sold under various brand names, is a medication used to treat stomach ulcers, gastroesophageal reflux disease (GERD), radiation proctitis, and stomach inflammation and to prevent stress ulcers. Its usefulness in people infected by H. pylori is limited. It is used by mouth (for upper GIT ulcers) and rectally (for radiation proctitis).Common side effects include constipation. Serious side effects may include bezoar formation and encephalopathy. Use appears to be safe in pregnancy and breastfeeding. How it works is unclear but is believed to involve binding to the ulcer and protecting it from further damage.Sucralfate was approved for medical use in the United States in 1981. It is available as a generic medication. In 2019, it was the 186th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Medical uses
Sucralfate is used for the treatment of active duodenal ulcers not related to the use of nonsteroidal anti-inflammatory drugs (NSAIDs), as the mechanism behind these ulcers is due to acid oversecretion. It is not FDA approved for gastric ulcers, but is widely used because of evidence of efficacy. The use for sucralfate in peptic ulcer disease has diminished recently, but it is still the preferred agent for stress ulcer prevention.Sucralfate has also been used for the following conditions:
Active duodenal ulcer not related to NSAID use
Maintenance therapy for resolved duodenal ulcers
Gastric ulcer not related to NSAID use and gastritis due to GERD—Triple combination therapy with lansoprazole + cisapride + sucralfate can significantly improve symptoms and quality of life and was more cost-effective than ranitidine combination group.
Aphthous ulcer and stomatitis due to radiation or chemotherapy—The 2013 guidelines of the International Society of Oral Oncology does not recommended sucralfate for the prevention of oral mucositis in head and neck cancer patients receiving radiotherapy or chemoradiation due to a lack of efficacy found in a randomized controlled trial.
Gastro-esophageal reflux disease during pregnancy—First-line drug therapy combined with lifestyle and diet modification.
Stress ulcer prophylaxis—The use of sucralfate rather than H2 antagonists for stress ulcer prophylaxis, and measures to prevent aspiration, such as continuous subglottic suctioning, have been shown to reduce the risk of ventilator-associated pneumonia (VAP). Sucralfate is less effective for prophylaxis against gastrointestinal bleeding than either a PPI or H2-blocker. For that reason, it is not commonly used for stress ulcer prophylaxis.
Prevention of stricture formation—Sucralfate has an inhibitory effect on stricture formation in experimental corrosive burns and can be used in the treatment of corrosive esophageal burns to enhance mucosal healing and suppress stricture formation
Proctitis from ulcerative colitis
Rectal bleeding due to proctitis from radiation to treat cancers of the cervix, prostate, and colon.Grade 1 bleeding experienced immediate relief with sucrasulfate enema for 1 month.
Grade 2 bleeding, sucrasulfate enema] and/or coagulation were effective.
Grade 3 bleeding lasted for 1 year despite frequent transfusions and coagulation.
Grade 2 and 3 rectal bleeding occurred in 8.5% of people. The most significant risk factor was the ICRU-CRBED. Prompt treatment with a combination of sucrasulfate enema and coagulation is effective in controlling Grade 1 and 2 rectal bleeding without the development of fistula or stricture.
Treatment of anastomotic ulcer after gastric bypass surgery
Sucralfate suspension is recommended by the US-based National Capital Poison Center (Poison Control) as an intervention for known or suspected button battery ingestions to reduce the risk and severity of injury to the esophagus prior to the batterys endoscopic removal.
Protection against ventilator-associated pneumonia - Reductions in gastric acidity and volumes increase bacterial overgrowth and the incidence of ventilator-associated pneumonia. Sucralfate may be considered to have the advantage over H2-blockers and PPIs in this regard because sucralfate does not change the pH of gastric fluid. A majority of meta-analyses found that sucralfate therapy decreased the incidence of ventilator-associated pneumonia compared to H2-antagonists.
Side effects
The most common side effect seen is constipation (2-3%). Less commonly reported side effects (<0.5%) include flatulence, headache, hypophosphatemia, xerostomia (dry mouth), and bezoar formation.
Use of this drug is not recommended for people with chronic kidney failure, as it might cause aluminium accumulation and toxicity.
A few well-controlled studies have been carried out investigating the safety and efficacy of sucralfate in children and pregnant women (Pregnancy Category B).
Mechanism of action
Sucralfate is a locally acting substance that in an acidic environment (pH < 4) reacts with hydrochloric acid in the stomach to form a cross-linking, viscous, paste-like material capable of acting as an acid buffer for as long as 6 to 8 hours after a single dose. It also attaches to proteins on the surface of ulcers, such as albumin and fibrinogen, to form stable insoluble complexes. These complexes serve as protective barriers at the ulcer surface, preventing further damage from acid, pepsin, and bile. In addition, sucralfate prevents back diffusion of hydrogen ions, and adsorbs both pepsin and bile acids.
It has been thought that sucralfate also stimulates the production of prostaglandin E2, epidermal growth factors (EGF), bFGF, and gastric mucus.
Pharmacokinetics
Onset: 1-2 hr (initial onset for peptic ulcer disease (PUD))
Absorption: <5% Orally
Duration: Up to 6 hours due to high affinity for defective mucosa (PUD)
Bioavailability: 5%, sucralfate is considered non-systemic, sucrose octasulfate: 5%, aluminum:0.005%
Metabolism: Not metabolized, excreted unchanged in urine
Excretion: Primarily in feces as unchanged drug
Brand names
Brand names include Carafate in U.S.A., Sucramal in Italy, Sucrafil, Sufrate, Sucralpro, Sucralcoat, Pepsigard, Sucral, Hapifate, Sucralpro in India, Sutra or Musin in parts of South-East Asia, Sulcrate in Canada, Discral (sucralfato) in México, Ulsanic in South Africa and Israel, Andapsin in Sweden and Antepsin. Sucracell in India.
References
External links
"Sucralfate". Drug Information Portal. U.S. National Library of Medicine. |
Olsalazine | Olsalazine is an anti-inflammatory medication used in the treatment of ulcerative colitis. It is sold under the brand name Dipentum.Olsalazine itself is a pro-drug of mesalazine (5-aminosalicyclic acid or 5-ASA) and is not absorbed in the small intestine. Instead it continues through to the colon where it is cleaved into two molecules of 5-ASA by azoreductases produced by colonic bacteria. Olsalazine thus exerts its anti-inflammatory effect by its colonic breakdown into 5-ASA which inhibits cyclooxygenase and lipoxygenase thereby reducing prostaglandin and leukotriene production.
History
Olsalazine gained Food and Drug Administration (FDA) approval in 1990.
Supply
The drug is supplied by UCB Pharma.
Research
In 2006 the Australian biotech company Giaconda received a European patent for a combination therapy for treating constipation-predominant irritable bowel syndrome that uses olsalazine and the anti-gout drug colchicine, for trials the following year.
References
External links
"Olsalazine". Drug Information Portal. U.S. National Library of Medicine. |
Fluticasone propionate | Fluticasone propionate, sold under the brand names Flovent and Flonase among others, is a steroid medication. When inhaled it is used for the long term management of asthma and COPD. In the nose it is used for hay fever and nasal polyps. It can also be used for mouth ulcers.Common side effects when inhaled include upper respiratory tract infections, sinusitis, thrush, and cough. Common side effects when used in the nose include nosebleeding and sore throat. It works by decreasing inflammation.Fluticasone propionate was patented in 1980, and approved for medical use in 1990. It is available as a generic medication. In 2020, fluticasone was the 23rd most commonly prescribed medication in the United States, with more than 24 million prescriptions.
Medical uses
Fluticasone propionate is used by powder or aerosol inhalation for the prophylaxis of asthma. The nasal spray is used for prevention and treatment of allergic rhinitis. Nasal drops are used in the treatment of nasal polyps. The nasal spray can also be used in the mouth for mouth ulcers.Fluticasone propionate in a topical form can be used to treat skin conditions such as eczema, psoriasis, and rashes.
Adverse effects
If taken correctly, the nasal spray and oral inhaler formulation have fewer corticosteroid side effects than the tablet formulation because they limit systemic (blood) absorption. However, systemic absorption is not negligible even with correct administration. Using the spray or inhaler at higher than recommended doses or with other corticosteroids can increase the risk for serious, systemic corticosteroid induced side effects. These side effects include weakened immune system, increased risk of systemic infections, osteoporosis, and elevated pressure in the eyes.
Nasal spray
Common side effects may include nasal irritation (burning, stinging, bleeding), headache, upset stomach (nausea, vomiting), and diarrhea. Rare side effects include infection (evidenced by, for example, fever, sore throat, and cough), vision problems, severe swelling, hoarse voice, and difficulty breathing or swallowing.
Inhaled
Common side effects may include upper respiratory tract infection, throat irritation, thrush, cough, and headache. Rare side effects include bruising, swelling of the face/neck, depression, tiredness, and shortness of breath.
Pharmacology
Fluticasone propionate is a highly selective agonist at the glucocorticoid receptor with negligible activity at androgen, estrogen, or mineralocorticoid receptors, thereby producing anti-inflammatory and vasoconstriction effects. It has been shown to have a wide range of inhibitory effects on multiple cell types (e.g. mast cell, eosinophil, neutrophil, macrophages, and lymphocytes) and mediators (e.g. histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. Fluticasone propionate is stated to exert a topical effect on the lungs without significant systemic effects at usual doses, due to its low systemic bioavailability.
Interactions
Fluticasone propionate is broken down by CYP3A4 (Cytochrome P450 3A4), and has been shown to interact with strong CYP3A4 inhibitors such as ritonavir and ketoconazole.Ritonavir is a common drug used in the treatment of HIV. Coadministration of ritonavir and fluticasone may lead to increased levels of fluticasone in the body, which may lead to Cushings Syndrome and adrenal insufficiency.Ketoconazole, an antifungal drug, has also been shown to increase fluticasone concentration leading to systemic corticosteroid side effects.
See also
Fluticasone
References
External links
"Fluticasone propionate". Drug Information Portal. U.S. National Library of Medicine.
"Fluticasone". Drug Information Portal. U.S. National Library of Medicine.
"Fluticasone Topical". MedlinePlus. |
Voclosporin | Voclosporin, sold under the brand name Lupkynis, is a calcineurin inhibitor used as an immunosuppressant medication for the treatment of lupus nephritis.It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.It was approved for medical use in the United States in January 2021, and in the European Union in September 2022.
Medical uses
Lupus nephritis is a common form of glomerular nephritis occurring in patients with systemic lupus nephritis. Lupus nephritis commonly leads patients to chronic kidney failure and therefore places an emphasis on early intervention for improving treatment outcomes. Early intervention with voclosporin in combination with kidney response is believed to lead to more positive clinical outcomes for lupus nephritis patients. Thus, voclosporin is used in combination with background immunosuppressive regimen for the treatment of lupus nephritis. Safety has not been established in combination with cyclophosphamide.
Contraindications
Patients who are breastfeeding or plan to breastfeed should not take this medication as it may cause fetal harm. Voclosporin is not recomnended in patients with a baseline eGFR less than or equal to 45 ml/min/1.73 m2 unless benefits exceeds risk. Dose should be reduced if the drug is used within this population as well as for patients who are hepatically impaired. Avoid the use of live attenuated vaccines when patients are on this medication. Avoid co-administration of voclosporin and other moderate to strong CYP3A4 inhibitors and if needed then reduce the dose of voclosporin. Dosages of PgP-substrate drugs should be reduced if co-administered with voclosporin.
Adverse effects
Voclosporin has a boxed warning for malignancies and serious infections. Patients taking Voclosporin along with other immunosuppressants have an increased risk for developing malignancies and serious infections that may lead to hospitalization or death. The most common adverse reactions of voclosporin were (>3%), glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain(upper), dyspepsia, alopecia, renal impairment, abdominal pain, mouth ulceration, fatigue. tremor, acute kidney injury, and decreased appetite.
Pharmacology
Voclosporin is a cyclosporin A analog, similar to cyclosporin A with modifications on an amino acid within one region that allows the drug to bind to Calcineurin. Voclosporin inhibits calcineurin, which then blocks the production of IL-2 and T-cell mediated immune responses. As a result of the calcineurin inhibition, podocytes (cells within the kidneys) are stabilized while inflammation is reduced. Reduction of inflammation within the kidneys prevents further renal damage.
Pharmacokinetics
When administered on an empty stomach, the median Tmax of voclosporin is 1.5 hours. The AUC is estimated to be 7693 ng/mL and the Cmax is estimated at 955 ng/mL. The volume of distribution is approximately 2,154 L and distributes within the red blood cells. The distribution between the plasma and whole blood is affected by temperature and concentration. The protein binding of voclosporin is 97%. The average terminal half-life of voclosporin is 63.6 L/h. The drug is mainly metabolized by the CYP3A4 hepatic cytochrome enzyme. Pharmacologic activity is mainly attributed to the parent molecule itself, with the major metabolite being 8-fold less potent than the parent drug.
History
Voclosporin was discovered by Isotechnika in the 1990s. Isotechnika was founded in 1993 and merged with Aurinia Pharmaceuticals in 2013. In January 2021, Aurinia Pharmaceuticals received approval from the Food & Drug Administration to sell the drug Lupkynis.
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 Lupkynis, intended for the treatment of lupus nephritis. The applicant for this medicinal product is Otsuka Pharmaceutical Netherlands B.V. Voclosporin was approved for medical use in the European Union in September 2022.
References
External links
"Voclosporin". Drug Information Portal. U.S. National Library of Medicine. |
Dolutegravir/rilpivirine | Dolutegravir/rilpivirine, sold under the brand name Juluca, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It contains the medicines dolutegravir and rilpivirine. It is taken by mouth.The most common adverse reactions (of all severity grades) are diarrhea and headache.Dolutegravir/rilpivirine was approved for use in the United States in November 2017, and for use in the European Union in May 2018.
Medical uses
Dolutegravir/rilpivirine is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least six months with no history of virological failure and no known or suspected resistance to any non-nucleoside reverse transcriptase inhibitor or integrase inhibitor.
References
External links
"Dolutegravir mixture with rilpivirine". Drug Information Portal. U.S. National Library of Medicine. |
Diazoxide | Diazoxide, sold under the brand name Proglycem and Balila (India), is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in refractory cases of sulfonylurea toxicity. It is generally taken by mouth.Common side effects include high blood sugar, fluid retention, low blood platelets, a fast heart rate, increased hair growth, and nausea. Other severe side effects include pulmonary hypertension and heart failure. It is chemically similar to thiazide diuretics. It works by decreasing insulin release from the pancreas and increasing glucose release by the liver.Diazoxide was approved for medical use in the United States in 1973. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.
Medical uses
Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension.Diazoxide also inhibits the secretion of insulin by opening ATP-sensitive potassium channel of beta cells of the pancreas; thus, it is used to counter hypoglycemia in disease states such as insulinoma (a tumor producing insulin) or congenital hyperinsulinism.
Diazoxide acts as a positive allosteric modulator of the AMPA and kainate receptors, suggesting potential application as a cognitive enhancer.
Side effects
Diazoxide interferes with insulin release through its action on potassium channels. Diazoxide is one of the most potent openers of the K+ ATP channels present on the insulin producing beta cells of the pancreas. Opening these channels leads to hyperpolarization of cell membrane, a decrease in calcium influx, and a subsequently reduced release of insulin. This mechanism of action is the mirror opposite of that of sulfonylureas, a class of medications used to increase insulin release in Type 2 Diabetics. Therefore, this medicine is not given to non-insulin dependent diabetic patients.
The Food and Drug Administration published a Safety Announcement in July 2015 highlighting the potential for development of pulmonary hypertension in newborns and infants treated with this drug.
See also
AMPA receptor positive allosteric modulator
Glucose-elevating agent
References
External links
"Diazoxide". Drug Information Portal. U.S. National Library of Medicine. |
Sumatriptan | Sumatriptan, sold commonly under brand names Imitrex and Treximet among others, is a medication used to treat migraine headaches and cluster headaches. It is taken orally, intranasally, or by subcutaneous injection. Therapeutic effects generally occur within three hours.Its primary effect as a serotonin 5-HT1B/1D receptor agonist can create common side effects such as chest pressure, fatigue, vomiting, tingling, and vertigo. Serious side effects may include serotonin syndrome, heart attacks, strokes, and seizures. With excessive medication overuse headaches may occur. It is unclear if use during pregnancy or breastfeeding is safe. The mechanism of action not entirely clear. It is in the triptan class of medications.Sumatriptan was patented in 1982 and approved for medical use in 1991. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 98th most commonly prescribed medication in the United States, with more than seven million prescriptions. It is also available as the combination product sumatriptan/naproxen.
Medical uses
Sumatriptan is effective for ending or relieving the intensity of migraine and cluster headaches. It is most effective when taken early after the start of the pain. Injected sumatriptan is more effective than other formulations.Oral sumatriptan can be used also in the treatment of post-dural puncture headache.
Adverse effects
Overdose of sumatriptan can cause sulfhemoglobinemia, a rare condition in which the blood changes from red to green, due to the integration of sulfur into the hemoglobin molecule. If sumatriptan is discontinued, the condition reverses within a few weeks.
Serious cardiac events, including some that have been fatal, have occurred following the use of sumatriptan injection or tablets. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation.The most common side effects reported by at least 2% of patients in controlled trials of sumatriptan (25-, 50-, and 100-mg tablets) for migraine are atypical sensations (paresthesias and warm/cold sensations) reported by 4% in the placebo group and 5–6% in the sumatriptan groups, pain and other pressure sensations (including chest pain) reported by 4% in the placebo group and 6–8% in the sumatriptan groups, neurological events (vertigo) reported by less than 1% in the placebo group and less than 1% to 2% in the sumatriptan groups. Malaise/fatigue occurred in less than 1% of the placebo group and 2–3% of the sumatriptan groups. Sleep disturbance occurred in less than 1% in the placebo group to 2% in the sumatriptan group.
Mechanism of action
Sumatriptan is molecularly similar to serotonin (5-HT), and is a 5-HT receptor (types 5-HT1D and 5-HT1B) agonist. Sumatriptans primary therapeutic effect is related in its inhibition of the release of Calcitonin gene-related peptide (CGRP), likely through its 5-HT1D/1B receptor-agonist action. This has been substantiated by the efficacy of more recently developed CGRP targeting drugs and antibodies developed for the preventive treatment of migraine. How agonism of the 5-HT1D/1B receptors inhibits CGRP release is not fully understood. CGRP is believed to cause sensitization of trigeminal nociceptive neurons, contributing to the pain experienced in migraine.Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which presumably accounts for sumatriptans efficacy in treating cluster headaches. The injectable form of the drug has been shown to abort a cluster headache within 30 minutes in 77% of cases.
Pharmacokinetics
Sumatriptan is administered in several forms: tablets, subcutaneous injection, and nasal spray. Oral administration (as succinate salt) has low bioavailability, partly due to presystemic metabolism—some of it gets broken down in the stomach and bloodstream before it reaches the target arteries. A rapid-release tablet formulation with the same bioavailability but a high concentration can achieve therapeutic effects on average 10–15 minutes earlier than other oral forumulations. When injected, sumatriptan is faster-acting (usually within 10 minutes), but the effect lasts for a shorter time. Sumatriptan is metabolised primarily by monoamine oxidase A into 2-{5-[(methylsulfamoyl)methyl]-indole-3-yl}acetic acid, which is then conjugated to glucuronic acid. These metabolites are excreted in the urine and bile. Only about 3% of the active drug may be recovered unchanged.
There is no simple, direct relationship between sumatriptan concentration (pharmacokinetics) per se in the blood and its anti-migraine effect (pharmacodynamics). This paradox has, to some extent, been resolved by comparing the rates of absorption of the various sumatriptan formulations, rather than the absolute amounts of drug that they deliver.
History
In 1991, Glaxo received approval for sumatriptan, which was the first available triptan.
In July 2009, the US FDA approved a single-use jet injector formulation of sumatriptan. The device delivers a subcutaneous injection of sumatriptan, without the use of a needle. Autoinjectors with needles have been previously available in Europe and North America.Phase III studies with an iontophoretic transdermal patch (Zelrix/Zecuity) started in July 2008. This patch uses low voltage controlled by a pre-programmed microchip to deliver a single dose of sumatriptan through the skin within 30 minutes. Zecuity was approved by the US FDA in January 2013. Sales of Zecuity have been stopped following reports of skin burns and irritation.
Society and culture
Legal status
In the United States, it is available only by medical prescription. This requirement for a medical prescription also exists in Australia. However, it can be bought over the counter in the UK and Sweden.In Russia versions of sumatriptan, which are not registered in the National registry of medications, may be regarded as narcotic drugs (derivatives of dimethyltriptamine).
Generics
Glaxo patents for sumatriptan expired in February 2009. At that time, Imitrex sold for about $25 a pill. Par Pharmaceutical then introduced generic versions of sumatriptan injection (sumatriptan succinate injection) 4- and 6-mg starter kits and 4- and 6-mg filled syringe cartridges, and 6-mg vials soon after.Mylan Laboratories Inc., Ranbaxy Laboratories, Sandoz (a subsidiary of Novartis), Dr. Reddys Laboratories, and other companies have been producing generic versions of sumatriptan tablets in 25-, 50-, and 100-mg doses. Generic forms of the drug are available in U.S. and European markets after Glaxos patent protections expired in the respective countries. A nasal spray form of sumatriptan known as AVP-825 has been developed by Avanir and is generically available in some countries.
Controversy
According to the American Headache Society, "Patients frequently state that they have difficulty accessing triptans prescribed to them." In the U.S. triptans cost from $12 to $120 each, and more that 80% of U.S. health insurance plans limit place a limit on the amount of pills available to a patient per month, which has been called "arbitrary and unfair."
References
External links
"Sumatriptan". Drug Information Portal. U.S. National Library of Medicine. |
Mobocertinib | Mobocertinib, sold under the brand name Exkivity, is used for the treatment of non-small cell lung cancer.The most common side effects include diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.Mobocertinib is a small molecule tyrosine kinase inhibitor. Its molecular target is epidermal growth factor receptor (EGFR) bearing mutations in the exon 20 region. Mobocertinib is an irreversible kinase inhibitor, forming a covalent bond with the cysteine 797 in the EGFR active site, leading to sustained inhibition of EGFR enzymatic activity. The irreversible binding leads to increased potency via higher affinity binding, more sustained EGFR kinase activity inhibition, and greater overall selectivity, as only a limited number of other kinases possess a cysteine in the equivalent position.Mobocertinib was approved for medical use in the United States in September 2021. It is a first-in-class oral treatment to target EGFR Exon20 insertion mutations.
Medical uses
Mobocertinib is indicated for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
Mechanism of action
Mobocertinib acts to inhibit EGFR exon 20 insertion mutations at a lower concentration than it does on wild-type proteins.
Pharmacokinetics
The volume of distribution of Mobocertinib at steady state is 3,509 L. The mean oral bioavailability of Mobocertinib is 37%. The median Tmax is 4 hours. The average half-life of Mobocertinib and its metabolites is 18 hours. Mobocertinib is metabolized by CYP3A enzymes.
Warnings
Mobocertinib may increase the chance of QTC prolongation, specifically Torsades de Pointes which can be fatal.
Adverse Effects
More serious side effects of Mobocertinib may include agitation, bloating of the eyes, lips, feet, blurred vision, coma, decreased urine output, headache, hostility, diarrhea, depression, dizziness, fainting, lethargy, anxiety, nausea, seizures, weight gain, fatigue as well as edema. Other side effects which may be less frequent are: chills, cough, dilated neck veins, ill-feeling and trouble with breathing. Other notable side effects of taking Mobocertinib are: having an acidic stomach, heartburn, acidity, hair loss/thinning, bone pain, sore throat, stuffy nose, trouble swallowing, vomiting and weakness in hands and feet.
History
Mobocertinib was studied in participants with previously treated metastatic non-small cell lung cancer with EGFR exon 20 insertions.
References
External links
"Mobocertinib". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT02716116 for "A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer" at ClinicalTrials.gov |
Beclometasone | Beclomethasone, also known as beclomethasone dipropionate, and sold under the brand name Qvar among others, is a steroid medication. It is available as an inhaler, cream, pills, and nasal spray. The inhaled form is used in the long-term management of asthma. The cream may be used for dermatitis and psoriasis. The pills have been used to treat ulcerative colitis. The nasal spray is used to treat allergic rhinitis and nasal polyps.Common side effects with the inhaled form include respiratory infections, headaches, and throat inflammation. Serious side effects include an increased risk of infection, cataracts, Cushings syndrome, and severe allergic reactions. Long-term use of the pill form may cause adrenal insufficiency. The pills may also cause mood or personality changes. The inhaled form is generally regarded as safe in pregnancy. Beclometasone is mainly a glucocorticoid.Beclomethasone dipropionate was first patented in 1962 and used medically in 1972. It was approved for medical use in the United States in 1976. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 153rd most commonly prescribed medication in the United States, with more than four million prescriptions.
Side effects
Common side effects with the inhaled form include respiratory infections, headaches, and throat inflammation. Serious side effects include an increased risk of infection, cataracts, Cushings syndrome, and severe allergic reactions. Long-term use of the pill form may cause adrenal insufficiency. The pills may also cause mood or personality changes. The inhaled form is generally regarded as safe in pregnancy.Occasionally, it may cause a cough upon inhalation. Deposition on the tongue and throat may promote oral candidiasis, which appears as a white coating, possibly with irritation.
This may usually be prevented by rinsing the mouth with water after using the inhaler. Other adverse drug reaction side effects may rarely include: a smell similar to burning plastic, unpleasant taste, hoarseness or nasal congestion, pain or headache, and visual changes. Allergic reactions may occur, but rarely.
Nasal corticosteroids may be associated with central serous retinopathy.
Pharmacology
Beclometasone is mainly a glucocorticoid. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The activated glucocorticoid receptor-glucocorticoid complex up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).Glucocorticoids are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as inflammation.
Names
Beclometasone dipropionate is the INN modified and beclomethasone dipropionate is the USAN and former BAN. It is a prodrug of the free form, beclometasone (INN). The prodrug beclometasone is marketed in Norway and Russia.Clenil, Qvar are brandnames for the inhalers. Beconase, Alanase, Vancenase, Qnasl for the nasal spray or aerosol.
References
External links
"Beclometasone". Drug Information Portal. U.S. National Library of Medicine. |
Vinorelbine | Vinorelbine (NVB), sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mouth.Common side effects include bone marrow suppression, pain at the site of injection, vomiting, feeling tired, numbness, and diarrhea. Other serious side effects include shortness of breath. Use during pregnancy may harm the baby. Vinorelbine is in the vinca alkaloid family of medications. It is believed to work by disrupting the normal function of microtubules and thereby stopping cell division.Vinorelbine was approved for medical use in the United States in 1994. It is on the World Health Organizations List of Essential Medicines.
Medical uses
Vinorelbine is approved for the treatment of non-small-cell lung cancer. It is used off-label for other cancers such as metastatic breast cancer. It is also active in rhabdomyosarcoma.
Side effects
Vinorelbine has a number of side-effects that can limit its use:
Chemotherapy-induced peripheral neuropathy (a progressive, enduring and often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs), lowered resistance to infection, bruising or bleeding, anaemia, constipation, vomitings, diarrhea, nausea, tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which it was injected (phlebitis). Seldom severe hyponatremia is seen.
Less common effects are hair loss and allergic reaction.
Pharmacology
The antitumor activity is due to inhibition of mitosis through interaction with tubulin.
History
Vinorelbine was invented by the pharmacist Pierre Potier and his team from the CNRS in France in the 1980s and was licensed to the oncology department of the Pierre Fabre Group. The drug was approved in France in 1989 under the brand name Navelbine for the treatment of non-small cell lung cancer. It gained approval to treat metastatic breast cancer in 1991. Vinorelbine received approval by the United States Food and Drug Administration (FDA) in December 1994 sponsored by Burroughs Wellcome Company. Pierre Fabre Group now markets Navelbine in the U.S., where the drug went generic in February 2003.
In most European countries, vinorelbine is approved to treat non-small cell lung cancer and breast cancer. In the United States it is approved only for non-small cell lung cancer.
Sources
The Madagascan periwinkle Catharanthus roseus L. is the source for a number of important natural products, including catharanthine and vindoline and the vinca alkaloids it produces from them: leurosine and the chemotherapy agents vinblastine and vincristine, all of which can be obtained from the plant. The newer semi-synthetic chemotherapeutic agent vinorelbine, which is used in the treatment of non-small-cell lung cancer and is not known to occur naturally. However, it can be prepared either from vindoline and catharanthine or from leurosine, in both cases by synthesis of anhydrovinblastine. The leurosine pathway uses the Nugent–RajanBabu reagent in a highly chemoselective de-oxygenation of leurosine. Anhydrovinblastine is then reacted sequentially with N-bromosuccinimide and trifluoroacetic acid followed by silver tetrafluoroborate to yield vinorelbine.
Oral formulation
An oral formulation has been marketed and registered in most European countries. It has similar efficacy as the intravenous formulation, but it avoids venous toxicities of an infusion and is easier to take. The oral form is not approved in the United States, or Australia.
References
External links
"Vinorelbine". Drug Information Portal. U.S. National Library of Medicine. |
Azithromycin | Azithromycin is an antibiotic medication used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumonia, travelers diarrhea, and certain other intestinal infections. Along with other medications, it may also be used for malaria. It can be taken by mouth or intravenously with doses once per day.Common side effects include nausea, vomiting, diarrhea and upset stomach. An allergic reaction, such as anaphylaxis, QT prolongation, or a type of diarrhea caused by Clostridium difficile is possible. No harm has been found with its use during pregnancy. Its safety during breastfeeding is not confirmed, but it is likely safe. Azithromycin is an azalide, a type of macrolide antibiotic. It works by decreasing the production of protein, thereby stopping bacterial growth.Azithromycin was discovered in 1980 by the Croatian pharmaceutical company Pliva and approved for medical use under the brand name Sumamed in 1988. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies it as critically important for human medicine. It is available as a generic medication and is sold under many trade names worldwide. In 2019, it was the 48th most commonly prescribed medication in the United States, with more than 15 million prescriptions.
Medical uses
Azithromycin is used to treat diverse infections, including:
Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patient-by-patient basis against the risk of cardiovascular and other adverse effects.
Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae
Uncomplicated skin infections due to S. aureus, S. pyogenes, or S. agalactiae
Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.
Trachoma due to C. trachomatis
Genital ulcer disease (chancroid) in men due to H. ducrey
Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.
Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.
Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy
Bacterial susceptibility
Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.
A strain of gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin, but the drug is not widely used as monotherapy due to a low barrier to resistance development. Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.Aerobic and facultative Gram-positive microorganisms
Staphylococcus aureus (Methicillin-sensitive only)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenesAerobic and facultative anaerobic Gram-negative microorganisms
Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Bordetella pertussis
Legionella pneumophilaAnaerobic microorganisms
Peptostreptococcus species
Prevotella biviaOther microorganisms
Chlamydophila pneumoniae
Chlamydia trachomatis
Mycoplasma genitalium
Mycoplasma pneumoniae
Ureaplasma urealyticum
Pregnancy and breastfeeding
No harm has been found with use during pregnancy. However, there are no adequate well-controlled studies in pregnant women.The safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would have adverse effects. Nevertheless, it is recommended that the drug be used with caution during breastfeeding.
Airway diseases
Azithromycin appears to be effective in the treatment of chronic obstructive pulmonary disease through its suppression of inflammatory processes. And potentially useful in asthma and sinusitis via this mechanism. Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.
Adverse effects
Most common adverse effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, skin reactions, and anaphylaxis have been reported. Clostridium difficile infection has been reported with use of azithromycin. Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.Occasionally, people have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.In 2013 the FDA issued a warning that azithromycin "can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm." The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal heart rhythms.It has been reported that azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.
Pharmacology
Mechanism of action
Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.
Pharmacokinetics
Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma due to ion trapping and its high lipid solubility. Azithromycins half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours. Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as an unchanged drug in urine.
History
A team of researchers at the pharmaceutical company Pliva in Zagreb, Croatia,—Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Slobodan Đokić—discovered azithromycin in 1980. The company Pliva patented it in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Plivas license in other markets under the brand name Zithromax in 1991. Patent protection ended in 2005.
Society and culture
Available forms
Azithromycin is available as a generic medication. Azithromycin is commonly administered in film-coated tablet, capsule, oral suspension, intravenous injection, granules for suspension in sachet, and ophthalmic solution.
Usage
In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US, whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions. In 2017, azithromycin was the second most prescribed antibiotic for outpatients in the United States.
Research
COVID-19
Despite early evidence showing azithromycin slowed down coronavirus multiplication in laboratory settings, further research indicates it to be ineffective as a treatment for COVID-19 in humans. After a large-scale trial showed no benefit of using azithromycin in treating COVID-19, the UKs National Institute for Health and Care Excellence (NICE) updated its guidance and no longer recommends the medication for COVID-19.
References
External links
"Azithromycin". Drug Information Portal. U.S. National Library of Medicine. |
Methylprednisolone succinate | Methylprednisolone succinate, sold under the brand names Solu-Medrol among others, is a synthetic glucocorticoid corticosteroid and a corticosteroid ester—specifically the C21 succinate ester of methylprednisolone—which is used by intravenous administration. Methylprednisolone succinate is provided as two different salts when used as a pharmaceutical drug: a sodium salt (methylprednisolone sodium succinate; brand name Solu-Medrol, others) and a hydrogen salt (methylprednisolone hemisuccinate or methylprednisolone hydrogen succinate; brand name Urbason).
See also
List of corticosteroid esters § Methylprednisolone esters
== References == |
Clofazimine | Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to support its use in other conditions though a retrospective study found it 95% effective in the treatment of Mycobacterium avium complex (MAC) when administered with a macrolide and ethambutol, as well as the drugs amikacin and clarithromycin. However, in the United States, clofazimine is considered an orphan drug, is unavailable in pharmacies, and its use in the treatment of MAC is overseen by the Food and Drug Administration. It is taken orally.Common side effects include abdominal pain, diarrhea, itchiness, dry skin, and change in skin color. It can also cause swelling of the lining of the gastrointestinal tract, increased blood sugar, and sensitivity to the sun. It is unclear if use during pregnancy is safe. Clofazimine is a phenazine dye and is believed to work by interfering with DNA.Clofazimine was discovered in the 1950s at Trinity College, Dublin, and approved for medical use in the United States in 1986. It is on the World Health Organizations List of Essential Medicines. In the United States it is not available commercially but can be obtained from the US Department of Health and Human Services.
Medical uses
The primary use of clofazimine is for the treatment of leprosy. Other uses have not been proven to be safe or effective.It has been studied in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in people with HIV/AIDS and Mycobacterium avium paratuberculosis. Clofazimine also has a marked anti-inflammatory effect and is given to control the leprosy reaction, erythema nodosum leprosum (ENL). (From AMA Drug Evaluations Annual, 1993, p1619). The drug is given as an alternative to people who can not tolerate the effects of dapsone for leprosy.Early research suggested clofazimine inhibits the replication of SARS-CoV-2 in vitro and reduce viral load and inflammation in the lung in animal models
Side effects
Clofazimine produces pink to brownish skin pigmentation in 75-100% of patients within a few weeks, as well as similar discoloration of most bodily fluids and secretions. These discolorations are reversible but may take months to years to disappear. There is evidence in medical literature that as a result of clofazimine administration, several patients have developed depression which in some cases resulted in suicide. It has been hypothesized that the depression was a result of this chronic skin discoloration.Cases of icthyosis and skin dryness are also reported in response to this drug (8%-28%), as well as rash and itchiness (1-5%).40-50% of patients develop gastrointestinal intolerance. Rarely, patients have died from bowel obstructions and intestinal bleeding, or required abdominal surgery to correct the same problem.
Mechanism
Clofazimine works by binding to the guanine bases of bacterial DNA, thereby blocking the template function of the DNA and inhibiting bacterial proliferation. It also increases activity of bacterial phospholipase A2, leading to release and accumulation of lysophospholipids, which are toxic and inhibit bacterial proliferation.Clofazimine is also a FIASMA (functional inhibitor of acid sphingomyelinase).
Metabolism
Clofazimine has a biological half life of about 70 days. Autopsies performed on those who have died while on clofazimine show crystal-like aggregates in the intestinal mucosa, liver, spleen, and lymph nodes.
History
Clofazimine, initially known as B663, was first synthesised in 1954 by a team of scientists at Trinity College, Dublin: Frank Winder, J.G. Belton, Stanley McElhinney, M.L. Conalty, Seán OSullivan, and Dermot Twomey, led by Vincent Barry. Clofazimine was originally intended as an anti-tuberculosis drug but proved ineffective. In 1959, a researcher named Y. T. Chang identified its effectiveness against leprosy. After clinical trials in Nigeria and elsewhere during the 1960s, Swiss pharmaceutical company Novartis launched the product in 1969 under the brand name Lamprene.Novartis was granted FDA approval of clofazimine in December 1986 as an orphan drug. The drug is currently no longer commercially available in the United States.
Society and culture
Clofazimine is marketed under the trade name Lamprene by Novartis. One producer of the clofazimine molecule is Sangrose Laboratories, located in Mavelikara, India.
Research
The immunosuppressive effects of clofazimine were immediately noticed when applied in animal model. Macrophages were first reported to be inhibited due to the stabilization of lysosomal membrane by clofazimine. Clofazimine also showed a dosage-dependent inhibition of neutrophil motility, lymphocyte transformation, mitogen-induced PBMC proliferation and complement-mediated solubilization of pre-formed immune complexes in vitro. A mechanistic studying of clofazimine in human T cells revealed that this drug is a Kv1.3 (KCNA3) channel blocker. This indicates that clofazimine will be potentially used for treatment of multiple sclerosis, rheumatoid arthritis and type 1 diabetes. Because the Kv1.3-high effector memory T cells (TEM) are actively involved in the development of these diseases, and Kv1.3 activity is essential for stimulation and proliferation of TEM by regulating calcium influx in the T cells.
