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PubMed1998

Mechanism of action of acamprosate. Part I. Characterization of spermidine-sensitive acamprosate binding site in rat brain.

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acamprosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 microM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 +/- 1.1 microM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50 of 645 microM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 microM range. However, under conditions of maximal receptor activation (100 microM glutamate, 30 microM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations >100 microM). When these binding studies were performed in the presence of 1 microM spermidine, the enhancing effects of acamprosate on [3H]dizocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

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PubMed1998

Mechanism of action of acamprosate. Part II. Ethanol dependence modifies effects of acamprosate on NMDA receptor binding in membranes from rat cerebral cortex.

Acamprosate is a putative anticraving drug used to maintain abstinence in alcohol-dependent patients. Its mechanism of action is uncertain, but the drug is thought to interact with neuronal NMDA receptors and calcium channels, and these proteins are implicated in the induction of alcohol dependence. In these experiments, the effects of acamprosate were studied on the binding of the NMDA receptor ligand [3H]dizocilpine to rat brain membranes under nonequilibrium conditions; 10 microM glutamate and 1 microM glycine were present in the binding assays to partially activate the receptor. At clinically relevant concentrations (in the micromolar range), acamprosate significantly enhanced [3H]dizocilpine binding to cortical membranes from control animals (suggesting that acamprosate may increase the rate of association of the radioligand), whereas at higher concentrations binding was inhibited. This effect is consistent with a partial agonist effect of acamprosate on the NMDA receptor protein. However, when rats were made dependent on ethanol (exposure to the drug for 10 days by inhalation) and cortical membranes were prepared from these animals, acamprosate in vitro no longer produced any enhancement of [3H]dizocilpine binding. Similar results were obtained when membranes were used from rats that had received 400 mg/kg/day of acamprosate in their drinking water with or without concurrent ethanol inhalation for 10 days. Thus, in brain membranes from all these treatment groups, acamprosate in vitro caused inhibition of [3H]dizocilpine binding only. The results suggest that acamprosate may have excitatory or inhibitory effects on NMDA receptors, depending on the experimental conditions. The effects of the drug on this system appear to be shifted toward inhibition in alcohol dependence, and this finding may be important to its clinical mechanism.

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PubMed1998

The cost effectiveness of acamprosate in the treatment of alcoholism in Germany. Economic evaluation of the Prevention of Relapse with Acamprosate in the Management of Alcoholism (PRAMA) Study.

Alcoholism places a considerable economic burden on society. The rate of relapse of previously weaned alcoholics has been shown to decrease following treatment with acamprosate. Therefore, this study investigated the cost effectiveness of acamprosate in the treatment of alcoholism in Germany from the perspective of the German healthcare system. In this retrospective analysis of clinical data, the additional direct medical costs per additional abstinent alcoholic incurred by adjuvant acamprosate therapy of previously weaned alcoholics were quantified. In the base-case analysis, average case-related direct costs were applied. The cost-effectiveness ratio was -2600 deutschmarks (DM) per additional abstinent patient. Thus, the administration of acamprosate is cost saving. The cost benefit of acamprosate was also shown in a sensitivity analysis. The variance of the target variable under 'real world' conditions was simulated and the impact of the model variables on the target variable was quantified using a deterministic model. The variance was broad and the rate of abstinence under acamprosate was the independent variable with the greatest impact on the target variable. From the perspective of both the German healthcare system (i.e. direct medical costs) and the Statutory Health Insurance expenses, adjuvant acamprosate therapy led to net savings, while at the same time improved the patient's state of health. Based on the naturalistic design of the underlying clinical trial and on this economic evaluation, it can be concluded that adjuvant acamprosate therapy leads to net savings under 'real world' conditions.

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PubMed1998

Central effects of acamprosate: part 2. Acamprosate modifies the brain in-vivo proton magnetic resonance spectrum in healthy young male volunteers.

