Role of alcohol dehydrogenase polymorphism in ethanol metabolism and alcohol-related diseases.
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Biomedical subjects
Publications and source records attributed to A Groppi.
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The lack of glutathione S-transferase mu (GST mu) was examined in 45 healthy French Caucasians and 45 alcoholic cirrhotic French Caucasians: microsamples of blood were taken and DNA amplified by the polymerase chain reaction. We have concluded that there is no relationship between this genotype and the development of alcoholic cirrhosis in these heavy consumers of ethanol.
Comparison of alcohol dehydrogenase polymorphism at the loci ADH2 and ADH3 is made in France between 46 alcoholic cirrhotic patients and 39 controls, by genotyping technique using polymerase chain reaction on blood microsample collected on blotting paper. The genotype distributions are similar, with low frequency of the ADH2(2) allele. Polymorphism at the ADH3 locus is not a genetic factor for alcoholic cirrhosis in France.
The human gene for producing alcohol dehydrogenase (ADH; EC 1.1.1.1) is polymorphic at ADH 2 and ADH 3 loci. Until now, the study of this polymorphism required liver biopsy or allele-specific radioactive probes. We have used directed mutagenesis by the polymerase chain reaction (PCR) to amplify and analyze the genotype of ADH 2 and ADH 3 loci. Thus, we could determine easily and unambiguously the complete genotype at these two loci by using a microsample of blood and restriction fragment length polymorphism after DNA amplification by PCR.
Beta-blockers are among the most widely used antihypertensive drugs. They differ from each other in regard to several factors such as: beta-agonist activity, beta 1-selectivity and solubility. Aim of this work was to evaluate the influence of obesity on the kinetics and the antihypertensive effect of two Beta-blockers with different solubility such as: the water-soluble, atenolol and the liposoluble, metoprolol. The study was carried out according to an open randomized cross-over design. Eight obese hypertensive patients, after a two week washout period, were randomly allocated to a four week treatment. After a two week intermediate washout period, each patient switched to the other treatment for an additional four week period. On the first and the last day of each treatment the subjects were hospitalized to collect blood samples for the assay of the two drugs and to measure cardiovascular parameters. Obesity does not exert any effect on the kinetics of the water-soluble beta-blocker, atenolol, while markedly interferes with that of the liposoluble, without any apparent influence on its anti-hypertensive effect. These findings extend to obese hypertensives the concept that the plasma concentrations of beta-blocking agents are not reliable predictors of their therapeutic effect.
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This work deals with the results of a clinical experience with viloxazine (VLZ) carried out on 43 depressed subjects of the female sex categorized with D.S.M. III criteria. Clinical ratings were made by means of the Hamilton Scale for depression and the Taylor self rating scale for anxiety. The results prove the efficacy of the drug in all the examined patients, along with the rapidity of effects in comparison with the tricyclic antidepressants. The elderly patients improved better than the adult subjects, especially when the depression was of the inhibited type.
Sotalol [4-(2-isopropylamino-1-hydroxyethyl)-methane-sulfonanilide hydrochloride] is a beta-adrenergic blocking agent. Despite the widespread use of these drugs, poisonings are not frequent. In this report the authors describe the first recorded case of fatal sotalol overdosage to their knowledge. The results of toxicological analysis, performed by a specially developed method, are presented, and compared with findings in fatal intoxications with other beta-adrenergic blocking agents.
In order to evaluate pharmacokinetic interactions between heroin and alcohol and their role in the etiology of heroin-related deaths (HRD), the alcohol concentration in blood (BAC), the free (FM) and total morphine (TM) concentrations in blood (determined by DPC Coat-A-Count radioimmunoassay before and after enzymatic hydrolysis), and the TM concentration in urine and bile (DPC Coat-A-Count after enzymatic hydrolysis) in a population of 39 lethal cases included in the records of the Department of Legal Medicine and Public Health at the University of Pavia from the period January 1997-April 1998 were examined. The cause of death in each case was attributed to either heroin or associated heroin-ethanol intoxication. Cases were arbitrarily divided into two groups according to BAC (low-ethanol group, LE, BAC < or = 1000 mg/L and high-ethanol group, HE, BAC > 1000 mg/L). The differences in the FM and TM concentrations in blood, bile, and urine and in the FM/TM ratios between the two . groups were statistically evaluated (Mann-Whitney U test). A similar statistical evaluation was carried out on data from a previously published study concerning the disposition of heroin and its metabolites (6-acetylmorphine and morphine) in blood and urine in 23 lethal cases attributed to either heroin or heroin and alcohol intoxication. The values of the following variables in the LE and HE groups were compared: FM, TM, and 6-acetylmorphine concentrations in blood (6-AM); the FM/ (FM + 6-AM) ratio; the FM/TM ratio; and the urinary concentrations of heroin, 6-acetylmorphine, and free morphine. Statistical analyses of data indicated that high BACs are associated with reduced hydrolysis of 6-AM to morphine (FM/[FM + 6-AM], p = 0.0022) and that a good inverse correlation exists between BAC and hydrolysis of 6-AM to morphine (r2 = 0.67). High BACs were also found to be associated with an increased FM/TM ratio and with reduced excretion of free and total morphine. These results suggest the hypothesis that pharmacokinetic interactions between heroin and alcohol do occur in individuals exposed to high doses of these substances.