WO2018113027A1 - Application du bilobalide comme activateur dans la préparation de médicaments pour la prévention de maladies de type lésions de nerfs crâniens - Google Patents

Application du bilobalide comme activateur dans la préparation de médicaments pour la prévention de maladies de type lésions de nerfs crâniens Download PDF

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WO2018113027A1
WO2018113027A1 PCT/CN2016/113602 CN2016113602W WO2018113027A1 WO 2018113027 A1 WO2018113027 A1 WO 2018113027A1 CN 2016113602 W CN2016113602 W CN 2016113602W WO 2018113027 A1 WO2018113027 A1 WO 2018113027A1
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synergist
ginkgolide
extract
lactone
group
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Chinese (zh)
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贝伟剑
郭姣
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广东药科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)

Definitions

  • the present invention relates to a novel application of a compound and a novel pharmaceutical or nutraceutical composition based on the application, and in particular to the use of ginkgolide as a synergist for the preparation of a medicament or a health care product for preventing and treating cranial nerve injury diseases.
  • Brain diseases related to the central nervous system such as ischemic heart disease, neurodegenerative diseases, such as ischemic stroke, chronic cerebral ischemia, stroke sequelae, senile dementia, Parkinson's disease, Alzheimer's disease Etc. has become an increasingly common disease, and the development of new drugs for the treatment of these diseases has been subject to many factors, the most important of which is how the drug passes through the blood-brain barrier.
  • 100% of macromolecular drugs including peptides, recombinant proteins, monoclonal antibodies, RNA interference-based drugs, gene therapy-related drugs, etc., cannot cross the blood-brain barrier, and more than 98% of small molecule drugs cannot pass through. Blood brain barrier.
  • the above-mentioned brain diseases related to the central nervous system will be more and more intensified, so research and development of drugs that promote the permeability of the blood-brain barrier has become a top priority.
  • the blood-brain barrier is a regulatory interface between capillaries and neural tissue in the brain and spinal cord. It is mainly composed of vascular endothelial cells of the central nervous system, perivascular glial cell processes and basement membrane, and is an important structure for maintaining the stability of the brain environment. Under physiological conditions, the blood-brain barrier can selectively pump harmful or excess substances in the brain out of the brain to keep the internal environment of the brain stable. However, in the treatment of brain diseases, the blood-brain barrier is a major obstacle to prevent the penetration of drugs into the brain, so that the drug can not achieve effective drug treatment concentration and affect the efficacy.
  • the blood-brain barrier includes: 1 blood cerebrospinal fluid barrier (BLB); 2 cerebrospinal fluid brain barrier (LBB); 3 blood-brain barrier (BBB); 4 cerebrospinal fluid-brain Tumor barrier and cerebrospinal fluid-lymphatic barrier. Since the surface area of BBB is about 5000 times the surface area of BLB, BBB is the main barrier to control the entry and exit of exogenous substances into the brain parenchyma.
  • ginsenoside extract and extract of Polygonum sinensis are important natural drugs for the treatment of brain diseases.
  • their active ingredients are ginsenoside Rb1, Rd, Re, Rg1, Shouwustilbene glycoside, Resveratrol, etc. It is not easy to enter the brain tissue through the blood-brain barrier.
  • commonly used chemical drugs for the prevention and treatment of cerebral ischemic diseases and neurodegenerative diseases such as levodopa, edaravone, vinpocetine, nigralin, citicoline, oxiracetam, etc.
  • Adenosine Receptor is a protein molecule that has been found to be extremely important in regulating the permeability of the blood-brain barrier in the tight junction of the blood-brain barrier in recent years. It is an endogenous adenosine molecule that regulates macromolecules through BBB.
  • a new, effective, endogenous blood-brain barrier regulation pathway in the brain is a pathway for promising drugs to enter the CNS in future clinical applications.