Although acamprosate is a drug which is successfully used for therapy in maintaining alcohol abstinence following alcohol withdrawal in chronic alcoholism, little is understood about its mechanism of action in the central nervous system. Our objective was to assess the effects of acamprosate on the central nervous system in healthy subjects by dynamic proton magnetic resonance spectroscopy (MRS) measurements localized in brain tissue in vivo. Recordings were performed after intravenous administration of acamprosate or placebo to eight healthy male volunteers participating in a double-blind, randomized, cross-over, placebo-controlled study. The data were acquired using a spin-echo volume selective localized spectroscopy scheme on a 3-T whole body MRS system. Spectra obtained at baseline and at 20-min time intervals after the beginning of drug infusion were analyzed on the basis of five non-overlapping spectral integration regions. In the acamprosate-treated group, the median integral values in the regions for which N-acetylaspartate and glutamate are the main signal contributors showed decreases relative to placebo 20 min after the infusion began. Results suggest a central glutamatergic effect of acamprosate consistent with cerebral microdialysis glutamate measurements in vivo obtained from alcoholized rats treated with acamprosate (Part 1 of this study). This study is to our knowledge the first one describing a central effect of acamprosate in humans by MRS.

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PubMedDate not supplied

United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol.

A 6-month randomized controlled study of acamprosate versus placebo in preventing relapse following withdrawal from alcohol was undertaken in 20 centres throughout the UK. Patients diagnosed as alcohol-dependent and detoxified within the preceding 5 weeks were randomly assigned to treatment with either acamprosate (A) 666 mg three times/day or identical placebo (P). A total of 664 patients were screened; 581 were entered into the treatment phase. One-third were episodic drinkers, 84% were male, 44% were unmarried and 48% were unemployed. Medication was first taken on average 24 days after the start of detoxification; 32% of patients had already relapsed by this time. The 6-month study period was completed by 35% of patients; adverse events led to withdrawal of a further 14% (A) and 9% (P) respectively. Compliance was poor in that, by the end of the second week, only 57% of patients were judged to be taking at least 90% of their tablets. The mean total of abstinent days achieved was 77 (A) and 81 (P). Complete abstinence for 6 months was achieved by 12% (A) and 11% (P); drinking remained within controlled limits in a further 3% (A) and 6% (P). An effect of acamprosate on consumption was not seen when subgroups, including those defined by the Lesch typology, were analysed separately. However, the mean percentage reduction in craving for alcohol measured on a visual analogue scale was greater in the acamprosate, than placebo, patients at week 2 and week 4 (P<0.001) and the mean decrease in the Hamilton Anxiety score at the 4th week was greater in the acamprosate than placebo patients (P = 0.017). In comparison with other published trials of acamprosate, patients started study medication after a longer time following detoxification, had more often recommenced drinking before medication was started and had a higher drop-out rate, and this might have contributed to the lack of a treatment effect in this study.

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PubMed1998

Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats.

One of the known behavioral actions of acamprosate is to decrease hypermotility during alcohol withdrawal. However, the mechanism of this effect remains unclear. In this study, the concentrations of excitatory and inhibitory amino acids were assayed by the microdialysis technique with OPA/BME precolumn derivatization and electrochemical detection in the nucleus accumbens of male Wistar rats which were either alcoholized by ethanol inhalation or simultaneously alcoholized and treated orally by acamprosate (400 mg/kg/day) for 4 weeks. Without treatment, extracellular glutamate increased during the withdrawal phase, while other amino acids tested (aspartate, arginine, taurine, alanine and GABA) remained stable. In contrast, the alcoholized rats treated with acamprosate failed to present the increase in glutamate during ethanol withdrawal, while other amino acids tested also remained stable. The observed glutamate increase could be responsible for the hyperexcitability observed during episodes of ethanol withdrawal. These results suggest that acamprosate is able to reduce the ethanol withdrawal syndrome by reducing the concentration of glutamate in the nucleus accumbens.

