Tag: Medication

What is Quipazine?

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Introduction

Quipazine, also known as 1-(2-quinolinyl)piperazine, is a serotonergic drug of the arylpiperazine family and an analogue of 1-(2-pyridinyl)piperazine which is used in scientific research.

It was first described in the 1960s and was originally intended as an antidepressant but was never developed or marketed for medical use.

Pharmacology

Pharmacodynamics

Quipazine is a serotonin 5-HT3 receptor agonist and to a lesser extent a serotonin 5-HT2A receptor agonist, ligand of the serotonin 5-HT2B and 5-HT2C receptors, and serotonin reuptake inhibitor. Activation of the serotonin 5-HT3 is implicated in inducing nausea and vomiting as well as anxiety, which has limited the potential clinical usefulness of quipazine.

Quipazine produces a head-twitch response and other psychedelic-consistent effects in animal studies including in mice, rats, and monkeys. These effects appear to be mediated by activation of the serotonin 5-HT2A receptor, as they are blocked by serotonin 5-HT2A receptor antagonists like ketanserin. The head twitches induced by quipazine are potentiated by the monoamine oxidase inhibitor (MAOI) pargyline. Based on this, it has been suggested that quipazine may act as a serotonin releasing agent and that it may induce the head twitch response by a dual action of serotonin 5-HT2A receptor agonism and induction of serotonin release.

Quipazine did not produce psychedelic effects in humans up to a dose of 25 mg, which was the highest dose tested due to serotonin 5-HT3 receptor-mediated side effects of nausea and gastrointestinal discomfort. Alexander Shulgin has anecdotally claimed that a fully effective psychedelic dose could be reached by blocking serotonin 5-HT3 receptors using the serotonin 5-HT3 receptor antagonist ondansetron.

Quipazine can produce tachycardia, including positive chronotropic and positive inotropic effects, through activation of the serotonin 5-HT3 receptor.

Although quipazine does not generalise to dextroamphetamine in drug discrimination tests of dextroamphetamine-trained rodents, dextroamphetamine and cathinone have been found to partially generalise to quipazine in assays of quipazine-trained rodents. In relation to this, it has been suggested that quipazine might possess some dopaminergic activity, as the discriminative stimulus properties of amphetamine appear to be mediated by dopamine signalling. Relatedly, quipazine has been said to act as a dopamine receptor agonist in addition to serotonin receptor agonist. Conversely however, the generalisation may be due to serotonergic activities of amphetamine and cathinone. Fenfluramine has been found to fully generalise to quipazine, but levofenfluramine, in contrast to quipazine, did not generalise to dextroamphetamine.

Chemistry

Quipazine is a substituted piperazine and quinoline.

It is structurally related to 6-nitroquipazine and 1-(1-naphthyl)piperazine.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Quipazine >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is 1-(2-Diphenyl)piperazine

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Introduction

1-(2-Diphenyl)piperazine, also known as RA-7 or Diphenylpiperazine, is a drug which acts as a potent and selective antagonist at the 5-HT7 serotonin receptor.

It was discovered as an active metabolite of the synthetic 5-HT7 agonists LP-12 and LP-211, and unexpectedly turned out to be a potent antagonist with selectivity approaching that of the parent molecules, despite its much simpler structure.

Refer to Naphthylpiperazine.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/1-(2-Diphenyl)piperazine >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Naphthylpiperainze?

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Introduction

1-(1-Naphthyl)piperazine (1-NP) is a drug which is a phenylpiperazine derivative.

It acts as a non-selective, mixed serotonergic agent, exerting partial agonism at the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F receptors, while antagonising the 5-HT2A, 5-HT2B, and 5-HT2C receptors. It has also been shown to possess high affinity for the 5-HT3, 5-HT5A, 5-HT6, and 5-HT7 receptors, and may bind to 5-HT4 and the SERT as well. In animals it produces effects including hyperphagia, hyperactivity, and anxiolysis, of which are all likely mediated predominantly or fully by blockade of the 5-HT2C receptor.

What is Fluprazine?

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Introduction

Fluprazine (DU-27,716) is a drug of the phenylpiperazine class.

It is a so-called serenic or antiaggressive agent.

It is closely related to several other piperazines, including eltoprazine and batoprazine, and TFMPP, as well as more distantly to the azapirones such as buspirone.

The pharmacology of fluprazine is unknown, but it is likely to act as an agonist at the 5-HT1A and 5-HT1B receptors like its sister compound eltoprazine.

What is Eltoprazine?

