Alcohol and histamine metabolic pathways in the body have the common enzymes aldehyde dehydrogenase and aldehyde oxidase. The metabolite of ethanol, acetaldehyde, can effectively compete with the metabolites of histamine, methylimidazole acetaldehyde, and imidazole acetaldehyde. At the periphery, alcohol and acetaldehyde liberate histamine from its store in mast cells and depress histamine elimination by inhibiting diamine oxidase, resulting in elevated histamine levels in tissues. Histamine mediates alcohol-induced gastric and intestinal damage and bronchial asthma as well as flushing in Orientals. On the other hand, alcohol provokes food-induced histaminosis and histamine intolerance, which is an epidemiological problem. There are many controversial reports concerning the effect of H2 receptor antagonists on ethanol metabolism and the activity of alcohol dehydrogenase in the stomach. In addition, alcohol affects histamine levels in the brain by modulating histamine synthesis, release, and turnover. Histamine receptor antagonists can affect ethanol metabolism and change the sensitivity of animals to the hypnotic effects of alcohol. In contrast to other neurotransmitters, the involvement of the brain histamine system in the mechanisms of the central actions of alcohol and in the pathogenesis of alcoholism is poorly studied and understood. (+info)
Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress.
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We have recently shown that priming injections of alcohol and footshock stress reinstate alcohol seeking in drug-free rats. Here we tested whether naltrexone and fluoxetine, two drugs used in the treatment of alcohol dependence, would affect reinstatement of alcohol seeking induced by these events. We also determined the effects of these drugs on alcohol self-administration during the maintenance phase. Rats were trained to press a lever for a 12% w/v alcohol solution. After stable drug-taking behavior was obtained, lever pressing for alcohol was extinguished. Reinstatement of drug seeking was then determined after priming injections of alcohol (0.24-0.96 g/kg) or exposure to intermittent footshock (5 and 15 min). Rats were pretreated with naltrexone (0.2-0.4 mg/kg) or fluoxetine (2.5-5 mg/kg) during maintenance or during tests for reinstatement. Both naltrexone and fluoxetine decreased lever presses for alcohol during the maintenance phase. Naltrexone blocked alcohol-induced, but not stress-induced reinstatement. In contrast, fluoxetine blocked stress-induced reinstatement, while its effect on alcohol-induced reinstatement was less consistent. The implications of these data to the understanding of relapse to alcohol are discussed. (+info)
Effects of Hypericum perforatum extraction on alcohol intake in Marchigian Sardinian alcohol-preferring rats.
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The present study investigated the effect of acute intragastric (i.g.) administration of dry Hypericum perforatum extract (HPE), containing 0.3% hypericin, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. The i.g. administration of HPE, 125 or 250 mg/kg, induced a 30-40% reduction in ethanol intake in rats offered 10% (v/v) ethanol for 2 h/day. The effect of these doses was selective, since they modified neither food intake nor food-associated drinking; neither did the same doses modify the rat's gross behaviour in the open-field test. A dose of 500 mg/kg frequently induced immobility and a general suppression of ingestive behaviour. In rats offered 10% ethanol for 12 h/day, ethanol intake following treatment with 250 mg/kg HPE was significantly lower than that of controls for up to 10 h. The effect on ethanol intake was not related to the antidepressant-like effect of HPE revealed in the forced swimming test. In this regard, the effect on ethanol intake was observed after a single administration of 125 mg/kg, whereas the antidepressant effect was observed only after repeated treatment with doses higher than 125 mg/kg HPE. The i.g. administration of HPE, 250 mg/kg, did not affect blood-alcohol levels following i.g. treatment with 0.7 g/kg ethanol, the amount usually ingested in a single drinking episode; thus, the effect is not related to changes in the pharmacokinetics of ethanol. The present study shows that HPE markedly reduces ethanol intake in msP rats, without significantly modifying food intake. (+info)
Attenuation of alcohol intake by extract of Hypericum perforatum (St. John's Wort) in two different strains of alcohol-preferring rats.
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Extract of the common plant Hypericum perforatum L. (St John's Wort, SJW) has been used successfully for the treatment of mild to moderate depression since ancient times and has recently been studied clinically. Depression and alcoholism have some neurochemical similarities, such as low brain serotonin activities. Thus, we hypothesized that SJW extract, which contains 0.22% hypericin and 4.05% hyperforin, also may be effective in suppressing alcohol intake. To test this hypothesis, the effects of SJW extract on voluntary alcohol intake were studied in two different genetic animal models of human alcoholism: fawn-hooded (FH) and high-alcohol drinking (HAD) rats. FH and HAD rats received a single oral administration (5 ml/kg) of either vehicle or one of the five doses (100, 200, 400, 600, and 800 mg/kg) of SJW extract. The oral administration of SJW extract significantly (P < 0.0001) reduced alcohol intake in both FH and HAD rats. In a third study, FH rats did not develop tolerance to the suppressant effects of SJW on alcohol intake and preference following oral administration of (400 mg/kg) of the extract for 15 consecutive days. These promising findings suggest that SJW extract should be evaluated clinically as a potential therapeutic agent in the treatment of alcoholism. (+info)
United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol.
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A 6-month randomized controlled study of acamprosate versus placebo in preventing relapse following withdrawal from alcohol was undertaken in 20 centres throughout the UK. Patients diagnosed as alcohol-dependent and detoxified within the preceding 5 weeks were randomly assigned to treatment with either acamprosate (A) 666 mg three times/day or identical placebo (P). A total of 664 patients were screened; 581 were entered into the treatment phase. One-third were episodic drinkers, 84% were male, 44% were unmarried and 48% were unemployed. Medication was first taken on average 24 days after the start of detoxification; 32% of patients had already relapsed by this time. The 6-month study period was completed by 35% of patients; adverse events led to withdrawal of a further 14% (A) and 9% (P) respectively. Compliance was poor in that, by the end of the second week, only 57% of patients were judged to be taking at least 90% of their tablets. The mean total of abstinent days achieved was 77 (A) and 81 (P). Complete abstinence for 6 months was achieved by 12% (A) and 11% (P); drinking remained within controlled limits in a further 3% (A) and 6% (P). An effect of acamprosate on consumption was not seen when subgroups, including those defined by the Lesch typology, were analysed separately. However, the mean percentage reduction in craving for alcohol measured on a visual analogue scale was greater in the acamprosate, than placebo, patients at week 2 and week 4 (P<0.001) and the mean decrease in the Hamilton Anxiety score at the 4th week was greater in the acamprosate than placebo patients (P = 0.017). In comparison with other published trials of acamprosate, patients started study medication after a longer time following detoxification, had more often recommenced drinking before medication was started and had a higher drop-out rate, and this might have contributed to the lack of a treatment effect in this study. (+info)
Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study.
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The objective of this study was to compare acamprosate with placebo in the treatment of alcohol-dependent patients during a 6-month post-detoxification treatment and a 3-month medication-free follow-up. Patients (n = 330) were detoxified and randomized to treatment with acamprosate (1998 mg/day) or placebo within an out-patient programme including medical counselling, psychotherapy and self-help groups. The main outcome criterion was drinking behaviour as assessed by: abstinence/relapse ratio, cumulative abstinence duration (CAD) and the period of continued abstinence. Anxiety, depression and craving were also monitored. Intention to treat (ITT) statistical principles were followed. Twenty-five per cent of patients dropped out over the first 6 months. At the end of the treatment period, the abstinence rate was 57.9% for acamprosate and 45.2% for placebo (P = 0.03). The CAD was 110+/-77 days for acamprosate and 89+/-77 days for placebo (P = 0.016). Patients on acamprosate had a higher continuous abstinence rate and experienced less severe relapses. No differential effect was noted for anxiety, depression or craving. Treatment remained positive, but not significant, 3 months after termination of study medication. No significant difference in adverse events was noted between treatment groups. Acamprosate treatment over 180 days was consistently more effective than placebo to maintain abstinence and to diminish relapse severity. (+info)
Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism.
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BACKGROUND: P-glycoprotein (P-gp) pumps a wide range of cytotoxic drugs out of cells. Inhibiting maturation of P-gp would be a novel method for circumventing P-gp-mediated multidrug resistance, which complicates cancer chemotherapy and treatment of patients infected with human immunodeficiency virus. We examined the effect of disulfiram (Antabuse(TM)) on the maturation and activity of P-gp. METHODS: Embryonic kidney cells were transfected with a complementary DNA for the P-pg gene, and the effects of disulfiram on the sensitivity of the transfected cells to cytotoxic agents were determined. Enzyme assays were used to determine the effects of disulfiram on the verapamil-stimulated adenosine triphosphatase (ATPase) activity of P-gp. Disulfiram modifies cysteine residues, and mutant forms of P-gp that lack individual cysteines were used to determine whether particular cysteine residues mediate disulfiram's effects on P-gp activity. Maturation of recombinant P-gp was followed on immunoblots. RESULTS: Disulfiram increased the sensitivity of P-gp-transfected cells to vinblastine and colchicine and inhibited P-gp's verapamil-stimulated ATPase activity. Half-maximal inhibition of ATPase activity occurred at 13.5 microM disulfiram. Disulfiram (at 100 microM) inhibited a P-gp mutant by 43% (95% confidence interval [CI] = 37%-48%) when cysteine was present at position 431 only and by 72% (95% CI = 66%-77%) when cysteine was present at position 1074 only. Treatment of P-gp-transfected cells with 50 nM disulfiram blocked maturation of recombinant P-gp. CONCLUSIONS: Disulfiram can potentially reduce P-gp-mediated drug resistance by inhibiting P-gp activity (possibly via cysteine modification) and/or by blocking its maturation. These results suggest that disulfiram has the potential to increase the efficacy of drug therapies for cancer and acquired immunodeficiency syndrome. (+info)
Identifying and treating patients with alcohol-related problems.
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Problem drinking is a serious health issue, but often patients whose alcohol consumption places them at risk are not diagnosed by physicians. Case finding is an essential component of "best practice." In many cases if given the appropriate advice, counselling and behavioural interventions, problem drinkers can be helped to reduce their use of alcohol and improve functioning in other areas of their lives. Some patients may benefit from more comprehensive therapy including the prescription of disulfiram, calcium carbimide or naltrexone. For those with serious problems with alcohol, referral to specialized addiction treatment programs and other community resource centres may also be appropriate. (+info)