U.S. patent application number 10/809617 was filed with the patent office on 2004-09-16 for use of extracts of ginkgo biloba for preparing a medicament.
This patent application is currently assigned to SOCIETE DE CONSEILS DE RECHERCHES D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.). Invention is credited to Drieu, Katy.
Application Number | 20040180105 10/809617 |
Document ID | / |
Family ID | 9514108 |
Filed Date | 2004-09-16 |
United States Patent
Application |
20040180105 |
Kind Code |
A1 |
Drieu, Katy |
September 16, 2004 |
Use of extracts of ginkgo biloba for preparing a medicament
Abstract
The invention relates to the use of Ginkgo biloba 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.
Inventors: |
Drieu, Katy; (Paris,
FR) |
Correspondence
Address: |
Charles A. Muserlian
c/o Muserlian, Lucas and Mercanti
475 Park Avenue South
New York
NY
10016
US
|
Assignee: |
SOCIETE DE CONSEILS DE RECHERCHES
D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.)
|
Family ID: |
9514108 |
Appl. No.: |
10/809617 |
Filed: |
March 25, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10809617 |
Mar 25, 2004 |
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09555906 |
Jun 2, 2000 |
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09555906 |
Jun 2, 2000 |
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PCT/FR98/02576 |
Dec 1, 1998 |
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Current U.S.
Class: |
424/752 ;
514/468 |
Current CPC
Class: |
A61K 36/16 20130101;
A61P 25/20 20180101; A61P 25/36 20180101; A61P 25/30 20180101; A61P
25/34 20180101; A61P 25/32 20180101 |
Class at
Publication: |
424/752 ;
514/468 |
International
Class: |
A61K 031/365; A61K
035/78 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 3, 1997 |
FR |
97-15230 |
Claims
1. Use of a Ginkgo biloba extract 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.
2. Use according to claim 1, characterized in that the Ginkgo
biloba extract is an extract of type EGb 761.
3. Use according to claim 1, characterized in that the Ginkgo
biloba extract is an extract of type CP 401.
4. Use according to claim 1, characterized in that the Ginkgo
biloba extract contains at least 5% of ginkgolides.
5. Use according to claim 4, characterized in that the Ginkgo
biloba extract contains at least 50% of ginkgolides.
6. Use of a compound of general formula (I) 5in which w, x, y and z
independently represent the H, OH, linear or branched alkoxy or
O-G.sub.S radicals, G.sub.S-OH representing a mono- or a
disaccharide, or one of their derivatives or analogues, it being
understood that at least one of W, X, Y or Z represents an
O-G.sub.S radical, 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.
7. Use according to claim 6, characterized in that: either W
represents an OH or O-G.sub.S radical, Y represents H and Z
represents H; or W represents an OH or O-G.sub.S radical, Y
represents an OH or O-G.sub.S radical and Z represents H; or W
represents an OH or O-G.sub.S radical, Y represents an OH or
O-G.sub.S radical and Z represents an OH or O-G.sub.S radical; or W
represents an OH or O-G.sub.S radical, Y represents H and Z
represents an OH or O-G.sub.S radical; or W represents H, Y
represents an OH or O-G.sub.S radical and Z represents an OH or
O-Gs radical; or W represents an OH or O-G.sub.S radical, Y
represents a linear or branched alkoxy radical and Z represents H;
it being understood that at least one of W, X, Y or Z represents an
O-G.sub.S. radical
8. Use according to claim 6 or 7, characterized in that: either W
represents an OH or O-G.sub.S radical, Y represents H and Z
represents H; or W represents an OH or O-G.sub.S radical, Y
represents an OH or O-G.sub.S radical and Z represents H; or W
represents an OH or O-G.sub.S radical, Y represents a linear or
branched alkoxy radical and Z represents H; it being understood
that at least one of W, X, Y or Z represents an O-G.sub.S.
radical
9. Use of a ginkgolide or one of its glycosylated, alkoxylated or
acetylated derivatives, or of a pharmaceutically active salt of the
latter for preparing a medicament intended to ease the withdrawal
of individuals dependent on the consumption of a substance
engendering habituation and/or addiction, such as in particular
alcohol, amphetamines, tobacco, drugs inducing toxicomania.
10. Use according to claim 9, characterized in that the ginkgolide
is ginkgolide A or ginkgolide B.
Description
[0001] The invention relates to the use of extracts of Ginkgo
biloba for preparing a medicament intended to ease the withdrawal
of individuals who are dependent on the consumption of a substance
engendering dependency and/or addiction, such as in particular
alcohol, amphetamines, tobacco, drugs inducing toxicomania.
[0002] It is already known that extracts of Ginkgo biloba have an
activity in the cardiovascular field (in particular the reduction
of platelet adhesion), in the central nervous field (in particular
a neuroprotective activity) or in the neurosensory system (in
particular retinal protection); cf. for example DeFeudis et al.,
Ginkgo biloba Extract (EGb 761.RTM.), Pharmaceutical Activities and
Clinical Applications (Elsevier, Paris, 1991). Their preparation
has been the subject of a certain number of patents, of which there
can be mentioned the European Patents EP 431 535 and EP 431 536,
and the American Patent U.S. Pat. No. 5,389,370.
[0003] Now the Applicant has just found that certain extracts of
Ginkgo biloba also have useful new pharmacological properties,
namely easing the withdrawal of subjects addicted to alcohol or
drugs, and more generally of subjects dependent on a substance
engendering dependency and/or addiction. The Applicant observed
that the administration of these extracts resulted in an
attenuation of the withdrawal symptoms.
[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 Ginkgo biloba is understood at least one of
the individual compounds which can be obtained by extraction from
the Ginkgo biloba L tree, and in particular a flavonoid compound or
a terpene such as a ginkgolide or a bilobalide, or also a mixture
of the latter. Preferably, the extract used will be such that it
contains an effective quantity of ginkgolides. For the uses
according to the invention, an extract of type EGb 761 or CP 401
can for example be chosen.
[0007] By ginkgolide is understood all the natural ginkgolides
obtained from the Ginkgo biloba tree, as well as synthetic
ginkgolides and their derivatives (resulting for example from an
acetylation or alkoxylation reaction) and pharmaceutically active
salts. The ginkgolides used can for example be ginkgolide A,
ginkgolide B, ginkgolide C, ginkgolide J or ginkgolide M
(structures given in the diagram below; these compounds can be
isolated from extracts of Ginkgo biloba leaves--see GINKGOLIDES,
Chemistry, Biology, Pharmacology and Clinical Perspectives,
published by P. Braquet, J. R. Prous Science Publishers, in
particular Volumes 1 (1988) and 2 (1989)). Glycosylated derivatives
of ginkgolides or alkoxylated or acetylated derivatives of
ginkgolides can also be used. By alkoxylated derivative of
ginkgolide is understood a ginkgolide derivative comprising at
least one linear or branched alkoxy group, instead of a hydroxy
group (these compounds are described in French Patent Application
No. FR 88.14392). Similarly, by acetylated derivative of ginkgolide
is understood a derivative of ginkgolide comprising at least one
acetate group instead of a hydroxy group.
1 Structure of ginkgolides A, B, C, J and M 1 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 mdicale, 31, 25 September 1986, supplement
devoted to the extract of Ginkgo biloba (EGb 761), 1455-1457; or in
the European Patents EP 431 535 and EP 431 536; by extract of type
EGb 761 is therefore understood in particular extracts of Ginkgo
biloba comprising 20 to 30% of flavoneglycosides, 2.5 to 4.5% of
ginkgolides A, B, C and J, 2 to 4% of bilobalide, less than 10% of
proanthocyanidines and less than 10 ppm, and preferably less than 5
ppm, of compounds of alkylphenol type, and in particular extracts
of Ginkgo biloba comprising approximately 24% of flavoneglycosides,
3.1% of ginkgolides A, B, C and J, 2.9% of bilobalide, 6.5% of
proanthocyanidines and less than 1 ppm of compounds of alkylphenol
type. By extract of type CP 401 is understood extracts such as
those which are presented in the Patent U.S. Pat. No. 5,389,370, in
particular extracts of Ginkgo biloba containing 5.5 to 8% of
ginkgolides A, B, C and J, 40 to 60% of flavoneglycosides and to 7%
of bilobalide, and quite particularly extracts containing
approximately 7% of ginkgolides A, B, C and J, 50% of
flavoneglycosides and 6% of bilobalide.
[0009] According to another aspect of the invention, the extract of
Ginkgo biloba used will comprise more than 5% of ginkgolides, and
more preferably more than 50% of ginkgolides.
[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) 2
[0012] in which W, X, Y and Z independently represent the H, OH,
linear or branched alkoxy or O-G.sub.S, G.sub.S-OH radicals
representing a mono- or disaccharide, or one of their derivatives
or analogues,
[0013] it being understood that at least one of W, X, Y or Z
represents an O-G.sub.S radical,
[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) 3
[0016] in which X represents an OH or O-G.sub.S radical, G.sub.S-OH
representing a mono- or disaccharide, or one of their derivatives
or analogues, and:
[0017] either W represents an OH or O-G.sub.S radical, Y represents
H and Z represents H;
[0018] or W represents an OH or O-G.sub.S radical, Y represents an
OH or O-G.sub.S radical and Z represents H;
[0019] or W represents an OH or O-G.sub.S radical, Y represents an
OH or O-G.sub.S radical and Z represents an OH or O-G.sub.S
radical;
[0020] or W represents an OH or O-G.sub.S radical, Y represents H
and Z represents an OH or O-Gs radical;
[0021] or W represents H, Y represents an OH or O-G.sub.S radical
and Z represents an OH or O-Gs radical;
[0022] or W represents an OH or O-G.sub.S radical, Y represents a
linear or branched alkoxy radical and Z represents H;
[0023] it being understood that at least one of W, X, Y or Z
represents an O-G.sub.S radical,
[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) 4
[0026] in which X represents an OH or O-G.sub.S radical, G.sub.S-OH
representing a mono- or disaccharide, or one of their derivatives
or analogues, and:
[0027] either W represents an OH or O-G.sub.S radical, Y represents
H and Z represents H;
[0028] or W represents an OH or O-G.sub.S radical, Y represents an
OH or O-G.sub.S radical and Z represents H;
[0029] or W represents an OH or O-G.sub.S radical, Y represents a
linear or branched alkoxy radical and Z represents H;
[0030] it being understood that at least one of W, X, Y or Z
represents an O-G.sub.S radical,
[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.sub.S will be chosen such that G.sub.S-OH
belongs to the group comprising abequose, rhamnose, arabinose,
ribose, xylose, 2-deoxy-ribose, glucose, galactose, mannose,
2-deoxyglucose, fructose, fucose, N-acetylglucosamine,
N-acetylalosamine, galactosamine, mannosamine, saccharose, lactose,
maltose, cellobiose and trehalose. Even more preferentially,
O-G.sub.S will be chosen such that G.sub.S-OH belongs to the group
comprising glucose and lactose.
[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 Ginkgo biloba on
Alcohol Dependency:
[0043] Two studies were carried out: one relates to the effects of
EGb 761, the other to the effects of another extract of Ginkgo
biloba, CP 401, which does not contain bilobalide but twice as much
ginkgolides as EGb 761 (6%).
[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 Ginkgo biloba Extracts on
Sensitization to Amphetamine:
[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 Ginkgo biloba Extract EGb 761 on
Morphine Withdrawal Syndrome:
[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.
2TABLE 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]
3TABLE 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
4 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).
5TABLE 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 Legend: Group
1: control; Group 2: group treated only with morphine (3 times 10
mg/kg/day); Group 3: group treated with morphine and with EGb 761
at a dose of 100 mg/kg.
* * * * *