  • PLC PLC activates phosphatidylinositol system to produce inositol triphosphate (IP3) and diglyceride (DG), DAG, DG activates corresponding protein kinase C (PKC) and activates MLC kinase (MLCK), IP3 can promote The release of Ca 2+ from the endoplasmic reticulum of the cell interacts with DAG to activate and translocate PKC to tight junctions, directly or indirectly affecting, leading to myosin light chain (MLC), tightly linked structural proteins such as Occludin and ZO- 1. Serine/threonine phosphorylation of cytoskeletal proteins such as ZO-2 and ZO-3, calmodulin binding proteins.
  • MLC myosin light chain
  • Ginkgolide is the only sesquiterpene extracted from the ginkgo biloba ginkgo, and its structural formula is as follows:
  • the molecular formula is C 15 H 18 O 8 and its molecular weight is 326.3. It has good curative effect on cardiovascular and cerebrovascular diseases such as angina pectoris, myocardial infarction, coronary heart disease, hypertension and arrhythmia, which can reduce blood pressure, slow heart rate and increase Coronary flow has a protective effect on myocardial ischemia-reperfusion injury, and can also antagonize abnormal platelet aggregation and thrombosis caused by platelet activating factor, thereby reducing plasma viscosity and whole blood viscosity, and protecting nerves.
  • cardiovascular and cerebrovascular diseases such as angina pectoris, myocardial infarction, coronary heart disease, hypertension and arrhythmia, which can reduce blood pressure, slow heart rate and increase Coronary flow has a protective effect on myocardial ischemia-reperfusion injury, and can also antagonize abnormal platelet aggregation and thrombosis caused by platelet activating factor, thereby reducing plasma viscosity
  • CN102670586A discloses the use of ginkgolide in the preparation of a medicament for treating ischemic cardiomyopathy, which regulates cell survival rate, regulates platelet activating factor receptor and platelet activating factor acetylation. Hydrolase and reduction of cardiomyocyte apoptosis in the treatment of ischemic cardiomyopathy.
  • a new use of albino lactone and its derivatives for the treatment of brain edema, which achieves cerebral edema by regulating aquaporins is disclosed. Therapeutic effect.
  • the object of the present invention is to provide a new use of ginkgolide, in particular, the use of ginkgolide as a synergist in the preparation of a medicament for preventing and treating cranial nerve damage diseases, wherein the ginkgolide can promote nerve damage diseases of the brain.
  • the therapeutic or health-care drugs pass through the blood-brain barrier and give full play to the drug's efficacy.
  • Another object of the present invention is to provide a composition for a novel or health care product which can effectively increase the effective concentration of a pharmaceutically active molecule in the brain.
  • the ginkgo lactone according to the present invention is at least one of a natural product of ginkgolide, a lactone lactone extract, a natural product ginkgolide or a hydroxy derivative of a ginkgolide extract.
  • the ginkgolide extract is at least one of a ginkgolide extract or a ginkgo leaf extract, and the ginkgolide extract has a ginkgolide content of from 1 to 99%.
  • the hydroxy derivative of the natural product ginkgolide or biloba lactone extract is its glycoside, ester or ether.
  • the inventors have conducted a large number of research experiments, showing that ginkgolide, biloba lactone extract, and its hydroxy derivatives, especially its glycosides, esters, ether derivatives, etc., can effectively improve blood-brain barrier permeability and promote drugs.
  • the molecules enter the brain tissue.
  • the ginkgolide, the biloba lactone extract, and the hydroxy derivative thereof, particularly the glycoside, ester, and ether derivative thereof, can promote the expression of adenosine receptors in the microvascular endothelium of the brain tissue and inhibit the tight junction protein (ZO). -1 protein and occlaudin protein) expression, improve blood-brain barrier permeability, and promote drug molecules into brain tissue.
