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What is Aripiprazole Lauroxil?

Published on by Andrew Marshall1 Comment

Introduction

Aripiprazole lauroxil, sold under the brand name Aristada among others, is a long-acting injectable atypical antipsychotic that was developed by Alkermes. It is an N-acyloxymethyl prodrug of aripiprazole that is administered via intramuscular injection once every four to eight weeks for the treatment of schizophrenia. Aripiprazole lauroxil was approved by the US Food and Drug Administration (FDA) in October 2015.

Medical Uses

Aripiprazole lauroxil is indicated for the treatment of schizophrenia in adults.

Aripiprazole lauroxil is a longer-lasting and injectable version of the schizophrenia pill aripiprazole. Aripiprazole lauroxil, along with other drugs in its family, are not approved for treatment of the elderly with dementia-related psychosis.

Side Effects

The most common side effects are akathisia. According to the drug’s warning label and safety information, the side effects are large in variety.

The complete list of side effects include: akathisia, contraindication cerebrovascular adverse reactions (including stroke), neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, hyperglycaemia/diabetes mellitus, dyslipidaemia, weight gain, orthostatic hypotension, leukopenia, neutropenia, agranulocytosis, seizures, potential for cognitive and motor impairment, difficulties with body temperature regulation, dysphagia, injection site reactions (rash, swelling, redness, irritation at the point of injection), dystonia and pregnancy and nursing complications.

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.

Overdosing

The largest known case of ingestion with a known outcome involved a 1260 mg of oral aripiprazole, 42 times the recommended dose. The patient survived and fully recovered.

Common adverse reactions, reported in at least 5% of overdose cases, included vomiting, somnolence, and tremor. Other clinically important signs and symptoms of overdoses include acidosis, aggression, atrial fibrillation, bradycardia, coma, confusion, convulsion, depressed level of consciousness, hypertension, hypokalaemia, hypotension, lethargy, loss of consciousness, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia.

Pharmacology

Mechanism of Action

Arristada is injected intramuscularly as an atypical antipsychotic. In one 12-week clinical trial involving 622 participants, the efficacy of extended aripiprazole was demonstrated. Its mechanism of action is not completely known, but is thought to be converted by enzyme-mediated hydrolysis to N-hydroxymethyl aripiprazole. The hydroxymethyl aripiprazole is then hydrolysed to aripiprazole. Efficacy could be mediated through a combination of partial agonist activity D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Since it is a newly approved drug by the FDA, many validation of mechanisms of action are still being studied.

Pharmacodynamics

Aripiprazole exhibits high affinity for serotonin 5-HT1A, 5-HT2A receptors, dopamine D2, and dopamine D3. Moderate affinity is exhibited for serotonin 5-HT7, α1-adrenergic, dopamine D4, histamine H1, and serotonin re-uptake site. No affinity for cholinergic muscarinic receptors have been found.

Pharmacokinetics

Aristada’s activity in the body is due to aripiprazole and also dehydro-aripiprazole. Dehydro-aripiprazole has been shown to have affinities for D2 receptors. These D2 receptors have similarities to aripiprazole whereas they represent 30-40% of exposure of aripiprazole in plasma.

After five to six days of the single intramuscular injection appearance of aripiprazole in circulation, it additionally will be released for 36 days. In the fourth monthly injection, consecutive doses of Aristada will reach steady-state. With additional supplements of the oral aripiprazole at a dosage of 21 days during the first dose of Aristada, aripiprazole concentrations within 4 days can reach therapeutic levels.

Chemistry

In contrast to many other depot antipsychotics, aripiprazole lauroxil is described as a non-ester chemical modification. It is specifically N-lauroyloxymethylaripiprazole. However, the N-lauroyloxymethyl moiety contains a laurate ester, technically making aripiprazole lauroxil an antipsychotic ester. More specifically, aripiprazole lauroxil is the laurate ester of N-hydroxymethylaripiprazole. Following cleavage of the laurate ester, N-hydroxymethylaripiprazole is further metabolised to aripiprazole, making aripiprazole lauroxil a prodrug of aripiprazole with N-hydroxymethylaripiprazole as an intermediate.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Aripiprazole_lauroxil >; 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 Timiperone?

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Introduction

Timiperone, sold under the brand name Tolopelon, is a typical antipsychotic of the butyrophenone class which is marketed in Japan for the treatment of schizophrenia.

It is similar in chemical structure to benperidol, but has a thiourea group instead of a urea group.

It acts as an antagonist for the D2 and 5-HT2A receptors.

What is Penfluridol?

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Introduction

Penfluridol (Semap, Micefal, Longoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic.

