[Disulfiram and addiction: reminders and new perspectives of use]. / Le disulfirame (Esperal(®)) dans le traitement des addictions : rappels et nouvelles perspectives d'utilisation.

Disulfiram is a relatively old molecule, which today remains marginal in the treatment of alcoholics diseases. Using this type of treatment is the subject of ethical debate. The prescription of this therapeutic requires clinical and biological rigorous evaluations before treatment. Its main action in treatment of alcoholism is related to the restraint of acetaldehyde dehydrogenase action causing the antabuse reaction. Prescription of disulfiram, supported by specialized programs of compartmental integrated care, brings significant benefit for alcoholic patients. Recently, following the discovery of its action on dopamine metabolism, disulfiram has been a renewed interest in the treatment of addictions to cocaine and pathological gambling. Although current data are insufficient to generalize its use in routine practice, they constitute a line of research interest for the future.

Acamprosate determinations in plasma and cerebrospinal fluid after multiple dosing measured by liquid chromatography-mass spectroscopy: a pharmacokinetic study in healthy volunteers.

The central nervous system-active medication acamprosate has been shown to modulate alcohol-related behavior in both preclinical and clinical studies. Although commonly used in the treatment of alcohol dependence, there are still unanswered questions concerning the pharmacokinetic properties of acamprosate. The aims of the present study were to 1) to validate liquid chromatography-mass spectrometry as a method to study the presence of acamprosate in plasma and cerebrospinal fluid (CSF) in humans; and 2) validate previous results on clinically important pharmacokinetic data for acamprosate. In an open label, single-site design, 13 healthy males and females were recruited to 22 days of oral acamprosate treatment (1998 mg/day). Subjects provided in all 256 plasma samples for analysis at regular intervals at Day 1, 7, 14, and 22 of treatment. On Day 22, subjects also left a sample of CSF for measurement of acamprosate. The results showed that steady-state level of acamprosate was accomplished within 5 days after the start of treatment and remained fairly stable for 2 to 3 days after termination of treatment. Variations in plasma concentrations corresponded to earlier studies and did not exceed those for comparable pharmacotherapeutic agents. Acamprosate concentrations in the CSF were below the limit of quantification, ie, estimated concentrations between 9 and 33 ng/mL. Plasma concentrations were more than 25 times higher than in lumbar CSF. The low CSF levels seen after 3 weeks of treatment may provide an explanation to the delay in therapeutic effect noticed in treatment studies on acamprosate. A longer duration of treatment might be necessary to obtain clinically significant brain levels of acamprosate. In summary, the present study validated liquid chromatography-mass spectrometry as a method for assessment of compliance to acamprosate treatment. Furthermore, the results suggest that the mechanism of action of acamprosate needs to be further explored with regard to the peripheral actions of the drug.

Delayed and prolonged coma after acute disulfiram overdose.

We report the case of a 35-year-old man presenting with a delayed and prolonged coma due to an intentional overdose with disulfiram without simultaneous alcohol ingestion. The clinical features--comprising a severe toxic encephalopathy with coma and convulsions, in combination with a quadriparesis outlasting the loss of consciousness--are summarized, and the physiopathology is reviewed.

A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration.

Acamprosate and naltrexone are widely used in the treatment of alcoholism. However, numerous studies in rodents have shown differential effects of these compounds on alcohol consumption and/or relapse-like behavior following acute versus repeated administration. In order to determine if these differential behavioral effects could be attributable to changes in extracellular levels of these compounds, we used in vivo microdialysis to monitor extracellular levels of acamprosate and naltrexone in the rat medial prefrontal cortex following acute and repeated intraperitoneal administration. For acute treatment, animals received a single administration of acamprosate (100 or 300 mg/kg) or naltrexone (1 or 3 mg/kg). For repeated treatment, animals received once daily treatment with saline, acamprosate (300 mg/kg) or naltrexone (3 mg/kg) for 10 days before a subsequent challenge with the compound according to their respective pretreatment group. Dialysate levels of acamprosate and naltrexone were analyzed by liquid chromatography-tandem mass spectrometry and high performance liquid chromatography, respectively. Following acute administration, peak dialysate concentrations of each compound were dose-dependent, observed within 1 hour of administration, and were found to be in the low micromolar range for acamprosate and in the low to mid-nanomolar range for naltrexone. Pretreatment with acamprosate, but not naltrexone, for 10 days resulted in higher dialysate concentrations of the compound relative to saline-pretreated controls. Thus, repeated administration of acamprosate, but not naltrexone, results in augmented extracellular levels of the compound in the brain relative to saline-pretreated controls, which may explain the need for repeated administration of acamprosate in order to observe effects on alcohol consumption and/or relapse.