  • ZO tight junction protein
  • the active ingredient in the medicine or health care product for preventing and treating brain nerve damage diseases is selected from the group consisting of natural medicinal active ingredients: ginseng total saponin (containing ginsenoside Rb1, ginsenoside Rd, ginsenoside Re and ginsenoside Rg1, etc.), Shouwu stilbene glycoside, resveratrol, etc., or chemical components: levodopa, edaravone, vinpocetine, nigralin, citicoline, oxiracetam and the like.
  • the present invention provides a pharmaceutical or nutraceutical composition for preventing and treating a brain nerve damage disease, the pharmaceutical or health care composition comprising a ginkgolide synergist and a treatment for a brain nerve damage disease or A pharmaceutically active molecule that acts as a health care.
  • the ginkgolide synergist is at least one of a natural product of ginkgolide, a lactone lactone extract, a natural product ginkgolide or a hydroxy derivative of a ginkgolide extract;
  • the ginkgolide extract is at least one of a ginkgolide extract or a ginkgo biloba extract, and the ginkgolide extract has a ginkgolide content of from 1 to 99%.
  • hydroxy derivative of the natural product ginkgolide or biloba lactone extract is a glycoside, ester or ether thereof.
  • the medicinal active molecule having therapeutic or health-care effects on brain nerve injury diseases is selected from the group consisting of ginseng total saponins, shouwu stilbene glycosides, resveratrol, levodopa, edaravone, and vinca At least one of statin, nigeroline, citicoline or oxiracetam.
  • the ginkgolide, the biloba lactone extract, and the hydroxy derivative thereof, particularly the glycoside, ester, and ether derivative thereof, can be used as a medicine having therapeutic or health-care effects on brain nerve damage diseases.
  • the active ingredients are used in combination in the form of a health supplement.
  • the inventors have conducted a large number of research experiments, showing that biloba lactones, especially bilobalide, ginkgolides and their hydroxy derivatives, especially their glycosides, esters, ether derivatives and ginsenosides, Shouwu diphenyl Promote these active ingredients when combined with natural medicinal active ingredients such as ethylene glycoside and resveratrol or chemical components such as levodopa, edaravone, vinpocetine, ergoline, citicoline, and oxiracetam.
  • natural medicinal active ingredients such as ethylene glycoside and resveratrol or chemical components such as levodopa, edaravone, vinpocetine, ergoline, citicoline, and oxiracetam.
  • the composition of ginsenosides, stilbene glucoside, resveratrol, levodopa, edaravone, vinpocetine, ergoline, citicoline, oligo The concentration of rasacetine in brain tissue, and promotes neural stem cell proliferation and directed differentiation, anti-cerebral ischemic injury, neuroprotection, promoted differentiation of neural stem cells, improved learning and memory, and anti-senile dementia, and the main active ingredients are clear
  • the quality is stable, and the side effects of the active ingredient in the peripheral tissues are reduced, thereby reducing the toxicity and increasing the effect.
  • the weight ratio of ginseng lactone synergist: ginseng total saponin: Shouwu stilbene glycoside is 1: 10 to 60: 10 to 50.
  • the weight ratio of biloba lactone synergist: ginseng total saponin: resveratrol is 1:10-25: 10 to 20.
  • the pharmaceutically active ingredient for preventing and treating brain nerve damage diseases is vinpocetine
  • the weight ratio of the biloba lactone synergist and vinpocetine is 1:10-25.
  • the weight ratio of the biloba lactone synergist and levodopa is 1:10 to 50;
  • the pharmaceutical active ingredient for preventing and treating brain nerve damage disease is nigeroline
  • the weight ratio of ginkgolide synergist and nigeroline is 1:10-50;
  • the weight ratio of the biloba lactone synergist and oxiracetam is 1:20-50;
  • the weight ratio of the biloba lactone synergist and edaravone is 1:20-50;
  • the weight ratio of the lactone lactone synergist and the citicoline is 1:20-50.
  • the brain nerve injury disease according to the present invention is a cerebral ischemic injury disease or a neurodegenerative disease, wherein the cerebral ischemic injury disease is ischemic stroke, chronic cerebral ischemia, stroke sequelae or vascular dementia.
