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At least 19 recordsLinked to original sources
PubMed2006

Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome.

OBJECTIVE: (1) To perform a 9-year study of abstinence, lapse, and relapse in 180 chronic alcoholic patients, participants of the Outpatient Longterm Intensive Therapy for Alcoholics (OLITA); (2) To investigate the role of supervised alcohol deterrents (AD) in relapse prevention and as an adjunct for maintenance of long-term abstinence. METHOD: This prospective open treatment study evaluates the long-term course of drinking outcomes and AD use of 180 chronic alcoholics consecutively admitted from 1993 to 2002. Subsamples are compared for (1) sham-AD versus verum-AD (disulfiram/calcium carbimide), (2) coped lapses versus finally detrimental lapses versus malignant relapses, and (3) AD use for 13 to 20 versus >20 months. RESULTS: In this 9-year study, the cumulative probability of not having relapsed was 0.52, and that of not having consumed any alcohol was 0.26. Despite long-term use, disulfiram/calcium carbimide was well tolerated. Patients on sham-AD (due to contraindications to verum-AD) showed higher cumulative abstinence probability than patients on verum (S = 0.86 vs. S = 0.49, p = 0.03). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p < 0.001); patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p < 0.001). The cumulative abstinence probability was S = 0.75 for patients with long-term intake compared with S = 0.50 for patients who stopped AD between months 13 and 20 (p < 0.001). CONCLUSIONS: An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be used as a predominantly psychologically acting ingredient of successful alcoholism therapy.

Adult↗
PubMed1986

Acyl, N-protected alpha-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide.

Cyanamide (H2NC identical to N), a potent aldehyde dehydrogenase (AlDH) inhibitor that is used therapeutically as an alcohol deterrent agent, is known to be rapidly metabolized and excreted in the urine as acetylcyanamide (1). On the basis of our observation that 1 is deacetylated to cyanamide in vivo, albeit very slightly, thereby serving as a precursor of prodrug form of the latter, several acyl derivatives of cyanamide were synthesized specifically as prodrugs, including benzoylcyanamide (2), pivaloylcyanamide (3), and 1-adamantoylcyanamide (4), as well as long- and medium-chain fatty acyl derivatives such as palmitoyl- (6), stearoyl- (7), and n-butyrylcyanamide (5). N-Protected alpha-aminoacyl and peptidyl derivatives of cyanamide were also synthesized, and these include N-carbobenzoxyglycyl- (10), hippuryl- (13), N-benzoyl-L-leucyl- (14), N-carbobenzoxyglycyl-L-leucyl- (18), N-carbobenzoxy-L-pyroglutamyl- (22), L-pyroglutamyl-L-leucyl- (19), and L-pyroglutamyl-L-phenylalanylcyanamide (20). All of these prodrugs of cyanamide raised ethanol-derived blood acetaldehyde levels in rats significantly over controls 3 h after ip drug administration, and some of these were still capable of elevating blood acetaldehyde 16 h post drug administration. A selected group of cyanamide prodrugs were also evaluated by the oral route of administration and showed nearly equivalent activity as the ip route in elevating ethanol-derived blood acetaldehyde. These results suggest potential utility of these prodrugs as deterrent agents for the treatment of alcoholism.

Acylation↗
PubMed1998

Mechanisms of inhibition of aldehyde dehydrogenase by nitroxyl, the active metabolite of the alcohol deterrent agent cyanamide.

