The use of extracts of ginkgo dicotyledonous for the preparation of medicines

 

The invention relates to medicine. The proposed use of Ginkgo extract bipartite to facilitate withdrawal syndrome for the treatment of persons with addictions to alcohol, amphetamines, morphine and its derivatives and opium and opium narcotic drugs. The invention expands the Arsenal of tools specified destination. 8 C.p. f-crystals, 4 tab., 1 Il.

The invention relates to the use of extracts of Ginkgo dicotyledonous for preparing a medicinal product intended for the relief of the syndrome in the treatment of persons with addiction to the consumption of substances that causes addiction and/or chronic addictive, such as, in particular, substances as alcohol, amphetamines, tobacco, drugs.

To date, it is known that extracts of Ginkgo dicots possess activity against cardio-vascular system (in particular, reduce the adhesion of platelets), Central nervous system (in particular, exhibit neuroprotective properties), or sense organs (in particular, protects the retina of the eye), see, for example, DeFeudis et al., Ginkgo Biloba Extract (Egb 761, Pharmaceutical Activities and Clinical applications (Elsevier, Paris, 1991). Prigotovleniya and EP 431536 and American patent US 5389370.

The applicant has found that certain extracts of Ginkgo bipartite have, in addition, new and interesting pharmacological properties, namely the ability to ease the withdrawal symptoms in individuals with alcohol or drug dependence, and in the more General case of persons with dependence on a substance that causes addiction and/or chronic addictive. The applicant failed to establish that the consequence of taking these extracts is the relief of symptoms of the syndrome.

The subject of the invention is thus the use of these extracts for obtaining a medicinal product intended for the relief of the syndrome in the treatment of persons with addiction to the consumption of substances that causes addiction and/or chronic addictive, for example, such substances as alcohol, amphetamines, tobacco, drugs.

Under narcotic drugs, in particular, understand the morphine and its derivatives, opium and opiates, cocaine, crack, and, more generally, any substance, including drugs that can cause drug dependence on his face.

Under the Ginkgo extract bipartite understand at least one of the individual compounds, which mo is Khalida or bilobalide, and mixtures of the latter. Mostly use the extract containing an effective amount of ginkgolides. For applications in accordance with the invention can be selected, for example, extract type EGb 761 or SR 401.

Under ginkgolides understand all natural ginkgolides, derived from the Ginkgo tree is a bipartite, and synthetic ginkgolides and derivatives thereof (obtained, for example, by the reaction of acetylation or alkoxysilane) and pharmacologically active salts. As ginkgolides can be, for example, used ginkgolide And ginkgolide, ginkgolide With, ginkgolide J or ginkgolide M (patterns depicted in the diagram below; these compounds can be isolated from extracts of leaves of Ginkgo bipartite see GINKGOLIDES, Chemistry, Biology, Pharmacology and Clinical Perspectives edited by P. Braquet, J. R. Ptous Sciences Publishers, volume 1 (1988) and 2 (1989)). Can also be used glycosylated derivatives of ginkgolides or alkoxysilane or acetylated derivatives of ginkgolides. Under alkoxycarbonyl ginkgolide derivative understand ginkgolide derivative containing at least one linear or branched alkoxygroup instead of one hydroxyl group (such compounds are described in French patent for the same, contains instead of one hydroxyl group at least one acetate group.

Under the extract type EGb 761 understand the extract composition, substantially similar to the standardized extract EGb 761, so that, in particular, is defined in the following article: K. Drieu La presse medicale, 31, 25 September 1986, Supplement dedicated to the Ginkgo extract bipartite (EGb 761), 1455-1457, or in European patent EP 431535 and EP 431536. Under extract EGb 761 see extracts of Ginkgo bipartite containing from 20 to 30% found in Ginkgo, from 2.5 to 4.5% of ginkgolides a, b, C and J and from 2 to 4% bilobalide, less than 10% of proanthocyanidins and less than 10, preferably less than 5, mn^-1compounds of the type of ALKYLPHENOLS and, more specifically, extracts of Ginkgo bipartite, containing approximately 24% found in Ginkgo, 3,1% of ginkolide a,b,C and J, 2.9% of bilobalide, 6.5% of proanthocyanidins and less than 1 million^-1compounds of the type of alkyl phenols. Under extract CF 401 understand these extracts, as described in patent US 5389370, in particular extracts of Ginkgo bipartite containing from 5.5 to 8% of ginkolide a, b, C and J, from 40 to 60% found in Ginkgo and from 5 to 7% bilobalide, and, most specifically, extracts containing approximately 7% of ginkolide a, b, C and J, 50% found in Ginkgo and 6% hit is t more than 5% of ginkgolides and most preferably, more than 50% of ginkgolides.