Analysis of acamprosate in beagle dog plasma by LC-MS-MS.

A rapid, sensitive, and specific analytical method was developed and validated to quantify acamprosate calcium in beagle dog plasma. The method employs a single plasma protein precipitation, and the analytes are separated by chromatography on an Acquity UPLC HSS T3 column and analyzed by mass spectrometry in the multiple reaction monitoring (MRM) mode. The method has a chromatographic run time of 1.25 min and a linear calibration curve over the range 200-10000 ng/mL (r(2)>0.9994). The intra-day and inter-day accuracy and precision were within 10.0% for the analyte. Acamprosate was stable during all sample storage, preparation, and analytical periods. This method was employed in a pharmacokinetic study of an acamprosate 333 mg enteric-coated tablet in 8 male beagle dogs that received single 666 mg doses (333 mg x 2 tablets). The proposed method enables identification and quantification in pharmacokinetic studies of acamprosate in beagle dog plasma.

Investigation of the relationship between in vitro and in vivo release behaviors of acamprosate from enteric-coated tablets.

Acamprosate calcium is a highly soluble drug with low permeability that is used to maintain abstinence in alcohol-dependent patients. The aim of this study was to investigate the relationship between in vitro and in vivo behaviors of acamprosate from enteric-coated tablets. The in vitro release behavior of acamprosate tablets in pH 6.8 buffer solution was determined in three dissolution conditions, 50 and 150 rpm (paddle method) and 180 rpm (basket method). The results of this in vitro experiment indicated that acamprosate tablets hardly disintegrated, and drug dissolution was retarded despite the extremely hydrophilic nature of the drug. A single dose (333 mgx2 tablets) of each formulation was orally administered to four beagle dogs under fasting conditions, and the pharmacokinetic parameters were calculated. The mean AUC0-48, Cmax, Tlag and Tmax for the two types of tablets ranged from 41.5-53.6 microg.h/mL, 4.3-4.5 microg/mL, 2.0-2.5 h and 3.8-4.0 h, respectively. In conclusion, it is suggested that retarded drug release from the tablets and the low drug permeability may result in poor absorption and erratic bioavailability of this drug in humans.

[Recent results in relaps prevention of alcoholism with Disulfiram]. / Aktueller Stand der pharmakotherapeutischen Rückfallprophylaxe mit Disulfiram.

OBJECTIVE: For more than 50 years, disulfiram has been approved for the treatment of chronic alcohol dependence. In the last years there has been observed an increase in the prescription of disulfiram in germany. It acts as a psychological deterrence of a possible disulfiram-alcohol reaction. This paper describes the current clinical impact and possible future of disulfiram. METHODS: Clinical trials using disulfiram for the treatment of alcohol dependence were discussed. Furthermore, the options of combining disulfiram with novel anti-craving agents were considered. Moreover, experiences and results of a cross section of the Mannheimer Disulfiram program will be presented. RESULTS AND CONCLUSIONS: Nowadays there exists consent in the matter that Disulfiram should only be adminsitered as part of a comprehensive therapy program, this means in the context of an intake under medical supervision. This paper is supposed to help estimate the value of disulfiram in recent addiction medicine.

Personalized Medicine of Alcohol Addiction: Pharmacogenomics and Beyond.

Alcohol addiction or alcoholism is the most severe form of problem drinking. A variety of treatment methods for alcoholism are currently available that combine medications, behavioral treatment and peer support. The drugs that are currently approved by the U.S. Food and Drug Administration (FDA) for treatment of alcohol dependence are disulfiram, naltrexone and acamprosate. For many patients, however, these treatments are not effective. Evidence from a number of studies suggests that various factors, both psychosocial and economic, as well as genetic variation, are significant contributors to interindividual variation both of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss different aspects of personalized medicine of alcohol addiction. We focus on pharmacogenomics and beyond, to include the genetics and epigenetics of alcohol addiction as well as other psychosocial and even economic factors that may affect response to alcohol addiction pharmacotherapy. It is anticipated that, within the next 5-10 years, personalized medicine of alcohol addiction will be a reality and it will help reduce the burden of alcoholism from society and increase the well-being and productivity of individuals addicted to alcohol.

