Befiradol (F-13,640; NLX-112) is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.
Brief History
Befiradol was discovered and developed by Pierre Fabre Médicament, a French pharmaceuticals company who initially developed it as a treatment for chronic pain. In September 2013, befiradol was out-licensed to Neurolixis, a US-based biotechnology company. Neurolixis announced that it intended to re-purpose befiradol for the treatment of levodopa-induced dyskinesia in Parkinson’s disease. In support of this indication, Neurolixis received several research grants from the Michael J. Fox Foundation and preclinical data was published describing the activity of befiradol in animal models of Parkinson’s disease. Studies published in 2020 using non-human primate models of Parkinson’s disease, (MPTP-treated marmosets and MPTP-treated macaques), found that befiradol potently reduced Levodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg. In January 2018, the British charity Parkinson’s UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson’s disease patients.
Pharmacology
In recombinant cell lines expressing human 5-HT1A receptors, befiradol exhibits high agonist efficacy for a variety of signal transduction read-outs, including ERK phosphorylation, G-protein activation, receptor internalisation and adenylyl cyclase inhibition. In rat hippocampal membranes it preferentially activates GalphaO proteins. In neurochemical experiments, befiradol activated 5-HT1A autoreceptors in rat dorsal Raphe nucleus as well as 5-HT1A heteroreceptors on pyramidal neurons in the frontal cortex. In rat models, it has powerful analgesic and antiallodynic effects comparable to those of high doses of opioid painkillers, but with fewer and less prominent side effects, as well as little or no development of tolerance with repeated use.
A structure–activity relationship (SAR) study revealed that replacement of the dihalophenyl moiety by 3-benzothienyl increases maximal efficacy from 84% to 124% (Ki=2.7 nM).
Clinical Ph2A Trial for Dyskinesia in Parkinson’s Disease
In March 2019, Neurolixis announced that the US Food and Drug Administration (FDA) gave a positive response to Neurolixis’ Investigational New Drug (IND) application for NLX-112 to be tested in a Phase 2 clinical study in Parkinson’s disease patients with troublesome levodopa-induced dyskinesia. On 22 November 2020, The Sunday Times reported that the two charities, Parkinson’s UK and Michael J. Fox Foundation, were jointly investing $2 million to support a clinical trial on befiradol in Parkinson’s disease patients with troublesome Levodopa-induced dyskinesia, a potentially “life changing” drug. On 23 November 2020, Parkinson’s UK and Michael J. Fox Foundation, confirmed their funding in an official announcement. Neurolixis announced on 30 November 2021 the start of patient recruitment in the clinical trial. The trial is listed on the US National Library of Medicine clinical trials register. On 20 March 2023, a joint press release from Neurolixis, Parkinson’s UK and Michael J. Fox Foundation announced that the clinical trial had met its primary endpoint of safety and tolerability, and also the secondary endpoint of efficacy in reducing Levodopa-induced dyskinesia in the patients. Moreover, a later announcement (07 July 2023) disclosed that the clinical trial had also found that befiradol reduced parkinsonism symptoms (such as slowness of movement, tremor and rigidity), as well as Levodopa-induced dyskinesia, raising the prospect of developing a “dual-efficacy therapy” for Parkinson’s disease.
18F-Befiradol as an Agonist PET Radiotracer for Brain Imaging
As well as studies on befiradol for treatment of movement disorders, other researchers have investigated it as a novel radiotracer for brain imaging studies by positron emission tomography. Thus befiradol labeled with [18F] (also known as 18F-F13640) has been used to study the distribution of serotonin 5-HT1A receptors in rat, cat, macaque and human. Because befiradol is an agonist, it enables the detection of 5-HT1A receptors which are specifically in a functionally active state, whereas antagonist radiotracers label the total receptor population.
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Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome (CDS). It may be used alone or along with stimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.
Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain.
It was approved for medical use in the US in 2002. In 2022, it was the 213th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Brief History
Atomoxetine is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current US patent owner. Atomoxetine was initially intended to be developed as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the US Food and Drug Administration (FDA) in 2002, for the treatment of ADHD. Its patent expired in May 2017. On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On 01 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the US. In a 29 July 2011 conference call, however, Sun Pharmaceutical’s Chairman stated “Lilly won that litigation on appeal so I think [generic Strattera]’s deferred.”
In 2017, the FDA approved the generic production of atomoxetine by four pharmaceutical companies.
Medical Uses
Atomoxetine is indicated for the treatment of ADHD.
