WO2006004386A1 - Utilisation d'un extrait de ginkgo biloba permettant la preparation d'un medicament traitant la maladie de parkinson - Google Patents

Utilisation d'un extrait de ginkgo biloba permettant la preparation d'un medicament traitant la maladie de parkinson Download PDF

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Publication number
WO2006004386A1
WO2006004386A1 PCT/MX2004/000042 MX2004000042W WO2006004386A1 WO 2006004386 A1 WO2006004386 A1 WO 2006004386A1 MX 2004000042 W MX2004000042 W MX 2004000042W WO 2006004386 A1 WO2006004386 A1 WO 2006004386A1
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extract
pharmaceutical composition
disease
mpp
ginkgo biloba
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PCT/MX2004/000042
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WO2006004386A8 (fr
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Patricia ROJAS CASTAÑEDA
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Rojas Castaneda Patricia
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Priority to PCT/MX2004/000042 priority Critical patent/WO2006004386A1/fr
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Publication of WO2006004386A8 publication Critical patent/WO2006004386A8/fr
Priority to MXPA06013787A priority patent/MXPA06013787A/es

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention is directed to the use of an extract of Ginkgo biloba, to prepare a medicine intended to treat Parkinson's disease. This represents a potential and important alternative for the treatment of Parkinson's disease.
  • the applicant was able to notice the beneficial effects of an extract of Ginkgo biloba in a pharmacological model of the disease, using the neurotoxin 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine named hereinafter like MPTP.
  • Parkinson's disease has an incidence of 168 / 100,000 and is a well-known disease especially in the population over the age of 60 years. Symptoms of this disease include uncontrolled movements, tremor at rest, gait disturbances, postural abnormalities, and muscle stiffness.
  • the primary neuropathology associated with this disorder is the progressive and persistent loss of dopaminergic neurons originating from the nigra pars compact substance that project to the striatum. This leads to a substantial decrease in the neurotransmitter dopamine in the nigrostriatal pathway (Jenner, P. 1989. Clues to the mechanism underlying dopamine cell death in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry. (Special suppl): 22-28). The subsequent decrease in the synthesis of dopamine correlates with the onset and severity of the mentioned symptoms. It is important to emphasize that the synthesis of dopamine is determined by the disposition of the activity of the tyrosine hydroxylase to carry out the synthesis of catecholamines including dopamine.
  • Free radicals are highly reactive molecules produced in the body as normal products of metabolism and in large quantities by Ia inflammation, alcoholism, smoking, radiation, etc. Those highly reactive molecules can oxidize other molecules in the body, making them unstable and potentially very harmful. Free radicals are highly unstable molecules that can cause damage to deoxyribonucleic acid, carbohydrates, lipids, and proteins in the body (Halliwell, B. and Gutteridge, JMC Free you are in biology and medicine. Oxford-Claredon, 1985). Of these effects, one of the most important is lipid peroxidation, the index most commonly used to measure the biological effect of free radicals. This damage known as oxidative stress, is implicated in the pathogenesis of a large number of chronic diseases, including Parkinson's disease.
  • Organisms have developed various defense mechanisms to protect themselves against free radical damage. Those defense mechanisms include antioxidant enzymes, free radical scavengers, and metal chelating agents (Reiter, RT. 1995. Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J. 9: 526-533).
  • the antioxidant enzymes are catalase, glutathione peroxidase, and superoxide dismutase. Normally, there is a balance between the generation of free radicals and antioxidant defense systems in vivo. When this balance is altered in favor of the production of free radicals due to the decrease in antioxidant systems or an increase in the generation of free radicals, oxidative stress occurs.
  • Oxidative stress leads to damage to polyunsaturated fatty acids by lipid peroxidation, a chain reaction that results in numerous degradation products (Niké, E., Noguchi, N. and Gotoh, N. 1993. Dynamics of lipid peroxidation and its inhibition by antioxidants. Biochem. Soc. Trans. 21: 313-317).
  • MPTP is referred to as the best experimental model of Parkinson's disease (Gerlach, M., Riederer, P., Przuntek, H., and Youdim, MBH 1991. MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. Eur J. Pharmacol. Mol. Pharmacol. 208: 273-286).
  • MPTP When MPTP is administered to primates that are not human and mice, it produces hypokinesia and neuronal damage similar to that observed in Parkinson's disease (Heikkila RE, Cabbat FS, Manzino L, Duvoisin RC 1984. Effects of MPTP on nigrostriatal dopamine in mice. Neuropharmacology 23: 711-713).