Acamprosate: a review of its use in the maintenance of abstinence in patients with alcohol dependence.

Acamprosate (Campral delayed-release tablet), a synthetic compound with a similar structure to that of the neurotransmitter GABA and the neuromodulator taurine, facilitates the maintenance of abstinence in detoxified alcohol-dependent patients. Although the precise mechanism(s) of action of the drug remains to be fully elucidated, it appears that it most likely involves beneficial modulation of the glutamatergic neurotransmitter system, including antagonism of the mGLu5 metabotropic glutamate receptor, to counteract the imbalance between the glutamatergic and GABAergic systems associated with chronic alcohol exposure and alcohol withdrawal. In several double-blind, placebo-controlled trials of up to 12 months' duration, acamprosate effectively maintained complete abstinence in detoxified alcohol-dependent patients, irrespective of disease severity or the type of psychosocial support. The drug showed better efficacy than placebo and was very well tolerated. Limited data from a relatively well designed trial indicate that the drug has similar efficacy to that of naltrexone and that combination therapy with these two agents provides better efficacy than acamprosate monotherapy, although multicentre direct head-to-head investigations are required to fully establish the potential of this combination. The drug may be particularly useful in those with hepatic impairment and/or liver disease. Thus, in combination with psychosocial and behavioural management programmes, acamprosate is a promising option for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal.

Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy.

Disulfiram is widely used in the treatment of chronic alcoholism. Adverse drug reactions with fatal outcome following disulfiram therapy are infrequent, and hepatic failure accounts for most of them. Since disulfiram is a cytochrome P450 (CYP450) enzyme system inhibitor, numerous interactions with several drugs metabolized in the liver have been reported. Like disulfiram, clarithromycin inhibits a CYP450 isoenzyme, but, despite its widespread use for the treatment of respiratory tract infections, no interactions with disulfiram have been described as yet. We report a case of fatal toxic epidermal necrolysis (Lyell disease) and fulminant hepatitis shortly after starting treatment with clarithromycin in a patient who was receiving disulfiram. This is the first case of such a severe dermatosis in a patient receiving either disulfiram or clarithromycin therapy. The temporal relationship between drug administration and clinical symptoms in this case suggests a probable interaction between the 2 drugs.

Topiramate in Alcohol Use Disorders: Review and Update.

To date, a limited number of pharmacological agents exist to treat alcohol use disorders (AUDs), and there is growing interest in new therapeutic tools. In this framework, topiramate may represent a useful treatment option, although its use is not yet approved for AUDs. The main focus of this review is to discuss all the existing data supporting the use of topiramate in AUDs, with an emphasis on the most recent and relevant clinical implications. In addition, the profile of the alcoholic patient who may benefit more from the use of topiramate is outlined. In this regard, the authors conducted a PubMed search of clinical human studies published in English using the following key words: topiramate alcohol dependence, topiramate alcohol withdrawal and topiramate alcoholism. The evidence suggests that topiramate could be an effective treatment option for the management of AUDs, while there are limited results for its use to treat alcohol withdrawal syndrome. In particular, topiramate shows a greater beneficial effect in subjects with a typology of craving characterised by drinking obsessions and automaticity of drinking. Topiramate, within the dosage range of 75-300 mg/day, could be considered as a first-line treatment option for the management of AUDs. Its use appears to be safe and well-tolerated, especially in light of very recent findings.

Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular Pressure in Rabbit Models.

PURPOSE: We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-ß-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models. METHODS: Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. ΔIOP and ΔNO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively. RESULTS: Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of ΔIOP or ΔNO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops. CONCLUSIONS: The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC-based drug delivery system promotes drug effectiveness and effective time.

The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study.

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone.

Acamprosate and naltrexone have each demonstrated safety and efficacy for alcohol dependence in placebo-controlled clinical trials. There is scientific and clinical interest in evaluating these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes. Thus, this is the first human pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Twenty-four normal, healthy adult volunteers participated in a double-blind, multiple dose, within subjects, randomized, 3-way crossover drug interaction study of the standard therapeutic dose of acamprosate (2 g/d) and the standard therapeutic dose of naltrexone (50 mg/d), given alone and in combination, with seven days per treatment condition and seven days washout between treatments. Blood samples were collected on a standardized schedule for pharmacokinetic analysis of naltrexone, 6-beta-naltrexol, and acamprosate. A computerized assessment system evaluated potential drug effects on cognitive functioning. Coadministration of acamprosate with naltrexone significantly increased the rate and extent of absorption of acamprosate, as indicated by an average 33% increase in acamprosate maximum plasma concentration, 33% reduction in time to maximum plasma concentration, and 25% increase in area under the plasma concentration-time curve. Acamprosate did not affect the pharmacokinetic parameters of naltrexone or 6-beta-naltrexol. A complete absence of negative interactions on measures of safety and cognitive function supports the absence of a contraindication to co-administration of acamprosate and naltrexone in clinical practice.