Attention Deficit Hyperactivity Disorder
Atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. One of the primary differences with the standard stimulant treatments for ADHD is that it has little known abuse potential. Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent.
While its efficacy may be less than that of lisdexamphetamine, there is some evidence that it may be used in combination with stimulants. Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness; when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history of substance use disorder.
Atomoxetine alleviates ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine in the prefrontal cortex, sharing 70-80% of the brain regions with stimulants in their produced effects.
Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine’s use can be abruptly stopped without significant withdrawal symptoms being observed.
The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. Incrementally increasing response may occur up to 1 year or longer. The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.
Other Uses
Cognitive Disengagement Syndrome
Atomoxetine may be used to treat cognitive disengagement syndrome (CDS), as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment. In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.
Traumatic Brain Injury
Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury (TBI). It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects. Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid haemorrhage in a case report.
Common side effects include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a “potentially least preferred agent based on safety” for treating ADHD. As of 2019, safety in pregnancy and breastfeeding is not clear; a 2018 review stated that, “[b]ecause of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy.”
The US Food and Drug Administration (FDA) has issued a black box warning for suicidal behaviour/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.
Overdose
Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.
Interactions
Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.
Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia. QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolisers.
Other notable drug interactions include:
Antihypertensive agents, due to atomoxetine acting as an indirect sympathomimetic.
Indirect-acting sympathomimetics, such as pseudoephedrine, other norepinephrine reuptake inhibitors (NRIs), or MAOIs.
Direct-acting sympathomimetics, such as phenylephrine or other α1-adrenergic receptor agonists, including vasopressors such as dobutamine or isoprenaline and β2-adrenergic receptor agonists.
Highly plasma protein-bound drugs: atomoxetine has the potential to displace these drugs from plasma proteins which may potentiate their adverse or toxic effects. In vitro, atomoxetine does not affect the plasma protein binding of aspirin, desipramine, diazepam, paroxetine, phenytoin, or warfarin.
Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.
Pharmacology
Pharmacodynamics
Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter (DAT) expression is minimal. In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.
Atomoxetine’s status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively. However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment. Supporting atomoxetine’s selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).
Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. Atomoxetine’s ability to increase prefrontal cortex firing rate in anaesthetised rats could not be blocked by D1 or α1-adrenergic receptor antagonists, but could be potentiated by NMDA or an α2-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels. Aberrant glutamate and NMDA receptor function have been implicated in the aetiology of ADHD.
Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolisers. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.
4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.
Pharmacokinetics
Orally administered atomoxetine is rapidly and completely absorbed. First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolisers and 94% for poor metabolisers. Maximum plasma concentration is reached in 1–2 hours. If taken with food, the maximum plasma concentration decreases by 10–40% and delays the tmax by 3 hours. Drugs affecting gastric pH have no effect on oral bioavailability.
Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells. It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%). Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.
The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours. As atomoxetine is metabolised by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolisers. Among CYP2D6 extensive metabolisers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours. By contrast, among CYP2D6 poor metabolisers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours. Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (Ctrough) residing around 30–40°ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient’s CYP2D6 profile.
Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L. Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of atomoxetine in CYP2D6 extensive metabolisers, and are 5% and 45% that of atomoxetine in CYP2D6 poor metabolizers.
Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolisers, with >96% and 80% of a total dose being excreted in urine, respectively. The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolisers, but only 40% in poor metabolisers. CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.
Pharmacogenomics
Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolisers.
Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolisers.
Chemistry
Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.
Detection in Biological Fluids
Atomoxetine may be quantitated in plasma, serum, or whole blood to distinguish extensive versus poor metabolisers in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims, or to assist in the forensic investigation in a case of fatal overdosage.
Society and Culture
The drug was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen.
Brand Names
In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland, and the US, atomoxetine is sold under the brand name Strattera. In France, hospitals dispense atomoxetine under the brand name Strattera (it is not marketed in France). In the Czech Republic, it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In Turkey, it is sold under the brand names Attex, Setinox, and Atominex. In 2017, a generic version was approved in the United States.
Research
There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.
Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well studied. Some benefit has also been seen in people with ADHD and autism. As with other norepinephrine reuptake inhibitors it appears to reduce anxiety and depression symptoms, although attention has focused mainly on specific patient groups such as those with concurrent ADHD or methamphetamine dependence.
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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 serotonin5-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.
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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-HT7serotonin 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.
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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.
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.
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.
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.
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:
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.
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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)
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.
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.
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