Published on by Andrew Marshall3 Comments

Introduction

Eltoprazine (developmental code name DU-28,853) is a serotonergic drug of the phenylpiperazine class which is described as a serenic, or anti-aggressive agent.

It acts as an agonist of the serotonin 5-HT1A and 5-HT1B receptors and as an antagonist of the serotonin 5-HT2C receptor. The drug is closely related to batoprazine, fluprazine and batoprazine, which are similarly acting agents, and is also a known chemical precursor to S-15535 and lecozotan.

Eltoprazine is or was under development for the treatment of aggression, attention deficit hyperactivity disorder (ADHD), cognitive disorders, and drug-induced dyskinesia, but no recent development has been reported for these indications as of February 2022. It was also under development for the treatment of psychotic disorders, but development for this indication was discontinued.

Eltoprazine was originated by Solvay and was developed by Elto Pharma, PsychoGenics, and Solvay.

What is Azapirone?

Published on by Andrew Marshall2 Comments

Introduction

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

List of Azapirones

The azapirones include the following agents:

Anxiolytics

Antipsychotics

Others

  • SNAP-8719 (CAS number: 255893-38-0 )
  • CID:14086451

Medical Uses

Azapirones have shown benefit in general anxiety and augmenting SSRIs in social anxiety and depression. Evidence is not clear for panic disorder and functional gastrointestinal disorders.

Tandospirone has also been used to augment antipsychotics in Japan as it improves cognitive and negative symptoms of schizophrenia. Buspirone is being investigated for this purpose as well.

Side Effects

Side effects of azapirones may include dizziness, headaches, restlessness, nausea, and diarrhoea.

Azapirones have more tolerable adverse effects than many other available anxiolytics, such as benzodiazepines or SSRIs. Unlike benzodiazepines, azapirones lack abuse potential and are not addictive, do not cause cognitive/memory impairment or sedation, and do not appear to induce appreciable tolerance or physical dependence. However, azapirones are considered less effective with slow onset in controlling symptoms.

Chemistry

Buspirone was originally classified as an azaspirodecanedione, shortened to azapirone or azaspirone due to the fact that its chemical structure contained this moiety, and other drugs with similar structures were labelled as such as well. However, despite all being called azapirones, not all of them actually contain the azapirodecanedione component, and most in fact do not or contain a variation of it. Additionally, many azapirones are also pyrimidinylpiperazines, though again this does not apply to them all.

Drugs classed as azapirones can be identified by their -spirone or -pirone suffix.

Pharmacology

Pharmacodynamics

On a pharmacological level, azapirones varyingly possess activity at the following receptors:

  • 5-HT1A receptor (as partial or full agonists)
  • 5-HT2A receptor (as inverse agonists)
  • D2 receptor (as antagonists or partial agonists)
  • α1-adrenergic receptor (as antagonists)
  • α2-adrenergic receptor (as antagonists)

Actions at D4, 5-HT2C, 5-HT7, and sigma receptors have also been shown for some azapirones.

While some of the listed properties such as 5-HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia (as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute to side effects. As a result, further development has commenced to bring more selective of anxiolytic agents to the market. An example of this initiative is gepirone, which was recently approved after completing clinical trials in the United States for the treatment of major depression and generalised anxiety disorder. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression.

5-HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials. Unfortunately, however, their efficacy is limited and they are only relatively mild antidepressants. Instead of being used as monotherapy treatments, they are more commonly employed as augmentations to serotonergic antidepressants like the SSRIs. It has been proposed that high intrinsic activity at 5-HT1A postsynaptic receptors is necessary for maximal therapeutic benefits to come to prominence, and as a result, investigation has commenced in azapirones which act as 5-HT1A receptor full agonists such as alnespirone and eptapirone. Indeed, in preclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine and paroxetine.

Pharmacokinetics

Azapirones are poorly but nonetheless appreciably absorbed and have a rapid onset of action, but have only very short half-lives ranging from 1–3 hours. As a result, they must be administered 2–3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours. Unfortunately, umespirone has not been commercialised. Although never commercially produced, Bristol-Myers Squibb applied for a patent on 28 October 1993, and received the patent on 11 July 1995, for an extended release formulation of buspirone. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue.

Metabolism of azapirones occurs in the liver and they are excreted in urine and feces. A common metabolite of several azapirones including buspirone, gepirone, ipsapirone, revospirone, and tandospirone is 1-(2-pyrimidinyl)piperazine (1-PP). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Azapirone >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Milnacipran?

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Introduction

Milnacipran (trade names Ixel, Savella, Dalcipran, Toledomin) is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the US, but it is in other countries.

Brief History

Milnacipran was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed (as Ixel) for this indication in over 45 countries worldwide including several European countries such as Austria, Bulgaria, Finland, France, Portugal, and Russia. It is also available in Japan (as Toledomin) and Mexico (as Dalcipran). Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the United States and Canada in 2003 from the manufacturer Laboratoires Pierre Fabre.

In January 2009 the US Food and Drug Administration (FDA) approved milnacipran (under the brand name Savella) only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States. In July and November 2009, the European Medicines Agency refused marketing authorisation for a milnacipran product (under the brand name Impulsor) for the treatment of fibromyalgia.

Medical Uses

Depression

In a pooled analysis of 7 comparative trials with imipramine, milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs concluded a superior efficacy for milnacipran with similar tolerability for milnacipran and SSRIs. A more recent meta-analysis of 6 studies involving more than 1,000 patients showed no distinction between milnacipran and SSRIs in efficacy or discontinuation rates, including discontinuation for side effects or lack of efficacy. A meta-analysis of a total of 16 randomised controlled trials with more than 2200 patients concluded that there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressant agents. However, compared with TCAs, significantly fewer patients taking milnacipran dropped out due to adverse events. As with other antidepressants, 1 to 3 weeks may elapse before significant antidepressant action becomes clinically evident.

Impulse Control

Milnacipran was found to improve impulse control in rats, which has been linked to its activation of D1-like receptors in the infralimbic cortex. However, high doses of milnacipran did not show this effect, likely because of increased dopamine in the nucleus accumbens. Depression has been associated with increased impulsivity.

Fibromyalgia

During its development for fibromyalgia, milnacipran was evaluated utilizing a composite responder approach. To be considered as a responder for the composite ‘treatment of fibromyalgia’ endpoint, each patient had to show concurrent and clinically meaningful improvements in pain, physical function, and global impression of disease status. A systematic review in 2015 showed moderate relief for a minority of people with fibromyalgia. Milnacipran was associated with increased adverse events when discontinuing use of the drug.

Social Anxiety

There is some evidence that milnacipran may be effective for social anxiety.

Contraindications

Administration of milnacipran should be avoided in individuals with the following:

  • Known hypersensitivity to milnacipran (absolute contraindication)
  • Patients under 15 years of age (no sufficient clinical data)
  • Concomitant treatment with irreversible MAO inhibitors (e.g. tranylcypromine (Parnate), phenelzine (Nardil), >10 mg selegiline) or digitalis glycosides is an absolute contraindication.

Administration of milnacipran should be done with caution in individuals with the following:

  • Concomitant treatment with parenteral epinephrine, norepinephrine, with clonidine, reversible MAO-A Inhibitors (such as moclobemide, toloxatone) or 5-HT1D-agonists (e.g. triptan migraine drugs)
  • Advanced renal disease (decreased dosage required)
  • Hypertrophy of the prostate gland (possibly urination hesitancy induced), with hypertension and heart disease (tachycardia may be a problem) as well as with open angle glaucoma.

Milnacipran should not be used during pregnancy because it may cross the placenta barrier and no clinical data exists on harmful effects in humans and animal studies. Milnacipran is contraindicated during lactation because it is excreted in the milk, and it is not known if it is harmful to the newborn.

Side Effects

The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhydrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension [FDA Savella prescribing information]. Milnacipran can have a significant impact on sexual functions, including both a decrease in sexual desire and ability. Milnacipran can cause pain of the testicles in men. The incidence of cardiovascular and anticholinergic side effects was significantly lower compared to TCAs as a controlled study with over 3,300 patients revealed. Elevation of liver enzymes without signs of symptomatic liver disease has been infrequent. Mood swing to mania has also been seen and dictates termination of treatment. In psychotic patients emergence of delirium has been noticed. Milnacipran has a low incidence of sedation but improves sleep (both duration and quality) in depressed patients. In agitated patients or those with suicidal thoughts additive sedative/anxiolytic treatment is usually indicated. However, several studies found that there seems to be no “activation syndrome” and no increased risk of suicidality in milnacipran therapy; instead it is said to reduce suicidality along with depressive symptoms.

Interactions

  • MAOIs — hyperserotonergia (serotonin syndrome), potentially lethal hypertensive crisis.
  • 5-HT1 receptor agonists — coronary vasoconstriction with risk of angina pectoris and myocardial infarction.
  • Epinephrine, norepinephrine (also in local anaesthesia) — hypertensive crisis and/or possible cardiac arrhythmia.
  • Clonidine — antihypertensive action of clonidine may be antagonised
  • Digitalis — haemodynamic actions increased.
  • Triptans — there have been rare postmarketing reports of hyperserotonergia (serotonin syndrome). If concomitant treatment of milnacipran with a triptan is clinically warranted, careful observation of patient is advised when starting or increasing dosages.
  • Alcohol — no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended; the FDA advises against the concomitant use of alcohol and milnacipran.

