Tag: Medication

What is Nomifensine?

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Introduction

Nomifensine, sold under the brand names Merital and Alival, is a norepinephrine–dopamine reuptake inhibitor (NDRI), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters. This is a mechanism of action shared by some recreational drugs like cocaine and the medication tametraline (see DRI). Research showed that the (S)-isomer is responsible for activity.

The drug was developed in the 1960s by Hoechst AG (now Sanofi-Aventis), who then test marketed it in the United States. It was an effective antidepressant, without sedative effects. Nomifensine did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse. In January 1986 the drug was withdrawn by its manufacturers for safety reasons.

Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).

In a 1989 study it was investigated for use in treating adult ADHD and proven effective. In a 1977 study it was not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.

Clinical Uses

Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.

Side Effects and Withdrawal From Market

During treatment with nomifensine there were relatively few adverse effects, mainly renal failure, paranoid symptoms, drowsiness or insomnia, headache, and dry mouth. Side effects affecting the cardiovascular system included tachycardia and palpitations, but nomifensine was significantly less cardiotoxic than the standard tricyclic antidepressants.

Due to a risk of haemolytic anaemia, the US Food and Drug Administration (FDA) withdrew approval for nomifensine on 20 March 1992. Nomifensine was subsequently withdrawn from the Canadian and UK markets as well. Some deaths were linked to immunohaemolytic anemia caused by this compound, although the mechanism remained unclear.

In 2012 structure-affinity relationship data (compare SAR) were published.

Synthesis

Nomifensine was a progenitor to Gastrophenzine (refer to Isatin derivatives).

The alkylation between N-methyl-2-nitrobenzylamine [56222-08-3] and phenacyl bromide gives CID:15326127. Catalytic hydrogenation over Raney Nickel reduces the nitro group to give CID:15113381. The reduction of the ketone group with sodium borohydride to alcohol gives [65514-97-8]. Acid catalysed ring closure completes the formation of nomifensine.

Research

Motivational Disorders

Nomifensine has been found to reverse tetrabenazine-induced motivational deficits in animals. It shares these pro-motivational effects with other NDRIs like bupropion and methylphenidate and with selective dopamine reuptake inhibitors like modafinil and its analogues. Conversely, selective norepinephrine reuptake inhibitors like desipramine and atomoxetine and selective serotonin reuptake inhibitors (SSRIs) like fluoxetine and citalopram have not shown pro-motivational effects in animals.

Wakefulness

Nomifensine shows wakefulness-promoting effects in animals and might be useful in the treatment of narcolepsy.

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What is Nitrazolam?

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Introduction

Nitrazolam is a triazolobenzodiazepine (TBZD) , which are benzodiazepine (BZD) derivatives, that has been sold online as a designer drug.

It is closely related to clonazolam or flunitrazolam, only differing by the removal of a chlorine or fluorine group respectively at the benzene ring.

A study in mice indicated that nitrazolam can be several times more potent than diazepam as an antagonist of electroshock-induced tonic-extensor convulsions but less potent than diazepam at preventing the righting reflex

Nitrazolam has been used as an example compound to demonstrate the microscale synthesis of reference materials utilising polymer‐supported reagents.

Legal Status

United Kingdom

In the UK, nitrazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

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What is Haloperidol Decanoate?

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Introduction

Haloperidol decanoate, sold under the brand name Haldol Decanoate among others, is a typical antipsychotic which is used in the treatment of schizophrenia.

Refer to Haloperidol.

It is administered by injection into muscle at a dose of 100 to 200 mg once every 4 weeks or monthly. The dorsogluteal site is recommended. A 3.75-cm (1.5-inch), 21-gauge needle is generally used, but obese individuals may require a 6.5-cm (2.5-inch) needle to ensure that the drug is indeed injected intramuscularly and not subcutaneously.

Haloperidol decanoate is provided in the form of 50 or 100 mg/mL oil solution of sesame oil and benzyl alcohol in ampoules or pre-filled syringes. Its elimination half-life after multiple doses is 21 days. The medication is marketed in many countries throughout the world.

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What is Clopenthixol?

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Introduction

Clopenthixol (Sordinol), also known as clopentixol, is a typical antipsychotic drug of the thioxanthene class. It was introduced by Lundbeck in 1961.

Clopenthixol is a mixture of cis and trans isomers. Zuclopenthixol, the pure cis isomer, was later introduced by Lundbeck in 1962, and has been much more widely used. Both drugs are equally effective as antipsychotics and have similar adverse effect profiles, but clopenthixol is half as active on a milligram-to-milligram basis and appears to produce more sedation in comparison.

Clopenthixol is not approved for use in the United States.

What is Bromperidol Decanoate?

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Introduction

Bromperidol decanoate, sold under the brand names Bromidol Depot, Bromodol Decanoato, and Impromen Decanoas, is an antipsychotic which has been marketed in Europe and Latin America.

It is an antipsychotic ester and long-acting prodrug of bromperidol which is administered by depot intramuscular injection once every 4 weeks.

What is Aripiprazole Lauroxil?

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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.

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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.

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