  • MPP + The 1-methyl-4-phenylpyridine ion that we will hereinafter refer to as MPP + is the largest neurotoxic metabolite of MPTP and is responsible for its neurotoxic effects.
  • the biotransformation of the MPTP to its toxic metabolite MPP + in the brain is initially carried out by the monoamine oxidase B enzyme that we will hereinafter refer to as MAO-B and this generates free radicals (Zang, LY and Misra, HP 1993. Generation of reactive oxygen species during the monoamine oxidase-catalyzed oxidation of the neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Biol. Chem. 268: 16504-16512).
  • the monoamine oxidase that we will hereinafter refer to as
  • MAO exists in 2 isoforms A and B.
  • MAO is the largest intracellular enzyme that metabolizes dopamine in the central nervous system.
  • the high oxidation of dopamine by MAO-B in Parkinson's disease may involve Ia production of hydrogen peroxide, a toxic molecule derived from oxygen capable of inducing the formation of free radicals, which could potentially harm dopaminergic neurons of the nigrostriatal pathway (Cohén, G. 1986. Monoamine oxidase, hydrogen peroxide, and Parkinson's disease . Pages 119- 125, in Yahr, MD, and Bergmann KJ (eds.), Advances in Neurplogy. Parkinson 's disease, vol 45, Raven Press, New York)..
  • Parkinson's disease As mentioned, currently the therapy of choice for patients who have Parkinson's disease is through the administration of L-DOPA, which is converted to dopamine in the brain. This pharmacological treatment is initially effective, but it often becomes less effective over time and in many cases the symptoms of the patients get worse. So far there is no clear and effective cure for Parkinson's disease.
  • the present invention represents a potential and important alternative for the therapy used for the treatment of Parkinson's disease. This is anticipated that treatment with an extract of Ginkgo biloba to patients with Parkinson's disease will inhibit or stop the progress of the disease by reducing the degeneration and dysfunction of dopaminergic neurons of the nigrostriatal pathway. Likewise, act as an antioxidant and / or antilipoperoxidant agent, regulate and / or inhibit the activity of the MAO that is generating free radicals; and increase the activity of tyrosine hydroxylase, enzyme required for the synthesis of dopamine.
  • Ginkgo biloba extract is meant that it is at least an extract of the individual compounds that can be obtained by extraction from the Ginkgo biloba tree and in particular a flavonoid compound or a terpene such as a ginkgolide or a bilobalide, or also a mixture.
  • an extract of the EGb 761 type can for example be chosen.
  • EGb 761 extract is a well-defined mixture of active compounds extracted from the leaves of Ginkgo biloba. This is an extract from the leaves of Ginkgo biloba which is substantially free of alkyphenol compounds, has a high content of flavonoid glycosides, and which contains substantially all of the ginkgolides and bilobalides originally present in the leaves.
  • extract of the EGb 761 type is meant an extract of a composition substantially identical to that of the standardized extract EGb 761 defined in the following article: K. Drieu, La presse med ⁇ cale, 31, Sep. 25,
  • extract of type EGb 761 is by Io understood in particular of extracts of Ginkgo biloba comprising 20 to 30% glycosides of flavones, 2.5 to 4.5% of ginkgolides A, B, C, and J, 2 to 4% of bilobalides, less 10% proanthocyanidins and less than 10 ppm, and preferably less than 5 ppm, of compounds of the alkylphenol type, and in particular extracts of Ginkgo biloba comprising approximately 24% flavone glycosides, 3.1% ginkgolides A, B, C and J , 2.9% of bilobalides, 6.5% of proanthocyanidins and less than 1 ppm of compounds of the alkylphenol type.
  • EGb 761 has been used in the clinic for the treatment of cerebrovascular insufficiency, degenerative dementia, peripheral vascular disorders and sensorineural disorders (DeFeudis, FV1998. Gingko biloba extract (EGb761): from Chemistry to the clinic. Pages 401. Ullstein Medical ,
  • a multipurpose action of EGb 761 is responsible for its effectiveness in treat clinical disorders of multifactorial origin.
  • the additive, antagonistic and synergistic effects of the active constituents of EGb 761 probably occur with respect to various molecular target sites in different tissues and organs.
  • the object of this invention is to provide drugs that contain this extract of Ginkgo biloba with a high content of flavonoid glycosides, ginkgolides and bilobalides originally present in the leaves and where there is no substantial danger of allergic reactions, precisely due to the removal of the compounds alkyphenols.
  • the extract in the present invention should contain: - from 20 to 30 percent by weight, in particular 22 to 26 percent by weight of flavonoid glycosides.