Nitroxyl, produced in the bioactivation of the alcohol deterrent agent cyanamide, is a potent inhibitor of aldehyde dehydrogenase (AIDH); however, the mechanism of inhibition of AlDH by nitroxyl has not been described previously. Nitroxyl is also generated from Angeli's salt (Na2N2O3) at physiological pH, and, indeed, Angeli's salt inhibited yeast AlDH in a time- and concentration-dependent manner, with IC50 values under anaerobic conditions with and without NAD+ of 1.3 and 1.8 microM, respectively. Benzaldehyde, a substrate for AlDH, competitively blocked the inhibition of this enzyme by nitroxyl in the presence of NAD+, but not in its absence, in accord with the ordered mechanism of this reaction. The sulfhydryl reagents dithiothreitol (5 mM) and reduced glutathione (10 mM) completely blocked the inhibition of AlDH by Angeli's salt. These thiols were also able to partially restore activity to the nitroxyl-inhibited enzyme, the extent of reactivation being dependent on the pH at which the inactivation occurred. This pH dependency indicates the formation of two inhibited forms of the enzyme, with an irreversible form predominant at pH 7.5 and below, and a reversible form predominant at pH 8.5 and above. The reversible form of the inhibited enzyme is postulated to be an intra-subunit disulfide, while the irreversible form is postulated to be a sulfinamide. Both forms of the inhibited enzyme are derived via a common N-hydroxysulfenamide intermediate produced by the addition of nitroxyl to active site cysteine thiol(s).

Alcoholism↗
PubMed1990

[Evaluation of accelerated development of stable alcoholic motivation in rats for studying potential alcohol deterrents].

The express technique reflecting an acquisition of a clear alcohol addiction during short-term voluntary alcoholization for further antialcoholic drugs testing was performed in male albino rats. By VARIMAX factor analysis of indexes related with preference of alcohol solutions with different tastes the conditions of short-term (2 months) voluntary alcoholization leading to persistent ethanol intake were studied. Isolation stress inducing a specific alcohol drive was excluded from rearing conditions. 0.1% saccharin solution in 15% ethanol was used for alcoholization. Statistical analysis revealed factor of "developed alcohol abuse" which may be detected in conditions of one-trail sweet ethanol intake after 3 days alcohol deprivation (similar to heavy drinking syndrome in humans). Using pharmacological drugs (pyrazidol, piracetam) validity of the method for specific drug design was confirmed.

Alcohol Deterrents↗
PubMedDate not supplied

[Changes in lipid metabolism with the use of alcohol deterrent preparations].

The available experimental and clinical data in the literature on the effect of antialcoholic drugs (disulfiram, cyanamide, pyrazol) on the lipid composition of tissues (blood serum, liver, brain) are systematized and generalized. Drugs used in the treatment of alcoholism were found to cause essential changes in the metabolism of lipid fractions. This indicates the necessity for recording the detected changes in lipid metabolism in pharmacotherapy of alcoholism.

Alcohol Deterrents↗
PubMed1984

Latent inhibitors of aldehyde dehydrogenase as alcohol deterrent agents.

A series of compounds structurally related to pargyline (N-methyl-N-propargylbenzylamine, 4) were synthesized with the propargyl group replaced by a cyclopropyl, allyl, or 2,2,2-trichloroethyl group and, additionally in several cases, with the methyl group replaced by H. The rationale for their preparation was based on the expectation that, like pargyline, which gives rise to propiolaldehyde, oxidative metabolism of the above compounds by the hepatic cytochrome P-450 enzymes would lead to the generation in vivo of the aldehyde dehydrogenase (AlDH) inhibitors, cyclopropanone, acrolein, or chloral. These compounds were evaluated for inhibition of liver AlDH in vivo by measuring the elevation of ethanol-derived blood acetaldehyde in rats and in vitro by the rate of oxidation of acetaldehyde by intact and osmotically disrupted liver mitochondria. Administration of N-methyl-N-cyclopropylbenzylamine (5) and its nor-methyl analogue (8) to rats raised blood acetaldehyde levels significantly over controls at 2 h. This effect was more pronounced at 9 h, with blood acetaldehyde levels reaching 19 to 27 times control values and approaching the values induced by pargyline. Other compounds elicited significant elevations in ethanol-derived blood acetaldehyde only at 9 h. We suggest that latent inhibitors of AlDH such as 5 or 8 might be useful as alcohol deterrent agents.