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PubMed2002

Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors.

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 trnas-ACPD (+/--1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1S, 3R and 1R, 3S-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 microM 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 microM -ACPD or 50 microM 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 microM 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 microM) and SIB-1893 (20-500 microM) 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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PubMed2005

Acamprosate for the treatment of alcohol dependence.

BACKGROUND: Both inpatient and outpatient treatment centers that focus solely on psychosocial therapies for the treatment of alcohol dependence have high relapse rates. Thus, extensive research has focused on the development of pharmacologic moieties to attenuate the craving for alcohol after acute alcohol detoxification. Three drug therapies are currently approved by the US Food and Drug Administration (FDA) for this purpose: disulfiram, naltrexone, and acamprosate. The latter was approved by the FDA in 2004. OBJECTIVE: This article describes the pharmacologic properties and clinical usefulness of acamprosate for the treatment of alcohol dependence. METHODS: Relevant information was identified through searches of MEDLINE (1966 to March 2005), International Pharmaceutical Abstracts (1970-2005), Current Contents (1996-2005), and Cumulative Index to Nursing and Allied Health Literature (1982-Week 2, 2004) using the key words acamprosate, alcohol dependence, and alcoholism (MeSH). RESULTS: Acamprosate limited to randomized, controlled clinical trials yielded 33 hits in MEDLINE. Twenty-two articles were reviewed for efficacy end points, and 10 were reviewed for pharmacology and pharmacokinetics data. Acamprosate plus pharmacokinetics and pharmacodynamics yielded 19 hits, some of which were duplicates from the previously described search. Acamprosate plus meta-analysis (MeSH) yielded 5 hits, naltrexone plus meta-analysis (MeSH) yielded 9 hits, and disulfiram plus meta-analysis yielded 3 hits. The most recent review articles and their reference lists were assessed to ensure completeness of literature searches. Based on these searches, acamprosate is known to be an analogue of taurine and gamma-aminobutyric acid (GABA), 2 central nervous system neuromodulators. Acamprosate is thought to share some of the cellular actions of taurine affecting GABA and glutaminergic receptors in the nucleus accumbens, a brain region that may be responsible for the reinforcing effects received after alcohol consumption. Acamprosate is thought to also suppress excitation-induced calcium entry that results from chronic alcohol exposure, thereby altering the conformation of the N-methyl-d-aspartate receptors. The percentage of patients taking acamprosate who were completely abstinent throughout the different durations of the studies varied from approximately 18% to 61%, compared with 4% to 45% with placebo. Diarrhea was the most common adverse effect accompanying acamprosate therapy, and this was generally described as dose related and transient. CONCLUSIONS: Acamprosate is associated with modest treatment effects. Its efficacy is similar to naltrexone, and the combination of acamprosate and naltrexone appears to be more efficacious than acamprosate alone, when combined with psychosocial interventions.

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PubMed1996

Acamprosate (calcium acetylhomotaurinate) enhances the N-methyl-D-aspartate component of excitatory neurotransmission in rat hippocampal CA1 neurons in vitro.

