[0002] It is already known that extracts of
[0003] Now the Applicant has just found that certain extracts of
[0004] A subject of the invention is therefore the use of these extracts for preparing a medicament intended to ease the withdrawal of individuals dependent on the consumption of a substance engendering dependency and/or addiction, such as in particular alcohol, amphetamines, tobacco, drugs inducing toxicomania.
[0005] By drugs inducing toxicomania is understood in particular morphine and its derivatives, opium and opiates, cocaine, crack, and more generally all substances, including any medicamentous substances, on which a subject can become dependent.
[0006] By extract of
[0007] By ginkgolide is understood all the natural ginkgolides obtained from the Structure of ginkgolides A, B, C, J and M
Ginkgolide W X Y Z A OH OH H H B OH OH OH H C OH OH OH OH J OH OH H OH M H OH OH OH
[0008] By extract of type EGb 761 is understood an extract of a composition substantially identical to that of the standardized extract EGb 761 as defined in particular in the following article: K. Drieu, La presse médicale, 31, 25 September 1986, supplement devoted to the extract of
[0009] According to another aspect of the invention, the extract of
[0010] The invention also relates to the use of a ginkgolide or one of its derivatives or pharmaceutically active salts for preparing a medicament intended to ease the withdrawal of individuals dependent on the consumption of a substance engendering dependency and/or addiction, such as in particular alcohol, amphetamines, tobacco, drugs inducing toxicomania. Preferably, the ginkgolide used for this aspect of the invention will be ginkgolide A or ginkgolide B.
[0011] The invention also relates to the use of a compound of general formula (I)
[0012] in which W, X, Y and Z independently represent the H, OH, linear or branched alkoxy or O-G
[0013] it being understood that at least one of W, X, Y or Z represents an O-G
[0014] for preparing a medicament intended to ease the withdrawal of individuals dependent on the consumption of a substance engendering dependency and/or addiction, such as in particular alcohol, tobacco, amphetamines, drugs inducing toxicomania.
[0015] The invention preferably relates to the use of a compound of general formula (I)
[0016] in which X represents an OH or O-G
[0017] either W represents an OH or O-G
[0018] or W represents an OH or O-G
[0019] or W represents an OH or O-G
[0020] or W represents an OH or O-G
[0021] or W represents H, Y represents an OH or O-G
[0022] or W represents an OH or O-G
[0023] it being understood that at least one of W, X, Y or Z represents an O-G
[0024] for preparing a medicament intended to ease the withdrawal of individuals dependent on the consumption of a substance engendering dependency and/or addiction, such as in particular alcohol, tobacco, amphetamines, drugs inducing toxicomania.
[0025] The invention relates quite particularly to the use of a compound of general formula (I)
[0026] in which X represents an OH or O-G
[0027] either W represents an OH or O-G
[0028] or W represents an OH or O-G
[0029] or W represents an OH or O-G
[0030] it being understood that at least one of W, X, Y or Z represents an O-G
[0031] for preparing a medicament intended to ease the withdrawal of individuals dependent on the consumption of a substance engendering dependency and/or addiction, such as in particular alcohol, tobacco, amphetamines, drugs inducing toxicomania.
[0032] By linear or branched alkoxy radical is understood in the present description an alkoxy radical the linear or branched carbon containing chain of which contains 1 to 6 carbon atoms. By derivative or analogue of mono- or disaccharides is understood compounds such as N-acetylglucosamine, N-acetylalosamine, galactosamine, mannoseamine, N-tosylhydrazone, etc.
[0033] Preferably, O-G
[0034] The invention therefore also relates to the use of glycosylated derivatives of ginkgolides, more particularly those of ginkgolides A and B, the glycosyl groups suitable for the invention having been described previously.
[0035] The different processes for obtaining glycosylated derivatives of ginkgolides or alkoxylated ginkgolides (i.e. those resulting from a glycosylation reaction carried out on at least one of the OH groups of ginkgolides or their alkoxylated derivatives) are described in the following publication: Weber, M. and Vasella, A., Helv. Chim. Acta, 80 (1997), 2352-2367.
[0036] The pharmaceutical compositions comprising a compound of the invention can be in the form of solids, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
[0037] The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
[0038] The administration of a medicament according to the invention can be carried out by topical, oral, parenteral route, by injection (intramuscular, sub-cutaneous, intravenous, etc.), etc.
[0039] The administration dose envisaged for a medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of substance on which the subject to be treated is dependent.
[0040] Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which this invention belongs. Similarly, all publications, patent applications, all patents and all other references mentioned here are incorporated by way of reference.
[0041] Pharmacological Study of the Products of the Invention:
[0042] 1. Study of the Effects of Extracts of
[0043] Two studies were carried out: one relates to the effects of EGb 761, the other to the effects of another extract of
[0044] 1) Rats are treated for 15 days with alcohol (they are administered 10% ethanol in their drinking water for the first week and then 12.5% ethanol). They are given 50 or 100 mg/kg of EGb 761 per day by oral route (gavage) for the 5 days before the absorption of alcohol is stopped (from the 11th day) and the 3 days after it is stopped.
