New pharmacological approaches for the treatment of alcoholism

Technische Universität München, München, Bavaria, Germany
Expert Opinion on Pharmacotherapy (Impact Factor: 3.53). 01/2007; 7(17):2341-53. DOI: 10.1517/14656566.7.17.2341
Source: PubMed


Pharmacological relapse prevention in alcoholism is a rather new clinical field with few drugs being available. Acamprosate, acting predominantly via glutamatergic pathways, and the opioid receptor antagonist naltrexone, were both shown to be efficient in improving rates for continuous abstinence, and not relapsing to heavy drinking in a number of clinical trials and meta-analyses. There are conflicting data on both drugs, especially for acamprosate, according to some recent US studies. However, overall, the evidence is good. Both drugs are approved in most European countries and the US. Efficacy data for disulfiram are mixed; it is a second-line medication compared with other drugs, and is probably most effective when used in a supervised setting. Recently, anticonvulsants including carbamazepine and topiramate have been discussed as possible anti-craving drugs, but there is still limited evidence for their efficacy. Although there is a significant comorbidity for alcoholism with affective disorder, anxiety and schizophrenia, relatively few controlled clinical trials have been performed in this area. Tricyclics have been found to be more effective than serotonin reuptake inhibitors in improving depressive symptoms in these patients.

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    • "Acamprosate is a weak NMDA modulator which acts as an antagonist at the mGluR5 metabotropic glutamate receptor [29]. Acamprosate is approved in many countries for the treatment of alcohol dependence [30] although some recent studies [31,32] have not found significant benefits. "
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    ABSTRACT: Alcohol dependence comorbid with major depressive disorder poses a major challenge in the clinical setting. The results in the treatment with selective serotonin re-uptake inhibitors have been conflicting. Thus, we compared in alcohol-dependent patients with co-morbid major depressive disorder the selective serotonin re-uptake inhibitor escitalopram to a compound that acts on different transporter system and may reduce craving, the glutamate receptor antagonist memantine. Eighty alcohol-dependent patients comorbid with major depressive disorder in municipal alcohol clinics were randomized 1:1 to receive memantine 20 mg or escitalopram 20 mg in a double-blind manner. During the 26-week study period patients continued their routine treatment at the clinics. Abstinence was not required but encouraged. The patients attended visits weekly during the first month, and then at 3 and at 6 months. Outcome measures were Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS) and Drinking Diary. The completion rate was high in both groups, especially among the patients who had been abstinent at the beginning of the study. However, among those patients who were not abstinent at baseline, 47% in both groups discontinued the study. Numbers of abstinent days were high in both groups throughout the study. Alcohol consumption measured by the AUDIT QF (quantity-frequency) score was significantly reduced in both groups, as was the craving for alcohol measured by the OCDS. Early age at first alcohol intoxication predicted poor treatment outcomes in patients treated with escitalopram, and the same was seen with the early onset of the first depressive episode. The same predictive effects were not found in patients treated with memantine. Our results indicate that both memantine and escitalopram are useful adjunct medications for the treatment of alcohol dependence co-morbid with major depression. Memantine was at least as effective with regard to drinking as escitalopram. We believe that a direct comparison of memantine, with the commonly used escitalopram, can provide useful information for clinicians on the treatment of alcohol dependency co-morbid with MDD.
    Substance Abuse Treatment Prevention and Policy 11/2008; 3(1):20. DOI:10.1186/1747-597X-3-20 · 1.16 Impact Factor
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    • "Expressed as homotetrameric protein with subunits of B54 kDa in the mitochondrial matrix, ALDH2 is thought to be essential for the detoxification of acetaldehyde produced during ethanol oxidation. About 40% of the East-Asian population that express a low-activity mutant (Glu487Lys) of ALDH2 (Larson et al., 2007) exhibit significantly lowered alcohol tolerance due to adverse effects of acetaldehyde accumulation (Crabb et al., 1989), and the ALDH inhibitor disulfiram is still approved in many countries as deterrent for the aversive pharmacotherapy of alcohol dependence (Soyka and Roesner, 2006). "
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    ABSTRACT: Nitroglycerin (glyceryl trinitrate; GTN) is the most prominent representative of the organic nitrates or nitrovasodilators, a class of compounds that have been used clinically since the late nineteenth century for the treatment of coronary artery disease (angina pectoris), congestive heart failure and myocardial infarction. Medline lists more than 15 000 publications on GTN and other organic nitrates, but the mode of action of these drugs is still largely a mystery. In the first part of this article, we give an overview on the molecular mechanisms of GTN biotransformation resulting in vascular cyclic GMP accumulation and vasodilation with focus on the role of mitochondrial aldehyde dehydrogenase (ALDH2) and the link between the ALDH2 reaction and activation of vascular soluble guanylate cyclase (sGC). In particular, we address the identity of the bioactive species that activates sGC and the potential involvement of nitrite as an intermediate, describe our recent findings suggesting that ALDH2 catalyses direct 3-electron reduction of GTN to NO and discuss possible reaction mechanisms. In the second part, we discuss contingent processes leading to markedly reduced sensitivity of blood vessels to GTN, referred to as vascular nitrate tolerance. Again, we focus on ALDH2 and describe the current controversy on the role of ALDH2 inactivation in tolerance development. Finally, we emphasize some of the most intriguing, in our opinion, unresolved puzzles of GTN pharmacology that urgently need to be addressed in future studies.
    British Journal of Pharmacology 07/2008; 155(2):170-84. DOI:10.1038/bjp.2008.263 · 4.84 Impact Factor
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    • "Acamprosate and naltrexone are widely used as pharmacological agents in the treatment of alcoholism (for recent reviews, see Heilig & Egli 2006; Roozen et al. 2006; Rosenthal 2006; Soyka & Roesner 2006). Naltrexone is a long-acting opioid antagonist with preferential affinity for m and k opioid receptors (Raynor et al. 1994), and primarily reduces alcohol consumption in the context of behavioral therapy. "
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    ABSTRACT: 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.
    Addiction Biology 04/2008; 13(1):70-9. DOI:10.1111/j.1369-1600.2008.00097.x · 5.36 Impact Factor
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