The invention relates also to the use of ginkgolides or their pharmaceutically active derivatives or salts to obtain a medicinal product intended for the relief of the syndrome in the treatment of persons with addiction to the consumption of substances that causes addiction and/or chronic addictive, such as, in particular, substances as alcohol, amphetamines, tobacco, drugs. Mainly used in this aspect of the invention ginkgolides is ginkgolic or ginkgolic Century

The invention relates also to the use of compounds of General formula I in which W, X, Y and Z independently represent radicals H, HE, linear or branched alkoxygroup or group Of Gs, and Gs-OH denotes a mono - or disaccharide or derivative thereof, or analogs, provided that at least one of W, X, Y and Z denotes O-G_sto obtain a medicinal product intended for the relief of the syndrome in the treatment of persons with addiction to the consumption of substances that causes addiction and/or chronic addictive, such as, in particular, substances as alcohol, amphetamines, tobacco, drugs.

The invention mainly s-OH denotes a mono - or disaccharide or derivative thereof, or analogs, and any W denotes a radical or O-Gs, Y represents N and Z represents N, or W denotes a radical or O-G_sY indicates HE or O-G_sand Z represents N, or W denotes a radical or O-G_sY indicates HE or O-G_sand Z denotes a radical or O-G_s; or W represents the radical or O-Gs, Y represents N and Z indicates HE or O-G_sor W represents N, Y represents HE or O-G_sand Z denotes a radical or O-G_sor W represents the radical or O-G_sY denotes a linear or branched alkoxyalkyl and Z represents N, provided that at least one of W, X, Y and Z denotes O-G_s,
for obtaining a medicinal product intended for the relief of the syndrome in the treatment of persons with addiction to the consumption of substances that causes addiction and/or chronic addictive, such as, in particular, substances as alcohol, amphetamines, tobacco, drugs.

The invention applies in particular to the use of compounds of General formula (I)
in which X denotes a radical or O-G_sand G_s-OH denotes a mono - or disaccharide, or one of their salts or analogues, and
-O-G_sY indicates HE or O-G_sand Z denotes H,
any W denotes a radical or O-Gs, Y denotes a linear or branched alkoxyalkyl and Z represents N; provided that at least one of W, X, Y and Z denotes O-G_s.

Under linear or branched alkoxyalkyl in the present description understand alkoxyalkyl, linear or branched carbon chain of which contains from 1 to 6 carbon atoms. Under a derivative or analogue mono - or disaccharides understand such compounds as N-acetylglucosamine, N-acetylglucosamine, galactosamine, mannosamine, N-tazelgettaze etc.

O-G_spick up mainly so that G_sHE belonged to a group that includes abequose, rhamnose, arabinose, ribose, xylose, 2-deoxyribose, glucose, galactose, mannose, 2-deoxyglucose, fructose, fucose, N-acetylglucosamine, N-acetylglucosamine, galactosamine, mannosamine, sucrose, lactose, maltose, cellobiose and trehalose. Even more preferably pick up On Gs so that G_s-OH belonged to the group that includes glucose and lactose.

The invention also relates to the use of glycosylated derivatives of ginkgolides, in particular of ginkgolides a and b, orientirlaydi glycosylated derivatives of ginkgolides or alkoxycarbonyl of ginkgolides (i.e., compounds formed by the reaction of glycosylation conducted at least two groups of ginkgolides or alkoxysilane derivatives) described in the following publication: M. Weber and Vasela A., Helv. Chim. Acta, 80(1997), 2352-2367.

Pharmaceutical compositions containing the compounds according to the invention can be solids, such as powders, granules, tablets, gelatin capsules, liposomes or suppositories. Suitable solid carriers can, for example, be calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine and wax.

Pharmaceutical compositions containing the compounds according to the invention can also be in liquid form, for example in the form of solutions, emulsions, suspensions or syrups. Suitable liquid carriers may, for example, be water, organic solvents, such as glycerol, glycols and mixtures thereof in water in different ratios.

The use of the drug in accordance with the present invention can be produced locally, orally, parenterally, by injection (intramuscular, subcutaneous, intravenous, and so on) and so on,

Predpoll is about 10 g depending on the type of the calling dependence substance.

Unless otherwise noted, all used here is the technical and scientific terms have the same meaning, which usually use an ordinary specialist in the field that applies the present invention. Moreover, all publications, patent applications, all patents and all other following links are part of the invention as reference material.

Pharmacological study of the products of the invention
1. The study of the effects of extracts of Ginkgo dicotyledonous on alcohol dependence.

Conducted two tests: one in relation to the effects of EGb 761, the other in respect of the other effects of Ginkgo extract bipartite - CF 401 which does not contain bilobalide, but contains ginkgolides twice in EGb 761 (6%).

