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John M. Littleton - One of the best experts on this subject based on the ideXlab platform.
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Acamprosate recent findings and future research directions
Alcoholism: Clinical and Experimental Research, 2008Co-Authors: Karl Mann, Rainer Spanagel, Falk Kiefer, John M. LittletonAbstract:This article explores the mechanisms of action and the potential responder profile of Acamprosate, a compound efficacious in relapse prevention of alcoholism. New evidence at the molecular and cellular level suggests that Acamprosate attenuates hyper-glutamatergic states that occur during early abstinence and involves iono (NMDA)- and metabotrotropic (mGluR5) glutamate receptors along with augmented intracellular calcium release and electrophysiological changes. Thus mutant mice with enhanced glutamate levels exhibit higher alcohol consumption than wild type mice and respond better to Acamprosate, demonstrating that Acamprosate acts mainly on a hyper-glutamatergic system. This mode of action further suggests that Acamprosate exhibits neuroprotective properties. In rats, cue-induced reinstatement behavior is significantly reduced by Acamprosate treatment whereas cue-induced craving responses in alcohol-dependent patients seem not to be affected by this treatment. An ongoing study ("Project Predict") defines specific responder profiles for an individualized use of Acamprosate and naltrexone. Neurophysiological as well as psychometric data are used to define 2 groups of patients: "reward cravers" and "relief cravers". While naltrexone should work better in the first group, Acamprosate is hypothesized to be efficacious in the latter where withdrawal associated and/or cue induced hyper-glutamatergic states are thought to trigger relapse. Further research should target the definition of subgroups applying endophenotypic approaches, e.g. by detecting a hyperglutamatergic syndrome using MR spectroscopy.
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neuroprotective and abstinence promoting effects of Acamprosate elucidating the mechanism of action
CNS Drugs, 2005Co-Authors: Philippe De Witte, John M. Littleton, Philippe Parot, George F KoobAbstract:Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, evidence has emerged that this drug may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular. These findings provide, for the first time, a satisfactory, unifying hypothesis that can bring together and explain the diverse neurochemical effects of Acamprosate. Glutamic acid is involved in several aspects of alcohol dependence and withdrawal, many of which can be modified by Acamprosate. For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by Acamprosate. The elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by Acamprosate. Moreover, glutamatergic neurotransmission plays an important role in the acquisition of cue-elicited drinking behaviours, which again can be modulated by Acamprosate. In conclusion, the glutamatergic hypothesis of the mechanism of action of Acamprosate helps explain many of its effects in human alcohol dependence and points the way to potential new activities, such as neuroprotection, that merit exploration in the clinic.
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Acamprosate inhibits the binding and neurotoxic effects of trans acpd suggesting a novel site of action at metabotropic glutamate receptors
Alcoholism: Clinical and Experimental Research, 2002Co-Authors: Barton R. Harris, Mark A. Prendergast, John A. Blanchard, Robert C. Holley, Stewart R. Hart, Norman W. Pedigo, Alex D Gibson, Trent D Rogers, John M. LittletonAbstract:Background Several reported effects of Acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether Acamprosate could compete with trans-ACPD (±-1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1 S, 3 R and 1 R, 3 S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD–induced neurotoxicity in organotypic hippocampal slice cultures. Methods A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-d-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of Acamprosate (sodium mono N-acetyl homotaurine or Na-Acamprosate). A comparison of the effects of 100 μM guanosine 5′-triphosphate on unlabeled glutamate, trans-ACPD, and Na-Acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 μM trans-ACPD or 50 μM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-Acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone. Results Na-Acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-Acamprosate displayed total competition with trans-ACPD. The presence of 100 μM guanosine 5′-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-Acamprosate. Na-Acamprosate (200–1000 μM) and SIB-1893 (20–500 μM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-Acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity. Conclusions Na-Acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-Acamprosate and SIB-1893 support an interaction of Na-Acamprosate at mGluR5s. The neuroprotective properties of Acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.
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potential neuroprotective effects of Acamprosate
Alcoholism: Clinical and Experimental Research, 2002Co-Authors: George F Koob, Barbara J. Mason, Philippe De Witte, John M. Littleton, G R SigginsAbstract:This article represents the proceedings of a symposium at the 2001 RSA Meeting in Montreal, Canada. The organizers were Barbara J. Mason and George F. Koob. Anita M. Goodman served as chair. The presentations were (1) Acamprosate inhibits alcohol withdrawal-induced neurotoxicity in organotypic hippocampal cultures, by John Littleton; (2) Acamprosate alteration of NMDA receptor-dependent synaptic transmission and synaptic plasticity, by George R. Siggins; (3) Acamprosate and glutamate during ethanol withdrawal, by Philippe De Witte; (4) Clinical evidence of protective CNS effects of Acamprosate in alcohol-dependent individuals, by Barbara J. Mason.
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Acamprosate Inhibits the Binding and Neurotoxic Effects of Trans‐ACPD, Suggesting a Novel Site of Action at Metabotropic Glutamate Receptors
Alcoholism clinical and experimental research, 2002Co-Authors: Barton R. Harris, Mark A. Prendergast, D. Alex Gibson, D. Trent Rogers, John A. Blanchard, Robert C. Holley, Stewart R. Hart, Norman W. Pedigo, John M. LittletonAbstract:Background Several reported effects of Acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether Acamprosate could compete with trans-ACPD (±-1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1 S, 3 R and 1 R, 3 S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD–induced neurotoxicity in organotypic hippocampal slice cultures. Methods A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-d-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of Acamprosate (sodium mono N-acetyl homotaurine or Na-Acamprosate). A comparison of the effects of 100 μM guanosine 5′-triphosphate on unlabeled glutamate, trans-ACPD, and Na-Acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 μM trans-ACPD or 50 μM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-Acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone. Results Na-Acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-Acamprosate displayed total competition with trans-ACPD. The presence of 100 μM guanosine 5′-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-Acamprosate. Na-Acamprosate (200–1000 μM) and SIB-1893 (20–500 μM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-Acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity. Conclusions Na-Acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-Acamprosate and SIB-1893 support an interaction of Na-Acamprosate at mGluR5s. The neuroprotective properties of Acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.
Philippe Lehert - One of the best experts on this subject based on the ideXlab platform.
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Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis
Alcohol and Alcoholism, 2018Co-Authors: Pascal Perney, Philippe LehertAbstract:Aims: The prevalence of insomnia ranges from 36% to 91% in alcohol-dependent patients and may persist after alcohol withdrawal. Acamprosate has been shown to decrease insomnia in abstinent patients. Based on a large clinical trial database, the aim of the present study is to assess the efficacy of Acamprosate in reducing insomnia, and if indeed it does reduce insomnia, to better understand its action mechanism. Short Summary: The aim of the study is to confirm the efficacy of Acamprosate to reduce insomnia using an individual patient data meta-analysis. Twelve studies were found including 3508 patients. After a 6-month follow-up, the mean insomnia decrease over baseline was -26% and -45% for the placebo and Acamprosate groups, respectively (P < 0.001). Methods: An individual patient data meta-analysis selected all the randomized trials of Acamprosate in which insomnia was documented. Our main endpoint was insomnia change after a 6-month follow-up, measured by the validated Short Sleep Index (SSI) derived from the Hamilton Depression and Anxiety Scale. The meta-analysis was conducted using a two-level multilevel (patient/trial) mixed model with random treatment effect, random study effect and adjusting for baseline severity covariates. Results: Twelve studies were found including 3508 patients, 59.8% of whom were suffering from insomnia (95% CI 58.1-61.4). Psychiatric history, severe addiction, living alone and abnormal gamma-GT levels were found to be the risk factors of insomnia. After 6 months, the mean SSI decrease over baseline was -26% and -45% for placebo and Acamprosate, respectively (treatment effect = 19%, 12.5-25.5; P < 0.001). By using a univariate mediation model, we found that the mediating effect of abstinence on insomnia accounted for 55.7% of the overall effect of Acamprosate on insomnia reduction. Conclusions: Insomnia is prevalent among alcohol-dependent patients. It decreases spontaneously with abstinence but more frequently with Acamprosate treatment.
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Acamprosate for alcohol dependence a sex specific meta analysis based on individual patient data
Alcoholism: Clinical and Experimental Research, 2012Co-Authors: Barbara J. Mason, Philippe LehertAbstract:Background: It is unknown whether women derive comparable benefits and have a similar safety and tolerability profile as men from Acamprosate, a widely prescribed drug for the maintenance of abstinence in alcohol dependence. The objective of this study was to assess sex-specific differences in the efficacy, safety, and tolerability of Acamprosate in the treatment of women and men with alcohol dependence. Methods: A sex-specific meta-analysis was conducted based on individual patient data (IPD). Data were obtained from double-blind, randomized controlled trials with quantitative drinking measures in patients with alcohol dependence receiving oral Acamprosate or placebo. Sources included PubMed, PsychInfo, and Cochrane electronic databases; reference lists from retrieved articles and presentations at professional meetings; and direct access to authors and companies who provided IPD. Results: Individual records were obtained from 1,317 women and 4,794 men who participated in 22 eligible studies conducted in 18 countries. IPD meta-analyses found a significant beneficial effect of Acamprosate relative to placebo across all 4 efficacy end points: an incremental gain of 10.4% (95% CI 7.1 to 13.7, p<0.001) in percentage of abstinent days, an incremental gain of 11.0% (7.4 to 14.6, p<0.001) in percentage of no heavy drinking days, an odds ratio of 1.9 (1.6 to 2.2, p<0.001) for rate of complete abstinence, and an odds ratio of 1.9 (1.6 to 2.3, p<0.001) for rate of no heavy drinking, over the study duration. Acamprosate was also associated with significantly higher rates of treatment completion (p=0.004) and medication compliance (p<0.001) than placebo. Men and women did not differ on any measure of Acamprosate efficacy, safety, or tolerability. Conclusions: This sex-specific IPD meta-analysis provides evidence that Acamprosate has a significant effect compared with placebo in improving rates of abstinence and no heavy drinking in both women and men with alcohol dependence. Further, Acamprosate was associated with significantly higher rates of treatment completion and medication compliance than placebo among both women and men and had a comparable safety and tolerability profile. © 2011 by the Research Society on Alcoholism.
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Acamprosate for alcohol dependence
Cochrane Database of Systematic Reviews, 2010Co-Authors: Susanne Rösner, Philippe Lehert, Andrea Hacklherrwerth, Stefan Leucht, Simona Vecchi, Michael SoykaAbstract:Alcohol dependence is among the main leading health risk factors in most developed and developing countries. Therapeutic success of psychosocial programs for relapse prevention is moderate, but could potentially be increased by an adjuvant treatment with the glutamate antagonist Acamprosate. The objective of this reiew is to determine the effectiveness and tolerability of Acamprosate in comparison to placebo and other pharmacological agents.
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predictors of Acamprosate efficacy results from a pooled analysis of seven european trials including 1485 alcohol dependent patients
Psychopharmacology, 2005Co-Authors: Roel Verheul, Maarten W. J. Koeter, Philippe Lehert, P J Geerlings, Wim Van Den BrinkAbstract:Rationale Acamprosate is a proven effective intervention in the treatment of alcohol dependence. However, Acamprosate prevents lapses or relapses only in a minority of patients. An important question, therefore, is whether there is a specific subgroup of patients who respond particularly well to Acamprosate.
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a pragmatic trial of Acamprosate in the treatment of alcohol dependence in primary care
Alcohol and Alcoholism, 2004Co-Authors: Paul Kiritzetopor, Dominique Huas, Claude Rosenzweig, Sylvie Comte, Francois Paille, Philippe LehertAbstract:Aims: To assess the effectiveness of pharmacotherapy with Acamprosate in alcohol-dependent patients treated in a naturalistic setting in primary care in France. Methods: The ARES ( Acamprosate et Repercussions Economiques et Sociales ; Acamprosate and Economic and Social Repercussions) study was performed by 149 general practitioners interested in treating alcohol use disorders in France who included patients fulfilling DSM-IV criteria for alcohol dependence. The only exclusion criteria concerned contra-indications to Acamprosate, co-medication with naltrexone and multiple substance abuse. Eligible patients were randomized to one of two treatment arms, either standard care alone or standard care with Acamprosate, using an open-label design and followed up quarterly for a period of 1 year. The primary outcome variable was the change from baseline on the Alcohol-Related Problems Questionnaire. Secondary efficacy variables were abstinence, Clinical Global Impression, quality of life measured with the SF-36 and incidence of adverse events. An intent-to-treat population was used for outcome analysis. Results: 422 patients were included, of whom 348 (82%) completed the protocol as planned. At the end of the study, patients randomized to the Acamprosate group had significantly better outcomes in terms of total ARPQ score, change from baseline (−2.61 vs −3.44) and number of subjects with no alcohol-related problem. On average, patients treated with Acamprosate had one less alcohol-related problem than did the controls. The number needed to treat in order to save one additional patient from alcohol-related problems compared to standard care was 7.14. Statistically significant differences in favour of the Acamprosate group were observed for all secondary efficacy outcome measures including quality of life. Conclusions: Adjunctive therapy with Acamprosate in primary care is associated with significantly better functional outcome. Pragmatic trials in alcohol dependence are both feasible and informative. ( Received 12 May 2003; first review notified 13 June 2003; in revised form 15 July 2004; accepted 15 July 2004 )
Karl Mann - One of the best experts on this subject based on the ideXlab platform.
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Acamprosate how where and for whom does it work mechanism of action treatment targets and individualized therapy
Current Pharmaceutical Design, 2010Co-Authors: Falk Kiefer, Karl MannAbstract:By updating John Littleton's work published 15 years ago this review summarizes recent work on pharmacodynamic aspects of Acamprosate and the perspective for future developments. In addition to insights into the role of glutamatergic receptor systems, craving and relapse inspired by Acamprosate, clinical research points towards one question: if we knew how Acamprosate works, we might also be able to generate hypotheses, for whom it does work. Recent research on Acamprosate tightly links pre-clinical and clinical research that includes molecular biology, animal models, pharmacogenetic and imaging genetic trials, and clinical efficacy studies. To increase the efficacy of this drug, targeted treatment and individualized therapy approaches seem useful and necessary.
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Acamprosate recent findings and future research directions
Alcoholism: Clinical and Experimental Research, 2008Co-Authors: Karl Mann, Rainer Spanagel, Falk Kiefer, John M. LittletonAbstract:This article explores the mechanisms of action and the potential responder profile of Acamprosate, a compound efficacious in relapse prevention of alcoholism. New evidence at the molecular and cellular level suggests that Acamprosate attenuates hyper-glutamatergic states that occur during early abstinence and involves iono (NMDA)- and metabotrotropic (mGluR5) glutamate receptors along with augmented intracellular calcium release and electrophysiological changes. Thus mutant mice with enhanced glutamate levels exhibit higher alcohol consumption than wild type mice and respond better to Acamprosate, demonstrating that Acamprosate acts mainly on a hyper-glutamatergic system. This mode of action further suggests that Acamprosate exhibits neuroprotective properties. In rats, cue-induced reinstatement behavior is significantly reduced by Acamprosate treatment whereas cue-induced craving responses in alcohol-dependent patients seem not to be affected by this treatment. An ongoing study ("Project Predict") defines specific responder profiles for an individualized use of Acamprosate and naltrexone. Neurophysiological as well as psychometric data are used to define 2 groups of patients: "reward cravers" and "relief cravers". While naltrexone should work better in the first group, Acamprosate is hypothesized to be efficacious in the latter where withdrawal associated and/or cue induced hyper-glutamatergic states are thought to trigger relapse. Further research should target the definition of subgroups applying endophenotypic approaches, e.g. by detecting a hyperglutamatergic syndrome using MR spectroscopy.
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Neue Ansätze in Diagnostik und Behandlung von Alkoholproblemen
Psychiatrie und Psychotherapie, 2007Co-Authors: Karl MannAbstract:Neue therapeutische Ansätze im Umgang mit Alkoholproblemen (Alkoholabhängigkeit und schädlicher Alkoholgebrauch) haben die Erfolgsraten verbessert und werden zunehmend häufiger eingesetzt. Früh- und Kurzinterventionen, neue psychotherapeutische Verfahren, die qualifizierte Entzugsbehandlung und medikamentöse Rückfallprophylaktika (Acamprosat, Naltrexon) werden skizziert. Gemeinsam mit weniger zeitaufwändigen Screeningverfahren (z. B. Audit C) bieten sie dem Psychiater aber auch dem Hausarzt wesentlich verbesserte Möglichkeiten zur erfolgreichen Intervention bei diesen "Menschen mit einer minderwertigen Krankheit" (R. Musil). In recent years a number of new approaches in the treatment of alcohol dependent patients and individuals with harmful alcohol use have been developed and tested. Early and brief interventions, motivational elements in the acute treatment in the medical sector as well as new and less time consuming screening tests (Audit C) can be recommended. Acamprosate and naltrexone in the hands of psychiatrists and/or general practitioners enhance patients' chances to stay sober or become abstinent after a relapse faster again.
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Neue Ansätze in Diagnostik und Behandlung von Alkoholproblemen
Psychiatrie und Psychotherapie, 2007Co-Authors: Karl MannAbstract:In recent years a number of new approaches in the treatment of alcohol dependent patients and individuals with harmful alcohol use have been developed and tested. Early and brief interventions, motivational elements in the acute treatment in the medical sector as well as new and less time consuming screening tests (Audit C) can be recommended. Acamprosate and naltrexone in the hands of psychiatrists and/or general practitioners enhance patients' chances to stay sober or become abstinent after a relapse faster again. Neue therapeutische Ansätze im Umgang mit Alkoholproblemen (Alkoholabhängigkeit und schädlicher Alkoholgebrauch) haben die Erfolgsraten verbessert und werden zunehmend häufiger eingesetzt. Früh- und Kurzinterventionen, neue psychotherapeutische Verfahren, die qualifizierte Entzugsbehandlung und medikamentöse Rückfallprophylaktika (Acamprosat, Naltrexon) werden skizziert. Gemeinsam mit weniger zeitaufwändigen Screeningverfahren (z. B. Audit C) bieten sie dem Psychiater aber auch dem Hausarzt wesentlich verbesserte Möglichkeiten zur erfolgreichen Intervention bei diesen "Menschen mit einer minderwertigen Krankheit" (R. Musil).
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the efficacy of Acamprosate in the maintenance of abstinence in alcohol dependent individuals results of a meta analysis
Alcoholism: Clinical and Experimental Research, 2004Co-Authors: Karl Mann, Philippe Lehert, M Y MorganAbstract:Abstract: Background: A number of clinical trials have been undertaken to determine the efficacy of Acamprosate in the maintenance of abstinence in alcohol-dependent individuals. However, the reported differences in patient populations, treatment duration, and study endpoints make comparisons difficult. An assessment of the efficacy of treatment with Acamprosate was, therefore, undertaken using meta-analytical techniques. Methods: All randomized, placebo-controlled trials (RCTs) that fulfilled predetermined criteria were identified using (1) a language unrestricted search of 10 electronic databases; (2) a manual search of relevant journals, symposia, and conference proceedings; (3) cross-referencing of all identified publications; (4) personal communications with investigators; and (5) scrutiny of Merck-Sante's internal reports of all European trials. Study quality was assessed, independently, by three blinded workers. Key outcome data were identified; some outcome variables were recalculated to ensure consistency across trials. The primary outcome measure was continuous abstinence at 6 months; abstinence rates were determined by estimating Relative Benefit (RB). Results: A total of 19 published 1 unpublished RCTs were identified that fulfilled the selection criteria; 3 were excluded because the documentation available was insufficient to allow adequate assessment. The remaining 17 studies, which included 4087 individuals, 53% of whom received active drug, were of good quality and were otherwise reasonably comparable. There was no evidence of publication bias. Continuous abstinence rates at 6 months were significantly higher in the Acamprosate-treated patients (Acamprosate, 36.1%; placebo, 23.4%; RB, 1.47; [95% confidence intervals (CI): 1.29–1.69]; p < 0.001). This effect was observed independently of the method used for assigning missing data. The effect sizes in abstinent rates at 3, 6, and 12 months were 1.33, 1.50, and 1.95, respectively. At 12 months, the overall pooled difference in success rates between Acamprosate and placebo was 13.3% (95% CI, 7.8–18.7%; number needed to treat, 7.5). Acamprosate also had a modest but significant beneficial effect on retention (6.01%; [95% CI, 2.90–8.82]; p= 0.0106). Conclusion:: Acamprosate has a significant beneficial effect in enhancing abstinence in recently detoxified, alcohol-dependent individuals.
Charles P. O'brien - One of the best experts on this subject based on the ideXlab platform.
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A double-blind, placebo-controlled pilot trial of Acamprosate for the treatment of cocaine dependence.
Addictive Behaviors, 2010Co-Authors: Kyle M. Kampman, Thorne Sparkman, Kevin G Lynch, Charles A. Dackis, Helen M. Pettinati, Charles P. O'brienAbstract:Abstract Background Acamprosate is a medication shown to be effective for the treatment of alcohol dependence. Although the exact mechanism of action of Acamprosate is unknown, evidence suggests that it decreases excitatory amino acid activity by post-synaptic inhibition of the NMDA subtype of glutamate receptors. It is possible that the activity of Acamprosate via modulating glutamatergic activity could also reduce craving for cocaine and impact abstinence in cocaine dependence. Therefore, we conducted a double-blind placebo-controlled pilot trial of Acamprosate for the treatment of cocaine dependence. Methods Sixty male and female cocaine dependent patients were included in a nine week double-blind, placebo-controlled trial. After a one-week baseline, patients were randomized to receive Acamprosate 666 mg three times daily or identical placebo tablets for eight weeks. The primary outcome measure was cocaine use as determined by twice weekly urine drug screens. Results Thirty-six patients (60%) completed the trial, with no significant between-group difference in treatment retention. Percent cocaine positive urine drug screens did not differ between the two groups. Acamprosate was no better than placebo in reducing cocaine craving, reducing cocaine withdrawal symptoms, or improving measures of drug use severity from the Addiction Severity Index. Adverse events in this trial were generally mild and were evenly distributed between the two groups. Discussion Acamprosate was well tolerated but was no more efficacious than placebo in promoting abstinence from cocaine in cocaine dependent patients. Acamprosate does not appear to be a promising medication for the treatment of cocaine dependence.
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Initiating Acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence.
