Title: Use of CDP-choline for the treatment of alcohol withdrawal
United States Patent: 6,894,032
Issued: May 17, 2005
Inventors: Foguet; Rafael (Barcelona, ES); Ramentol; Jorge
(Barcelona, ES); Lozano; Rafael (Barcelona, ES); Agut; Julián (San Cugat,
ES); Torres; Jesús (Barcelona, ES); Raga; Manuel M. (Barcelona, ES);
Castello; Josep M. (Barcelona, ES); Ortiz; José A. (Barcelona, ES)
Assignee: Ferrer Internacional, S.A. (Barcelona, ES)
Appl. No.: 240159
Filed: March 28, 2001
PCT Filed: March 28, 2001
PCT NO: PCTEP01/03536
371 Date: September 30, 2002
102(e) Date: September 30, 2002
PCT PUB.NO.: WO0172288
PCT PUB. Date: October 4, 2001
The invention relates to the use of CDP-Choline or its pharmaceutically
acceptable salts for the preparation of a medicinal product for the
treatment of alcohol withdrawal syndrome at daily doses equivalent to 0.5-2
g of free CDP-Choline.
Description of the Invention
DESCRIPTION OF THE INVENTION
The present invention relates to the use of CDP-choline for the treatment
of alcohol withdrawal syndrome.
The toxic effects of alcohol on central nervous system are basically exerted
on neuronal membrane and synapses (Leonard B. E., Alcohol Alcohol.,
1986: 21(4), 325-338). Histological alterations of neuronal structure
consist in a lesser branching of hippocampus nerve cells and Purkinje's
cells. Comparison of brains from healthy subjects with those from alcoholic
patients revealed a lesser branching of pyramidal neuronal basal dendrites
in upper cerebral cortex and motor cortex (Ledig M. and Mandel P., M S-Medecine
Sciences, 1988: 4(6), 352-357).
Chronic alcohol abuse has also been reported to impair dopamine receptor
sensitivity. This effect is probably related to changes in neuronal membrane
fluidity and in the number and functionality of receptors, as well as to a
decrease in acetylcholine reuptake and dopamine deficiency (Carlen P. L. and
col., Ann. Neurol., 1981: 9(1), 84-86).
CDP-choline (cytidine diphosphate choline, Citicoline) is a key intermediate
in the synthesis of structural phospholipids present in the neuronal
membrane (Kennedy E. P. and Weiss S. B., J. Biol. Chem., 1956; 222,
193-214) and plays an important role in its formation and repair when the
phospholipidic structure is damaged by endogenous or exogenous causes
involving a decrease in cytidine and choline uptake.
The administration of CDP-choline enhances dopamine synthesis and release
(Martinet M. et al., Biochem. Pharmacol., 1981: 30(5), 539-541) as
well as choline and acetylcholine brain levels. The administration of
repeated doses of CDP-choline produces an increase of brain phospholipid
levels, which is secondary to an increase of cytidine and choline plasma
levels (Agut J. et al., Ann. New York Acad. Sci., 1993: 695,
Surprisingly, the applicants have found out that the administration of
CDP-choline to alcoholic patients reduces the duration and intensity of
their withdrawal symptoms and induces an evident recovery in a significant
proportion of patients.
The use of CDP-choline according to the present invention, which includes a
method for treating alcohol withdrawal syndrome, comprises the
administration of an effective amount of CDP-choline or a pharmaceutically
acceptable salt thereof to an alcoholic patient.
According to the present invention, CDP-choline is administered as free
compound or as a pharmaceutically acceptable salt, whether in anhydrous or
hydrated form, conveniently mixed with pharmaceutical carriers and/or
excipients, to humans at daily doses of 0.5 to 2 g inclusive in free
CDP-choline, preferably from 0.5 to 1 g inclusive, both orally and
parentally. Pharmaceutically acceptable salts of CDP-choline include its
alkaline or alkaline earth salts, such as its sodium, potassium, calcium and
magnesium salts or its acid addition salts with a mineral or organic acid,
such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric
acid, acetic acid, trifluoroacetic acid, citric acid, lactic acid, malonic
acid, tartaric acid, acrylic acid, metacrylic acid, malic acid, maleic acid,
fumaric acid, benzoic acid, salicylic acid, cinnamic acid, methane sulphonic
acid, benzenesulphonic acid, p-toluensulphonic acid and nicotinic acid.
CDP-choline and its salts, whether as anhydrous or hydrated substances,
under the invention may be administered orally in the form of tablets,
capsules, powder, granules, cachets, lozenges, solution, suspension,
emulsion, syrup, gel and the like; or parenterally in the form of solution,
suspension, emulsion or the like for intravenous or intramuscular injection.
The present invention is illustrated by the Examples that follow. Those
skilled in the art will be able to make any change provided the specific
embodiment of the invention is not modified and, therefore, the invention is
not limited to the specific details of the Examples.
500 mg Tablets
|CDP-choline, sodium salt
|| 30.0 mg
|| 3.0 mg
|| 2.5 mg
|| 20.0 mg
|| 20.0 mg
|Microcrystalline cellulose s.q.
25% Oral Solution
|CDP-choline, sodium salt
|Red Punzo 4R
|Anhydrous citric acid
|Purified water s.q.
Solution for Injection
|CDP-choline, sodium salt
|Hydrochloric acid, pH 6.0-6.5 s.q.
|Water for injection s.q.
Open Clinical Study of CDP-choline in Alcohol Withdrawal Syndrome
The progress of alcohol withdrawal syndrome was assessed in an open study
conducted in 197 patients. CDP-choline was administered at doses of 500 mg/d
i.m. or 600 mg/d p.o. for 60 days. At 30 and 60 days following treatment,
significant differences (p<0.001) were observed in the assessments
performed. At 60 days, 55.83% of patients had given up drinking alcohol and
31.97% of patients drank much less. A significant improvement was observed
on anxiety, tremor, disorientation, insomnia, dysarthria, tendency to
suicide and neuritic pains.
Open, Randomized, Comparative Clinical Study of CDP-Choline in Alcohol
Withdrawal Syndrome Versus Clomethiazole and Vitamin B
An open, randomized and comparative study on the conventional therapy of
alcohol withdrawal syndrome was conducted in 40 patients. Patients were
randomly distributed in two groups of 20. One of the groups was used as
control and received clomethiazole and vitamin B1, B6
and B12. This treatment regimen was maintained for 8 days, and
then patients were given diazepam until completion of treatment (60 days).
The other group of patients received the same treatment regimen plus
CDP-choline 500 mg i.m. every 12 h for the first 30 days and CDP-choline 200
mg p.o. every 8 h for the remaining 30 days. The patients who received
CDP-choline plus the conventional therapy showed significant differences
versus control at 30 days following treatment in tremor incidence (p<0.05),
cramps (p<0.05), asthenia (p<0.05), emotional lability (p<0.01), nervousness
(p<0.05) and social withdrawal (p<0.05).
Claim 1 of 5 Claims
1. A method for the treatment of alcohol withdrawal syndrome comprising
administering to an alcoholic patient in need thereof an effective amount
of CDP-choline or of a pharmaceutically acceptable salt thereof.
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