Acamprosate Appears to Decrease Alcohol Intake in Weaned Alcoholics

Lhuintre, J. P.; Moore, Nicholas; Tran, Giang N.; Stéru, L.; Langrenon, S.; Daoust, S.; Parot, P.; Ladure, P.; Libert, Claude; Boismare, F; Hillemand, B

doi:10.1093/oxfordjournals.alcalc.a045057

Cited by 164 publications

(65 citation statements)

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“…Considering these observations, acamprosate may act on the mGluR5 receptors reducing its positive feedback control over the NMDARs [217]. Although the exact mechanism of action of acamprosate is still a matter of debate, the glutamatergic hypothesis may help to explain many of the effects of acamprosate in human alcohol dependence, especially in the acquisition of cue-elicited drinking behaviours [17,41,80,86,116,117,199].…”

Section: Acamprosatementioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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Section: Acamprosatementioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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“…While many central nervous system and ethanol-sensitizing agents have been shown to suppress the ethanol intake of animals commonly employed as models for the human problem, only acamprosate and naltrexone have been judged suitable for the treatment of this human ailment. Even those drugs are only marginally effective in a relatively minor segment of the aff licted population and then only when used in conjunction with psychotherapy (2)(3)(4). The manifestations of alcoholism are complex, encompassing both physical and psychiatric features seemingly unique to humans.…”

mentioning

confidence: 99%

Daidzin inhibits mitochondrial aldehyde dehydrogenase and suppresses ethanol intake of Syrian golden hamsters

Keung

Klyosov²,

Vallée³

1997

Proc. Natl. Acad. Sci. U.S.A.

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Daidzin is the major active principle in extracts of radix puerariae, a traditional Chinese medication that suppresses the ethanol intake of Syrian golden hamsters. It is the first isof lavone recognized to have this effect. Daidzin is also a potent and selective inhibitor of human mitochondrial aldehyde dehydrogenase (ALDH-2). To establish a link between these two activities, we have tested a series of synthetic structural analogs of daidzin. The results demonstrate a direct correlation between ALDH-2 inhibition and ethanol intake suppression and raise the possibility that daidzin may, in fact, suppress ethanol intake of golden hamsters by inhibiting ALDH-2. Hamster liver contains not only mitochondrial ALDH-2 but also high concentrations of a cytosolic form, ALDH-1, which is a very efficient catalyst of acetaldehyde oxidation. Further, the cytosolic isozyme is completely resistant to daidzin inhibition. This unusual property of the hamster ALDH-1 isozyme accounts for the fact we previously observed that daidzin can suppress ethanol intake of this species without blocking acetaldehyde metabolism. Thus, the mechanism by which daidzin suppresses ethanol intake in golden hamsters clearly differs from that proposed for the classic ALDH inhibitor disulfiram. We postulate that a physiological pathway catalyzed by ALDH-2, so far undefined, controls ethanol intake of golden hamsters and mediates the antidipsotropic effect of daidzin.The identification of pharmaceutical agents that selectively suppress compulsive human ethanol consumption has been a principal aim of biochemical and pharmacological studies of alcohol abuse, its causes, and control. However, the lack of a specific and well identified molecular target (receptor) for ethanol and a suitable animal model for human alcoholism have made this an elusive goal (1). While many central nervous system and ethanol-sensitizing agents have been shown to suppress the ethanol intake of animals commonly employed as models for the human problem, only acamprosate and naltrexone have been judged suitable for the treatment of this human ailment. Even those drugs are only marginally effective in a relatively minor segment of the aff licted population and then only when used in conjunction with psychotherapy (2-4). The manifestations of alcoholism are complex, encompassing both physical and psychiatric features seemingly unique to humans. Hence, it is not surprising that the extension of results from animal studies to the human situation has not resulted in the identification of agents that cure alcohol abuse.The search for new antidipsotropic agents, nevertheless, calls for a laboratory animal that voluntarily consumes ethanol, ideally in significant amounts. For this purpose, we have chosen the Syrian golden hamster (Mesocricetus auratus) because of its known natural preference to consume large quantities of ethanol compared with water and its predictive validity (5). Neither selective breeding, special training, nor the addition of dietary sweeteners is required to ma...

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“…It does not interact with alcohol, diazepam, oxazepam or imipramine [16], and there is no evidence of an interaction with disulfiram [17], although naltrexone increases its plasma levels in vivo [13]. It appears generally safe in patients with impaired hepatic function [13,18]: in the RCTs reported here [19,20] there were two deaths of patients on acamprosate, due to acute hepatic failure with pre-existing hepatic cirrhosis and carcinoma, respectively. Due to its predominately renal excretion, potential risks and benefits need to be considered on an individual basis in the elderly and patients with renal insufficiency, the recommendation being to start at a lower dose (333mg tds) and monitor renal function [16].…”

Section: Pharmacokinetic Considerations and Implications For Safetymentioning

confidence: 99%

“…there are reports from two studies of three patients taking intentional overdoses of 8-120 tablets with no 'untoward symptoms' [19,22].…”

Section: Pharmacokinetic Considerations and Implications For Safetymentioning

confidence: 99%

Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence

et al. 2016

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Alcohol use disorders (AUD) cause significant morbidity and mortality worldwide, but pharmacological treatments for them are underused, despite evidence of efficacy.Acamprosate, naltrexone, nalmefene and disulfiram are all approved in one or more region for the treatment of alcohol use disorders. Baclofen currently has a temporary indication in France. Safety considerations for using psychopharmacological treatments in this patient group include the impact of concurrent alcohol consumption at high levels, multiple physical comorbidities which may interfere with pharmacological effects, distribution and metabolism, and concomitant medication for the treatment of comorbid physical and psychiatric conditions. The five drugs, including an extended-release injectable suspension of naltrexone, have different safety profiles which need to be balanced with the objective of treatment (initiation or continuation of abstinence, or reduction of drinking), individual patient preferences and comorbid conditions. Appropriate treatment will be based on the unique riskbenefit profile in each case. KEY POINTS Acamprosate has an excellent safety profile and is recommended as first line treatment for patients wishing abstinence. Naltrexone and nalmefene are contraindicated with opioid-containing medication, but have reasonable tolerability  The disulfiram-alcohol reaction is integral to its use, but careful patient selection and monitoring can mitigate safety risks  Baclofen is a CNS depressant so there are potential concerns regarding overdose: it may have a role in patients with severe liver disease Pharmacological treatments for alcohol dependence 3

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Acamprosate Appears to Decrease Alcohol Intake in Weaned Alcoholics

Cited by 164 publications

References 0 publications

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Daidzin inhibits mitochondrial aldehyde dehydrogenase and suppresses ethanol intake of Syrian golden hamsters

Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence

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