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.

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.

Inhibition of recombinant human mitochondrial aldehyde dehydrogenase by two intermediate metabolites of disulfiram.

Disulfiram is used in aversion therapy for alcoholism. S-Methyl-N,N-diethylthiocarbamate (MeDTC) sulfoxide, a potent inhibitor of the target enzyme mitochondrial aldehyde dehydrogenase (ALDH2), is thought to be the principal active metabolite of disulfiram in vivo. We examined the effects on recombinant human ALDH2 of two intermediate metabolites of disulfiram, S-methyl-N,N-diethyldithiocarbamate (MeDDC) sulfoxide and MeDDC sulfine. MeDDC sulfoxide was a potent inhibitor of ALDH2 with an IC50 of 2.2 +/- 0.5 microM (mean +/- SD, N = 4) after preincubation with enzyme for 30 min. MeDDC sulfine was a relatively weak inhibitor of ALDH2 under the same conditions with an IC50 value of 62 +/- 14 microM. The inhibition of ALDH2 by both compounds was irreversible and did not require the cofactor NAD. The latter finding demonstrates that inactivation of ALDH2 is independent of the dehydrogenase activity of the enzyme. GSH blocked almost completely the inhibition by 20 microM of MeDDC sulfoxide and greatly diminished the inhibition by 200 microM of MeDDC sulfine. Inactivation by MeDDC sulfoxide was time dependent. MeDTC sulfoxide was a more potent inhibitor of recombinant human ALDH2 (IC50 = 1.4 +/- 0.3 microM after preincubation for 15 min) than either of the intermediate metabolites, and its inhibition was unaffected by GSH. Our results suggest that these newer intermediate metabolites of disulfiram, especially the more potent MeDTC sulfoxide, have the potential to inhibit the target enzyme ALDH2 in patients receiving disulfiram. However, until the significance of the interactions of the inhibitors with GSH is more fully understood, the contribution of MeDDC sulfine and MeDDC sulfoxide to the pharmacological effects of disulfiram in vivo is uncertain.

Metadoxine in the treatment of acute and chronic alcoholism: a review.

Alcohol abuse and alcoholism are responsible for a wide variety of medical problems. The pharmaco-therapeutic aspect of alcoholism includes the use of drugs, with different actions and objectives. Among them, metadoxine seems to be of interest. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, to help restore the functional structure of the liver and to relieve neuro-psychological disorders associated with alcohol intoxication. Metadoxine also seems to be safe; in more than 15 years of post-marketing surveillance only minor aspecific and reversible events were monitored in patients exposed to the treatment. In this review the preclinical and clinical results obtained using metadoxine in acute and chronic alcohol intoxication are reported.

The development of acamprosate as a treatment against alcohol relapse.

INTRODUCTION: Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism. AREAS COVERED: Herein, the authors review the preclinical studies which have assessed the efficacy of acamprosate in various animal models of alcohol dependence and discuss the disparate findings from the major clinical trials. Moreover, the authors discuss the major limitations of these preclinical and clinical studies and offer explanations for the often-contradictory findings. The article also looks at the importance of the calcium moiety that accompanies the salt form of acamprosate and its relevance to its activity. EXPERT OPINION: The recent discovery that large doses of calcium largely duplicate the effects of acamprosate in animal models has introduced a serious challenge to the widely held functional association between this drug and the glutamate neurotransmission system. Future research on acamprosate or newer pharmacotherapeutics should consider assessing plasma and/or brain levels of calcium as a correlate or mediating factor in anti-relapse efficacy. Further, preclinical research on acamprosate has thus far lacked animal models of chemical dependence on alcohol, and the testing of rodents with histories of alcohol intoxication and withdrawal is suggested.

Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice.

RATIONALE: A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents. OBJECTIVE: The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA). METHODS: Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control. RESULTS: In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h. CONCLUSIONS: These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration.