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Acamprosate Mechanism

Acamprosate Mechanism

Mechanism of action of acamprosate

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.

Acamprosate, or N-acetyl homotaurine, is an N-methyl-D-aspartate receptor modulator approved by the Food and Drug Administration (FDA) as a pharmacological treatment for alcohol dependence. The exact mechanism of action of acamprosate is still under investigation, but the drug appears to work by promoting a balance between the excitatory and inhibitory neurotransmitters, glutamate and gamma-aminobutyric acid, respectively, and it may help individuals with alcohol dependence by reducing withdrawal-associated distress. Acamprosate has low bioavailability, but also has an excellent tolerability and safety profile.

In comparison with naltrexone and disulfiram, which are the other FDA-approved treatments for alcohol dependence, acamprosate is unique in that it is not metabolized by the liver and is also not impacted by alcohol use, so can be administered to patients with hepatitis or liver disease (a common comorbid condition among individuals with alcohol dependence) and to patients who continue drinking alcohol. Acamprosate has demonstrated its efficacy in more than 25 placebo-controlled, double-blind trials for individuals with alcohol dependence, and has generally been found to be more efficacious than placebo in significantly reducing the risk of returning to any drinking and increasing the cumulative duration of abstinence.

However, acamprosate appears to be no more efficacious than placebo in reducing heavy drinking days. Numerous trials have found that acamprosate is not significantly more efficacious than naltrexone or disulfiram, and the efficacy of acamprosate does not appear to be improved by combining acamprosate with other active medications (eg, naltrexone) or with psychosocial treatment (eg, cognitive-behavioral therapy). In this review, we present the data on acamprosate, including its pharmacology, efficacy, safety, and tolerability in the treatment of alcohol dependence.

Acamprosate, calcium acetyl homotaurinate, was first developed and tested in the early 1980s in France and has been available in the USA since 2004. Its major mechanism of action is the reduction of cerebral hyperexcitability by interacting with glutamate receptors. More than 20 randomized, placebo-controlled trials have been conducted.

With very few exceptions, these studies have demonstrated a significant benefit of acamprosate over placebo. Side effects of acamprosate, such as diarrhoea, are benign and transient. Studies in which acamprosate was given in combination with disulfiram or naltrexone also showed promising results. Further studies are underway to identify potential acamprosate responders on a neurobiological basis. If successful, this would allow an individually targeted prescription of acamprosate that would then further improve its efficacy and cost–effectiveness.

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