Addictive behaviors, 2009Co-Authors: Kyle M. Kampman, Thorne Sparkman, Kevin G Lynch, Charles A. Dackis, Helen M. Pettinati, Hu Xie, David W Oslin, Tiffany Sharkoski, Charles P. O'brienAbstract:This trial compared the efficacy of Acamprosate, started at the beginning of detoxification, to Acamprosate started at the completion of detoxification, in the treatment of alcohol dependence. This biphasic clinical trial consisted of a randomized, double-blind, placebo-controlled Detoxification Phase (DP), followed by a 10-week open-label Rehabilitation Phase (RP). Forty alcohol dependent patients were randomly assigned to receive either 1998 mg of Acamprosate daily, or matching placebo, during the DP (5-14 days). After completing detoxification, all patients received open label Acamprosate (1998 mg daily) in the RP. Outcome measures during the DP included: treatment retention, alcohol withdrawal, alcohol consumption, and oxazepam used. Outcome measures during the RP included: treatment retention and alcohol consumption. There were no significant outcome differences between Acamprosate and placebo-treated patients during the DP. Patients given Acamprosate, compared to placebo, during the DP drank more alcohol in the RP. Starting Acamprosate at the beginning of detoxification did not improve DP outcomes. Starting Acamprosate after detoxification was completed was associated with better drinking outcomes during subsequent alcohol rehabilitation treatment.
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Initiating Acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence
Addictive Behaviors, 2009Co-Authors: Kyle M. Kampman, Thorne Sparkman, Kevin G Lynch, Charles A. Dackis, Helen M. Pettinati, Hu Xie, David W Oslin, Tiffany Sharkoski, Charles P. O'brienAbstract:Abstract Objectives This trial compared the efficacy of Acamprosate, started at the beginning of detoxification, to Acamprosate started at the completion of detoxification, in the treatment of alcohol dependence. Methods This biphasic clinical trial consisted of a randomized, double-blind, placebo-controlled Detoxification Phase (DP), followed by a 10-week open-label Rehabilitation Phase (RP). Forty alcohol dependent patients were randomly assigned to receive either 1998 mg of Acamprosate daily, or matching placebo, during the DP (5–14 days). After completing detoxification, all patients received open label Acamprosate (1998 mg daily) in the RP. Outcome measures during the DP included: treatment retention, alcohol withdrawal, alcohol consumption, and oxazepam used. Outcome measures during the RP included: treatment retention and alcohol consumption. Results There were no significant outcome differences between Acamprosate and placebo-treated patients during the DP. Patients given Acamprosate, compared to placebo, during the DP drank more alcohol in the RP. Conclusions Starting Acamprosate at the beginning of detoxification did not improve DP outcomes. Starting Acamprosate after detoxification was completed was associated with better drinking outcomes during subsequent alcohol rehabilitation treatment.
Kimberly M. Huber - One of the best experts on this subject based on the ideXlab platform.
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Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety
Journal of Neurodevelopmental Disorders, 2017Co-Authors: Tori L. Schaefer, Matthew H. Davenport, Lindsay M. Grainger, Chandler K. Robinson, Anthony T. Earnheart, Melinda S. Stegman, Anna L. Lang, Amy A. Ashworth, Gemma Molinaro, Kimberly M. HuberAbstract:Background Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene ( FMR1 ) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of Acamprosate and the significance of the molecule’s calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of Acamprosate were assessed in the Fmr1 ^ -/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments. Methods Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess Acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic Acamprosate treatment and any potential effects of the calcium moiety using CaCl_2 treatment on behavior and nuclear ERK1/2 activation. Results Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl_2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation. Conclusions These data indicate that Acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that Acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of Acamprosate in these instances.
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Acamprosate in a mouse model of fragile x syndrome modulation of spontaneous cortical activity erk1 2 activation locomotor behavior and anxiety
Journal of Neurodevelopmental Disorders, 2017Co-Authors: Tori L. Schaefer, Matthew H. Davenport, Lindsay M. Grainger, Chandler K. Robinson, Anthony T. Earnheart, Melinda S. Stegman, Anna L. Lang, Amy A. Ashworth, Gemma Molinaro, Kimberly M. HuberAbstract:Abstract Background Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene ( FMR1 ) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of Acamprosate and the significance of the molecule’s calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of Acamprosate were assessed in the Fmr1 -/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments. Methods Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess Acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic Acamprosate treatment and any potential effects of the calcium moiety using CaCl 2 treatment on behavior and nuclear ERK1/2 activation. Results Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl 2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation. Conclusions These data indicate that Acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that Acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of Acamprosate in these instances.