Several clinical trials were also conducted looking for its immunosuppressive activity even before it was approved for leprosy by FDA. It was first reported to be effective in treating chronic discoid lupus erythematosus with 17 out of 26 patients got remission. But later another group found it was ineffective in treating diffuse, photosensitive, systemic lupus erythematosus. Clofazimine also has been sporadically reported with some success in other autoimmune diseases such as psoriasis, Mieschers granulomatous cheilitis.
References
External links
"Lamprene (clofazimine) capsules, for oral use Initial U.S. Approval: 1986". DailyMed. 31 January 2019. Retrieved 14 June 2020.</ref> |
Lonafarnib | Lonafarnib, sold under the brand name Zokinvy, is a medication used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in people one year of age and older.The most common side effects included nausea vomiting, headache, diarrhea, infection, decreased appetite and fatigue.Lonafarnib was approved for medical use in the United States in November 2020, and in the European Union in July 2022. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.
Medical uses
Lonafarnib is indicated to be used to reduce the risk of death due to Hutchinson-Gilford progeria syndrome and for the treatment of certain other processing-deficient progeroid laminopathies in people one year of age and older.
Contraindications
Lonafarnib is contraindicated for co-administration with strong or moderate CYP3A inhibitors and inducers, as well as midazolam and certain cholesterol-lowering medications.
History
Lonafarnib, a farnesyltransferase inhibitor, is an oral medication that helps prevent the buildup of defective progerin or progerin-like protein. The effectiveness of lonafarnib for the treatment of Hutchinson-Gilford progeria syndrome was demonstrated in 62 patients from two single-arm trials (Trial 1/NCT00425607 and Trial 2/NCT00916747) that were compared to matched, untreated patients from a separate natural history study. Compared to untreated patients, the lifespan of Hutchinson-Gilford progeria syndrome patients treated with lonafarnib increased by an average of three months through the first three years of treatment and by an average of 2.5 years through the maximum follow-up time of 11 years. Lonafarnibs approval for the treatment of certain processing-deficient progeroid laminopathies that are very rare took into account similarities in the underlying genetic mechanism of disease and other available data. The participants were from 34 countries around the world, including the United States.The U.S. Food and Drug Administration (FDA) granted the application for lonafarnib priority review, orphan drug, and breakthrough therapy designations. In addition, the manufacturer received a rare pediatric disease priority review voucher. The FDA granted the approval of Zokinvy to Eiger BioPharmaceuticals, Inc.
Society and culture
Legal status
On 19 May 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Zokinvy, intended for the treatment of patients with progeroid syndromes. The applicant for this medicinal product is EigerBio Europe Limited. It was approved for medical use in the European Union in July 2022.
Research
Lonafarnib is a farnesyltransferase inhibitor (FTI) that has been investigated in a human clinical trial as a treatment for progeria, which is an extremely rare genetic disorder in which symptoms resembling aspects of aging are manifested at a very early age.Lonafarnib is a synthetic tricyclic halogenated carboxamide with antineoplastic properties. As such, it is used primarily for cancer treatment. For those with progeria, research has shown that the drug reduces the prevalence of stroke and transient ischemic attack, and the prevalence and frequency of headaches while taking the medication. A phase II clinical trial was completed in 2012, which showed that a cocktail of drugs that included lonafarnib and two other drugs met clinical efficacy endpoints that improved the height and diminished the rigidity of the bones of progeria patients.
References
External links
"Lonafarnib". Drug Information Portal. U.S. National Library of Medicine.
"Experimental Drug Is First To Help Kids With Premature-Aging Disease", NPR, September 24, 2012
Clinical trial number NCT00425607 for "Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria" at ClinicalTrials.gov
Clinical trial number NCT00916747 for "Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria" at ClinicalTrials.gov |
Atovaquone/proguanil | Atovaquone/proguanil, sold under the brand name Malarone among others, is a fixed-dose combination medication used to treat and prevent malaria, including chloroquine-resistant malaria. It contains atovaquone and proguanil. It is not recommended for severe or complicated malaria. It is taken by mouth.Common side effects include abdominal pain, vomiting, diarrhea, cough, and itchiness. Serious side effects may include anaphylaxis, Stevens–Johnson syndrome, hallucinations, and liver problems. It is unclear if use during pregnancy or breastfeeding is safe for the baby. It is not recommended to prevent malaria in those with poor kidney function. Atovaquone works by interfering with the function of mitochondria in malaria while proguanil by blocking dihydrofolate reductase.Atovaquone/proguanil was approved for medical use in the United States in 2000. It has been available as a generic medication since 2011.
Medical uses
Malaria treatment
Atovaquone/proguanil is not normally used to treat severe malaria, when an injectable drug such as quinine is used instead.
Malaria prevention
Since some malaria strains are resistant to atovaquone/proguanil, it is not effective in all parts of the world. It must be taken with a fatty meal, or at least some milk, for the body to absorb it adequately—and to avoid painful stomach irritation, which proguanil frequently causes if taken without food. Also, stomach irritation may occur if one lies down within a half hour after taking this medicine.
Resistance
Proguanil acts as a mitochondrial sensitiser and synergizes with atovaquone. When atovaquone is used as a sole agent, a high natural frequency of cytochrome b mutants leads to a high failure rate. This is potentially due to the high lipophilicity and slow uptake of atovaquone, which results in a relatively prolonged period of parasite exposure at ineffective concentrations. Specific mutations (Y268S, Y268C) have been shown to confer resistance in vivo, but the other mechanisms of resistance remain unknown.
Adverse effects
Side effects are generally mild. While some people experience side effects, such as coughing, diarrhea, dizziness, headache, loss of appetite, mouth sores, nausea, stomach pain, vomiting, or weakness, the majority have none or few of these.
Mechanism of action
Atovaquone selectively inhibits the malarial cytochrome bc1 complex in the parasitic electron transport chain, collapsing the mitochondrial membrane potential. The malarial electron transport chain does not contribute significantly to ATP synthesis; thus, it is believed that parasite death is due to the indirect inhibition of dihydroorotate dehydrogenase, which requires transport chain function and is essential to pyrimidine biosynthesis.Proguanil, via its metabolite cycloguanil, functions as a dihydrofolate reductase inhibitor, halting parasitic deoxythymidylate synthesis.
Chemistry
A standard tablet of Malarone contains 100 mg of proguanil hydrochloride and 250 mg of atovaquone. A pediatric tablet contains 25 mg of proguanil hydrochloride and 62.5 mg of atovaquone.
History
Glaxo Wellcome patented the combination of atovaquone and proguanil to treat malaria in 1999. Patent protection expired in 2013. The U.S. Food and Drug Administration (FDA) approved a generic formulation from Glenmark Generics in 2011. In February 2013, the United Kingdom High Court revoked Glaxos patent on grounds of obviousness, which clears the way for firms to sell generic versions there.
References
External links
"Atovaquone mixture with proguanil hydrochloride". Drug Information Portal. U.S. National Library of Medicine. |
Alora | Alora may refer to:
Alora (gastropod), a genus of wentletraps in the family Epitoniidae
Alora (drug), a brand name for transdermal Estradiol
Álora, a town in southern Spain |
Loratadine | Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis (hay fever) and hives. It is also available in combination with pseudoephedrine, a decongestant, known as loratadine/pseudoephedrine. It is taken orally.Common side effects include sleepiness, dry mouth, and headache. Serious side effects are rare and include allergic reactions, seizures, and liver problems. Use during pregnancy appears to be safe but has not been well studied. It is not recommended in children less than two years old. It is in the second-generation antihistamine family of medication.Loratadine was patented in 1980 and came to market in 1988. It is on the World Health Organizations List of Essential Medicines. Loratadine is available as a generic medication. In the United States, it is available over the counter. In 2019, it was the 66th most commonly prescribed medication in the United States, with more than 11 million prescriptions.
Medical uses
Loratadine is indicated for the symptomatic relief of allergy such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria, and other skin allergies. For allergic rhinitis, loratadine is indicated for both nasal and eye symptoms - sneezing, runny nose, and itchy or burning eyes.Similarly to cetirizine, loratadine attenuates the itching associated with Kimuras disease.
Forms
The drug is available in many different forms, including tablets, oral suspension, and syrup, and in combination with pseudoephedrine. Also available are quick-dissolving tablets.
Contraindications
Patients with severe hepatic (liver) disorders may need to start with a lower dose. No dose adaptation is necessary for elderly or renally (kidney) impaired patients.Loratadine is usually compatible with breastfeeding (classified category L-2 - probably compatible, by the American Academy of Pediatrics). In the U.S., it is classified as category B in pregnancy, meaning animal reproduction studies have failed to demonstrate a risk to the fetus, but no adequate and well-controlled studies in pregnant women have been conducted.
Adverse effects
As a "non-sedating" antihistamine, loratadine causes less (but still significant, in some cases) sedation and psychomotor retardation than the older antihistamines, because it penetrates the blood/brain barrier less.Other side effects include headache and antimuscarinic effects, such as urinary retention, dry mouth, blurred vision, and gastrointestinal problems.
Interactions
Substances that act as inhibitors of the CYP3A4 enzyme such as ketoconazole, erythromycin, cimetidine, and furanocoumarin derivatives (found in grapefruit) lead to increased plasma levels of loratadine — that is, more of the drug was present in the bloodstream than typical for a dose. This had clinically significant effects in controlled trials of 10 mg loratadine treatment Antihistamines should be discontinued 48 hours prior to skin allergy tests, since these drugs may prevent or diminish otherwise-positive reactions to dermal activity indicators.
Pharmacology
Pharmacodynamics
Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1 receptors. The potency of second generation histamine antagonists is (from strongest to weakest) desloratadine (Ki 0.4 nM) > levocetirizine (Ki 3 nM) > cetirizine (Ki 6 nM) > fexofenadine (Ki 10 nM) > terfenadine > loratadine. However, the onset of action varies significantly and clinical efficacy is not always directly related to only the H1 receptor potency, as concentration of free drug at the receptor must also be considered. Loratadine also shows anti-inflammatory properties independent of H1 receptors. The effect is exhibited through suppression of the NF-κB pathway, and by regulating the release of cytokines and chemokines, thereby regulating the recruitment of inflammatory cells.
Pharmacokinetics
Loratadine is given orally, is well absorbed from the gastrointestinal tract, and has rapid first-pass hepatic metabolism; it is metabolized by isoenzymes of the cytochrome P450 system, including CYP3A4, CYP2D6, and, to a lesser extent, several others. Loratadine is almost totally (97–99%) bound to plasma proteins. Its metabolite desloratadine, which is largely responsible for the antihistaminergic effects, binds to plasma proteins by 73–76%.Loratadines peak effect occurs after 1–2 hours, and its biological half life is on average eight hours (range 3 to 20 hours) with desloratadines half-life being 27 hours (range 9 to 92 hours), accounting for its long-lasting effect. About 40% is excreted as conjugated metabolites into the urine, and a similar amount is excreted into the feces. Traces of unmetabolised loratadine can be found in the urine.In structure, it is closely related to tricyclic antidepressants, such as imipramine, and is distantly related to the atypical antipsychotic quetiapine.
History
Schering-Plough developed loratadine as part of a quest for a potential blockbuster drug: a nonsedating antihistamine. By the time Schering submitted the drug to the U.S. Food and Drug Administration (FDA) for approval, the agency had already approved a competitors nonsedating antihistamine, terfenadine (trade name Seldane), and, therefore, put loratadine on a lower priority. However, terfenadine had to be removed from the U.S. market by the manufacturer in late 1997 after reports of serious ventricular arrhythmias among those taking the drug.Loratadine was approved by the FDA in 1993. The drug continued to be available only by prescription in the U.S. until it went off patent in 2002. It was then subsequently approved for over-the-counter sales. Once it became an unpatented over-the-counter drug, the price dropped significantly.Schering also developed desloratadine (Clarinex/Aerius), which is an active metabolite of loratadine.
Society and culture
Over the counter
In 1998, in an unprecedented action in the United States, an American insurance company, Anthem Inc., petitioned the federal Food and Drug Administration to allow loratadine and two other antihistamines to be made available over the counter (OTC) while they were still protected by patents; the administration granted the request, which was not binding on manufacturers. In the United States, Schering-Plough made loratadine available over the counter in 2002. In 2015, loratadine was available over the counter in many countries.
Brands
In 2017, loratadine was available under many brand names and in many forms worldwide, including several combination drug formulations with pseudoephedrine, paracetamol, betamethasone, ambroxol, salbutamol, phenylephrine, and dexamethasone.