The taurinate analog acamprosate (calcium acetylhomotaurinate) has received considerable attention in Europe for its ability to prevent relapse in abstained alcoholics. To determine the mechanism of acamprosate actions in the CNS, we superfused acamprosate onto rat hippocampal CA1 pyramidal neurons using an in vitro slice preparation. In current-and voltage-clamp recordings, acamprosate (100 to 100 microM) superfusion had little effect on resting membrane potential or input slope resistance. Acamprosate had no effect on Ca(2+)-dependent action potentials when tetrodotoxin was used to block Na+ spikes. In whole-cell voltage-clamp recordings, and in the presence of tetraethylammonium and Cs+ to block K+ channels, acamprosate had little effect on a Cd(2+)-sensitive inward current likely to be a high voltage-activated Ca2+ current. However, in both current- and voltage-clamp recordings, acamprosate significantly increased the N-methyl-D-aspartate (NMDA) component of excitatory postsynaptic potentials evoked by stimulation of Schaffer collaterals in the stratum radiatum, in the presence of the selective non-NMDA (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid kainate) glutamate receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione and the GABAA receptor antagonist bicuculline. Acamprosate had inconsistent or no effects on the stratum radiatum-evoked non-NMDA component of the excitatory postsynaptic potentials, in the presence of bicuculline and the NMDA antagonist DL-2-amino-5-phosphonovalerate. Acamprosate, on average, had little effect on the late inhibitory postsynaptic potentials thought to be mediated by GABAB receptors. In the presence of tetrodotoxin to block synaptic transmission, acamprosate dramatically increased inward current responses in most CA1 neurons to exogenous NMDA applied by pressure or superfusion, with reversal on washout of acamprosate. These data suggest that acamprosate may act postsynaptically to increase the NMDA component of excitatory transmission to hippocampal CA1 pyramidal neurons. Considering the known interaction of ethanol with NMDA receptors, this acamprosate modulation of NMDA receptor-mediated neurotransmission could provide a mechanism of action underlying the clinical efficacy of acamprosate.

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PubMed1998

Clinical pharmacokinetics of acamprosate.

Acamprosate is a new psychotropic drug used in the treatment of alcohol (ethanol)-dependence. Recent studies suggest that acamprosate inhibits neuronal hyperexcitability by antagonising excitatory amino acids. It is available as a 333 mg enteric-coated tablet, with a recommended dosage of 1.3 g/day for patients with a bodyweight < 60 kg and 2 g/day for patients with a bodyweight > or = 60 kg. Treatment with higher dose strength tablets 2 x 500 mg twice daily is bioequivalent to treatment with the 2 x 333 mg 3 times daily dosage regimen. Acamprosate is absorbed via the paracellular route in the gastrointestinal tract. Absorption is rapid but limited after oral administration. At steady-state, acamprosate has a moderate distribution volume of about 20L. Acamprosate is not protein bound or metabolised. Half of the elimination of acamprosate occurs as unchanged acetyl-homotaurine in urine, the other half might be eliminated by biliary excretion. The administration of the enteric-coated tablets showed a flip-flop mechanism with a terminal elimination half-life 10-fold higher than the 3-hour half-life reported after intravenous infusion. During repeated oral administration of 666 mg 3 times daily, steady-state is reached after 5 to 7 days and leads to plasma concentrations ranging from 370 to 650 micrograms/L. The pharmacokinetics of acamprosate administered as an enteric-coated tablets are time- and dose-independent, and its accumulation ratio is about 2.4 at steady-state. Acamprosate disposition does not differ between males and females. The pharmacokinetics of acamprosate are not modified in patients with hepatic insufficiency or chronic alcoholism. In contrast, renal insufficiency influences the elimination of acamprosate and it is, therefore, contraindicated under such circumstances. Interaction studies have confirmed that when acamprosate is concomitantly administered with food, the amount absorbed is decreased. When combined with diazepam, disulfiram or alcohol, the pharmacokinetic disposition of acamprosate is not modified. Acamprosate does not influence the kinetics of diazepam, alcohol or imipramine and its metabolite desipramine.

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PubMed1996

Acamprosate and alcohol: III. Effects on alcohol discrimination in the rat.