  • the Ginkgo biloba extract of the invention can be processed in Ia usual route of pharmaceutical preparations, for example for solutions, coated tablets, tablet preparations or injections.
  • the object of the present invention is the use of an extract of Ginkgo biloba, to prepare a medicine intended to treat Parkinson's disease.
  • the compounds can be administered for several months for treatment.
  • the pharmaceutical compositions comprise a compound of the invention that can be in the form of solids, for example powders, tablets, capsules, liposomes or suppositories.
  • the excipients can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, gelatin, starch, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
  • compositions containing a compound of the invention may also be present in the form of a liquid, for example, solutions, emulsions, suspensions or syrup.
  • Suitable excipients for liquids can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in various proportions.
  • the administration of the medicine according to the invention can be topical, oral, parenteral route, by injection, such as intramuscular, subcutaneous, intravenous administration, etc.
  • the daily administration dose of the active ingredients that can be used according to the invention is between 0.1 mg to 1 g depending on the severity of the Parkinson's disease of the patient to be treated.
  • a dose ranging from approximately 5 mg to 600 mg per day may be chosen.
  • FIG. 1 This graph shows that treatment with an extract of Ginkgo biloba type EGb 761 regulates the activity of MAO B in the striatum in parkinsonism induced with MPP + .
  • the results are expressed in ⁇ moles of 4 HOQV / g / h.
  • Each bar represents the average +/- standard error of 4-6 experiments per group.
  • + Statistically different from the MPP + group represented as "saline + MPP + ", p ⁇ 0.05, Tukey test.
  • Figure 2 It is a graph that shows the restoration that produces the extract of Ginkgo biloba type EGb 761 in the levels of dopamine in the striatum in animals that were previously parkinsonized with MPTP.
  • A represents the "saline + saline” group
  • B represents the “saline + EGb 761 group at a dose of 40 mg / kg”
  • C represents the "saline + EGb 761 group at a dose of 120 mg / kg
  • D represents the” MPTP + saline "group
  • E represents the” MPTP + EGb 761 group at a dose of 40 mg / kg
  • F represents the” MPTP + EGb 761 group at a dose of 120 mg / kg ".
  • Examples 3 to 7 were carried out using male mice of the C-57 black strain of 25-30 g in weight. The animals were kept in standard conditions with a cycle of 12: 12h light / dark, 21-22 ° C, relative humidity 40%, with food and water ad libitum.
  • Ginkgo biloba extract type EGb 761 was generously donated by Dr. Willmar Schwabe GmbH & Co. KG in Düsseldorf, Germany. EGb 761 was dissolved in saline and adjusted to a pH of 7.4.
  • Solution for oral administration where 10O ml of solution contain:
  • group I saline intraperitoneally, hereinafter referred to as ip + saline intracerebroventricular, hereinafter referred to as icv
  • group II EGb 761 by ip route + saline solution by icv route
  • group III saline by ip route + MPP + by icv route
  • group IV EGb 761 by ip route + MPP + by icv route.
  • the tissue was homogenized in 2.5 ml of phosphate buffer with a pH of 7.0. 1 ml aliquots of the homogenate were taken and placed in glass tubes with lids. Subsequently I added 3 ml of a chloroform-methanol mixture at a 2: 1 volume / volume dilution. The tubes were capped and the mixture was gently shaken and placed on ice for 30 minutes. The aqueous phase was discarded and 1 ml of the chloroform phase was transferred in quartz cells, 0.1 ml of methanol were subsequently added.
  • Table 1 shows that the administration of extract type EGb 761 did not produce significant increases in the formation of PFL at the different doses tested, which were 2.5, 5 and 10 mg / kg, at 2 h after the administration of MPP + compared to control animals.
  • the lipid peroxidation at 2 h after the administration of MPP + without pretreatment with EGb 761 type extract produced an increase in lipid peroxidation of 72%.
  • the pretreatment with extract type EGb 761 at 10 mg / kg blocked 100% the lipid peroxidation induced by MPP + , that is, the levels of lipid peroxidation are not statistically different from controls treated with saline.
  • Table 1 shows the dose response study of the EGb type extract
  • the degree of protection increased with increasing dose of the EGb 761 type extract.
  • the degree of protection was 65%, 93% and 100% for 2.5, 5 and 10 mg / kg of EGb 761, respectively, when compared to the "saline + MPP + " group.
  • MAO inhibitors deprenil for MAO-B and clorgiline for MAO-A, at a concentration of 500 nM in the final volume and preincubated for 10 min. These were used to measure these MAO isoforms only in the 6h group.
  • the administration of the extract of Ginkgo biloba type EGb 761 to the mice did not produce significant increases in the activity of the total MAO at different times tested of 2, 6, 12 and 24 h, when compared with the group treated with saline.