It was discovered at Janssen Pharmaceutica in 1968. Related to other diphenylbutylpiperidine antipsychotics, pimozide and fluspirilene, penfluridol has an extremely long elimination half-life and its effects last for many days after single oral dose. Its antipsychotic potency, in terms of dose needed to produce comparable effects, is similar to both haloperidol and pimozide. It is only slightly sedative, but often causes extrapyramidal side-effects, such as akathisia, dyskinesiae and pseudo-Parkinsonism. Penfluridol is indicated for antipsychotic treatment of chronic schizophrenia and similar psychotic disorders, it is, however, like most typical antipsychotics, being increasingly replaced by the atypical antipsychotics. Due to its extremely long-lasting effects, it is often prescribed to be taken orally as tablets only once a week (q 7 days). The once-weekly dose is usually 10–60 mg.

A 2006 systematic review examined the use of penfluridol for people with schizophrenia:

Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The effectiveness and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for people with long-term schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention. (Soares & Lima, 2006).

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What is Imidazopyridine?

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Introduction

An imidazopyridine is a nitrogen containing heterocycle that is also a class of drugs that contain this same chemical substructure. In general, they are GABAA receptor agonists, however recently proton pump inhibitors, aromatase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) and other classes of drugs in this class have been developed as well.

Despite usually being similar to them in effect, they are not chemically related to benzodiazepines. As such, GABAA-agonising imidazopyridines, pyrazolopyrimidines, and cyclopyrrones are sometimes grouped together and referred to as “nonbenzodiazepines.”

Imidazopyridines include the following.

Sedatives

Anxiolytics, sedatives and hypnotics (GABAA receptor positive allosteric modulators):

  • Imidazo[1,2-a]pyridines:
    • Alpidem (original brand name Ananxyl) – an anxiolytic that was withdrawn from the market worldwide in 1995 due to hepatotoxicity.
    • DS-1—a GABAA receptor positive allosteric modulator selective for the α4β3δ subtype, which is not targeted by other GABAergics such as benzodiazepines or other nonbenzodiazepines.
    • Necopidem—an anxiolytic. It has not found clinical use.
    • Saripidem—a sedative and anxiolytic. It is not used clinically.
    • TP-003—a subtype-selective partial agonist at GABAA receptors, binding to GABAA receptor complexes bearing either α2, α3 or α5 subunits, but only showing significant efficacy at α3.
    • Zolpidem (original brand name Ambien)—a widely used hypnotic. Generic versions are widely available.
  • Imidazo[4,5-c]pyridines:
    • Bamaluzole—a GABAA receptor-agonising anticonvulsant that was never marketed.

Antipsychotic

Antipsychotics:

Gastrointestinal

Drugs used for peptic ulcer disease (PUD), GERD and gastroprokinetic agents (motility stimulants):

  • Imidazo[1,2-a]pyridines:
    • CJ-033466—an experimental gastroprokinetic acting as a selective 5-HT4 serotonin receptor partial agonist.
    • Zolimidine—a gastroprotective agent.
    • Linaprazan—a potassium-competitive acid blocker which demonstrated similar efficacy as esomeprazole in healing and controlling symptoms of GERD patients with erosive esophagitis.
    • SCH28080—the prototypical potassium-competitive acid blocker which has not found clinical use because of liver toxicity in animal trials and elevated liver enzyme activity in the serum of human volunteers.
  • Imidazo[4,5-b]pyridines:
    • Tenatoprazole—it blocks the gastric proton pump leading to decline of gastric acid production.

Anti-Inflammatories

NSAIDs, analgesics and antimigraine drugs:

  • Imidazo[1,2-a]pyridines:
    • Miroprofen—a derivative of propionic acid.
  • Imidazo[4,5-b]pyridines:
    • Telcagepant—a calcitonin gene-related peptide receptor antagonist which was in clinical trials as a remedy for migraine. Its development was terminated.

Cardiovascular

Drugs acting on the cardiovascular system:

  • Imidazo[1,2-a]pyridines:
    • Olprinone (loprinone) – a cardiac stimulant.

Bone

Drugs for treatment of bone diseases:

  • Imidazo[1,2-a]pyridines:
    • Minodronic acid (brand names Bonoteo, Recalbon)—a third-generation bisphosphonate used for the treatment of osteoporosis.

Antineoplastic

Antineoplastic agents:

  • Imidazo[1,5-a]pyridines:
    • Fadrozole (brand name Afema)—an aromatase inhibitor.
  • Imidazo[4,5-c]pyridines:
    • 3-Deazaneplanocin A—an S-adenosyl-L-homocysteine synthesis inhibitor and histone methyltransferase EZH2 inhibitor.

Antiviral

Directly-acting antiviral agents:

  • Imidazo[1,2-a]pyridines:
    • Tegobuvir (GS-9190) – an allosteric, non-nucleoside hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitor targeting the thumb II allosteric site.

