-
The Journal of Pharmacology and... May 2001Because mecamylamine, a nicotinic receptor antagonist, is used so often in nicotine research and because mecamylamine may have important therapeutic properties... (Comparative Study)
Comparative Study
Because mecamylamine, a nicotinic receptor antagonist, is used so often in nicotine research and because mecamylamine may have important therapeutic properties clinically, it is important to fully explore and understand its pharmacology. In the present study, the efficacy and potency of mecamylamine and its stereoisomers were evaluated as inhibitors of human alpha 3 beta 4, alpha 3 beta 2, alpha 7, and alpha 4 beta 2 nicotinic acetylcholine receptors (nAChRs), as well as mouse adult type muscle nAChRs and rat N-methyl-D-aspartate (NMDA) receptors expressed in Xenopus oocytes. The selectivity of mecamylamine for neuronal nAChR was manifested primarily in terms of slow recovery rates from mecamylamine-induced inhibition. Neuronal receptors showed a prolonged inhibition after exposure to low micromolar concentrations of mecamylamine. Muscle-type receptors showed a transient inhibition by similar concentrations of mecamylamine, and NMDA receptors were only transiently inhibited by higher micromolar concentrations. Mecamylamine inhibition of neuronal nAChR was noncompetitive and voltage dependent. Although there was little difference between S-(+)-mecamylamine and R-(-)-mecamylamine in terms of 50% inhibition concentration values for a given receptor subtype, there appeared to be significant differences in the off-rates for the mecamylamine isomers from the receptors. Specifically, S-(+)-mecamylamine appeared to dissociate more slowly from alpha 4 beta 2 and alpha 3 beta 4 receptors than did R-(-)-mecamylamine. In addition, it was found that muscle-type receptors appeared to be somewhat more sensitive to R-(-)-mecamylamine than to S-(+)-mecamylamine. Together, these findings suggest that in chronic (i.e., therapeutic) application, S-(+)-mecamylamine might be preferable to R-(-)-mecamylamine in terms of equilibrium inactivation of neuronal receptors with decreased side effects associated with muscle-type receptors.
Topics: Animals; Binding, Competitive; Electrophysiology; Humans; In Vitro Techniques; Mecamylamine; Neurons; Nicotinic Antagonists; Oocytes; RNA, Messenger; Receptors, Nicotinic; Stereoisomerism; Xenopus laevis
PubMed: 11303054
DOI: No ID Found -
American Journal of Ophthalmology May 2010Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and...
PURPOSE
Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema.
DESIGN
A multicenter phase I/II clinical trial.
METHODS
Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks.
RESULTS
Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine.
CONCLUSIONS
This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.
Topics: Administration, Topical; Adolescent; Adult; Aqueous Humor; Chronic Disease; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Fluorescein Angiography; Fovea Centralis; Humans; Intraocular Pressure; Macular Edema; Mecamylamine; Nicotinic Antagonists; Tomography, Optical Coherence; Treatment Outcome; Vascular Endothelial Growth Factor A; Visual Acuity
PubMed: 20189159
DOI: 10.1016/j.ajo.2009.12.005 -
Clinical Pharmacology and Therapeutics Jul 1994To evaluate concurrent administration of mecamylamine (nicotine antagonist) with nicotine skin patch treatment for smoking cessation. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To evaluate concurrent administration of mecamylamine (nicotine antagonist) with nicotine skin patch treatment for smoking cessation.
METHODS
This was a randomized, double-blind, placebo-controlled trial. Forty-eight healthy smokers who smoked at least one pack per day were studied at an outpatient smoking cessation research clinic. The subjects ranged in age from 20 to 40 years. Intervention with the nicotine skin patch (6 to 8 weeks) plus oral mecamylamine (2.5 to 5 mg twice a day for 5 weeks) was compared to nicotine patch plus placebo. Mecamylamine treatment began 2 weeks before smoking cessation. The primary outcome was continuous abstinence through 7 weeks after cessation (1 week after treatment), confirmed by expired air carbon monoxide measurements. Secondary measures included point abstinence at 7 weeks, continuous abstinence at 6- and 12-month follow-up, and self-reported withdrawal symptoms.
RESULTS
The continuous abstinence rate at 7 weeks was three times higher in the mecamylamine condition: 50% versus 16.7%, p = 0.015. Point abstinence at 7 weeks was 58% for mecamylamine versus 29% for placebo, p = 0.044. At follow-up, continuous abstinence remained higher for mecamylamine: 37.5% versus 12.5% at 6 months (p = 0.046) and 37.5% versus 4.2% at 12 months (p = 0.004). Mecamylamine also significantly reduced craving for cigarettes, negative affect, and appetite.
CONCLUSIONS
Agonist-antagonist therapy, consisting of the nicotine patch with oral mecamylamine, may substantially improve current smoking cessation treatment.
Topics: Administration, Cutaneous; Adult; Affect; Blood Pressure; Breath Tests; Carbon Monoxide; Double-Blind Method; Drug Therapy, Combination; Female; Heart Rate; Humans; Male; Mecamylamine; Nicotine; Patient Compliance; Smoking Cessation; Substance Withdrawal Syndrome; Treatment Outcome
PubMed: 8033499
DOI: 10.1038/clpt.1994.105 -
Psychopharmacology Jan 2013The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that...
RATIONALE
The ability of nicotine to induce dependence (result in a withdrawal syndrome) is typically thought to require long-term, daily smoking. Emerging evidence suggests that symptoms of nicotine withdrawal may occur following only a few cigarettes. Whether acute exposure to nicotine can induce dependence in animals has not been well established.
OBJECTIVE
The objective of this paper is to examine whether the nicotinic acetylcholine receptor antagonist mecamylamine elicits withdrawal-like signs in rats following acute nicotine exposure.
METHODS AND RESULTS
Mecamylamine (3.0 mg/kg, s.c.) administered ≈2 h after a single dose of nicotine (0.5 mg/kg, s.c.) elicited increases in intracranial self-stimulation (ICSS) thresholds and somatic signs, two well-established effects of withdrawal from long-term (chronic) nicotine exposure. The magnitude of these effects remained constant across five daily test sessions. A lower dose of mecamylamine (1.5 mg/kg, s.c.) had little or no effect on ICSS thresholds or somatic signs following acute nicotine exposure, but precipitated robust increases in these measures during a chronic nicotine infusion. Finally, rats exhibited a small increase in ICSS thresholds over time following a single nicotine injection (0.5 mg/kg, s.c.), possibly reflecting a modest spontaneous withdrawal-like effect.
CONCLUSIONS
Mecamylamine elicited withdrawal-like signs in rats following a single dose of nicotine. The different effects of mecamylamine 1.5 mg/kg following acute versus chronic nicotine exposure supports the notion that these models simulate the early and more advanced stages of nicotine dependence, respectively. While further optimization and validation of these models is necessary, they may provide a novel approach for studying the earliest stages of nicotine dependence.
Topics: Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Injections, Subcutaneous; Male; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Wistar; Self Stimulation; Substance Withdrawal Syndrome; Tobacco Use Disorder
PubMed: 22868410
DOI: 10.1007/s00213-012-2814-x -
European Journal of Pharmacology Nov 2013A previous characterization of mecamylamine stereoisomers using nicotinic acetylcholine receptors expressed in Xenopus oocytes revealed only small differences between...
A previous characterization of mecamylamine stereoisomers using nicotinic acetylcholine receptors expressed in Xenopus oocytes revealed only small differences between the activity of the R and S forms of mecamylamine. However, that work was limited in the breadth of receptor subtypes tested, especially in regard to the discrimination of high and low sensitivity receptors, which differ in the ratios of alpha and beta subunits. We report new data using subunit concatamers, which produce uniform populations of high-sensitivity or low-sensitivity receptors, as well as alpha2, alpha5, and alpha6-containing receptors, which were not studied previously. Consistent with previous studies, we found that beta4-containing receptors were most sensitive to mecamylamine and that the IC50 values for the inhibition of net charge were lower than for inhibition of peak currents. No large differences were seen between the activities of the mecamylamine isomers. Additionally, a previously reported potentiation of high-sensitivity α4β2 receptors by S-mecamylamine could not be reproduced in the oocyte system, even with mutants that had greatly reduced sensitivity to mecamylamine inhibition or when the selective agonist TC-2559 was used. In vivo studies suggested that the R-isomer might be somewhat more potent than the S isomer at blocking CNS effects of nicotine. Although the potency difference was no more than a factor of two, it is consistent with lower LD50 estimates previously reported for the R isomer. Our results significantly extend knowledge of the nicotinic acetylcholine receptor activity profile of mecamylamine and support the hypothesis that these effects are not strongly stereoisomer selective.
Topics: Analgesics; Animals; Hot Temperature; Humans; Male; Mecamylamine; Mice; Mice, Inbred ICR; Nicotinic Antagonists; Oocytes; Pain; Protein Subunits; Receptors, Nicotinic; Stereoisomerism; Xenopus laevis
PubMed: 24161916
DOI: 10.1016/j.ejphar.2013.10.018 -
Pharmacology, Biochemistry, and Behavior Sep 2003Previous studies of human cigarette smoking have shown that administration of the nicotinic acetylcholine receptor antagonist mecamylamine produces acute increases in... (Clinical Trial)
Clinical Trial
Previous studies of human cigarette smoking have shown that administration of the nicotinic acetylcholine receptor antagonist mecamylamine produces acute increases in smoking behavior. In contrast, studies of intravenous nicotine self-administration in animals typically show an immediate decrease in self-administration behavior following mecamylamine administration. To investigate whether this discrepancy might be due in part to the mode of nicotine self-administration (intravenous vs. cigarette smoke), we measured the rate of intravenous nicotine self-administration in tobacco-dependent human smokers. After being trained in a preliminary session to self-administer puff-sized bolus doses of nicotine, 16 subjects were exposed to two sessions (4 h duration) in which they could self-administer intravenous nicotine ad lib. Two hours prior to one session, subjects swallowed a capsule containing 10 mg mecamylamine, and before the other session they took a placebo capsule. Rates of responding for nicotine were assessed, as were subjective reports of withdrawal symptoms and plasma nicotine levels. There was a significantly higher rate of nicotine self-administration in the mecamylamine condition, and mecamylamine attenuated the reduction in craving over the session that occurred during nicotine self-administration. These results indicate that route of administration is not likely the major source of the discrepancy between findings from animal and human studies of nicotine administration. Instead, it is likely that the higher rates of nicotine self-administration induced by mecamylamine were due to an attenuation of the effects of nicotine (e.g., alleviation of withdrawal symptoms) in nicotine-dependent subjects. Thus, animal models of nicotine dependence may need to be employed in conjunction with self-administration procedures in order to duplicate the effects of mecamylamine observed in studies of human smokers.
Topics: Adolescent; Adult; Affect; Female; Humans; Injections, Intravenous; Male; Mecamylamine; Middle Aged; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Saliva; Self Administration; Smoking; Substance Withdrawal Syndrome
PubMed: 14592683
DOI: 10.1016/j.pbb.2003.08.011 -
Pharmacology, Biochemistry, and Behavior Apr 1989Eight subjects evaluated various qualities of cigarette smoke after being given a range of doses (0, 2.5, 10 and 20 mg) of the nicotinic receptor blocker mecamylamine.... (Clinical Trial)
Clinical Trial
Eight subjects evaluated various qualities of cigarette smoke after being given a range of doses (0, 2.5, 10 and 20 mg) of the nicotinic receptor blocker mecamylamine. In one test condition, subjects were given either high or low nicotine tobacco smoke to determine the effects of mecamylamine on their subjective responses. In another test condition, subjects were allowed to adjust the nicotine dose level of the smoke to determine the effects of mecamylamine on dose preference. When the subjects evaluated puffs of smoke with high and low nicotine content, mecamylamine caused a dose-related decrease in the self-rated strength and harshness of the high nicotine dose level smoke. In contrast, there was little effect on the low dose smoke. At the highest mecamylamine dose (20 mg) there was no significant difference in the ratings of high and low nicotine cigarettes. Low doses of mecamylamine decreased the reported desire for a cigarette, and also attenuated the reduction in desire for a cigarette caused by smoking. When the subjects were allowed to select their preferred level of nicotine intake using a smoke mixing device, the 10 and 20 mg doses of mecamylamine caused a significant increase in self-administered nicotine dose level. Despite this compensatory increase in nicotine self-administration, the reduction in desire for a cigarette after smoking was still less than after placebo.
Topics: Adult; Discrimination, Psychological; Dose-Response Relationship, Drug; Drive; Humans; Male; Mecamylamine; Middle Aged; Nicotine; Personal Satisfaction; Self Administration; Smoking
PubMed: 2798542
DOI: 10.1016/0091-3057(89)90061-0 -
Lancet (London, England) Aug 1957
Topics: Autonomic Agents; Mecamylamine
PubMed: 13450379
DOI: 10.1016/s0140-6736(57)91598-2 -
Journal of Child and Adolescent... 2000To test the efficacy and safety of a nicotinic, acetylcholine antagonist, mecamylamine, in the treatment of Tourette's syndrome (TS). (Clinical Trial)
Clinical Trial
OBJECTIVE
To test the efficacy and safety of a nicotinic, acetylcholine antagonist, mecamylamine, in the treatment of Tourette's syndrome (TS).
METHODS
This is a retrospective, open-label study of 24 patients; 18 of whom were not responding to accepted medication for treatment of their TS and six of whom were receiving no medication. All 24 of them received mecamylamine in 2.5-6.25 mgm/day dose, at varying starting dates during the years June 1997 to June 1999. There were four females, 20 males, with 19 patients under the age of 18 years and five over the age of 18. Efficacy was evaluated by the Clinical Global Impression Scale (CGI); safety by adverse events notes during the time mecamylamine was administered.
RESULTS
The number of days each patient received mecamylamine varied from 8 days to 550 days; with nine patients more than 200 days, six patients from 100-200 days, five patients for 50-100 days, and four patients 0-50 days. Comparing baseline CGI with that obtained on the date of last evaluation for each patient, a significant improvement in clinical assessment of severity of illness was obtained for the total group (Wilcoxon signed rank test, p < 0.0001). The six patients who received mecamylamine only also significantly improved (Wilcoxon signed rank test, p < 0.2). Case vignettes are described.
CONCLUSIONS
Mecamylamine at 2.5-6.25 mgm/day has no significant peripheral parasympathetic activity and may be safely taken long term (up to 550 days in this study). It has a significant effect in relieving motor and vocal tics and in mood and behavior disturbances of children, adolescents, and adults with TS.
Topics: Adolescent; Adult; Age Factors; Child; Drug Therapy, Combination; Female; Humans; Male; Mecamylamine; Nicotinic Antagonists; Psychiatric Status Rating Scales; Retrospective Studies; Tourette Syndrome
PubMed: 10933116
DOI: 10.1089/cap.2000.10.59 -
Pharmacology, Biochemistry, and Behavior Jun 2021Relief from increases in anxiety during nicotine withdrawal contributes to tobacco addiction. While a variety of anxiogenic stimuli elicit avoidance of the center of an...
Magnitude of open-field thigmotaxis during mecamylamine-precipitated nicotine withdrawal in rats is influenced by mecamylamine dose, duration of nicotine infusion, number of withdrawal episodes, and age.
Relief from increases in anxiety during nicotine withdrawal contributes to tobacco addiction. While a variety of anxiogenic stimuli elicit avoidance of the center of an open field (thigmotaxis) in rodents, effects of nicotine withdrawal on thigmotaxis have not been studied extensively. The goal of this study was to evaluate determinants of increases in thigmotaxis during mecamylamine-precipitated nicotine withdrawal in rats. We evaluated several variables implicated in severity of other measures of precipitated nicotine withdrawal: mecamylamine dose, duration of nicotine infusion, number of withdrawal episodes, and age. In Experiment 1, mecamylamine elicited increases in thigmotaxis in adult rats receiving a chronic nicotine infusion (3.2 mg/kg/day for >7 days) at only the highest mecamylamine dose tested (4.0 mg/kg). In Experiment 2, repeated administration of 4.0 mg/kg mecamylamine throughout the course of a 2-week chronic nicotine infusion (3.2 mg/kg/day) did not affect thigmotaxis when administered following 2 days of the infusion, but elicited significant increases in thigmotaxis at longer infusion durations. In Experiment 3, adolescents tested under the same protocol used in adults in Experiment 2 did not exhibit increased thigmotaxis at any point during the 2-week nicotine infusion, even though we used higher nicotine doses (4.7 or 6.4 mg/kg/day) to account for the faster metabolism of nicotine in adolescents compared to adults. Our findings provide the first systematic characterization of determinants of increases in thigmotaxis during precipitated nicotine withdrawal in rats. Further use of this model may be useful for characterizing the mechanisms underlying the anxiogenic component of nicotine withdrawal.
Topics: Age Factors; Animals; Avoidance Learning; Dose-Response Relationship, Drug; Locomotion; Male; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Taxis Response; Time Factors
PubMed: 33831460
DOI: 10.1016/j.pbb.2021.173185