Gamma Hydroxybutyric Acid (GHB) for the Treatment of Alcohol Dependence: A Review

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid structurally similar to the inhibitory neurotransmitter γ-aminobutyric acid. Clinical trials have demonstrated that 50–100 mg/kg of GHB fractioned into three or six daily doses is able to suppress alcohol withdrawal symptoms and facilitates the maintenance of abstinence from alcohol. These studies have also shown that GHB craving episodes are a very limited phenomenon (about 10–15%). Thus, physicians with access should consider the clinical efficacy of GHB as a valid pharmacological tool for the treatment of alcohol addiction

Effetto della memantina su modelli animali di disturbi dell'umore

AIM: Mood disorders are one of the leading causes of morbidity, disability and premature mortality contributing for about 50% of the non-fatal burden of mental disorders. Bipolar disorder (BD) has a lifetime prevalence of approximately 1.0% for BD-I, 1.1% for BD-II and 2.4% for BD-NOS. Eighty-three percent of BD cases are classified as “seriously severe” and 17.1% as “moderately severe”. Long-term prophylactic treatment of BD aimed at preventing recurrences of the various phases is a leading clinical and research challenge for contemporary psychiatry. Dopaminergic behavioural supersensitivity induced by chronic treatment with antidepressants might be involved both in the antidepressant action and in the mechanisms underlying antidepressant treatment-related mania (antidepressant-induced mood switch and possibly, rapid cycling bipolar disorder). The stimulation of NMDA receptors is required for the development of dopamine receptor sensitization induced by antidepressants. Indeed, the administration of MK-801, a selective non-competitive NMDA receptor blocker, completely prevents the dopamine receptor sensitization induced by imipramine and by electroconvulsive shock. These observations strongly suggest that the non-competitive blockade of NMDA receptors should result in an anti-manic and mood stabilizing action, and that it should also be effective in the treatment of the disorders resistant to currently used antimanic and mood stabilizers. Memantine is a non-competitve NMDA receptor antagonist, she has been on the market in since 1982 for the treatment of Parkinsonism, before its approval in 2002 and 2004 by EMEA and FDA for the treatment of moderate to severe Alzheimer's Disease. Although its actual efficacy on the AD patient's quality of life has proven to be moderate, several pre-marketing and post marketing studies have demonstrated the excellent safety and tolerability profile of the drug. Moreover, the drug has been used off-label in a number of neurological and psychiatric conditions, including depression, with conflicting and inconclusive results. To further clarify the farmacology of memantine, I studied hers effect in animal models of in mood disorders. METHOD: Male and Female rats treated with memantine in animal model of: • dopaminergic behavioural supersensitivity • bipolard disorders by chronic antidepressant • stress • catatonia by haloperidol • tardive dyskinesia by cronic haloperidol RESULTS: The results show that memantine, at variance with antidepressant treatments (including drugs, electroconvulsive schock, REM-sleep deprivation), fails to induce dopaminergic behavioural supersensitivity. Therefore has not an antidepressant action. Memantine prevents not only, as observed with MK-801, the sensitization of dopamine receptors induced by chronic imipramine (mania), but also the ensuing desensitization of those receptors and the associated depressive-like behavior. Thus stabilizes the course of the manic-depressive illness Furthermore, memantine prevents stress, catatonia and tardive dyskinesia. This observation is consistent with the results of clinical studies suggesting that memantine has not an antidepressant action but an antimanic and mood-stabilizing effect.</br

Gender Differences among Sardinians with Alcohol Use Disorder

Sardinia is an Italian island in the Mediterranean characterized by secular isolation and the singular genetic characteristics of its inhabitants. Findings obtained in populations with diverse genetic make-up and cultural background indicate gender differences and/or similarities in drinking characteristics of patients with alcohol use disorder (AUD). Knowledge of these characteristics in AUD patients is useful to improve access to treatments. This paper investigated the drinking characteristics of 66 female and 282 male outpatients with AUD, born from 1937 to 1991, living in Sardinia, and compared their characteristics with those of AUD patients living in other countries. Most Sardinian patients were men, approximately 3 years younger than women; women consumed lower amounts of alcohol than men but did not differ from men in the severity of AUD. Men were more often single than women, while a higher proportion of women reported that their mother or spouse was affected by AUD. Anxiety and depression were more prevalent among women while a higher proportion of men were affected by substance use disorders. Women were older than men at the age of first drink, regular drinking, and onset of AUD, and progressed faster than men from regular use to AUD onset. Women did not differ from men in age at first request for care, and in the lapse from AUD onset to first request for care. Women and men waited for more than 8 and 9 years, respectively, before receiving medical treatment. Gender differences progressively decreased among younger patients. Although the scarce number of women in some cohorts limits the strength of these findings, drinking characteristics of Sardinian patients did not vary significantly from those of AUD patients living in other countries. These results suggest that the number of Sardinian women with AUD is increasing and services for treatment of AUD should (a) consider women’s specific needs, and (b) realize effective policies to reduce latency prior to accessing medical treatment for both men and women with AUD

Anti-Alcohol and Anxiolytic Properties of a New Chemical Entity, GET73

N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide (GET73) is a newly synthesized compound structurally related to the clinically used, alcohol-substituting agent, gamma-hydroxybutyric acid (GHB). The present study was designed to assess whether GET73 may share with GHB the capacity to reduce alcohol intake in rats. Additionally, the effect of treatment with GET73 on anxiety-related behaviors and cognitive tasks in rats was investigated. A series of in vitro binding assays investigated the capacity of GET73 to bind to the GHB binding site and multiple other receptors. GET73 (10−9–10−3 M) failed to inhibit [3H]GHB binding at both high- and low-affinity GHB recognition sites in rat cortical membranes. GET73 displayed minimal, if any, binding at dopamine, serotonin, GABA, and glutamate receptors in membranes from different rat brain areas. Acute treatment with low-to-moderate, non-sedative doses of GET73 (5–50 mg/kg, i.g. or i.p.) (a) reduced alcohol intake and suppressed “alcohol deprivation effect” (a model of alcohol relapse) in selectively bred, Sardinian alcohol-preferring (sP) rats, (b) exerted anxiolytic effects in Sprague-Dawley (SD) and sP rats exposed to the Elevated Plus Maze test, and (c) tended to induce promnestic effects in SD rats exposed to a modified water version of the Hebb–Williams maze test. Although the mechanism of GET73 action is currently unknown, the results of the present study suggest that GET73 has a multifaceted pharmacological profile, including the capacity to reduce alcohol drinking and anxiety-related behaviors in rats

Detection of Exogenous GHB in Blood by Gas Chromatography-Combustion-Isotope Ratio Mass Spectrometry: Implications in Postmortem Toxicology

Because GHB (γ-hydroxybutyrate) is present in both blood and urine of the general population, toxicologists must be able to discriminate between endogenous levels and a concentration resulting from exposure. In this paper, we propose a procedure for the detection of exogenous GHB in blood by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Following liquid-liquid and solid-phase extractions, GHB is derivatized to GHB di-TMS before analysis by GC-C-IRMS. Significant differences in the carbon isotopic ratio (Δδ13C-values > 13.5‰) were found between endogenous and synthetic GHB. Indeed, for postmortem blood samples with different GHB concentrations (range: 13.8-86.3 mg/L), we have obtained GHB δ13C-values ranging from −20.6 to −24.7‰, whereas δ13C-values for the GHB from police seizure were in the range −38.2 to −50.2‰. In contrast to the use of cut-off concentrations for positive postmortem blood GHB concentrations, this method should provide an unambiguous indication of the drug origi

باکلوفن در درمان نگهدارنده‌ی وابستگی به مواد افيونی: کارآزمايی بالينی دوسوکور تصادفی شده با کنترل دارونما

هدف: هدف از انجام اين بررسی نشان دادن تأثير باکلوفن در نگهداشتن معتادان مواد افيونی در درمان نگهدارنده و کاهش مصرف مواد افيونی و برتری آن بر دارونما است. روش: در يک بررسی آزمايشی دوسوکور40 بيمار با تشخيص وابستگی به مواد افيونی (برپايه‌ی معيارهایDSM-IV) پس از دوره‌ی سم‌زدايی به‌تصادف در دو گروه جای داده شدند. در يک گروه، 20 نفر باکلوفن (60 ميلی گرم روزانه در 3 دوز جداگانه) و در گروه ديگر 20 نفر دارونما، به مدت 12 هفته دريافت کردند. سنجه‌های اصلی شامل ماندن بيماران در درمان نگهدارنده و آزمايش‌‌های ادراری مثبت بودند. داده‌های پژوهش به‌کمک آزمون‌های آماری من- ويتنی و خی‌دو تحليل گرديد. يافته‌ها: ماندن بيماران در درمان در گروه باکلوفن از گروه دارونما به‌طور معنی‌داری بيشتر بود. بيماران گروه باکلوفن کمتر از گروه دارونما، علايم ترک و افسردگی داشتند. دو گروه از نظر آزمايش‌های ادراری مثبت، شدت گرايش به مصرف مواد افيونی، عوارض جانبی دارويی و ميانگين روزهای مصرف مواد افيونی و الکل در طی درمان تفاوت معنی‌داری نداشتند. نتيجه: اثر بخشی باکلوفن از نظر ماندن بيماران در درمان و کاهش علايم ترک و افسردگی بر دارونما برتری چشم‌گيری دارد