It has been shown that acamprosate (calcium-acetyl homotaurinate) decreases voluntary ethanol drinking in laboratory animals as well as relapse behaviour in human alcoholics. Although glutamatergic mechanisms have been implicated in several recent studies in the action of acamprosate, the basic mechanism remains unknown. In order to gain more insight into possible mechanisms underlying the ethanol intake-suppressing effects of acamprosate, we investigated this compound in an ethanol discrimination test. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses for food following ethanol (1 g/kg i.p.; 12% v/v ethanol solution) or saline vehicle injections with a fixed ratio schedule of food reinforcement (FR 10) and a post-administration interval of 10 min. Once rats had acquired the discrimination, the criterion for stimulus control was set as at least 90% ethanol- or vehicle appropriate responding during ten consecutive sessions, an ethanol dose-response test (0.25-1.5 g/kg i.p.) was conducted. The effects of acamprosate on the discrimination were assessed in two ways: (i) Generalization test: acamprosate (25-250 mg/kg i.p.) was given either 30 or 120 min before the animals were put in the operant chambers. (ii) Antagonism test: acamprosate (25-250 mg/kg i.p.) was given 120 min before the animals were injected with ethanol, 10 min later the animals were tested. Data obtained in the dose-response test showed a dose-dependent effect with an ED50 of 0.53 g/kg ethanol. The results of generalization testing revealed that acamprosate failed to substitute for the ethanol cue, whereas, in comparison, dizocilpine (0.01-0.2 mg/kg i.p.) completely generalized for the ethanol cue (ED50 = 0.05 mg/kg). Acamprosate also had no effect when tested as an antagonist. Thus, neither the ethanol nor the saline discrimination was altered by acamprosate pretreatment. Furthermore, acamprosate had no effect on response latencies at all doses tested. In conclusion, acamprosate does not generalize for the ethanol cue, suggesting that it is not a substitution drug. Further, acamprosate does not seem to act via the dizocilpine binding site of the N-methyl-D-aspartic acid (NMDA) channel.

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PubMed1996

Comparison of acamprosate and placebo in long-term treatment of alcohol dependence.

BACKGROUND: About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence. METHODS: In this multicentre, double-blind, placebo-controlled study, we recruited 455 patients, aged 18-65 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1998 mg daily for bodyweight > 60 kg; 1332 mg daily for < or = kg) or placebo for 360 days. Patients were assessed on the day treatment started and on days 30, 90, 180, 270, and 360 by interview, self-report, questionnaire, and laboratory screening. Patients were classified as abstinent, relapsing, or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. FINDINGS: Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication. The acamprosate (n = 224) and placebo (n = 224) groups were well matched in terms of baseline demographic and alcohol-related variables. 94 acamprosate-treated and 85 placebo-treated patients completed the treatment phase: of those withdrawn, 104 (52 in each group) relapsed, 69 (33 vs 36, respectively) were lost to follow-up, 63 (31 vs 32) refused to continue treatment, 16 (15 vs 11) had concurrent illness, three (two vs one) died, ten (six vs four) had adverse side-effects, one (acamprosate treated) received the wrong medication, and three (placebo treated) were non-compliant. The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period (p < 0.001, Mantel-Cox). At the end of treatment, 41 (18.3%) acamprosate-treated and 16 (7.1%) placebo-treated patients had been continuously abstinent (p = 0.007). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (138.8 [SD 137.5] vs 103.8 [119.0] days; p = 0.012). 148 patients (79 acamprosate, 69 placebo) completed 27 months follow-up: 27 (11.9%) acamprosate-treated and 11 (4.9%) placebo-treated patients remained continuously abstinent, and the mean cumulative abstinence duration was 230.8 days (259.1) and 183.0 days (235.2), respectively. Apart from occasional diarrhoea, there was no difference in side-effects between groups. INTERPRETATION: Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients.

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PubMed2004

Alcohol effects during acamprosate treatment: a dose-response study in humans.