  • the neurodegenerative disease is senile dementia, Parkinson's disease, Alzheimer's disease or mild cognitive impairment.
  • ginkgolide compounds particularly ginkgolide, ginkgolide extract (ginkgolide extract or ginkgo biloba extract), and its hydroxy derivatives, especially its glycosides, have been extensively tested.
  • esters, ether derivatives can promote the treatment or health care of brain nerve damage diseases, such as ginseng total saponins, Shouwu stilbene or resveratrol, or other natural medicinal active ingredients or Levodopa, edaravone, vinpocetine, nigralin, citicoline, oxiracetam and other chemical components pass through the blood-brain barrier and enter the brain tissue without increasing the blood drug concentration of the drug molecule.
  • the concentration of drug molecules in brain tissue is greatly increased, and the effects of promoting neural stem cell proliferation and directed differentiation, anti-cerebral ischemic injury, neuroprotection, promoting differentiation of neural stem cells, improving learning and memory, and resisting senile dementia are effective.
  • the efficacy of the drug has been improved and unexpected technical effects have been achieved.
  • the pharmaceutical composition for preventing and treating brain nerve damage diseases provided by the invention has the main active ingredients and stable quality, and reduces the side effects of the active ingredients in the peripheral tissues by promoting the entry of the active drug molecules into the brain tissue, thereby reducing toxicity and increasing efficiency. effect.
  • the use of a small dose can be made into a variety of sustained release controlled release preparations and large-scale production.
  • the ginkgolide compound used in the present invention has a wide range of sources, is low in production cost, and is easy to use widely.
  • Figure 1 shows the reduction of cell resistance in the BBB model by ginkgolide.
  • Control normal control group
  • Bilo bilobalide group
  • SCH A2a adenosine receptor inhibitor group
  • SCH+ A2a adenosine receptor inhibitor + bilobalide group
  • DPCPX A1 adenosine receptor inhibitor Group
  • DPCPX+ A1 adenosine receptor inhibitor group + bilobalide group, compared with the normal group, ** P ⁇ 0.01; *** P ⁇ 0.001.
  • Figure 2 is a graph showing the effect of ginkgolide on the penetration of sodium fluorescein into the microvascular endothelium of brain tissue.
  • Control normal control group
  • Bilo bilobalide group
  • DPCPX A1 adenosine receptor inhibitor group
  • DPCPX+ A1 adenosine receptor inhibitor group + bilobalide group
  • Figure 3 is a graph showing the effect of bilobalide on the expression of BBB microvascular endothelial adenosine receptor.
  • Control normal control group
  • Bilo L low dose of bilobalide
  • Bilo H high dose of bilobalide
  • Egb L low dose of Ginkgo biloba extract
  • Egb H high dose of Ginkgo biloba extract
  • CCPA adenosine A1 receptor agonist (2-chlorocyclopentadenosine) group
  • Lexican A2a adenosine receptor agonist group
  • NECA non-selective adenosine receptor agonist (5-N-ethyl amide group) Adenosine group
  • Figure 4 is a graph showing the inhibition of BBB microvascular endothelial ZO-protein receptor expression by ginkgolide.
  • Control normal control group
  • DPCPX+ A1 adenosine receptor inhibitor group
  • DPCPX+Bilo A1 adenosine receptor inhibitor + bilobalide group
  • DPCPX+Egb A1 adenosine receptor inhibitor + ginkgo leaf Extract group.
  • the ginkgolide and the biloba lactone extract according to the present invention can be obtained by purchasing a commercially available product, or can be isolated and purified by the existing method, wherein the preparation and identification method of the ginkgolide can be referred to the China with the publication number CN101829109B.
  • the patent "the new use of albino lactone and its derivatives with aquaporin regulation in the treatment of brain edema” is disclosed by using a reflux extraction combined with column chromatography separation method to obtain ginkgolide from the ginkgo leaf powder, and The purity of bilobalide was determined by HPLC technique, and the structure of bilobalide was confirmed by IR, MS and NMR techniques.
  • the preparation method of ginkgo lactone can also be referred to from the Ginkgo biloba leaf by high-speed countercurrent chromatography (HSCCC) disclosed in Chinese Patent Application No. CN102670586A, "Application of Ginkgolide in Preparation of Medicine for Treating Ischemic Cardiomyopathy"
  • HSCCC high-speed countercurrent chromatography
  • BBB blood-brain barrier model
  • HEB human glial cells
  • hCMEC/D3 cells immortalized brain microvascular endothelial cells
  • the trans-endothelial resistance (TEER) of the co-culture model was determined by Millicell ERS as the sum of endothelial cells (EC) and TEER, in a cell-free culture cell.
  • the BBB in vitro model is basically established;
  • ginkgolide and its hydroxy derivatives can reduce the electrical resistance of BBB cells, increase the permeability of BBB, and promote the entry of drug molecules into brain tissue.
  • bilobalide significantly increased the osmotic concentration of sodium fluorescein by 70%; the osmolality of sodium fluorescein was also significantly increased after administration of the A2a adenosine receptor inhibitor SCH (P ⁇ 0.05).
  • ginkgolide and its hydroxy derivatives can promote the expression of adenosine receptor (AR) in the microvascular endothelium of brain tissue and inhibit tight junction protein ZO. -1 protein expression, improve BBB permeability, and promote the entry of drug molecules into brain tissue.
  • AR adenosine receptor
  • Ginkgolide extract (glycolide content ⁇ 99.0%) 5, 15g;
  • ginsenoside extract (ginsenoside Rg1 content ⁇ 95%) 300g;
  • Treatment group YXN1-1 and YXN1-2 were made into a suspension, and the YXN1-1 treatment group was dosed at 101.6 mg/kg (equivalent to ginsenoside extract 100 mg/kg), 20 mL/kg capacity, and 5 SD were administered. Rats; YXN1-2 treatment group was administered with 105 SD/kg dose (corresponding to ginsenoside extract 100 mg/kg), 20 mL/kg capacity, and 5 SD rats were intragastrically administered;
  • Control group another ginsenoside extract was prepared as a suspension. According to the ginsenoside extract 100 mg/kg dose, 20 mL/kg capacity, 5 SD rats were intragastrically administered;
  • UPLC-MS was used to detect the content of ginsenoside Rg1 in blood and brain tissue.
  • Another 40 MCAO forebrain ischemia was prepared and divided into 4 groups and 10 groups/group.
  • the vehicle saline, YXN1-1, YXN1-2 and ginsenoside extract were administered respectively.
  • the administration method and dosage were the same as above.
  • the experimental results showed that the concentration of ginsenoside Rg1 in the brain tissue of YXN1 was 5.4/9.4 times higher than that of ginsenoside-administered rats, when YXN1 and ginsenoside extracts containing the same amount of Rg1 were administered.
  • Ginkgolide extract (glycolide content ⁇ 20.0%) 20, 40g;
  • ginsenoside extract (ginsenoside Rg1 content ⁇ 30%) 200g;
  • Treatment group YXN2-1 and YXN2-2 were made into suspension.
  • the YXN2-1 treatment group was dosed at 220 mg/kg (equivalent to ginsenoside extract 200 mg/kg), 20 mL/kg capacity, and 5 SD large. Rats;
  • YXN2-2 treatment group according to the dose of 240mg / kg (equivalent to ginsenoside extract 200mg / kg), 20mL / kg capacity, gavage 5 SD rats;
  • Control group another ginsenoside extract was prepared as a suspension. According to the ginsenoside extract 200mg/kg dose, 20mL/kg capacity, 5 SD rats were intragastrically administered;
  • UPLC-MS was used to detect the content of ginsenoside Rg1 in blood and brain tissue.
  • Another 40 MCAO forebrain ischemia was prepared and divided into 4 groups and 10 groups/group.
  • the vehicle saline, YXN2-1, YXN2-2 and ginsenoside extract were administered respectively.
  • the administration method and dosage were the same as above.
  • the animals were sacrificed and the improvement rate of cerebral infarct size was observed.
  • the experimental results showed that the concentration of ginsenoside Rg1 in the brain tissue of YXN2 was 6.5/10 higher than that of ginsenoside extract alone, when YXN2 and ginsenoside extracts containing equal amounts of Rg1 were administered. Times. It indicates that the combination of ginsenoside and ginsenoside Rg1 can promote the ginsenoside Rg1 to penetrate the blood-brain barrier and improve the protective effect of cerebral ischemia.
  • Ginkgolide extract (glycolide content ⁇ 95.0%) 5, 10g;
  • Treatment group YXN3-1 and YXN3-2 were prepared as suspension.
  • the YXN3-1 treatment group was dosed at 102.5 mg/kg (equivalent to 100 mg/kg of Polygonum multiflorum extract), 20 mL/kg capacity, and 5 SD large. Rats;
  • YXN3-2 treatment group according to the dose of 105mg / kg (equivalent to Polygonum multiflorum extract 100mg / kg), 20mL / kg capacity, gavage 5 SD rats;
  • Control group Another extract of Polygonum multiflorum was prepared as a suspension. According to the dose of 100 mg/kg of Polygonum multiflorum extract, 20 mL/kg capacity, 5 SD rats were intragastrically administered;
  • Another 40 cases of 4-VO cerebral ischemia were prepared and divided into 4 groups, 10 rats/group, respectively, and the vehicle saline, YXN3-1, YXN3-2 and Polygonum multiflorum extract were administered. The administration method and dosage were the same as above. Animals were sacrificed in the day to observe the rate of nerve regeneration and learning and memory improvement.
  • Ginkgolide extract (glycolide content ⁇ 98.0%) 5g;
  • Resveratrol (resin content of 99%) 100g;
  • Treatment group YXN4 was made into a suspension, and 5 SD rats were intragastrically administered at a dose of 105 mg/kg (corresponding to 100 mg/kg of resveratrol) and a volume of 20 mL/kg.
  • Control group another suspension of resveratrol was prepared, and 5 SD rats were intragastrically administered with a dose of resveratrol at a dose of 100 mg/kg and a volume of 20 mL/kg.
  • UPLC-MS was used to detect the content of resveratrol in blood and brain tissue.
  • Another 30 MCAO forebrain ischemia was prepared and divided into 3 groups, 10 rats/group, respectively.
  • the vehicle was treated with normal saline, YXN4, and resveratrol.
  • the administration method and dosage were the same. After 7 days of administration, the animals were sacrificed and the brain was observed. Infarct area improvement rate.
  • the experimental results showed that the blood concentration of YXN4 and resveratrol alone was not significant, but the content of resveratrol in the brain tissue of YXN4 was higher than that of rats treated with resveratrol alone. At 8.1 times higher, the improvement rate of cerebral infarct size in MCAO cerebral ischemia rats was increased by 1.54 times. It shows that the combination of ginkgolide derivatives and resveratrol can promote the respiration of resveratrol through the blood-brain barrier, have a brain-targeting effect, and can improve the anti-cerebral ischemic injury.
  • YXN5 commercially available ginkgolide extract (content ⁇ 20%), ginseng total saponin extract (content ⁇ 30%), Shouwu stilbene glycoside (content ⁇ 50%), according to the weight of 1:12:8 composition.
  • YXN6 commercially available ginkgolide (content ⁇ 60%), ginseng total saponin extract (content ⁇ 90%), Shouwu stilbene glycoside (content ⁇ 60%), composed of 1:10:5 by weight .
  • RSSW ginseng total saponin extract (content ⁇ 90%), Shouwu stilbene glycoside (content ⁇ 60%), composed of 10:5 parts by weight.
  • Treatment group YXN5, YXN6, RSSS were made into suspension, and 5 SD rats were intragastrically administered at a dose of 100 mg/kg and a volume of 20 mL/kg.
  • Control group Another ginseng total saponin extract (content ⁇ 90%) was prepared as a suspension, and 5 SD rats were intragastrically administered at a dose of 50 mg/kg and a volume of 20 mL/kg.
  • UPLC-MS was used to detect the content of active ingredients in blood and brain tissue.
  • Another 50 MCAO forebrain ischemia was prepared and divided into 5 groups and 10 groups/group.
  • the vehicle was treated with normal saline, YXN5, YXN6, RSSW and total ginsenoside extract.
  • the administration method and dosage were the same as above. After 7 days of administration, the drug was sacrificed. Animals, observe the improvement rate of cerebral infarction area, observe the rate of nerve regeneration and learning and memory improvement.
  • the area of cerebral infarction can be reduced, the rate of brain nerve regeneration can be improved, and the improvement, improvement of learning and memory, and spatial exploration distance (cm) can be prolonged.
  • the potency is stronger than the ginseng total saponin extract or RSSW alone.
  • Ginkgolide extract promotes the penetration of active ingredients of traditional Chinese medicine through the blood-brain barrier, enhances anti-cerebral ischemic injury and neuroprotection, and improves learning and memory.
  • YXN7 commercially available ginkgolide extract (content ⁇ 60%), vinpocetine (content ⁇ 98%), composed of 10:25 parts by weight, made into tablets 5mg / tablet;
  • YXN8 commercially available ginkgolide (content ⁇ 98%), edaravone (content ⁇ 98%), composed of 10:30 parts by weight;
  • YXN9 commercially available ginkgolide (content ⁇ 98%), oxiracetam (content ⁇ 98%), composed of 10:35 parts by weight, made into capsules, 400 mg / granule.
  • Treatment group YXN7, YXN8, YXN9 were separately prepared as suspension, YXN7 was administered with 5 SD rats at a dose of 5 mg/kg and 20 mL/kg; YXN8 was administered at a dose of 15 mg/kg and 20 mL/kg for 5 SD large Rats; YXN9 was administered with 5 SD rats at a dose of 400 mg/kg and a volume of 20 mL/kg.
  • Control group Another suspension of vinpocetine, edaravone, and oxiracetam was prepared at a dose of 5 mg/kg, 15 mg/kg, and 400 mg/kg, and a volume of 20 mL/kg was administered to 5 SD large groups. mouse.
  • UPLC-MS was used to detect the content of active ingredients in blood and brain tissue.
  • Another 70 MCAO forebrain ischemia rats were prepared and divided into 7 groups, 10 rats in each group, respectively, given vehicle physiological saline, YXN7, YXN8, YXN9, vinpocetine, edaravone, oxiracetam, and administered. The method and dose were the same as above. After 7 days of administration, the animals were sacrificed to observe the improvement rate of cerebral infarct area, and the rate of nerve regeneration and learning and memory improvement was observed.
  • the infarct size can be reduced, the rate of brain nerve regeneration can be improved, and the improvement, the improvement of learning and memory, and the space exploration distance (cm) can be prolonged.
  • the efficacy is stronger than that of vinpocetine, edaravone, and oxiracetam.
  • Ginkgolide extract promotes the penetration of active ingredients of traditional Chinese medicine through the blood-brain barrier, enhances anti-cerebral ischemic injury and neuroprotection, and improves learning and memory.
  • YXN10 commercially available ginkgolide extract (content ⁇ 60%), levodopa, composed of 10:40 parts by weight;
  • YXN11 commercially available ginkgolide (content ⁇ 98%), levodopa, consisting of 10:50 parts by weight.
  • Treatment group YXN10 and YXN11 were prepared as suspensions, and 5 SD rats were intragastrically administered with a dose of 150 mg/kg of levodopa and a volume of 20 mL/kg.
  • