ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03308.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractDisulfiram (Antabuse®) is one of several aldehyde dehydrogenase (ALDH) inhibitors that raise the plasma level of acetaldehyde following ethanol ingestion. The usually pleasant reaction to ethanol is thereby changed to an unpleasant one, owing to a number of bodily reactions to acetaldehyde. Populations showing genetic polymorphism with a lack of some isozymes of ALDH have exhibited an intolerance to ethanol similar to that seen with disulfiram. A normal isozyme pattern seems to be a prerequisite for the development of alcoholism, which supports the principle of disulfiram treatment. Disulfiram is an irreversible ALDH inhibitor when administered in vivo. Diethylthiomethylcarbamate (Me‐DTC) is formed from disulfiram in three metabolic steps. This compound and two further oxidized metabolites appear to be active metabolites of disulfiram. Measurements of plasma Me‐DTC or the reduction of leucocyte ALDH 1 activity may be valuable markers for the proper dose titration of disulfiram and the rational use of this drug. Some toxicological points are discu

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03309.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractAfter ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex. Consequently, absorption and distribution via the gastrointestinal mucosa into the blood might involve both the parent drug and its copper complex. In the blood, both compounds are rapidly degraded to form diethyldithiocarbamic acid (DDC), which is unstable and is further degraded to form diethylamine and carbon disulphide. DDC is also a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me‐DDC) and the glucuronic acid of DDC. Me‐DDC also undergoes oxidative biotransformation to diethylthiomethylcarbamate (Me‐DTC), which is further oxidized to its corresponding sulphoxide and sulphone metabolites. Me‐DTC may to act as a suicide inhibitor with a preference for the mitochondrial low Kmisozyme of aldehyde dehydrogenases (ALDH 1), whereas the two S‐oxidized metabolites, especially the sulfone metabolite, are more potent inhibitors not only of ALDH 1, but also of the cytosolic high Kmisozyme of ALDH (ALDH 2). The inhibitory reaction between the enzyme and each of the three metabolites is characterized by a covalent adduct formation, probably with the cysteine residue at the active site of the enzymes. The adduct formed is nonreducible at a physiological concentration of glutatione, and inactivation in the presence of this endogenous tripeptide was increased by action in vitro of the sulphoxide and sulphone metabolites. Those findings are all in concordance with the in vivo observations made on DSF. In human volunteers treated with increasing doses of DSF and challenged with ethanol between each of the dosage periods, the mean plasma concentrations of Me‐DTC at steady state were proportional to the DSF doses given. There was also a close relationship between increased oxidative metabolic formation of Me‐DTC, high oxidative formation of acetaldehyde, and the full complements of a valid disulfiram ethanol reaction (DER). Consequently, Me‐DTC in plasma may not only serve as a marker of the oxidative metabolic function of the liver, but also of the therapeutic effectiveness of the treatment in subjects at steady state. Obviously, there is a need for individual dose‐titration regimens. In patients with alcohol‐related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me‐DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent. The consequence for the patient may be an insufficient DER.A large variety of solvents, drugs, pesticides and secondary metabolites of mushrooms interact with DSF in different ways. Organic solvents, mushrooms and several drugs sensitize humans to alcohol in a similar way as DSF, but usually with a less pronounced physiological response. However, more important is the metabolic interaction between DSF and drugs which utilize the same metabolic pathways. As a consequence of e. g. oxidative metabolic interaction, a rise in plasma concentration, prolonged half‐life, and a decrease in plasma clearance of the int

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03310.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractPatient compliance with disulfiram is a troublesome clinical problem. Several strategies have been proposed as a solution to the problem, including subcutaneous implantation of disulfiram. However, well controlled studies of alcoholics and healthy volunteers have failed to discover a pharmacological effect of implanted disulfiram. A major reason for this failure appears to be poor absorption from an inadequate dose. Assessment of new sustained release formulation of depot disulfiram has been found to provoke a mild disulfiram‐ethanol reaction (DER). Only a more severe DER would be expected to deter further drinking. If problems with absorption and appropriate dosing of disulfiram can be resolved or a depot preparation of the active metabolite of disulfiram can be prepared, implants might find continued clinical us

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03311.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractA comparison of the bioavailability of disulfiram (DSF) after administration of non‐effervescent Antabuse®tablets (CP Pharmaceuticals, UK) and Antabuse®effervescent tablets Antabus®(A/S Dumex, DK) has been made in two cross‐over studies.The first study included 6 volunteers who were given 400 mg DSF after an overnight fast. The bioavailability of DSF after administration of non‐effervescent was found to be only 27ff/o of that achieved with effervescent tablets.The second study included 24 volunteers who were given 800 mg DSF after a light standardized meal. The relative bioavailability of DSF after administration of non‐effervescent compared with effervescent tablets was found to be only 34%.In addition to the difference in bioavailability of DSF after administration of the two preparations, a considerable difference was seen between the two studies. A light meal seems both to increase the bioavailability of DSF and to reduce the interindividual variation. A two to threefold increase in the bioavailability of DSF was found.Thus, the bioavailability of DSF appears to depend on both the formulation (preparation) and the mode of administration. A lack of bioequivalence between the two investigated DSF preparations

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03312.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractAntabuse treatment has mostly been applied to alcohol dependent patients although the heavy users of alcohol are responsible for the major parts of alcohol related problems in our societies.The heavy users of alcohol should be identified both by the general practitioners and the hospital doctors in any field and the first intervention should be a health interview connected with a biological monitoring of alcohol damages and thereby many patients would be motivated for moderate drinking. If this is not the case, heavy users should be encouraged to a 6 or better a 12 months supervised treatment with Antabuse. This treatment has especially been effective in employees with work‐related alcohol problem

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03313.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractAntabuse taken under supervision is effective and useful in the treatment of selected patients in the very long term. Relapses during treatment are the rule rather than the exception as is also illustrated in five case reports, but Antabuse treatment contributes to longer periods of sobriety. Continued support by nurses is necessary in the treatment of alcohol dependent patients and appointments with a psychiatrist are important for patients with alcohol dependence and psychiatric disorders. The personal perception of the severity of the drinking problem seems to be of decisive importance for compliance with the treatment. A high degree of motivation to stop drinking leads to long‐term use of Antabuse, a stronger internal locus of control and a favourable outcome. Measurements of liver enzymes are useful for monitoring the treatment outcome as well as for detecting toxic effects on the live

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03314.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractWe studied 210 alcoholics, who were re‐admitted to a disulfiram treatment programme after having voluntarily discontinued disulfiram therapy, primarily to ascertain whether illness, hospitalization, or serious adverse effects were the cause of the withdrawal. A simple 9‐ item questionnaire was used. About 70 % of the patients gave either “a wish to drink again” or “no need for further treatment” as the reason. Withdrawal in the remaining patients was in no case related to adverse effects of disulfiram.The low incidence of adverse effects was confirmed in another group comprising 93 patients treated under supervision with disulfiram 600–800 mg twice a week for at least a year (i. e. total dose at least 70 g disulfiram). They were monitored by standard laboratory blood and urine tests. There were no clinically significant changes in the measures used. Indeed, many of the patients improved during the year of abstinence. These two studies add weight to the evidence that disulfiram is not a drug with a high incidence of ad

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03315.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractMethods of using Antabuse have changed since its introduction over 40 years ago. Several randomised controlled trials have shown that Antabuse can make a statistically and clinically significant contribution to treatment outcome in alcoholism but only if its administration is carefully supervised. The recent literature is reviewed. Adequate dosage is important and the recommended maximum in some countries is often insufficient. Both prescribes and supervisors of Antabuse need to be aware of the ways in which some patients try to evade medication.

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03316.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

AbstractAdverse drug reactions (ADR) to disulfiram treatment have been reported as single cases, but few systematic investigations exist. In this study we analysed the spontaneous ADR reports to the Danish Committee on Adverse Drug Reactions during 1968–1991. In that period 154 ADRs to disulfiram were reported, mainly of hepatic, neurological, skin, and psychiatric reactions, in decreasing order of frequency. The safety of disulfiram, estimated on the amount produced and the number of reactions reported, corresponds to an intermediate rate of adverse reactions (1 per 200–2000 treatment year). Over the 23‐year period, 14 deaths were reported in Denmark and this corresponds to a rate of 1 per 25,000 treatment year; the chief cause was liver toxicity. Reports to the WHO collaborating Centre for International Drug Monitoring in Uppsala, Sweden, showed the same ADR profile, although with a higher rate of neurological and psychiatric and a lower rate of hepatic reactions.The latency time from the start of treatment to the manifestion of the ADR differed according to organ. Hepatitis occurred with a distinct peak after 2 months of treatment, skin reactions peaked after 2 weeks, and the rate of neurological ADR increased with duration of therapy. The relation of skin reactions and hepatitis to nickel allergy is discussed, as is the dose‐dependency of neuropathy.Concomitant disulfiram treatment affects the metabolism of several drugs and the dynamics of others, leading to a number of clinically important drug interactions. The disulfiram drug interactions are r

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1992.tb03317.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY