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The Cochrane Database of Systematic... 2000Mecamylamine is a nicotine antagonist (that is it blocks the effect of nicotine). The rationale for its use in smoking cessation is that it may block the rewarding... (Comparative Study)
Comparative Study Review
BACKGROUND
Mecamylamine is a nicotine antagonist (that is it blocks the effect of nicotine). The rationale for its use in smoking cessation is that it may block the rewarding effect of nicotine and thus reduce the urge to smoke.
OBJECTIVES
The objective of this review was to determine the effectiveness of mecamylamine in promoting smoking cessation, either alone or in combination with nicotine replacement therapy.
SEARCH STRATEGY
We searched the Cochrane Tobacco Addiction Group trials register.
SELECTION CRITERIA
Randomised trials of mecamylamine, either alone or in combination with nicotine replacement therapy, which reported smoking cessation rates at least six months after intervention.
DATA COLLECTION AND ANALYSIS
We extracted data in duplicate on the type of subjects, the dose and duration of the mecamylamine and nicotine treatments, side-effects of treatment, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was sustained abstinence from smoking (biochemically validated) after at least six months follow-up in patients smoking at baseline. Smokers lost to follow-up were regarded as being continuing smokers. Because of the preliminary nature of available data, we did not perform meta-analysis but report the results narratively.
MAIN RESULTS
We identified two studies, both from the same investigators. In a study of 48 volunteers, a combination of mecamylamine plus nicotine patch was more effective than nicotine patch alone (abstinence rate at one year 37.5% vs 4.2%). In a second study, 80 volunteers were treated for four weeks prior to cessation with one of four treatments: 1. Nicotine patch plus mecamylamine capsules 2. Nicotine alone 3. Mecamylamine alone 4. No active drug. All four groups received combination treatment with nicotine and mecamylamine after the scheduled quit date. The abstinence rates in these four groups were respectively 40%, 20%, 15% and 15%. The higher abstinence rate in the group treated with combination therapy was not statistically significant. The authors reported a statistically significant benefit of mecamylamine using Kaplan-Meier survival analysis. In the doses used, mecamylamine was well tolerated, although up to 40% of subjects required reductions in dose, usually because of constipation.
REVIEWER'S CONCLUSIONS
Data from two small studies suggest that the combination of nicotine and mecamylamine may be superior to nicotine alone in promoting smoking cessation. However, these results require confirmation in larger studies before the treatment can be recommended clinically.
Topics: Administration, Cutaneous; Drug Therapy, Combination; Humans; Mecamylamine; Nicotine; Nicotinic Antagonists; Smoking Cessation; Smoking Prevention
PubMed: 10796584
DOI: 10.1002/14651858.CD001009 -
Clinical Therapeutics Apr 2001Mecamylamine hydrochloride was initially developed for its ganglion-blocking activity and has been marketed as an antihypertensive agent in the United States for >40... (Review)
Review
BACKGROUND
Mecamylamine hydrochloride was initially developed for its ganglion-blocking activity and has been marketed as an antihypertensive agent in the United States for >40 years. Several other potential therapeutic applications are being investigated, most of them focusing on the drug's ability to cross the blood-brain barrier and selectively antagonize neuronal nicotinic acetylcholine receptors. This central activity of mecamylamine is demonstrable at much lower doses than the effective antihypertensive dose, thus avoiding many of the bothersome side effects associated with the drug's inhibition of parasympathetic activity.
OBJECTIVE
Because investigations are being conducted in new patient populations, including pediatric patients, an update of the toxicity/risk profile of mecamylamine is timely. This review describes nonclinical and clinical data pertaining to the pharmacology, toxicity, and tolerability of mecamylamine, including some previously unpublished toxicology and clinical pharmacokinetics data. Potential new therapeutic applications are discussed, including the use of mecamylamine in treating autonomic dysreflexia; dependencies on nicotine, cocaine, and other substances of abuse; Tourette's syndrome; and other neuropsychiatric disorders.
METHODS
Information for this review of mecamylamine was identified through a search of MEDLINE from 1966 to the present, as well as from the master files of Merck & Co, Inc, the drug's original manufacturer, and Layton BioScience, Inc, its present manufacturer.
CONCLUSIONS
The available data concerning potential new applications of mecamylamine, although sparse, suggest that the drug's toxicity/risk profile may be much improved at lower doses.
Topics: Animals; Antihypertensive Agents; Area Under Curve; Autonomic Dysreflexia; Central Nervous System; Cognition; Drug Therapy, Combination; Humans; Hypertension; Lethal Dose 50; Mecamylamine; Mutagenicity Tests; Peripheral Nerves; Receptors, Cholinergic; Receptors, Nicotinic; Reproduction; Risk Factors; Rodentia
PubMed: 11354389
DOI: 10.1016/s0149-2918(01)80059-x -
Expert Opinion on Pharmacotherapy Nov 2009Mecamylamine (Inversine), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread... (Review)
Review
Mecamylamine (Inversine), the first orally available antihypertensive agent launched in the 1950s, is rarely used today for hypertension because of its widespread ganglionic side effects at antihypertensive doses (25 - 90 mg/day). However, more recent clinical studies suggest that mecamylamine is effective at much lower doses for blocking the central and peripheral effects of nicotine. Pharmacologically, mecamylamine has been well characterized as a nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). Because mecamylamine easily crosses the blood - brain barrier at relatively low doses (2.5 - 10 mg), it has been used by several research groups over the past two decades investigating the role of central nAChRs in the etiology and treatment of various neuropsychiatric disorders, including addiction disorders, Tourette's syndrome, schizophrenia and various cognitive and mood disorders. Two independent Phase II clinical trials recently confirmed mecamylamine's hypothesized antidepressant activity and suggest that it may be effective as an augmentation pharmacotherapy for SSRI treatment resistant major depression. These areas of investigation for mecamylamine are reviewed and recommendations for future research directions are proposed.
Topics: Humans; Mecamylamine; Mental Disorders; Nicotinic Antagonists
PubMed: 19874251
DOI: 10.1517/14656560903329102 -
Expert Review of Clinical Pharmacology Mar 2019Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting,... (Review)
Review
Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting, headache, and abdominal cramps. Prevalence has shifted from the United States and Europe to China, India, and Brazil. Worldwide 8 million individuals are afflicted, including women and children. Areas covered: Mecamylamine (Inversine®, Vecamyl®), a nicotinic acetylcholine receptor (nAChR) antagonist, should be tested as a remedy for green tobacco sickness. Mecamylamine is approved as an oral tablet for the treatment of hypertension, is safe, and is off-patent. Mecamylamine attenuates many of the effects of nicotine and tobacco including seizures, thereby supporting its use as an effective pharmacotherapy for tobacco dependence. Varenicline (Chantix®) and cytisine (Tabex®) are low efficacy (i.e. intrinsic activity) nAChR agonists, are used as smoking cessation aids, and are viable options to test as remedies against green tobacco sickness. Nicotine immunization strategies may provide further options for future testing. Expert commentary: Efforts to demonstrate reversal and/or prevention of green tobacco sickness by mecamylamine will underscore the importance of nicotine in this illness and highlight a new medication for effective treatment of tobacco poisoning.
Topics: Agricultural Workers' Diseases; Humans; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Plant Leaves; Nicotiana; Vaccines; Varenicline
PubMed: 30650314
DOI: 10.1080/17512433.2019.1570844 -
Pharmacology, Biochemistry, and Behavior Jul 2013Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat... (Review)
Review
Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side effects at therapeutically relevant doses. As such, mecamylamine's use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(-)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder.
Topics: Animals; Drug Evaluation, Preclinical; Humans; Mecamylamine; Nicotinic Antagonists; Stereoisomerism
PubMed: 23603417
DOI: 10.1016/j.pbb.2013.04.005 -
Journal of Human Hypertension Jul 2002Mecamylamine (Inversine), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour... (Review)
Review
Mecamylamine (Inversine), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30-90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5-5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the treatment of hypertension. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. Though currently untested, the available evidence suggests that low-dose mecamylamine therapy might reduce blood pressure variability and atherogenetic lipid profile in smokers. With this in mind, mecamylamine should be an important research tool in the field of hypertension research, particularly in recalcitrant smokers with mild to moderate hypertension.
Topics: Antihypertensive Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Mecamylamine; Nicotinic Antagonists; Smoking Cessation
PubMed: 12080428
DOI: 10.1038/sj.jhh.1001416 -
Journal of the American Medical... Dec 1956
Topics: Autonomic Agents; Hypertension; Mecamylamine
PubMed: 13376320
DOI: No ID Found -
Biochemical Pharmacology Oct 1989
Review
Topics: Animals; Brain; Humans; Mecamylamine; Nicotine; Receptors, Nicotinic; Structure-Activity Relationship
PubMed: 2684166
DOI: 10.1016/0006-2952(89)90106-8 -
PloS One 2021Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine...
Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
Topics: Animals; Bicuculline; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Excitatory Amino Acid Antagonists; GABA Antagonists; In Vitro Techniques; Mecamylamine; Nicotinic Antagonists; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, Nicotinic; Seizures; Synaptic Transmission
PubMed: 33711021
DOI: 10.1371/journal.pone.0240074 -
CNS Neuroscience & Therapeutics 2008Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and... (Review)
Review
Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and anxiety disorders. Based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214 (S-(+) enantiomer of mecamylamine), a noncompetitive NNR antagonist. TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety. TC-5214 was active in the forced swim test in rats (minimum effective dose (MED)=3 mg/kg i.p.), a classical depression model. It was also active in the behavioral despair test in mice (0.1-3.0 mg/kg i.p.), another model of depression. In the social interaction paradigm in rats, a model of generalized anxiety disorder (GAD), TC-5214 was active at a dose of 0.05 mg/kg s.c. In the light/dark chamber paradigm in rats, a model of GAD and phobia, TC-5214 was also active at a dose of 0.05 mg/kg s.c. Although TC-5214 shows modest selectivity among NNR subtypes, the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the alpha4beta2 NNRs. This is supported by the observation of similar effects with alpha4beta2-selective partial agonists such as cytisine and with alpha4beta2-selective antagonists such as TC-2216. TC-5214 was well tolerated in acute and chronic toxicity studies in mice, rats, and dogs, showed no mutagenicity and displayed safety pharmacology, pharmacokinetic and metabolic profiles appropriate for therapeutic development. Overall, the results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic effects and highlight the potential of NNR antagonists such as TC-5214 as therapeutics for the treatment of anxiety and depression.
Topics: Animals; Antidepressive Agents; Chromosome Aberrations; Dogs; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Female; Gastrointestinal Motility; Humans; Male; Mecamylamine; Mice; Micronucleus Tests; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Social Behavior; Stereoisomerism
PubMed: 19040552
DOI: 10.1111/j.1755-5949.2008.00054.x