BACKGROUND: Acamprosate (calcium acetyl homotaurinate) reduces alcohol intake in animals and increases abstinence rates in alcohol-dependent persons. Acamprosate's mechanism of action, however, remains poorly understood. In order to examine whether acamprosate/alcohol interactions contribute to acamprosate's efficacy, the present double-blind, placebo-controlled human laboratory study examined effects of acamprosate on the pharmacokinetics and subjective, psychomotor, and physiological effects of alcohol in heavy drinkers. METHODS: In a six-week within-subject design, participants were maintained on acamprosate (0, 2, and 4 g, p.o., double-blind, in counterbalanced order) for 11 days at each dose. Physiological, subjective, and psychomotor measures were collected daily during each dosing cycle. During each acamprosate dose condition, subjects were challenged with 0, 0.5, and 1.0 g/kg ethanol (p.o., counterbalanced order) during three separate laboratory sessions. Subjective, physiological, and psychomotor effects of alcohol, and breath alcohol levels were collected at baseline and at 30-min intervals for a 3-hr post-administration period. RESULTS: Acamprosate alone did not substantially affect subjective, physiological, or psychomotor performance measures. Acamprosate did not alter alcohol pharmacokinetics, or alcohol-induced behavioral impairment or tachycardia, and most subjective alcohol effects were also unaltered by acamprosate as well. Although a trend appeared for acamprosate to increase subjective ratings of intoxication following the lower (0.5 g/kg) alcohol dose, adjustment for individual differences in blood alcohol level eliminated this effect, suggesting the trend was not due to a central effect of acamprosate. CONCLUSIONS: Acamprosate does not alter alcohol pharmacokinetics, acute physiological or psychomotor alcohol effects, or most subjective alcohol effects.

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PubMed1998

Acamprosate enhances N-methyl-D-apartate receptor-mediated neurotransmission but inhibits presynaptic GABA(B) receptors in nucleus accumbens neurons.

Acamprosate (calcium acetylhomotaurine) is used therapeutically in Europe to reduce relapse in weaned alcoholics. However, the mechanisms of acamprosate action in the central nervous system are still obscure, although early studies suggested an action on GABA receptors. The nucleus accumbens (NAcc) is a brain region thought to underlie ethanol reinforcement. Recent studies from our laboratory have demonstrated that ethanol inhibits both N-methyl-D-aspartate (NMDA) and non-NMDA types of glutamatergic synaptic transmission in the NAcc. In the present study, we used voltage- and current-clamp intracellular recording of NAcc core neurons in a slice preparation to examine acamprosate actions on resting membrane properties and pharmacologically isolated synaptic responses. We isolated NMDA and non-NMDA receptor-mediated excitatory postsynaptic potentials or currents (EPSP/Cs) with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovalerate (d-APV), respectively. Bicuculline was also included to block GABA(A) receptors. Superfusion of acamprosate (5, 50, and 300 microM) did not alter the resting membrane properties of NAcc neurons. However, 300 microM acamprosate significantly increased the NMDA receptor-mediated components of EPSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 microM acamprosate had no significant effect on the non-NMDA receptor component of the EPSP/Cs (non-NMDA-EPSP/Cs). To test acamprosate actions on the GABA system, we superfused 60 microM d-APV and 20 microM CNQX to block glutamatergic transmission and evoked monosynaptic GABA(A) receptor-mediated synaptic responses within the NAcc. Acamprosate (300 microM) did not change these monosynaptic GABA(A)-IPSCs. We also used a paired-pulse paradigm to test whether acamprosate could act on presynaptic GABA(B) autoreceptors, in the presence of d-APV and CNQX to block glutamatergic transmission. Like 0.5 microM CGP 34358 (a GABA[B] receptor blocker), acamprosate significantly decreased the paired-pulse inhibition (PPI) of GABA(A)-IPSCs at short interstimulus intervals (ISIs). Thus, acamprosate may concomitantly enhance NMDA-EPSP/Cs while blocking presynaptic GABA(B) receptor-mediated inhibition of GABA release. These results suggest that acamprosate's clinical efficacy in preventing relapse in weaned alcoholics could derive from its interactions with both the glutamatergic and GABAergic systems in the NAcc.

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PubMed2004

Biphasic effect of acamprosate on NMDA but not on GABAA receptors in spontaneous rhythmic activity from the isolated neonatal rat respiratory network.