DAergic

  • PIP3EA [885446-91-3] D4 agonist supported to have penile erectant properties.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Imidazopyridine >; 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 Spiperone?

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Introduction

Spiperone (Spiroperidol; brand name: Spiropitan (JP)) is a typical antipsychotic and research chemical belonging to the butyrophenone chemical class.

It is licensed for clinical use in Japan as a treatment for schizophrenia.

Additionally, spiperone was identified by compound screening to be an activator of Ca2+ activated Cl− channels (CaCCs), thus a potential target for therapy of cystic fibrosis.

N-Methylspiperone (NMSP) is a derivate of spiperone that is used to study the dopamine and serotonin neurotransmitter system. Labeled with the radioisotope carbon-11, it can be used for positron emission tomography.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Spiperone >; 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 Fluspirilene?

Published on by Andrew Marshall1 Comment

Introduction

Fluspirilene (Redeptin, Imap, R6218) is a diphenylbutylpiperidine typical antipsychotic drug, used for the treatment of schizophrenia.

It is administered intramuscularly.

It was discovered at Janssen Pharmaceutica in 1963.

A 2007 systematic review investigated the efficacy of fluspirilene decanoate for people with schizophrenia:

“Participant numbers in each comparison were small so power to identify clear difference is limited. Randomized controlled trial data identified no clear differences between the long-acting injection of fluspirilene and oral medication for outcomes that include adverse effects.” (Abhijnhan et al., 2007).

References

Abhijnhan A, Adams CE, David A, Ozbilen M (January 2007). “Depot fluspirilene for schizophrenia”. The Cochrane Database of Systematic Reviews. 2007 (1): CD001718. doi:10.1002/14651858.CD001718.pub2. PMC 7025783. PMID 17253464.

What is Clocapramine?

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Introduction

Clocapramine (Clofekton, Padrasen), also known as 3-chlorocarpipramine, is an atypical antipsychotic of the iminostilbene class which was introduced in Japan in 1974 by Yoshitomi for the treatment of schizophrenia. In addition to psychosis, clocapramine has also been used to augment antidepressants in the treatment of anxiety and panic.

Clocapramine has been reported to act as an antagonist of the D2, 5-HT2A, α1-adrenergic, and α2-adrenergic receptors, and does not inhibit the reuptake of either serotonin or norepinephrine. It has also been shown to have affinity for SIGMAR1. Clocapramine’s affinity for the 5-HT2A receptor is greater than that for the D2 receptor and it has a lower propensity for inducing extrapyramidal symptoms compared to typical antipsychotics, thus underlying its atypical nature.

Clinical Trials

In several clinical trials, clocapramine has been compared to other neuroleptic agents. Against haloperidol, though there was no significant difference in efficacy at the end of the study, clocapramine tended to be superior in alleviating motor retardation, alogia, and thought disorder, and also produced fewer side effects. Against sulpiride, clocapramine demonstrated more favourable effects in the treatment of both positive and negative symptoms, including motor retardation, delusions, hallucinations, and social isolation, though it produced more side effects. Against timiperone, clocapramine showed lower efficacy against both positive and negative symptoms and produced more side effects such as dyskinesia, insomnia, constipation, and nausea.

Clocapramine has been implicated in at least one fatality, a suicide in which there were two self-inflicted stab wounds and an overdose of clocapramine as well as three other antipsychotics was taken. The stab wounds could not explain the death, and thus, it was attributed to multiple drug toxicity instead.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Clocapramine >; 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 Carpipramine?

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Introduction

Carpipramine (Prazinil, Defekton) is an atypical antipsychotic used for the treatment of schizophrenia and anxiety in France and Japan.

In addition to its neuroleptic and anxiolytic effects, carpipramine also has hypnotic properties.

It is structurally related to both tricyclics like imipramine and butyrophenones like haloperidol.

What is Brofaromine?

Published on by Andrew Marshall1 Comment

Introduction

Brofaromine (proposed brand name Consonar) is a reversible inhibitor of monoamine oxidase A (RIMA) discovered by Ciba-Geigy. The compound was primarily researched in the treatment of depression and anxiety but its development was dropped before it was brought to market.

Brofaromine also acts as a serotonin reuptake inhibitor, and its dual pharmacologic effects offered promise in the treatment of a wide spectrum of depressed patients while producing less severe anticholinergic side effects in comparison with older standard drugs like certain of the tricyclic antidepressants.

Pharmacology

Brofaromine is a reversible inhibitor of monoamine oxidase A (RIMA, a type of monoamine oxidase inhibitor (MAOI)) and acts on epinephrine (adrenaline), norepinephrine (noradrenaline), serotonin, and dopamine. Unlike standard MAOIs, possible side effects do not include cardiovascular complications (hypertension) with encephalopathy, liver toxicity or hyperthermia.

Refer to Moclobemide.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Brofaromine >; 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.