Pharmacology

Pharmacodynamics

Milnacipran inhibits the reuptake of serotonin and norepinephrine in an approximately 2:1 ratio, respectively. Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors, nor on benzodiazepine and opioid binding sites.

Recently, levomilnacipran, the levorotatory enantiomer of milnacipran, has been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which is responsible for β-amyloid plaque formation, and hence may be a potentially useful drug in the treatment of Alzheimer’s disease. Other BACE-1 inhibitors, such as CTS-21166 (ASP1720), MK-8931, and AZD3293 were in clinical trials for the treatment of Alzheimer’s disease, but in both cases clinical trials were halted due to a lack of positive evidence of a favourable benefit to risk ratio and both were considered unlikely to return satisfactory results.

Pharmacokinetics

Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%. Meals do not have an influence on the rapidity and extent of absorption. Peak plasma concentrations are reached 2 hours after oral dosing. The elimination half-life of 8 hours is not increased by liver impairment and old age, but by significant renal disease. Milnacipran is conjugated to the inactive glucuronide and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Milnacipran >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is 8-OH-DPAT?

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Introduction

8-OH-DPAT is a research chemical of the aminotetralin chemical class which was developed in the 1980s and has been widely used to study the function of the 5-HT1A receptor. It was one of the first major 5-HT1A receptor full agonists to be discovered.

Refer to Azapirone.

Originally believed to be selective for the 5-HT1A receptor, 8-OH-DPAT was later found to act as a 5-HT7 receptor agonist and serotonin reuptake inhibitor/releasing agent as well.

In animal studies, 8-OH-DPAT has been shown to possess antidepressant, anxiolytic, serenic, anorectic, antiemetic, hypothermic, hypotensive, bradycardic, hyperventilative, and analgesic effects.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/8-OH-DPAT >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Tandospirone?

Published on by Andrew Marshall2 Comments

Introduction

Tandospirone, sold under the brand name Sediel, is an anxiolytic and antidepressant medication used in Japan and China, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone class of drugs and is closely related to other azapirones like buspirone and gepirone.

Tandospirone was introduced for medical use in Japan in 1996 and in China in 2004.

Medical Uses

Anxiety and Depression

Tandospirone is most commonly used as a treatment for anxiety and depressive disorders, such as generalised anxiety disorder and dysthymia respectively. For both indications it usually takes a couple of weeks for therapeutic effects to begin to be seen, although at higher doses more rapid anxiolytic responses have been seen. It has also been used successfully as a treatment for bruxism.

Augmentation for Depression

Tandospirone can be used as an effective augmentation, especially when coupled with fluoxetine or clomipramine.

Other Uses

Tandospirone has been tried successfully as an adjunctive treatment for cognitive symptoms in schizophrenic individuals.

Side Effects

Common adverse effects include:

  • Dizziness
  • Drowsiness
  • Insomnia
  • Headache
  • Gastrointestinal disorders
  • Dry mouth
  • Negative influence on explicit memory function
  • Nausea

Adverse effects with unknown frequency include:

  • Hypotension (low blood pressure)
  • Dysphoria
  • Tachycardia
  • Malaise
  • Psychomotor impairment

It is not believed to be addictive but is known to produce mild withdrawal effects (e.g. anorexia) after abrupt discontinuation.

Pharmacology

Pharmacodynamics

Tandospirone acts as a potent and selective 5-HT1A receptor partial agonist, with a Ki affinity value of 27 ± 5 nM and approximately 55 to 85% intrinsic activity. It has relatively weak affinity for the 5-HT2A (1,300 ± 200), 5-HT2C (2,600 ± 60), α1-adrenergic (1,600 ± 80), α2-adrenergic (1,900 ± 400), D1 (41,000 ± 10,000), and D2 (1,700 ± 300) receptors, and is essentially inactive at the 5-HT1B, 5-HT1D, β-adrenergic, and muscarinic acetylcholine receptors, serotonin transporter, and benzodiazepine allosteric site of the GABAA receptor (all of which are > 100,000). There is evidence of tandospirone having low but significant antagonistic activity at the α2-adrenergic receptor through its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP).

Society and Culture

Name

Tandospirone is also known as metanopirone and by the developmental code name SM-3997. It is marketed in Japan under the brand name Sediel.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Tandospirone >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.