Acamprosate (calcium acetylhomotaurinate) has been shown to be effective in attenuating relapse in human alcoholics. The precise mechanism for acamprosate has been yet to be determined as there may be multiple sites of action for this drug. We investigated the mechanism of action of acamprosate on a spontaneous rhythmic activity recorded from hypoglossal nerve rootlet (XII) in neonatal rat brainstem slices. At 30 microM, acamprosate reversibly increased burst amplitude and reduced burst frequency, whereas at higher concentrations (100-400 microM) it induced a reversible and concentration-dependent inhibition of this activity. Interestingly, acamprosate (30 microM) enhanced the effects of low NMDA-induced excitation (1.5 microM), but inhibited higher NMDA-induced excitation (2.5, 5 microM) by 50-70%, demonstrating a differential effect on NMDA-induced excitation. Blockade of GABAA receptors did not affect the increase in amplitude of 30 microM acamprosate and partially abolished the inhibitory effects of 200 microM acamprosate. At 200 microM, acamprosate reduced high NMDA-induced excitation and abolished NMDA-evoked excitatory tonic phase, suggesting that excitatory effect of low concentrations of acamprosate mainly involved NMDA receptors, while the inhibitory effects at higher concentration included an increase in GABAA-mediated inhibition with a reduction of NMDA-mediated excitation. Consequently, combined blockade of both receptors abolished all effects of acamprosate tested at all concentrations. These results show that the effects of acamprosate are mediated via both GABAA and NMDA receptors and suggest a partial co-agonist role on NMDA receptors, at the level of a spontaneously active network.

Acamprosate↗

PubMed2002

Cognitive behavioural therapy combined with the relapse-prevention medication acamprosate: are short-term treatment outcomes for alcohol dependence improved?

OBJECTIVE: The relapse prevention medication acamprosate has been recently introduced to the Australian Pharmaceutical Benefits Scheme (PBS) for the treatment of alcohol dependence. Overseas clinical trials have demonstrated the efficacy of using acamprosate as an adjunct to existing psychotherapeutic approaches. Research has not examined treatment outcomes using a standardized clinical approach. The objective of this study is to investigate the impact of adding acamprosate to an established abstinence-based outpatient alcohol rehabilitation programme in an Australian population. METHODS: Fifty patients participated in an established 12-week, outpatient, "contract" based Cognitive Behavioural Therapy (CBT) alcohol abstinence programme and received acamprosate (CBT + acamprosate). Patients weighing > or = 60 kg were prescribed acamprosate calcium 333 mg tablets, two tablets three times daily (1998 mg/day) and those weighing < 60 kg received four tablets (1332 mg/day) daily. Outcomes were compared with 50 historical, matched controls, all of whom participated in the same program without a relapse prevention medication (CBT alone). All patients met DSM-IV criteria for alcohol dependence and the majority were socially disadvantaged. RESULTS: Programme attendance across the eight treatment sessions was similar in both the CBT + acamprosate and the CBT alone conditions (P = 0.268). Relapse to alcohol use occurred sooner and more frequently in the CBT alone group (P = < 0.0005). Rehabilitation programme completion at 12 weeks was 42% (CBT + acamprosate) compared with 32% for (CBT alone) (P = < 0.204). Alcohol abstinence at 12 weeks was 38% (CBT + acamprosate) compared with 14% (CBT alone) (P = < 0.006). CONCLUSION: Even within an alcohol dependent population characterized by poor prognostic indices, the addition of acamprosate to an established CBT outpatient programme significantly improved abstinence rates over a 12-week period. The use of acamprosate as an adjunctive treatment for alcohol dependence should be encouraged in Australia.

Acamprosate↗

PubMed2005

The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine system.

