Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-06-06
2001-07-03
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06255346
ABSTRACT:
The present invention relates to a combination composition of L-carnitine and lower alkanoyl L-carnitines or the pharmacologically acceptable salts thereof for the treatment of alcoholism. The use of the combination composition suppresses withdrawal symptoms (such as tremors, perspiration, hyperreflexia, nausea, anxiety and convulsions) and the craving for alcohol.
All the drugs used to date for the treatment of alcoholism present substantial drawbacks.
A number of the drugs commonly used in the treatment of alcohol withdrawal syndrome are similar to this with regard to their pharmacological effects. In fact, the most useful of those currently used are those with which alcohol develops a cross-tolerance. All patients treated for withdrawal syndromes are potential candidates for SNC depressants though not all of them need them.
Paraldehyde, which was once extensively used in therapy, was completely abandoned on account of its disagreeable odour and a series of sudden, inexplicable deaths following its use.
Rarely used today is the fast-acting barbiturate (pentobarbital and secobarbital).
The drugs of choice are benzodiazepines such as chlorodiazepoxide and diazepam. One serious drawback they present, however, is the fact that alcoholics taking chlordiazepoxide or diazepam may become intoxicated and even develop physical addiction and withdrawal syndrome.
The phenothiazines are not recommended since they do not control severe delirium tremens and also lower the threshold for attacks of epilepsy.
Lastly, a matter of some controversy is the therapeutic use of disulfiram which interferes with the metabolism of acetaldehyde (an intermediate product of the oxidation of alcohol) and produces an accumulation of it, thus causing toxic symptoms and severe discomfort. Drinking alcohol within 12 hours of taking disulfiram produces facial flushing within 5-15 minutes, followed by intense vasodilatation of the face and neck with clouding of the conjunctiva, throbbing headache, tachycardia, hyperpnoea and perspiration. Within 30-60 minutes nausea and vomiting appear and can be so intense as to lead to hypertension, dizziness and sometimes fainting or collapse. The reaction lasts from one to three hours. The sense of malaise is so intense that few patients will risk drinking alcohol while taking disulfiram. Occasionally, this drug has also caused convulsions, cardiac arrhythmias and myocardial infarction.
The efficacy of carnitine in decreasing the withdrawal symptoms in test animals has been reported.
Abu Murad et al. (Brit. J. Pathol. vol. 58. n. 6, Dec. 1977) discloses that in mice “the addition of DL-carnitine to diet during the administration of ethanol . . . significantly reduced the intensity of the ethanol withdrawal syndrome”.
Corbett et al. (Neuropharmacology, vol. 23, n. 2B, pp. 269-271, 1984) postulate that carnitine administration can counteract “at least some of the effects of prolonged administration and withdrawal of ethanol . . . by preventing the alcohol-induced change in the activity of (calcium/magnesium) ATPase”.
As regards acetyl L-carnitine, Tempesta et al. (Int. J. Clin. Pharm. Res. X (1/2) 101-107, 1990) report preliminary data from a multicentred double-blind placebo-controlled study which suggest a possible efficacy of acetyl L-carnitine in decreasing some cognitive deficits in at least one month-abstinent chronic alcoholics.
The efficacy of other alkanoyl L-carnitines, particularly propionyl L-carnitine, in the treatment of alcoholics, has never been postulated nor tested.
It has now been found that a combination composition comprising L-carnitine, acetyl L-carnitine, propionyl L-carnitine or the pharmacologically acceptable salts thereof not only suppresses the withdrawal symptoms (such as tremors, perspiration, hyperreflexia, nausea, anxiety and convulsions) and the craving for alcohol in alcoholics, but can also be used effectively as a preventive or prophylactic means in substantially healthy subjects who, however, overindulge in an excessive, although occasional and discontinuous, intake of alcoholic drinks.
It is worth noticing that the users of the compositions of the present invention may also be substantially healthy individuals, particularly young subjects, who, although they cannot be clinically regarded as alcohol-addicted, occasionally indulge in an excessive intake of strongly alcoholic drinks under circumstances which take place more frequently than in the past, as a consequence of the profound changes in lifestyle which have occurred, particularly with regard to young individuals, over a relatively short space of time. This phenomenon can affect important aspects of family life as well as social and personal relations, with worrying consequences even of a socio-economic nature.
The combination compositions of the present invention can, therefore, occur not only as pharmaceutical compositions but also as dietary supplements, health foods, medical foods or nutraceuticals or as components of the aforesaid products. Then, the compositions may also comprise, in admixture with L-carnitine and the aforesaid alkanoyl L-carnitines, further active ingredients, such as dietary supplements, vitamins, co-enzymes, minerals and the like.
The molar ratio L-carnitine/acetyl L-carnitine/propionyl L-carnitine or the pharmacologically acceptable salts thereof ranges from 6:4:1 to 3:2:1. Preferable, this ratio is 5:4:1.
In unit dosage forms, the compositions comprise 0.44 to 0.66 g of L-carnitine inner salt; 0.44 to 0.66 g of acetyl L-carnitine inner salt; and 0.12 to 0.18 g of propionyl L-carnitine inner salt or equimolar amounts of their pharmacologically acceptable salts.
What is meant by pharmacologically acceptable salt of L-carnitine, acetyl L-carnitine and propionyl L-carnitine is any salt of these active ingredients with an acid that does not give rise to unwanted toxic or side effects. These acids are well known to pharmacy experts.
Non-limiting examples of suitable salts are the following: chloride; bromide; iodide; aspartate, particularly acid aspartate; citrate, particularly acid citrate; tartrate; phosphate, particularly acid phosphate; fumarate, particularly acid fumarate; glycerophosphate; glucose phosphate; lactate; maleate, particularly acid maleate; orotate; oxalate, particularly acid oxalate; sulphate, particularly acid sulphate; trichloroacetate; trifluoroacetate and methanesulphonate.
A list of FDA-approved pharmacologically acceptable salts is given in Int. J. of Pharm. 33, (1986), 201-217; this latter publication is incorporated herein by reference.
Since L-carnitine and the aforesaid alkanoyl L-carnitine are practically atoxic, the combination composition of the present invention does not bring about any of the previously mentioned unwanted toxic or side effects.
REFERENCES:
patent: 195 27 281 (1997-01-01), None
patent: 0 517 125 (1992-12-01), None
patent: 0 793 962 (1997-09-01), None
Tempesta et al, (II) Int. J. Clin. Pharmacol Res., vol. 10, pp 1-2 (abstract), 1990.*
Conte et al, Int. J. Tissue React., vol. 17, pp. 21-31 (abstract), 1995.*
Tempesta E., et al, “Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism”International Journal of Clinical Pharmacology Research, vol. 10, No. 1/2, 1990, pp. 101-107.
Abu Murad C., et al, “Hepatic trigylceride accumulation and the ethanol physical withdrawal syndrome in mice”,British Journal of Experimental Pethology, vol. 58, No. 6, 1977, p. 606-615.
Corbett R. and Leonard B.E., “Effects of carnitine on changes caused by chronic administration of alcohol”,Neuropharmacology, vol. 23, No. 2B, 1984, p. 269-271.
Schmidl M K et al, “Medical Foods”,Food Technology, vol. 46, No. 4, Apr. 1992, pp. 87-96.
Leibovitz B et al, “Carnitine”Journal of Optimal Nutrition, vol. 2, No. 2, 1993, pp. 90-109.
Cavazza Claudio
Fassi Aldo
Nixon & Vanderhye P.C.
Reamer James H.
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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