Marketing
The marketing of the Claritin brand is important in the history of direct-to-consumer advertising of drugs.The first television commercial for a prescription drug was broadcast in the United States in 1983, by Boots. It caused controversy. The federal Food and Drug Administration responded with strong regulation requiring disclosure of side effects and other information. These rules made pharmaceutical manufacturers balk at spending money on ads that had to highlight negative aspects.In the mid-1990s, the marketing team for Claritin at Schering-Plough found a way around these rules. They created brand awareness commercials that never actually said what the drug was for, but instead showed sunny images, and the voiceover said such things as "At last, a clear day is here" and "Its time for Claritin" and repeatedly told viewers "Ask your doctor [about Claritin]." The first ads made people aware of the brand and increased prescriptions, which led Schering-Plough and others to aggressively pursue the advertising strategy.In 1998, a 12-page one-shot comic based in the Batman: The Animated Series was given away to advertise Claritin. The book, written by PRIEST, penciled by Joe Staton, and inked by Mike DeCarlo, sees Tim Drake unable to perform his crime-fighting duties because hay fever and antihistamines make him drowsy. After being given a prescription for Claritin, he saved Batman from Poison Ivy.This trend, along with advice from the Food and Drug Administrations attorneys that it could not win a First Amendment case on the issue, prompted the administration to issue new rules for television commercials in 1997. Instead of including the "brief summary" that took up a full page in magazine ads and would take too long to explain in a short television advertisement, drug makers were allowed to refer viewers to print ads, informative telephone lines, and websites, and to urge people to talk to their doctors if they wanted additional information.Schering-Plough invested US$322 million in Claritin direct-to-consumer advertising in 1998 and 1999, far more than any other brand. Spending on direct-to-consumer advertising by the pharmaceutical industry rose from US$360 million in 1995 to US$1.3 billion in 1998, and by 2006, was US$5 billion.
See also
Benzocycloheptenes
Azatadine (loratidine minus chlorine atom and ester)
References
External links
"Loratadine". Drug Information Portal. U.S. National Library of Medicine. |
Cidofovir | Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis (an infection of the retina of the eye) in people with AIDS.Cidofovir was approved for medical use in 1996.
Medical use
DNA virus
Its only indication that has received regulatory approval worldwide is cytomegalovirus retinitis. Cidofovir has also shown efficacy in the treatment of aciclovir-resistant HSV infections. Cidofovir has also been investigated as a treatment for progressive multifocal leukoencephalopathy with successful case reports of its use. Despite this, the drug failed to demonstrate any efficacy in controlled studies. Cidofovir might have anti-smallpox efficacy and might be used on a limited basis in the event of a bioterror incident involving smallpox cases. Brincidofovir, a cidofovir derivative with much higher activity against smallpox that can be taken orally has been developed. It has inhibitory effects on varicella-zoster virus replication in vitro although no clinical trials have been done to date, likely due to the abundance of safer alternatives such as aciclovir. Cidofovir shows anti-BK virus activity in a subgroup of transplant recipients. Cidofovir is being investigated as a complementary intralesional therapy against papillomatosis caused by HPV.It first received FDA approval on 26 June 1996, TGA approval on 30 April 1998 and EMA approval on 23 April 1997.It has been used topically to treat warts.
Other
It has been suggested as an antitumour agent, due to its suppression of FGF2.
Administration
Cidofovir is only available as an intravenous formulation. Cidofovir is to be administered with probenecid which decreases side effects to the kidney. Probenecid mitigates nephrotoxicity by inhibiting organic anion transport of the proximal tubule epithelial cells of the kidney. In addition, hydration must be administered to patients receiving cidofovir. 1 liter of normal saline is recommended in conjunction with each dose of cidofovir.
Side effects
The major dose-limiting side effect of cidofovir is nephrotoxicity (i.e., kidney damage). Other common side effects (occurring in >1% of people treated with the drug) include:
Whereas uncommon side effects include: anaemia and elevated liver enzymes and rare side effects include: tachycardia and Fanconi syndrome. Probenecid (a uricosuric drug) and intravenous saline should always be administered with each cidofovir infusion to prevent this nephrotoxicity.
Contraindications
Hypersensitivity to cidofovir or probenecid (as probenecid needs to be given concurrently to avoid nephrotoxicity).
Interactions
It is known to interact with nephrotoxic agents (e.g. amphotericin B, foscarnet, IV aminoglycosides, IV pentamide, vancomycin, tacrolimus, non-steroid anti-inflammatory drugs, etc.) to increase their nephrotoxic potential. As it must be given concurrently with probenecid it is advised that drugs that are known to interact with probenecid (e.g. drugs that probenecid interferes with the renal tubular secretion of, such as paracetamol, aciclovir, aminosalicylic acid, etc.) are also withheld.
Mechanism of action
Its active metabolite, cidofovir diphosphate, inhibits viral replication by selectively inhibiting viral DNA polymerases. It also inhibits human polymerases, but this action is 8–600 times weaker than its actions on viral DNA polymerases. It also incorporates itself into viral DNA, hence inhibiting viral DNA synthesis during reproduction.It possesses in vitro activity against the following viruses:
Human herpesviruses
Adenoviruses
Human poxviruses (including the smallpox virus)
Human papillomavirus
History
Cidofovir was discovered at the Institute of Organic Chemistry and Biochemistry, Prague, by Antonín Holý, and developed by Gilead Sciences and is marketed with the brand name Vistide by Gilead in the US, and by Pfizer elsewhere.
Synthesis
Cidofovir can be synthesized from a pyrimidone derivative and a protected derivative of glycidol.
See also
Brincidofovir, a novel prodrug of cidofovir that can be taken orally
== References == |
Ropeginterferon alfa-2b | Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera. It is an interferon. It is given by injection.The most common side effects include low levels of white blood cells and platelets (blood components that help the blood to clot), muscle and joint pain, tiredness, flu-like symptoms and increased blood levels of gamma-glutamyl transferase (a sign of liver problems). Ropeginterferon alfa-2b can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness. Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).It was approved for medical use in the European Union in February 2019, and in the United States in November 2021. Ropeginterferon alfa-2b is the first medication approved by the U.S. Food and Drug Administration (FDA) to treat polycythemia vera that people can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.
Medical uses
In the European Union, ropeginterferon alfa-2b is indicated as monotherapy in adults for the treatment of polycythemia vera without symptomatic splenomegaly. In the United States it is indicated for the treatment of polycythemia vera.
History
The effectiveness and safety of ropeginterferon alfa-2b were evaluated in a multicenter, single-arm trial that lasted 7.5 years. In this trial, 51 adults with polycythemia vera received ropeginterferon alfa-2b for an average of about five years. The effectiveness of ropeginterferon alfa-2b was assessed by looking at how many participants achieved complete hematological response, which meant that participants had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots. Overall, 61% of participants had a complete hematological response. The U.S. Food and Drug Administration (FDA) granted the application for Ropeginterferon_alfa-2b orphan drug designation and granted the approval of Besremi to PharmaEssentia Corporation
References
External links
"Ropeginterferon alfa-2b". Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT01193699 for "Safety Study of Pegylated Interferon Alpha 2b to Treat Polycythemia Vera (PEGINVERA)" at ClinicalTrials.gov
Clinical trial number NCT02218047 for "AOP2014 vs. BAT in Patients With Polycythemia Vera Who Previously Participated in the PROUD-PV Study. (CONTI-PV)" at ClinicalTrials.gov |
Butenafine | Butenafine, sold under the brand names Lotrimin Ultra, Mentax, and Butop (India), is a synthetic benzylamine antifungal. It is structurally related to synthetic allylamine antifungals such as terbinafine.
Medical uses
Butenafine is indicated for the topical treatment of tinea (pityriasis) versicolor due to Malassezia furfur, as well as athletes foot (Tinea pedis), ringworm (Tinea corporis) and jock itch (Tinea cruris) due to Epidermophyton floccosum, Trichophyton mentagrophytes, Trichophyton rubrum, and Trichophyton tonsurans.
It also displays superior activity against Candida albicans than terbinafine and naftifine. Butenafine demonstrates low minimum inhibitory concentrations against Cryptococcus and Aspergillus.
There is some evidence that it is effective against dermatophyte infections of the toenails, but needs to be applied daily for prolonged periods (at least one year).
Typical usage
For 1% cream:
for adults and children 12 years and older:
wash the affected skin with soap and water and dry completely before applying
apply once a day to affected skin for 2 weeks or as directed by a doctor
wash hands after each use
children under 12 years: ask a doctor
Available forms
Butenafine is typically available as a 1% topical cream.
Pharmacology
Like the allylamine antifungals, butenafine works by inhibiting the synthesis of ergosterol by inhibiting squalene epoxidase, an enzyme responsible for the creation of sterols needed in fungal cell membranes. Lacking ergosterol, the cell membranes increase in permeability, allowing their contents to leak out. Furthermore, inhibition of squalene epoxidase leads to a toxic buildup of squalene. This double action of butenafine (increased membrane permeability and toxic buildup of squalene) makes butenafine fungicidal rather than merely fungistatic.
In addition to being an antifungal, butenafine is an anti inflammatory. Because fungal skin infections are often accompanied by significant inflammation, this is a desirable property. The fact that butenafine has intrinsic anti inflammatory properties is also desirable since it is not necessary to add cortical steroids (which decrease the ability to fight infection) to reduce inflammation.
Chemistry
Butenafine hydrochloride is an odorless white crystalline powder that is freely soluble in methanol, ethanol, and chloroform, and slightly soluble in water.
== References == |
Streptozotocin | Streptozotocin or streptozocin (INN, USP) (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the islets of Langerhans and used in medical research to produce an animal model for hyperglycemia and Alzheimers in a large dose, as well as type 2 diabetes or type 1 diabetes with multiple low doses.
Usage
Streptozotocin is approved by the U.S. Food and Drug Administration (FDA) for treating metastatic cancer of the pancreatic islet cells. Since it carries a substantial risk of toxicity and rarely cures the cancer, its use is generally limited to patients whose cancer cannot be removed by surgery. In these patients, streptozotocin can reduce the tumor size and reduce symptoms (especially hypoglycemia due to excessive insulin secretion by insulinomas). A typical dose is 500 mg/m2/day by intravenous injection, for 5 days, repeated every 4–6 weeks.
Due to its high toxicity to beta cells, in scientific research, streptozotocin has also been long used for inducing insulitis and diabetes on experimental animals. Streptozotocin has also been used for modeling Alzheimers disease through memory loss in mice.
Mechanism
Streptozotocin is a glucosamine-nitrosourea compound. As with other alkylating agents in the nitrosourea class, it is toxic to cells by causing damage to the DNA, though other mechanisms may also contribute. DNA damage induces activation of PARP which is likely more important for diabetes induction than the DNA damage itself. Streptozotocin is similar enough to glucose to be transported into the cell by the glucose transport protein GLUT2, but is not recognized by the other glucose transporters. This explains its relative toxicity to beta cells, since these cells have relatively high levels of GLUT2.
History
Streptozotocin was originally identified in the late 1950s as an antibiotic. The drug was discovered in a strain of the soil microbe Streptomyces achromogenes by scientists at the drug company Upjohn (now part of Pfizer) in Kalamazoo, Michigan. The soil sample in which the microbe turned up had been taken from Blue Rapids, Kansas, which can therefore be considered the birthplace of streptozotocin. Upjohn filed for patent protection for the drug in August 1958 and U.S. Patent 3,027,300 was granted in March 1962.
In the mid-1960s, streptozotocin was found to be selectively toxic to the beta cells of the pancreatic islets, the cells that normally regulate blood glucose levels by producing the hormone insulin. This suggested the drugs use as an animal model of diabetes, and as a medical treatment for cancers of the beta cells. In the 1960s and 1970s, the National Cancer Institute investigated streptozotocins use in cancer chemotherapy. Upjohn filed for FDA approval of streptozotocin as a treatment for pancreatic islet cell cancer in November 1976, and approval was granted in July 1982. The drug was subsequently marketed as Zanosar.
More recently, a growing body of studies has provided evidence that derangement of insulin signaling underlying type-2 diabetes significantly increase the risk of cognitive impairment and Alzheimers disease (AD) progression (12). On this ground, the direct administration of STZ in the brain (i.e., by intracerebroventricular (ICV) infusion) has been used to develop an animal model of brain insulin resistance to mimic in rodents the pathophysiology of sporadic AD, which represents the most common form of AD in humans. STZ infusion in the brain induced accumulation of Amyloid beta (Aβ) protein (13), oxidative stress and cognitive impairment (14). Notably, there is now evidence that STZ infusion within the brain produced up-regulation of amyloid precursor protein (APP), tau hyperphosphorylation and neuroinflammation (15). This study (15), also shows that treatment with the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) can relieve APP upregulation, neuroinflammation and reduce cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations, as well as induce a nearly complete recovery of cognitive impairment in the STZ-induced SAD mouse model.
Streptozotocin is now long off patent and many generic formulations are available.
Biosynthesis
Recent advancements in understanding the biosynthesis of this natural product have been made by Balskus et al. In short, the authors found the gene cluster responsible for production of Streptozotocin in Streptomyces achromogenes and identified novel function of a non-heme iron enzyme, SznF, which forms the N-N bond in the N-nitrosourea pharmacophore by oxidative rearrangement.
See also
Alloxan
References
12. Velayudhan, L. et al. Risk of developing dementia in people with diabetes and mild cognitive impairment. Br. J. Psychiatry 2010, 196, 36–40.
13. Knezovic, A.; Osmanovic-Barilar, J.; Curlin, M.; Hof, P.R.; Šimić, G.; Riederer, P.; Salkovic-Petrisic, M. et al. Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimers disease. J. Neural Transm. 2015, 122, 577–592.
14. Sharma, M. et al. Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment. Life Sci. 2001, 68, 1021–1029.
15. Latina, V. et al., Tau Cleavage Contributes to Cognitive Dysfunction in Streptozotocin-Induced Sporadic Alzheimers Disease (sAD) Mouse Model. Int. J. Mol. Sci. 2021, 22, 12158. https://doi.org/10.3390/ijms222212158.
External links
U.S. Patent 3,027,300
FDA drug details |
Phenoxymethylpenicillin | Phenoxymethylpenicillin, also known as penicillin V (PcV) and penicillin VK, is an antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for the treatment of strep throat, otitis media, and cellulitis. It is also used to prevent rheumatic fever and to prevent infections following removal of the spleen. It is given by mouth.Side effects include diarrhea, nausea, and allergic reactions including anaphylaxis. It is not recommended in those with a history of penicillin allergy. It is relatively safe for use during pregnancy. It is in the penicillin and beta lactam family of medications. It usually results in bacterial death.Phenoxymethylpenicillin was first made in 1948 by Eli Lilly.: 121 It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2017, it was the 242nd most commonly prescribed medication in the United States, with more than two million prescriptions.
Medical uses
Specific uses for phenoxymethylpenicillin include:
Infections caused by Streptococcus pyogenes
Tonsillitis
Pharyngitis
Skin infections
Anthrax (mild uncomplicated infections)
Lyme disease (early stage in pregnant women or young children)
Rheumatic fever (primary and secondary prophylaxis)
Streptococcal skin infections
Spleen disorders (pneumococcal infection prophylaxis)
Initial treatment for dental abscesses
Moderate-to-severe gingivitis (with metronidazole)
Avulsion injuries of teeth (as an alternative to tetracycline)
Blood infection prophylaxis in children with sickle cell disease.Penicillin V is sometimes used in the treatment of odontogenic infections.
It is less active than benzylpenicillin (penicillin G) against Gram-negative bacteria. Phenoxymethylpenicillin has a range of antimicrobial activity against Gram-positive bacteria that is similar to that of benzylpenicillin and a similar mode of action, but it is substantially less active than benzylpenicillin against Gram-negative bacteria.Phenoxymethylpenicillin is more acid-stable than benzylpenicillin, which allows it to be given orally.
Phenoxymethylpenicillin is usually used only for the treatment of mild to moderate infections, and not for severe or deep-seated infections since absorption can be unpredictable. Except for the treatment or prevention of infection with Streptococcus pyogenes (which is uniformly sensitive to penicillin), therapy should be guided by bacteriological studies (including sensitivity tests) and by clinical response. People treated initially with parenteral benzylpenicillin may continue treatment with phenoxymethylpenicillin by mouth once a satisfactory response has been obtained.It is not active against beta-lactamase-producing bacteria, which include many strains of Staphylococci.
Adverse effects
Phenoxymethylpenicillin is usually well tolerated but may occasionally cause transient nausea, vomiting, epigastric distress, diarrhea, constipation, acidic smell to urine and black hairy tongue. A previous hypersensitivity reaction to any penicillin is a contraindication.
Mechanism of action
The mechanism of phenoxymethylpenicillin is identical to that of all other penicillins. It exerts a bactericidal action against penicillin-sensitive microorganisms during the stage of active multiplication. It acts by inhibiting the biosynthesis of cell-wall peptidoglycan.
Compendial status
British Pharmacopoeia
History
The Austrian pharmaceutical company, Biochemie, was founded in Kundl in July 1946 at the site of a derelict brewery, at the suggestion of a French officer, Michel Rambaud (a chemist), who was able to obtain a small amount of Penicillium start culture from France. Contamination of the fermentation tanks was a persistent problem and in 1951, the company biologist, Ernst Brandl, attempted to solve this by adding phenoxyethanol to the tanks as an anti-bacterial disinfectant. This resulted unexpectedly in an increase in penicillin production: but, the penicillin produced was not benzylpenicillin, but phenoxymethylpenicillin. Phenoxyethanol was fermented to phenoxyacetic acid in the tanks, which was then incorporated into penicillin via biosynthesis. Importantly, Brandl realised that phenoxymethylpenicillin is not destroyed by stomach acid and can therefore be given by mouth. Phenoxymethyl penicillin was originally discovered by Eli Lilly in 1948 as part of their efforts to study penicillin precursors, but was not further exploited, and there is no evidence that Lilly understood the significance of their discovery at the time.: 119–121 Biochemie is now part of Sandoz.
Names
There were four named penicillins at the time penicillin V was discovered (penicillins I, II, III, IV), however, Penicillin V was named "V" for Vertraulich (confidential);: 121 it was not named for the Roman numeral "5".
Penicillin VK is the potassium salt of penicillin V (K is the chemical symbol for potassium).
References
External links
"Penicillin V". Drug Information Portal. U.S. National Library of Medicine. |
Enalaprilat | Enalaprilat is the active metabolite of enalapril. It is the first dicarboxylate-containing ACE inhibitor and was developed partly to overcome these limitations of captopril. The thiol functional group of captopril was replaced with a carboxylic acid group, but additional modifications were required to achieve a potency similar to captopril.
Enalaprilat, however, had a problem of its own. The consequence of the structural modifications was that its ionisation characteristics do not allow for sufficient GI absorption. Thus, enalaprilat was only suitable for intravenous administration. This was overcome by the monoesterification of enalaprilat with ethanol to produce enalapril.
As a prodrug, enalapril is hydrolyzed in vivo to the active form enalaprilat by various esterases. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites.
The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.
== References == |
Rajani | Rajani may refer to:
Rajani (name), people named Rajani
Rajani (actress) (born 1965), Indian film actress
Rajani (TV series), a 1980s Indian TV series
Rajani (film), a 2009 Indian Kannada romantic comedy
Rajani, an 1877 novel by Bankimchandra Chattopadhyay
See also
Rajini (disambiguation) |
Raxibacumab | Raxibacumab is a human monoclonal antibody intended for the prophylaxis and treatment of inhaled anthrax. Its efficacy has been proven in rabbits and monkeys. In December 2012 raxibacumab was approved in the United States for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate.The antibody was discovered in a joint venture between Cambridge Antibody Technology and Human Genome Sciences. Cambridge Antibody Technology discovered the antibody to Human Genome Sciencess target and, in 2012, HGS were purchased by GlaxoSmithKline (GSK). In 2017, it was acquired by Emergent BioSolutions
Side effects
The most commonly observed adverse events are headaches, upper respiratory tract infection, nausea, pain in extremity and pruritus skin itching.
Pharmacology
Raxibacumab injection is a monoclonal antibody targeting the protective antigen (PA) component of the lethal toxin of Bacillus anthracis.
Development history
Raxibacumab was developed by Human Genome Sciences (HGS) in conjunction with the U.S. Department of Health and Human Services (HHS) under contract number HHS010020050006C. At the 2 November 2012 meeting of the Anti-Infective Drugs Advisory Committee to the US Food and Drug Administration (FDA) members "voted 16 to 1 in support of the clinical benefit of raxibacumab for the treatment of inhalational anthrax, with one abstention. In addition, the committee voted 18 – 0 in favour of the risk-benefit profile of raxibacumab". In 2009, support from the FDA was denied after it "expressed doubt on the agents added benefit over the antibiotic levofloxacin (Levaquin) alone". On Dec. 14, 2012, FDA approved raxibacumab injection to treat inhalational anthrax, a form of the infectious disease caused by breathing in the spores of the bacterium Bacillus anthracis. Raxibacumab also is approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate.
== References == |
Uridine triacetate | Uridine triacetate (INN), formerly known as vistonuridine, is an orally active tri-acetylated prodrug of uridine used:
in the treatment of hereditary orotic aciduria (brand name Xuriden ZOOR-ə-den);
to treat people following an overdose of chemotherapy drugs 5-fluorouracil (5-FU) or capecitabine regardless of the presence of symptoms, or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration (brand name Vistogard).Uridine triacetate was developed, manufactured and distributed by Wellstat Therapeutics. It was granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) and approved for use in the United States in 2015.
References
External links
"Uridine triacetate". Drug Information Portal. U.S. National Library of Medicine. |
Neomycin/polymyxin B/bacitracin | Neomycin/polymyxin B/bacitracin, also known as triple antibiotic ointment, is a medication used to reduce the risk of infections following minor skin injuries. It contains three antibiotics: neomycin, polymyxin B, and bacitracin. It is for topical use only and should not be ingested due to risk of kidney damage.Possible side effects include itchiness and skin rash, and in rare cases hearing loss. Use in pregnancy is generally recommended. It is relatively broad spectrum, being effective against both Gram-negative and Gram-positive bacteria.The combination was approved for medical use in the United States in 1971. It is available over the counter in the United States. In 2017, it was the 78th most commonly prescribed medication in the United States, with more than ten million prescriptions. It is sold under the brand name Globe and Neosporin, among others and is available generically at most major pharmaceutical retailers.
Medical uses
Neomycin/polymyxin B/bacitracin ointment is reported to be a safe and effective topical agent for preventing infections in minor skin trauma.It is used for burns, scratches, cuts, and minor skin infections. The ointment is most effective when applied after cleaning the affected area.The use of neomycin/polymyxin B/bacitracin, decreases infection rates in minor-contaminated wounds. However, if the wound is sterile, then there are no benefits compared to petrolatum (placebo).
Side effects
It is for external use only and should not be applied near mucous membranes such as the eyes or mouth. It is not recommended for children under the age of two. Users should immediately seek medical attention if they experience hives, rashes, or itching. Any skin irritations such as pain, burning, or cracked skin that were not present prior to use of ointment must receive immediate care.It has been shown to cause contact dermatitis in some cases.
Antibiotic-resistant bacteria
Concern exists that its use contributes to the emergence of antibiotic-resistant bacteria. In the US, the only large market for the ointment, it may increase antibiotic resistance. For instance, it may increase the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) bacteria, specifically the highly lethal ST8:USA300 strain.
Components
The original ointment contains three different antibiotics: bacitracin, neomycin, and polymyxin B, in a relatively low-molecular-weight base of cocoa butter, cottonseed oil, sodium pyruvate, tocopheryl acetate, and petroleum jelly.The generic name for these products, regardless of the base, is "triple antibiotic ointment".
In China, the product is named "compound polymyxin B ointment" and is manufactured there by Zhejiang Fonow Medicine Co. Ltd. The product was also marketed by the Upjohn Company under the name "Mycitracin", until 1997 when that name was acquired by Johnson & Johnson.Some people have allergic reactions to neomycin, so a "double antibiotic ointment" is sold without it, containing only
bacitracin and polymyxin B: one such example is Polysporin branded product.A "Plus" variant of the ointment exists that adds the analgesic pramoxine, but uses the cheap, simple, long-lasting, but heavier petroleum jelly base, common to many over-the-counter topicals. The latest version of this analgesic formulation, a high-absorption cream, excludes bacitracin because it is unstable in such a base.
Active ingredients
The three main active ingredients in Neomycin are neomycin sulfate, polymyxin B sulfate, and bacitracin zinc.One of the main components is neomycin sulfate, which is a type of antibiotic discovered in 1949 by microbiologist Selman Waksman at Rutgers University. Neomycin belongs to the aminoglycoside class of antibiotics and fights against Gram positive and gram negative bacteria. The antibiotic is often used to prevent risk of bacterial infections. Aminoglycosides work by binding to bacterial RNA and changing the ability to produce proteins while exerting little to no effect on DNA. Thus, neomycin kills bacteria as a result of irregular protein production in the bacterial cell. When the cell can no longer produce the correct proteins, its membrane becomes damaged. As a result of damaged membrane, the affected bacterial cells die, and the infection is prevented or limited.Like neomycin, polymyxin B is an antibiotic. Polymyxin B forms holes in the bacterial cell wall causing the internal cellular components to leak out, resulting in cell death.
Pramoxine is used to temporarily reduce pain from burns, insect bites, and minor cuts. It works like an anesthetic by decreasing the permeability of neuron membranes. As a result, pain neurons in the area have difficulty sending signals (or signals are blocked entirely), resulting in numbness.In some countries bacitracin is replaced with gramicidin.
History
There is no exact date as to when the antibacterial ointment was invented, but it was used as early as the 1950s. This antibiotic ointment was patented in the United States on August 27, 1951.
References
External links
"Bacitracin mixture with neomycin and polymyxin". Drug Information Portal. U.S. National Library of Medicine.
"Neomycin, Polymyxin, and Bacitracin Ophthalmic". MedlinePlus.
"Gramicidin mixture with Neomycin sulfate and Polymyxin B sulfate". Drug Information Portal. U.S. National Library of Medicine. |
Sodium thiosulfate | Sodium thiosulfate (sodium thiosulphate) is an inorganic compound with the formula Na2S2O3.xH2O. Typically it is available as the white or colorless pentahydrate, Na2S2O3·5H2O. The solid is an efflorescent (loses water readily) crystalline substance that dissolves well in water.Sodium thiosulfate is used in gold mining, water treatment, analytical chemistry, the development of silver-based photographic film and prints, and medicine. The medical uses of sodium thiosulfate include treatment of cyanide poisoning and pityriasis. It is on the World Health Organizations List of Essential Medicines.
Uses
Sodium thiosulfate is used predominantly in industry. For example, it is used to convert dyes to their soluble leuco form. It is also used to bleach "wool, cotton, silk, ...soaps, glues, clay, sand, bauxite, and... edible oils, edible fats, and gelatin."
Medical uses
Sodium thiosulfate is used in the treatment of cyanide poisoning. Other uses include topical treatment of ringworm and tinea versicolor, and treating some side effects of hemodialysis and chemotherapy.
Photographic processing
Silver halides, e.g., AgBr, typical components of photographic emulsions, dissolve upon treatment with aqueous thiosulfate.This application as a photographic fixer was discovered by John Herschel. It is used for both film and photographic paper processing; the sodium thiosulfate is known as a photographic fixer, and is often referred to as hypo, from the original chemical name, hyposulphite of soda. Ammonium thiosulfate is typically preferred to sodium thiosulfate for this application.
Neutralizing chlorinated water
It is used to dechlorinate tap water including lowering chlorine levels for use in aquariums, swimming pools, and spas (e.g., following superchlorination) and within water treatment plants to treat settled backwash water prior to release into rivers. The reduction reaction is analogous to the iodine reduction reaction.
In pH testing of bleach substances, sodium thiosulfate neutralizes the color-removing effects of bleach and allows one to test the pH of bleach solutions with liquid indicators. The relevant reaction is akin to the iodine reaction: thiosulfate reduces the hypochlorite (active ingredient in bleach) and in so doing becomes oxidized to sulfate. The complete reaction is:
4 NaClO + Na2S2O3 + 2 NaOH → 4 NaCl + 2 Na2SO4 + H2OSimilarly, sodium thiosulfate reacts with bromine, removing the free bromine from solution. Solutions of sodium thiosulfate are commonly used as a precaution in chemistry laboratories when working with bromine and for the safe disposal of bromine, iodine, or other strong oxidizers.
Structure
Two polymorphs are known of the pentahydrate. The anhydrous salt exists in several polymorphs. In the solid state, the thiosulfate anion is tetrahedral in shape and is notionally derived by replacing one of the oxygen atoms by a sulfur atom in a sulfate anion. The S-S distance indicates a single bond, implying that the terminal sulfur holds a significant negative charge and the S-O interactions have more double-bond character.
Production
On an industrial scale, sodium thiosulfate is produced chiefly from liquid waste products of sodium sulfide or sulfur dye manufacture.In the laboratory, this salt can be prepared by heating an aqueous solution of sodium sulfite with sulfur or by boiling aqueous sodium hydroxide and sulfur according to this equation:
6 NaOH + 4 S → 2 Na2S + Na2S2O3 + 3 H2O
Principal reactions
Upon heating to 300 °C, it decomposes to sodium sulfate and sodium polysulfide:
4 Na2S2O3 → 3 Na2SO4 + Na2S5Thiosulfate salts characteristically decompose upon treatment with acids. Initial protonation occurs at sulfur. When the protonation is conducted in diethyl ether at −78 °C, H2S2O3 (thiosulfuric acid) can be obtained. It is a somewhat strong acid with pKas of 0.6 and 1.7 for the first and second dissociations, respectively.
Under normal conditions, acidification of solutions of this salt excess with even dilute acids results in complete decomposition to sulfur, sulfur dioxide, and water:
Na2S2O3 + 2 HCl → 2 NaCl + 1/8 S8 + SO2 + H2O
Coordination chemistry
Thiosulfate is a potent ligand for soft metal ions. A typical complex is [Pd(S2O3)2(ethylenediamine)]2-, which features a pair of S-bonded thiosulfate ligands. Sodium thiosulfate and ammonium thiosulfate have been proposed as alternative lixiviants to cyanide for extraction of gold. The advantages of this approach are that (i) thiosulfate is far less toxic than cyanide and (ii) that ore types that are refractory to gold cyanidation (e.g. carbonaceous or Carlin-type ores) can be leached by thiosulfate. Some problems with this alternative process include the high consumption of thiosulfate, and the lack of a suitable recovery technique, since [Au(S2O3)2]3− does not adsorb to activated carbon, which is the standard technique used in gold cyanidation to separate the gold complex from the ore slurry.
Iodometry
In analytical chemistry, the most important use comes because the thiosulfate anion reacts stoichiometrically with iodine in aqueous solution, reducing it to iodide as the thiosulfate is oxidized to tetrathionate:
2 S2O2−3 + I2 → S4O2−6 + 2 I−Due to the quantitative nature of this reaction, as well as because Na2S2O3·5H2O has an excellent shelf-life, it is used as a titrant in iodometry. Na2S2O3·5H2O is also a component of iodine clock experiments.
This particular use can be set up to measure the oxygen content of water through a long series of reactions in the Winkler test for dissolved oxygen. It is also used in estimating volumetrically the concentrations of certain compounds in solution (hydrogen peroxide, for instance) and in estimating the chlorine content in commercial bleaching powder and water.
Aluminium cation reaction
Sodium thiosulfate is used in analytical chemistry. It can, when heated with a sample containing aluminium cations, produce a white precipitate:
2 Al3+ + 3 S2O2−3 + 3 H2O → 3 SO2 + 3 S + 2 Al(OH)3
Organic chemistry
Alkylation of sodium thiosulfate gives S-alkylthiosulfates, which are called Bunte salts. The alkylthiosulfates are susceptible to hydrolysis, affording the thiol. This reaction is illustrated by one synthesis of thioglycolic acid:
ClCH2CO2H + Na2S2O3 → Na[O3S2CH2CO2H] + NaCl
Na[O3S2CH2CO2H] + H2O → HSCH2CO2H + NaHSO4
== References == |
Chlortalidone | Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling including that due to heart failure, liver failure, and nephrotic syndrome, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is reliably effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.Common adverse effects include low blood potassium, low blood sodium, high blood sugar, dizziness, and erectile dysfunction. Other adverse effects may include gout, low blood magnesium, high blood calcium, allergic reactions, and low blood pressure. Some reviews have found chlortalidone and hydrochlorothiazide to have a similar risk of adverse effects, while other reviews have found chlortalidone to have a higher risk. While it may be used in pregnancy it is a less preferred option. How it works is not completely clear but is believed to involve increasing the amount of sodium and water lost by the kidneys.Chlortalidone was patented in 1957 and came into medical use in 1960. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 135th most commonly prescribed medication in the United States, with more than 4 million prescriptions.
Medical use
High blood pressure
Chlortalidone is considered a first-line medication for treatment high blood pressure. Some recommend chlortalidone over hydrochlorothiazide. A meta-analysis of randomized controlled trials found that chlortalidone is more effective than hydrochlorothiazide for lowering blood pressure, while the two drugs have similar toxicity.Trials of chlortalidone for high blood pressure found that lower doses of chlortalidone (e.g., 12.5 mg daily in ALLHAT study) had maximal blood pressure lowering effect and that higher doses did not lower it more. Chlortalidone and other thiazide diuretics are effective for lowering high blood pressure in persons with chronic kidney disease, although the risk of adverse effects is higher in these persons.
Left ventricular hypertrophy
Chlortalidone is used to treat left ventricular hypertrophy in the heart; it works chiefly by lowering blood pressure, and thereby reducing systemic vascular resistance. There is evidence that chlortalidone is superior to hydrochlorothiazide for reducing the mass of the left ventricle of the heart in persons with enlargement of the left ventricle of the heart. Chlortalidone is superior to angiotensin converting enzyme Inhibitors or angiotensin II receptor blockers for inducing regression of enlargement of the left ventricle, which is the main pumping chamber of the heart.
Swelling
Chlortalidone reduces edema (swelling) by increasing urinary salt and water excretion, lowering intravascular hydrostatic pressure and thereby lowering transcapillary pressure (see Starling Equation). Edema may be caused by either increased hydrostatic pressure or reduced oncotic pressure in the blood vessels. Edema due to increased hydrostatic pressure may be a result of serious cardiopulmonary disease (which reduces glomerular perfusion in the kidney) or to kidney injury or disease (which may reduce glomerular excretion of salt and water by the kidney) or due to relatively benign conditions such as menstrual-related fluid retention, or as an adverse effect of dihydropyridine calcium channel blockers, which commonly cause swelling of the feet and lower legs. Edema due to decreased oncotic pressure may be a result of leaking of blood proteins through the glomeruli of an injured kidney or a result of diminished synthesis of blood proteins by a damaged liver. Regardless of cause, chlortalidone may reduce the severity of edema by reducing intravascular volume and thereby reducing intravascular hydrostatic pressure.
Bone fracture prevention
Chlortalidone decreases mineral bone loss by promoting calcium retention by the kidney, and by directly stimulating osteoblast differentiation and bone mineral formation. A Cochrane review found tentative evidence that thiazide exposure was associated with a reduced risk of hip fracture. A secondary analysis of data from the ALLHAT study found that chlortalidone reduced risk of hip and pelvis fracture.
Kidney stone prevention
Chlortalidone reduces the amount of calcium excreted in urine, reducing the risk of calcium oxalate kidney stones. In people who have had multiple episodes of calcium oxalate kidney stones, chlortalidone lowers the risk of having another episode of kidney stones. Chlortalidone is more effective than hydrochlorothiazide for lowering urine calcium levels and is therefore probably more effective.
Ménières disease
Chlortalidone reduces the volume and thereby reduces the pressure in the inner ear chambers; elevated endolymph pressure in the inner ear is thought to be the cause of Ménières disease or ’Endolymphatic hydrops.’ Synthesis of evidence from multiple small, low-quality studies indicates that chlortalidone or other thiazide diuretics are effective for Ménières Disease.
Diabetes insipidus
Chlortalidone (or other thiazide medication) is a key component of treatment of nephrogenic diabetes insipidus. Nephrogenic diabetes insipidus occurs when the kidney is unable to produce concentrated urine because it has an inadequate response to vasopressin-dependent removal of free water from the renal tubular filtrate. By blocking sodium ion resorption in the distal convoluted tubule, chlortalidone induces an increase in excretion of sodium ion in urine (natriuresis). Giving chlortalidone while simultaneously restricting dietary sodium intake causes mild hypovolemia (low intravascular volume), which induces isotonic reabsorption of solute from the proximal renal tubule, reducing solute delivery in the renal collecting tubule and renal medullary collecting duct. This reduced delivery of solute to the collecting tubule and medullary collecting duct allows increased water resorption and higher concentration of urine, which leads to reversal of nephrogenic diabetes insipidus by a means that is independent of vasopressin.
Adverse effects
Some reviews have found a similar risk as hydrochlorothiazide, while other reviews found a higher risk of side effects.
Hypokalemia (low blood potassium) occurs occasionally; the risk of hypokalemia is higher in persons who are magnesium deficient
Hypomagnesemia (low blood magnesium) a review of four clinical trials found that low blood magnesium occurred in 20% of persons within a few weeks of beginning treatment with 50 mg of chlortalidone daily. The risk of chlortalidone-associated hypomagnesemia is higher in persons with diabetes mellitus who have low dietary magnesium intake.
Hyponatremia (low blood sodium) occurred in 4.1% of subjects randomized to chlortalidone in the Systolic Hypertension in the Elderly Trial, compared to 1.3% of control subjects. The risk of hyponatremia varies from 5 per 100,000 person-years for those younger than 40 years of age to 730 per 100,000 person-years in those older than 80 years of age. Hyponatremia is more likely in persons with certain genetic variants of the prostaglandin transporter SLCO2A1 associated with elevated urinary PGE2 and inappropriately low plasma ADH levels in the setting of low plasma osmolality. Thiazide-associated hyponatremia is often more severe than loop diuretic-associated hyponatremia because the predominant action of thiazides occurs late in the tubular flow, reducing opportunity to apply additional corrective action further along the tubule.
Hypercalcemia (high blood calcium level) can occur in normal persons exposed to chlortalidone but is more likely to occur when persons with sub-clinical hyperparathyroidism are exposed to chlortalidone.
Hyperuricemia, high levels of uric acid in the blood
Hyperglycemia, high blood sugar is more common in persons who are magnesium deficient
Hyperlipidemia, high cholesterol and triglycerides
Headache
Nausea/vomiting
Photosensitivity increased susceptibility to sunburn of skin with sun exposure
Photoonycholysis detachment of nails from nailbed with sun exposure
Weight gain
Gout; approximately doubles the risk
PancreatitisThe frequency and severity of these adverse effects is much reduced when chlortalidone is used at lower doses (e.g., 12.5 mg per day).
Mechanism of action
Chlortalidone reduces reabsorption of sodium and chloride primarily through inhibition of the Na+/Cl− symporter in the apical membrane of distal convoluted tubule cells in the kidney. Although chlortalidone is often referred to as a "thiazide-like" diuretic, it is unlike thiazide diuretics in that, in addition to its inhibition of the Na+/Cl− symporter, it also strongly inhibits multiple isoforms of carbonic anhydrase. Some of chlortalidones diuretic effect is also due to this inhibition of carbonic anhydrase in the proximal tubule. Chronic exposure to chlortalidone decreases the glomerular filtration rate. Chlortalidones diuretic effect is diminished in persons with kidney impairment. By increasing the delivery of sodium to the distal renal tubule, chlortalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism (i.e. apical ROMK/Na channels coupled with basolateral Na+/K ATPases). This can result in a low blood concentration of potassium and chloride as well as a mild metabolic alkalosis; however, the diuretic effect of chlortalidone is not affected by the acid-base balance of the person being treated.
There is uncertainty about the mechanism of the blood pressure-lowering effect that occurs during chronic exposure to chlortalidone. Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Eventually, cardiac output returns to normal, and plasma and extracellular fluid volume return to slightly less than normal, but a reduction in peripheral vascular resistance is maintained, thus resulting in an overall lower blood pressure. The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.
Pharmacokinetics
Chlortalidone is slowly absorbed from the gastrointestinal tract after oral ingestion. It has a long half-life and therefore a prolonged diuretic action, which results in continued diuretic effects despite a skipped dose. This prolonged action of chlortalidone despite missing doses may account for the higher efficacy of chlortalidone compared to the shorter half-life medication, hydrochlorothiazide. Chlortalidone is eliminated from the body mostly by the kidney, as unchanged drug. Thus, in persons with diminished kidney function, the clearance of chlortalidone is reduced and the elimination half-life is increased.As with other thiazide diuretics, chlortalidone crosses the placenta and is excreted in breast milk. Chlortalidone may suppress lactation, and has been used for this indication. Due to its long half-life, chlortalidone may accumulate in newborns via breast milk, despite receiving only about 6% of the maternal weight-adjusted dose.
Chemistry
Chlortalidone is in the sulfamoylbenzamide class. As it lacks the benzothiadiazine structure of the thiazide-type diuretics, it is called a thiazide-like diuretic. Chlortalidone is freely soluble in dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), and methanol; it is also soluble in warm ethanol.Chlortalidone is the official name of the medication according to the (INN/BAN), which is the medication naming system coordinated by the World Health Organization. Chlorthalidone is the official name of the medication according to the (USAN), which is the medication naming system coordinated by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United States Pharmacopeial Convention (USP), and the American Pharmacists Association (APhA).
Society and culture
Chlortalidone is banned for some sports (including cricket) because it is a diuretic, and can be used to reduce body weight or to mask the concomitant use of performance-enhancing drugs. Sports such as wrestling or boxing categorize athletes according to body weight; taking a diuretic such as chlortalidone may lower body weight, and thereby permit an athlete to compete in a lighter weight class, which would provide an advantage. Diuretics such as chlortalidone also reduce the urine concentration of concomitantly-taken performance-enhancing drugs or of their metabolites, thus making it more difficult to detect these drugs using urine testing.
See also
Chlorothiazide
References
External links
"Chlorthalidone". Drug Information Portal. U.S. National Library of Medicine. |
Efinaconazole | Efinaconazole, sold under the brand name Jublia among others, is a triazole antifungal medication. It is approved for use in the United States, Canada, and Japan as a 10% topical solution for the treatment of onychomycosis (fungal infection of the nail). Efinaconazole acts as a 14α-demethylase inhibitor.It was approved as a generic medication in the United States in 2020.
Medical uses
Efinaconazole is an azole antifungal indicated in the US for the topical treatment of onychomycosis of the toenails due to Trichophyton rubrum and Trichophyton mentagrophytes.
Efficacy
In two clinical trials 17.8% (trial 1) and 15.2% (trial 2) of participants using efinaconazole were completely cured (0% clinical involvement of the target toenail, plus negative KOH test and negative culture), compared with 3.3% (trial 1) and 5.5% (trial 2) of participants using a placebo. The "complete cure or almost complete cure" rate (≤5% affected target toenail area involved, and negative KOH and culture) for efinaconazole was 26.4% (trial 1) and 23.4% (trial 2) (compared with 7.0% (trial 1) and 7.5% (trial 2)).
History
In 2014, the U.S. Food and Drug Administration (FDA) approved the New Drug Application (NDA). According to Valeant Pharmaceuticals International Inc CEO J. Michael Pearson they acquired Jublia through their purchase of Dow Pharmaceutical Sciences in 2008.In 2020, the FDA approved a supplemental New Drug Application for efinaconazole topical solution, 10%, which extended the age range included in the products label to children six years of age and older; it was first approved in 2014, in people aged 18 years of age and older.
Society and culture
Economics
In 2015, the cost of treatment with efinaconazole in the United States was said to be US$2,307 per nail.In 2019, a study by the Canadian Agency for Drugs and Technologies in Health found the cost for a 48-week course to be $178 for a big toe, and $89 for an other toe.
References
External links
"Efinaconazole". Drug Information Portal. U.S. National Library of Medicine. |
Sipuleucel-T | Sipuleucel-T, sold under the brand name Provenge, developed by Dendreon Pharmaceuticals, LLC, is a cell-based cancer immunotherapy for prostate cancer (CaP). It is an autologous cellular immunotherapy.
Medical uses
Sipuleucel-T is indicated for the treatment of metastatic, asymptomatic or minimally symptomatic, metastatic castrate-resistant hormone-refractory prostate cancer (HRPC). Other names for this stage are metastatic castrate-resistant (mCRPC) and androgen independent (AI) or (AIPC). This stage leads to mCRPC with lymph node involvement and distal (distant) tumors; this is the lethal stage of CaP. The prostate cancer staging designation is T4,N1,M1c.
Treatment method
A course of treatment consists of three basic steps:
The patients white blood cells, primarily dendritic cells, a type of antigen-presenting cells (APCs), are extracted in a leukapheresis procedure.
The blood product is sent to a production facility and incubated with a fusion protein (PA2024) consisting of two parts:
The antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells and
An immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.
The activated blood product (APC8015) is returned from the production facility to the infusion center and reinfused into the patient.Premedication with acetaminophen and antihistamine is recommended to minimize side effects.
Side effects
Common side effects include: bladder pain; bloating or swelling of the face, arms, hands, lower legs, or feet; bloody or cloudy urine; body aches or pain; chest pain; chills; confusion; cough; diarrhea; difficult, burning, or painful urination; difficulty with breathing; difficulty with speaking up to inability to speak; double vision; sleeplessness; and inability to move the arms, legs, or facial muscles.
Society and culture
Legal status
Sipuleucel-T was approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC.Shortly afterward, sipuleucel-T was added to the compendium of cancer treatments published by the National Comprehensive Cancer Network (NCCN) as a "category 1" (highest recommendation) treatment for HRPC. The NCCN Compendium is used by Medicare and major health care insurance providers to decide whether a treatment should be reimbursed.
Research
Clinical trials
Completed
Sipuleucel-T showed overall survival (OS) benefit to patients in three double-blind randomized phase III clinical trials, D9901, D9902a, and IMPACT.The IMPACT trial served as the basis for FDA licensing. This trial enrolled 512 patients with asymptomatic or minimally symptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-treated patients, an increase of 4.1 months. 31.7% of treated patients survived for 36 months vs. 23.0% in the control arm. Overall survival was statistically significant (P=0.032). The longer survival without tumor shrinkage or change in progression is surprising. This may suggest the effect of an unmeasured variable. The trial was conducted pursuant to a FDA Special Protocol Assessment (SPA), a set of guidelines binding trial investigators to specific agreed-upon parameters with respect to trial design, procedures and endpoints; compliance ensured overall scientific integrity and accelerated FDA approval.The D9901 trial enrolled 127 patients with asymptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for patients treated with sipuleucel-T was 25.9 months comparing to 21.4 months for placebo-treated patients. Overall survival was statistically significant (P=0.01).The D9902a trial was designed like the D9901 trial but enrolled 98 patients. The median survival time for patients treated with sipuleucel-T was 19.0 months comparing to 15.3 months for placebo-treated patients, but did not reach statistical significance.
Ongoing
As of August 2014, the PRO Treatment and Early Cancer Treatment (PROTECT) trial, a phase IIIB clinical trial started in 2001, was tracking subjects but no longer enrolling new subjects. Its purpose is to test efficacy for patients whose CaP is still controlled by either suppression of testosterone by hormone treatment or by surgical castration. Such patients have usually failed primary treatment of either surgical removal of the prostate, (EBRT), internal radiation, BNCT or (HIFU) for curative intent. Such failure is called biochemical failure and is defined as a PSA reading of 2.0 ng/mL above nadir (the lowest reading taken post primary treatment).As of August 2014, a clinical trial administering sipuleucel-T in conjunction with ipilimumab (Yervoy) was tracking subjects but no longer enrolling new subjects; the trial evaluates the clinical safety and anti-cancer effects (quantified in PSA, radiographic and T cell response) of the combination therapy in patients with advanced prostate cancer.
References
This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.
Further reading
Huber ML, Haynes L, Parker C, Iversen P (February 2012). "Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer". Journal of the National Cancer Institute. 104 (4): 273–9. doi:10.1093/jnci/djr514. PMC 3283534. PMID 22232132.
"Sipuleucel-T: APC 8015, APC-8015, prostate cancer vaccine--Dendreon". Drugs in R&D. 7 (3): 197–201. 2006. doi:10.2165/00126839-200607030-00006. PMID 16752945.
External links
"Sipuleucel-T". Drug Information Portal. U.S. National Library of Medicine. |
Tretten | Tretten is a village in Øyer Municipality in Innlandet county, Norway. The village is located on the Losna lake, which is part of the Gudbrandsdalslågen river. Tretten is located in the Gudbrandsdal valley, along the Gudbrandsdalslågen river in the southern part of the municipality. It is located along the European route E6 highway, about 25 kilometres (16 mi) north of the town of Lillehammer. The municipal center of Tingberg lies about 5 kilometres (3.1 mi) to the southeast of Tretten.
The 1.22-square-kilometre (300-acre) village has a population (2021) of 860 and a population density of 707 inhabitants per square kilometre (1,830/sq mi).The village had its own sports team Tretten IL until 1990, when a merger created Øyer-Tretten IF. The village is also the site of Tretten Church which serves the northern part of the municipality.
Tretten was the location of the biggest train disaster in Norways history. The Tretten train disaster occurred on 22 February 1975 when two passenger trains collided head on. The tragedy resulted in 27 people being killed.
On 15 August 2022, the Tretten Bridge over the Gudbrandsdalslågen river completely collapsed; it had beams of glued laminated timber and others of weathering steel. There were no fatalities. One vehicle driver was rescued by helicopter and the driver of a car escaped by himself.
Name
The village (and church parish) is named after the old Tretten farm (Old Norse: Þrœttin or Þróttvin) since the first church was built there. This farm is now named Prestgarden which means the vicarage. The first element of the name is þróttr which means force or power. The last element is vin which means meadow. The farm is lying close to the river Moksa, and the first element is probably referring to the stream and the waterfalls in the river here.
See also
Bridge collapse in 2022
== References == |
Efavirenz/lamivudine/tenofovir | Efavirenz/lamivudine/tenofovir (EFV/3TC/TDF), sold under the brand name Symfi among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It combines efavirenz, lamivudine, and tenofovir disoproxil. As of 2019, it is listed by the World Health Organization as an alternative first line option to dolutegravir/lamivudine/tenofovir. It is taken by mouth.Side effects can include joint pain, sleepiness, headaches, depression, trouble sleeping, and itchiness. Severe side effects may include depression, psychosis, or osteonecrosis. In those with a history of epilepsy, it may increase the frequency of seizures. Greater care should also be taken in those with kidney problems. Its use during pregnancy appears to be unsafe.It is on the World Health Organizations List of Essential Medicines. The combination received tentative approval in the United States in 2014, and was granted approval in February 2018. Its availability and importance is supported by Medecins Sans Frontieres. It is available as a generic medication.
References
External links
"Efavirenz". Drug Information Portal. U.S. National Library of Medicine.
"Lamivudine". Drug Information Portal. U.S. National Library of Medicine.
"Tenofovir disoproxil". Drug Information Portal. U.S. National Library of Medicine.
"Tenofovir disoproxil fumarate". Drug Information Portal. U.S. National Library of Medicine. |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.