Carbamic acid ester for treatment of addiction to alcohol

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai

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A61K 3127

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051009161

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BRIEF SUMMARY
The present invention relates to a carbamic acid ester for use as a drug. The invention also relates to a preparation for treatment of addiction to alcohol, and to the use of the carbamic acid ester for producing a preparation for treatment of addiction to alcohol.
Disulfiram (Antabuse.RTM.) is widely used as a drug for treatment of addiction to alcohol. If a person takes disulfiram and then drinks alcohol, he experiences the unpleasant disulfiram/alcohol reaction which is characterized by nausea, a ruddy complexion, palpitation of the heart, low blood pressure, vomiting, and a pulsating headache.
Theoretically, treatment with disulfiram should make an alcoholic abstain from drinking alcohol. However, it has been found, in actual practice, that treatment with disulfiram frequently fails because the patient stops taking disulfiram and then resumes his drinking. The reason is that disulfiram can only be administered orally in the form of tablets or as a mixture and therefore requires daily administration.
In view hereof, there is need of a different form of administration by which disulfiram can be taken systematically in the form of a depot drug from which the substance is slowly released.
For many years, the so-called "implantation technique" has been tried, by which disulfiram tablets are inserted under the skin by operative surgery. However, experience has shown that this treatment has no effect because disulfiram is released so slowly that the patient experiences no disulfiram/alcohol reaction when consuming alcohol.
In course of time, several injection drugs containing disulfiram have been proposed. USSR patent specification 390,206 proposes a solution of disulfiram in benzyl benzoate and vegetable oil. M. Phillips, in U.S. Pat. specification No. 4,678,809, has proposed the intramuscular injection of disulfiram as an aqueous suspension, or operated into a matrix of poly(lactic acid-co-glycolic acid). The specification of EP 0,169,618 proposes injecting disulfiram in a uniform microcrystalline form suitable for absorption by the reticulo-endothelial system.
However, none of these forms of administration has found to be useful in actual practice. The reason is that disulfiram mainly acts by an irreversible blocking of a liver enzyme, acetaldehyde dehydrogenase. Alcohol is metabolised mainly in the liver. The first step of this metabolism is an enzymatic oxidation to acetaldehyde which is then oxidised by another enzyme system called acetaldehyde dehydrogenase which is the enzyme irreversably blocked by disulfiram.
When a patient undergoing disulfiram treatment consumes alcohol, an accumulation of acetaldehyde occurs which leads to the above-mentioned toxic reactions in the disulfiram/alcohol reaction.
If disulfiram is taken perorally, it will, like other drugs, after intestinal absorption be immediately carried to the liver via the portal vein system.
It is known that disulfiram, besides being very sparingly soluble in water, is metabolised very quickly in blood at a t.sup.1 /2 of but 4 min. It may therefore be assumed that disulfiram can be administered only perorally because this is the only way in which it can affect the liver enzyme acetaldehyde dehydrogenase to a sufficient degree. If disulfiram is given parenterally, for example in the form of an injected local depot in a muscle, it will never reach the liver in such quantities that a therapeutical effect is obtained.
This shows that there is a definite need of novel compounds which have the therapeutical effect of disulfiram, but whose physiochemical properties are better suited for parenteral administration so that suitable depot formulations can be prepared from these compounds.
Substituted S-alkyl esters of thiocarbamic acid have been known for many years. For example, H. Tilles (JACS 81, page 714, 1959) has prepared 256 thiocarbamic acid esters with different substituents on the N atom for the purpose of developing novel herbicides.
GB patent specification 868,111 discloses 140 thiocarbamic acid esters with herbicidal activity. Many of the thi

REFERENCES:
patent: 2913327 (1959-11-01), Tilles et al.
patent: 4678809 (1987-07-01), Phillips
Yourick & Faiman, 1987 Biosis #85042991 Diethyldithiocarbamic Acid Methyl Ester a Metabolite of Disulfiram and Its Alcohol Sensitizing Properties in the Disulfiram-Ethanol Reaction.
Mackerell et al., 1985, Brosis #28103228 Human Mitochondrial Aldehyde Dehydrogenase EC-1.2.1.3 Inhibition by Diethyldithiocarbamic Acid Methanethiol Mixed Disulfe a Derivative of Disulfiram.
Faiman et al., 1983, Biosis #77048045 Diethyldithiocarbamic Acid Methyl Ester Distribution Elimination and LD-50 in the Rat after Intraperitoneal Administration.
Pedersen, 1980, Biosis #71006066 Analysis and Preliminary Pharmacokinetics of Disulfiram.
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