1) to Rats for 15 days to introduce alcohol (they are given as a drink 10% ethanol in the first week and then a 12.5% ethanol). Animals injected oral (in feed) 50 or 100 mg/kg EGb 761 daily for five days prior to the termination of the input of the alcohol (starting from the 11th day) and during the next three days.

Estimated behavioral symptoms within three days after you stop typing alcohol in three groups of rats (n=6): control groggy group, receiving alcohol with concomitant administration of 100 mg/kg EGb 761 (in the last two groups EGb 761 was used in the conditions described above). The results of the tests are presented in table I.

Found that animals treated with EGb 761, the symptoms of the syndrome (7 criteria) is reduced in proportion to the input dose and that animals have also reduced locomotor hyperactivity.

2) to Rats for 15 days to introduce alcohol (they are given as a drink 10% ethanol in the first week and then a 12.5% ethanol). They also introduce oral (in feed) 50 mg/kg of the extract CF 401 daily for five days prior to the termination of the input of the alcohol (starting from the 11th day) and in the next three days.

Estimated behavioral symptoms within three days after you stop typing alcohol in two groups of rats (n=6): control group, receiving only the alcohol, and in the group treated with alcohol with concomitant administration of 50 mg/kg of the extract CF 401 in the above-described conditions. The test results presented in table III.

Found that animals treated with the extract CF 401, the symptoms associated with the syndrome, reduced in comparison with symptoms in intoxicating control stomach is etamine (0.5 mg/kg) causes rat locomotor hyperactivity (measured using actimetry). Eight equal doses of amphetamine, applied every other day, cause a progressive increase in locomotor activity: a phenomenon called "sensitization".

Rats (n=8), which was injected amphetamine described above, within 8 days prior to the use of amphetamine, and during the whole period of use of amphetamine were treated orally with EGb 761 at a dose of 100 mg/kg / day and ginkgolide And at a dose of 5 mg/kg / day.

Measurements using actimetry was performed within 1 hour after application of amphetamine on the 9th (the first day of use of amphetamine), 13th, 17th, 21st and 25th day. The results are given in the graph in Annex II.

Found that behavioral sensitization by amphetamine reduced in animals treated with ginkgolide And at a dose of 5 mg/kg / day. Even higher and quite remarkable effect was observed with EGb 761 at a dose of 100 mg/kg / day.

3. The study of the effects of Ginkgo extract bipartite EGb 761 on the withdrawal syndrome after the use of morphine.

Rats every 8 hours (three times a day) for 10 days injected subcutaneously with a dose of morphine, causing locomotor hyperactivity (as measured by the method of actimetry). On the 11th day of the rats injected with naloxone (3 mg/kg) and observed for signs of withdrawal within 60 m which are assessed on a 4-point scale.

Two groups of rats for 8 rats in each give EGb 761 (50 or 100 mg/kg / day) for 4 days before the introduction of naloxone and two hours before him. Intoksicazionny rats from the control group will receive only injections of morphine before naloxone, and rats from the other absolute control group will receive only naloxon.

Statistical analysis among the parties is carried out using the following tests: parametric ANOVA test Barletta to verify the homogeneity of variantdata and test Dunnett for multiple comparisons.

The results of quantitative calculations of the various identified behavioural parameters are given in table IV.

Claims

1. The use of Ginkgo extract bipartite as a medicinal product intended for the relief of the syndrome in the treatment of persons with addiction to the consumption of addictive substances and/or chronic addictive, and specified substance selected from alcohol, amphetamines, morphine and its derivatives and opium and opium narcotic drugs.

2. Application under item 1, characterized in that the extract of Ginkgo bipartite represents an extract containing 20-30% found in Ginkgo, 2,5-4,5% gingu.

3. Application under item 1, characterized in that the extract of Ginkgo bipartite represents an extract containing 5.5-8% of ginkgolides a, b, C and J, 40-60% found in Ginkgo and 5-7% bilobalide.

4. Application under item 1, characterized in that the extract of Ginkgo bipartite contains at least 5% of gingkolides.

5. Use one of the PP.1-4, characterized in that the substance that causes addiction and/or chronic addiction is alcohol.

6. Use one of the PP.1-4, characterized in that the substance that causes addiction and/or chronic addictive, choose from amphetamines.

7. Use one of the PP.1-4, characterized in that the substance that causes addiction and/or chronic addictive, choose from morphine and its derivatives and opium and opium narcotic drugs.

8. Application under item 7, characterized in that the narcotic drug is chosen from morphine and its derivatives.

9. Application under item 7, characterized in that the narcotic drug is morphine.