  • the total activity of the MAO was significantly elevated at 2 and 6 h after its administration, that is, 29% and 30% respectively compared to the control group, p ⁇ 0.05, without pretreatment.
  • Ginkgo biloba extract type EGb 761 no changes in the total activity of the MAO were observed at 12 and 24 h after the administration of MPP + compared to the group treated with saline solution.
  • pretreatment with Ginkgo biloba extract type EGb 761 in the MPP + group prevented the increase in MAO activity in the MPP + group at 6 h, observed without pretreatment. This means that the levels of the activity of the MAO were not statistically different from those of the controls treated with saline solution. Although the pretreatment with the EGb 761 type extract seemed to prevent the increase in the activity of the MAO produced by the MPP + at 2 h, but it was not statistically significant.
  • This table shows the beneficial effects of the regulation and / or inhibition of the enzymatic activity of the total MAO in the striatum by pretreatment with Ginkgo biloba extract type EGb 761 in parkinsonism experimentally induced with MPP + .
  • the results are expressed in activity of the total MAO in ⁇ moles 4-OHQ / g / h.
  • Each group represents the average +/- standard error of the average of 6-8 experiments per group.
  • mice The brains of the mice were immediately removed and the striatum was dissected. A 500 ⁇ l aliquot of 0.1% w / v sodium perchloric-metabisulfite solution was added to the tissue weight and sonicated with a Labsonic Lab-line instruments model system, Melrose Park.IL. Subsequently the samples were centrifuged at 4,000 g for 10 min and the supernatants were kept at -70 0 C until analysis.
  • the activity of the tyrosine hydroxylase was assayed in the striatum using a Perkin-Elmer model series 200 LC high-performance liquid chromatography system, connected to an ESA Coulochem 5100A detector with the following reference electrode potentials of +0.4 V and oxidation of Ia CeWa 1 ZCeWa 2 + 0.03 / + 0.35 V.
  • ESA Coulochem 5100A detector with the following reference electrode potentials of +0.4 V and oxidation of Ia CeWa 1 ZCeWa 2 + 0.03 / + 0.35 V.
  • the calibration curves were built for dopamine, L-DOPA and the concentration was obtained by interpolation of the respective standard curve.
  • the mobile phase consisted of an aqueous phosphate buffer at a pH of 3.1, which contained sodium octyl sufate at 0.2 mM, EDTA at 0.1 mM, methanol 15% volume / volume, at a pH of 2.6.
  • the EGb 761 type extract only does not influence the activity of the tyrosine hydroxylase at all the times tested when it is only compared with the "saline + saline” group.
  • Dopamine concentrations were analyzed according to the previously described method (Larsson LG, Rényi L, Ross SB, Svensson B, and ⁇ ngeby-Móller K. 1990. Different effects on the responses of functional pre- and postsynaptic 5-HT 1A receptors by repeated treatment of rats with the 5-HT-IA receptor agonist 8-OH-DPAT. Neuropharmacology. 29: 85-91). A 500 ⁇ l aliquot of 0.1% w / v sodium perchloric-metabisulfite solution was added to the tissue weight and sonicated with a Labson line brand Labsonic system, Melrose Park.IL.
  • This table shows the increase in tyrosine hydroxylase activity in the striatum by pretreatment with EGb 761-type extract as a protective response in parkinsonism experimentally induced with MPP + .
  • the results are expressed as tyrosine hydroxylase activity in ⁇ g / g of tissue.
  • Each group represents the average +/- standard error of the average of 6-8 experiments per group. * Statistically different from the control group represented as "saline + saline", p ⁇ 0.05, Tukey's test. + Statistically different from the group treated with MPP + represented as "saline + MPP + ", p ⁇ 0.05, Tukey's test.
  • group I saline solution via i.p + saline solution via i.p route
  • group II saline by the i.p + EGb 761 route by the i.p route
  • group III MPTP via ip + saline via i.p .
  • Group IV MPTP via i.p. + EGb 761 via i.p.
  • mice in groups I and Il received saline ip and groups III and IV received MPTP at a dose of 30 mg / kg, ip daily for 5 days.
  • animals in groups Il and IV were administered with EGb 761 type extract at a dose of 40 or 120 mg / kg for 18 days or saline was administered in groups I and III using them as a control group.
  • the animals were sacrificed by cervical dislocation after the last administration of the type extract.
  • EGb 761 The brains were immediately removed and the striatum was dissected, and the dopamine content in the striatum was analyzed by high-performance liquid chromatography as described in Example 6. TABLE 4.
  • This table shows the protection produced by pretreatment with extract type EGb 761 in the levels of dopamine in the striatum in parkinsonism experimentally induced with MPP + .
  • the results are expressed in dopamine content in ⁇ g / g of tissue.
  • Each group represents the average of +/- standard error of the average of 6-8 experiments per group.

Abstract

Utilisation d'extraits de <i
PCT/MX2004/000042 2004-07-02 2004-07-02 Utilisation d'un extrait de ginkgo biloba permettant la preparation d'un medicament traitant la maladie de parkinson WO2006004386A1 (fr)

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PCT/MX2004/000042 WO2006004386A1 (fr) 2004-07-02 2004-07-02 Utilisation d'un extrait de ginkgo biloba permettant la preparation d'un medicament traitant la maladie de parkinson
MXPA06013787A MXPA06013787A (es) 2004-07-02 2006-11-28 Uso de un extracto del ginko biloba para preparar una medicina para tratar la enfermedad de parkinson.

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Citations (6)

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Publication number Priority date Publication date Assignee Title
EP0431535A1 (fr) * 1989-12-04 1991-06-12 Dr. Willmar Schwabe GmbH &amp; Co. Extrait de feuilles de Ginkgo biloba, méthode de préparation et médicaments contenant l'extrait
EP0431536A1 (fr) * 1989-12-04 1991-06-12 Dr. Willmar Schwabe GmbH &amp; Co. Une méthode de préparation d'un extrait de feuilles de Ginkgo biloba
WO2000007592A1 (fr) * 1998-08-07 2000-02-17 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation d'extraits de ginkgo biloba pour preparer un medicament destine a traiter la sclerose laterale amyotrophique
WO2000064462A1 (fr) * 1999-04-21 2000-11-02 Yuyu Industrial Co., Ltd. Compositions pharmaceutiques contenant de la selegiline et de l'extrait de ginkgo biloba pour traiter la demence
WO2002083158A1 (fr) * 2001-04-10 2002-10-24 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Procede de preparation d'un extrait de feuilles de ginkgo biloba hautement enrichi en principes actifs
WO2004014405A1 (fr) * 2002-07-16 2004-02-19 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation d’extraits de ginkgo biloba pour favoriser la masse musculaire au detriment de la masse graisseuse

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Publication number Priority date Publication date Assignee Title
EP0431535A1 (fr) * 1989-12-04 1991-06-12 Dr. Willmar Schwabe GmbH &amp; Co. Extrait de feuilles de Ginkgo biloba, méthode de préparation et médicaments contenant l'extrait
EP0431536A1 (fr) * 1989-12-04 1991-06-12 Dr. Willmar Schwabe GmbH &amp; Co. Une méthode de préparation d'un extrait de feuilles de Ginkgo biloba
WO2000007592A1 (fr) * 1998-08-07 2000-02-17 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation d'extraits de ginkgo biloba pour preparer un medicament destine a traiter la sclerose laterale amyotrophique
WO2000064462A1 (fr) * 1999-04-21 2000-11-02 Yuyu Industrial Co., Ltd. Compositions pharmaceutiques contenant de la selegiline et de l'extrait de ginkgo biloba pour traiter la demence
WO2002083158A1 (fr) * 2001-04-10 2002-10-24 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Procede de preparation d'un extrait de feuilles de ginkgo biloba hautement enrichi en principes actifs
WO2004014405A1 (fr) * 2002-07-16 2004-02-19 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation d’extraits de ginkgo biloba pour favoriser la masse musculaire au detriment de la masse graisseuse

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YANG SU FEN ET AL: "Protective effect and mechanism of ginkgo biloba leaf extracts for parkinson didease induced by 1-methyl-4phenyl-1,2,3,6-tetrahydrpyridine", ACTA PHARMACOLOGICA CINICA, vol. 22, no. 12, 2001, pages 1089 - 1093 *

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