Acamprosate (Campral) is a drug used clinically for the treatment of alcoholism. In order to examine further the time-course and mechanism of action of acamprosate, the effect of acute and repeated acamprosate administration was examined on (i) operant ethanol self-administration and (ii) voluntary home cage ethanol consumption by alcohol-preferring Fawn-Hooded, iP and Alko Alcohol (AA) rats. Acutely, acamprosate was shown to cause a significant decrease in operant ethanol self-administration by Fawn-Hooded and alcohol-preferring iP rats in part by decreasing the motivational relevance of a specific ethanol cue; however, repeated injection of acamprosate led to tolerance to this effect. Voluntary alcohol consumption in the home cage in Fawn-Hooded and AA rats was also reduced by an acute acamprosate injection; however, again tolerance developed to repeated injections. In a separate experiment, the effect of acamprosate on markers of the dopaminergic system was examined. Interestingly, acute acamprosate was also shown to cause increased dopamine transporter density and decreased dopamine D2-like receptor density within the nucleus accumbens but not in the caudate-putamen, suggesting a link between the decreased motivational salience of the ethanol cue and altered dopaminergic signalling within the nucleus accumbens. With repeated injections of acamprosate, markers of the dopaminergic system returned to steady state levels with a similar temporal profile to the development of tolerance in the behavioural studies. Along with previous studies, our findings indicate that acamprosate modulates the mesolimbic dopaminergic system and may thereby decrease ethanol reinforcement processes; however, these effects undergo tolerance in alcohol-preferring rats and may in part explain the fact why some subjects are non-responders to chronic acamprosate treatment.

Acamprosate↗

PubMed1997

Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification.

Acamprosate (calcium acetylhomotaurinate), a synthetic compound with a similar chemical structure to that of gamma-aminobutyric acid, is thought to act via several mechanisms affecting multiple neurotransmitter systems; inhibition of neuronal hyperexcitability by antagonism of excitatory amino acid activity and reduction of calcium ion fluxes has been suggested as its predominant mechanism of action. The drug is the first agent specifically designed to maintain abstinence in alcohol (ethanol)-dependent patients after detoxification. Voluntary oral ethanol consumption in ethanol-preferring or ethanol-dependent rats is dose-dependently reduced by acamprosate: total fluid intake and food consumption are not affected. The drug does not potentiate the acute or chronic toxic effects of ethanol and has no hypnotic, antidepressant, anxiolytic or muscle-relaxant effects in animals. There is no evidence of abuse potential with acamprosate. Oral acamprosate 1.3 or 2 g/day in 3 divided doses administered for 3 to 12 months to alcohol-dependent patients after detoxification was more effective than placebo in preventing alcohol relapse according to abstinence rates, duration of abstinence, gamma-glutamyl transferase levels and/or a variety of other clinical or biological end-points. Concomitant psychosocial/behavioural therapies were used in some trials. Compared with those with placebo, the superior abstinence rates and durations of abstinence with acamprosate were maintained during 6- to 12-month post-treatment follow-up periods, and greater abstinence rates with acamprosate were confirmed in a pooled analysis of data from 11 randomised placebo-controlled trials involving a total of 3338 patients with alcohol dependence. The efficacy of acamprosate appears to be dose dependent and enhanced by the addition of disulfiram. Acamprosate was generally well tolerated in placebo-controlled trials. The most common adverse events were gastrointestinal (especially diarrhoea) or dermatological and were mostly mild and transient. The percentage of patient withdrawals because of adverse events was similar in acamprosate and placebo groups. No trials have compared the efficacy or tolerability of acamprosate with those of other treatment approaches (including opiate antagonists or selective serotonin reuptake inhibitors) aimed at maintaining abstinence in detoxified alcohol-dependent patients. Thus, acamprosate, as an adjunct to psychosocial/behavioural therapies, represents a novel advance for the management of alcohol-dependent patients in the postdetoxification period. Longer term and comparative trials with other active therapies are required to confirm these promising results.

Acamprosate↗