[0045] The behavioural symptoms were evaluated for 3 days after the absorption of alcohol is stopped in three groups of rats (n=6): the control group having received only alcohol, one group having received alcohol and treatment with 50 mg/kg of EGb 761 and another group having received alcohol and treatment with 100 mg/kg of EGb 761, the treatments with EGb 761 having been administered under the conditions described above. The results of these tests are shown in table (I) which can be found in appendix I.
[0046] In the animals which received EGb 761, it can be observed that the withdrawal symptoms (7 criteria) are reduced in a dose-dependent manner and that the animals also have reduced motor hyperactivity.
[0047] 2) Rats are treated for 15 days with alcohol (they are given 10% ethanol in their drinking water for the first week and then 12.5% ethanol). They are administered 50 mg/kg of CP 401 extract per day by oral route (gavage) for the 5 days before the absorption of alcohol is stopped (from the 11th day) and the 3 days after it is stopped.
[0048] The behavioural symptoms were evaluated for the 3 days after the absorption of alcohol was stopped in three groups of rats (n=6): the control group only having received alcohol and the other group having received alcohol and treatment with 50 mg/kg of CP 401 extract administered under the conditions described above. The results of these tests are shown in table (II) which can be found in appendix I.
[0049] It is observed that the animals which received the CP 401 extract show a reduction in the symptoms linked with withdrawal compared with the intoxicated control animals.
[0050] 2. Study of the Effects of
[0051] An injection of amphetamine (0.5 mg/kg IP) provokes motor hyperactivity in the rat (measured by actimetry). Administration eight times, every other day, of the same dose of amphetamine results in a progressive increase in locomotive activity: this phenomenon is called “sensitization”.
[0052] For 8 days before the administration of amphetamine and throughout this administration, rats (n=8) subjected to the administration of amphetamine as described above were subjected to treatment by oral route with a dose of EGb 761 of 100 mg/kg per day or of a dose of 5 mg/kg per day of ginkgolide A.
[0053] Actimetry measurements were carried out for 1 hour after the administration of the amphetamine on the 9th (first day on which amphetamine was administered), 13th, 17th, 21st and 25th day. The results of these tests are shown in A which can be found in appendix II.
[0054] It is observed that behavioural sensitization to amphetamine is reduced in the animals which received 5 mg/kg per day of ginkgolide A. An enhanced and quite significant effect is observed with EGb 761 at 100 mg/kg per day.
[0055] 3. Study of the Effects of
[0056] Rats are treated every 8 hours (3 times per day) for 10 days with a dose of morphine by sub-cutaneous route resulting in motor hyperactivity (measured by actimetry). On the 11th day, they are administered naloxone (3 mg/kg IP) and the withdrawal signs are observed for 60 minutes: a series of behavioural signs is quantified, a series measured (hypothermia, weight loss) or a series graded (scale with 4 levels).
[0057] Two groups of 8 rats are treated with EGb 761 (50 or 100 mg/kg per day) for 4 days before the administration of naloxone and 2 hours before it. A group of intoxicated control rats only receives injections of morphine before the naloxone and an absolute control group only receives naloxone.
[0058] Statistical analysis of the batches is carried out using the following tests: parametric Anova, Barlett's test to check the homogeneity of variances and Dunnett's test for multiple comparisons.
[0059] The results quantified by counting for the different behavioural parameters analyzed are shown in table (III) which can be found in appendix III.
TABLE I Influence of treatment with substance EGb 761 on the number of observations of each symptom of abstinence at 24 hours after withdrawal Treatment (mg/kg) TRE SNO CHA TWI MOT ESC JUM none 7 17 15 12 11 6 5 EGb 761 (50) 5 9 8 6 6 3 2 EGb 761 (100) 0 5 4 2 3 0 1
[0060]
TABLE II Influence of treatment with substance CP 401 on the number of observations of each symptom of abstinence at 24 hours after withdrawal Treatment (mg/kg) TRE SNO CHA TWI MOT ESC JUM none 6 19 12 15 9 6 6 CP 401 (50) 4 11 6 7 5 4 3
[0061] Legend common to Tables I and II
TRE: trembling in body SNO: snorting CHA: chattering of teeth TWI: twitching of ears MOT: motor activity ESC: attempted escapes JUM: jumps
[0062] The symptoms are graded from 0 to 3 according to their intensity (0=slight; 3=very pronounced).
TABLE III Influence of treatment with substance EGb 761 on the number of observations of each of the symptoms of abstinence during morphine withdrawal Symptoms Group 1 Group 2 Group 3 Jumps 0.0 ± 0.0 1.00 ± 0.33 0.50 ± 0.19 Stiffening 9.88 ± 1.03 1.13 ± 0.40 5.63 ± 1.00 Snorting 0.25 ± 0.16 2.75 ± 0.70 0.88 ± 0.29 Jerking of head 0.0 ± 0.0 5.50 ± 1.13 2.43 ± 0.48 Yawning 0.75 ± 0.41 2.00 ± 0.78 0.88 ± 0.40 Chattering or grinding of 0.0 ± 0.0 4.75 ± 0.86 1.75 ± 0.45 teeth Burying 0.25 ± 0.16 1.38 ± 0.46 0.25 ± 0.16 Excessive scratching 0.0 ± 0.0 1.13 ± 0.48 0.38 ± 0.26 Grooming 6.00 ± 1.39 1.38 ± 0.53 4.25 ± 1.31