Alcoholism↗
PubMedDate not supplied

[Activity of enzymes of ethanol metabolism as a test in evaluating the effectiveness of sensitizing alcohol deterrents].

A procedure is developed for determination of the efficiency of the antialcoholic drugs' action on the system of ethanol oxidation in vitro: alcohol dehydrogenase by the direct and reverse reactions and aldehyde dehydrogenase of subcellular fractions of the rat liver. This procedure is also used to determine the antialcoholic activity of a number of new compounds and to compare them with disulphiram (antabus, teturam), the known antialcoholic drug.

Alcohol Dehydrogenase↗
PubMed1987

Cyanide is a product of the catalase-mediated oxidation of the alcohol deterrent agent, cyanamide.

Cyanide was detected as a product of cyanamide oxidation by bovine liver catalase in vitro under conditions that also produced an active aldehyde dehydrogenase (AlDH) inhibitor. Cyanide formation was directly related to both cyanamide and catalase concentrations and was also dependent on incubation time. The apparent Km for this reaction was 172 microM. Cyanide formation was blocked by ethanol, a known substrate for catalase Compound I. The toxic effects of cyanamide in the dog, a species with limited capacity to conjugate cyanamide by N-acetylation, may be causally related to enhancement of this catalase-mediated pathway for cyanamide metabolism.

Alcohol Deterrents↗
PubMed1996

Nitrosyl cyanide, a putative metabolic oxidation product of the alcohol-deterrent agent cyanamide.

When incubated with catalase/glucose-glucose oxidase, 13C-labeled cyanamide gave rise not only to 13C-labeled cyanide, but also to 13C-labeled CO2. Moreover, a time-dependent formation of nitrite was observed when cyanamide was oxidized in this system. These results suggested that the initial product of cyanamide oxidation, viz. N-hydroxycyanamide, was being further oxidized by catalase/H2O2 to nitrosyl cyanide (O = N-C = N). Theoretically, nitrosyl cyanide can hydrolyze to the four end-products detected in the oxidative metabolism of cyanamide in vitro, viz. nitroxyl, cyanide, nitrite, and CO2. Accordingly, both unlabeled and 13C-labeled nitrosyl cyanide were synthesized by the low temperature (-40 to -50 degrees) nitrosylation of K-(18-crown-6)cyanide with nitrosyl tetrafluoroborate. The product, a faint blue liquid at this temperature, was transferred as a gas to phosphate-buffered solution, pH 7.4, where it was solvolyzed. Analysis of the headspace by gas chromatography showed the presence of N2O, the dimerization/dehydration product of nitroxyl, while cyanide was detected in the aqueous solution, as measured colorimetrically. [13C]CO2 was analyzed by GC/MS. An oxidative biotransformation pathway for cyanamide that accounts for all the products detected and involving both N-hydroxycyanamide and nitrosyl cyanide as tandem intermediates is proposed.

Alcohol Deterrents↗
PubMedDate not supplied

[Aldehyde dehydrogenases in the rat liver after implantation of a prolonged-action preparation of an alcohol deterrent].

Activity of aldehyde dehydrogenase isoenzymes was studied in rat liver mitochondria and microsomes after implantation of the new antialcohol drug of the long-term effect synthesized on the basis of disulphirame. Disulphirame, both in vivo and in vitro was shown to inhibit dissimilarly these isoenzymes. The degree of sensitivity of various aldehyde dehydrogenase isoenzymes to disulphirame is important for estimation of the drug efficiency.

Alcohol Oxidoreductases↗
PubMed1998

Glutathione carbamoylation with S-methyl N,N-diethylthiolcarbamate sulfoxide and sulfone. Mitochondrial low Km aldehyde dehydrogenase inhibition and implications for its alcohol-deterrent action.

S-Methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) and sulfone (DETC-MeSO2) both inhibit rat liver low Km aldehyde dehydrogenase (ALDH2) in vitro and in vivo (Nagendra et al., Biochem Pharmacol 47: 1465-1467, 1994). DETC-MeSO has been shown to be a metabolite of disulfiram, but DETC-MeSO2 has not. Studies were carried out to further investigate the inhibition of ALDH2 by DETC-MeSO and DETC-MeSO2. In an in vitro system containing hydrogen peroxide and horseradish peroxidase, the rate of DETC-MeSO oxidation corresponded to the rate of DETC-MeSO2 formation. Carbamoylation of GSH by both DETC-MeSO and DETC-MeSO2 was observed in a rat liver S9 fraction. Carbamoylation of GSH was not observed in the presence of N-methylmaleimide. In in vitro studies, DETC-MeSO and DETC-MeSO2 were equipotent ALDH2 inhibitors when solubilized mitochondria were used, but DETC-MeSO was approximately four times more potent than DETC-MeSO2 in intact mitochondria. In studies with rats, the dose (i.p. or oral) required to inhibit 50% ALDH2 (ED50) was 3.5 mg/kg for DETC-MeSO and approximately 35 mg/kg for DETC-MeSO2, approximately a 10-fold difference. Furthermore, maximum ALDH2 inhibition occurred 1 hr after DET(-MeSO administration, whereas maximal ALDH2 inhibition occurred 8 hr after DETC-MeSO2 dosing. DETC-MeSO is, therefore, not only a more potent ALDH2 inhibitor than DETC-MeSO2 in vivo, but also in vitro when intact mitochondria are utilized. The in vitro results thus support the in vivo findings. Since oxidation of DETC-MeSO can occur both enzymatically and non-enzymatically, it is possible that DETC-MeSO2 is formed in vivo. DETC-MeSO2, however, is not as effective as DETC-MeSO in inhibiting ALDH2, probably because it has difficulty penetrating the mitochondrial membrane. Thus, even if DETC-MeSO2 is formed in vivo from DETC-MeSO, it is the metabolite DETC-MeSO that is most likely responsible for the inhibition of ALDH2 after disulfiram administration.

Aldehyde Dehydrogenase↗
PubMed2007

Preclinical and clinical pharmacology of alcohol dependence.

In recent years, advances in neuroscience led to the development of new medications to treat alcohol dependence and especially to prevent alcohol relapse after detoxification. Whereas the earliest medications against alcohol dependence were fortuitously discovered, recently developed drugs are increasingly based on alcohol's neurobiological mechanisms of action. This review discusses the most recent developments in alcohol pharmacotherapy and emphasizes the neurobiological basis of anti-alcohol medications. There are currently three approved drugs for the treatment of alcohol dependence with quite different mechanisms of action. Disulfiram is an inhibitor of the enzyme aldehyde dehydrogenase and acts as an alcohol-deterrent drug. Naltrexone, an opiate antagonist, reduces alcohol craving and relapse in heavy drinking, probably via a modulation of the mesolimbic dopamine activity. Finally, acamprosate helps maintaining alcohol abstinence, probably through a normalization of the chronic alcohol-induced hyperglutamatergic state. In addition to these approved medications, many other drugs have been suggested for preventing alcohol consumption on the basis of preclinical studies. Some of these drugs remain promising, whereas others have produced disappointing results in preliminary clinical studies. These new drugs in the field of alcohol pharmacotherapy are also discussed, together with their mechanisms of action.

Acamprosate↗
PubMed2006

Adverse hepatic reactions associated with calcium carbimide and disulfiram therapy: is there still a role for these drugs?

Disulfiram and calcium carbimide are two alcohol deterrants widely used in alcoholism treatment, however, there exist great concerns over their safety. Reports on hepatotoxicity, mainly related to disulfiram therapy, have been published. The hepatotoxic potential of calcium carbimide is less well characterized. Here, we describe four cases of liver damage related to this therapeutic group that were submitted to a Registry of hepatotoxicity and point out the limitations that we face when prescribing these compounds. A reassessment of the role of these compounds in the management of alcohol dependence is clearly needed.

Adult↗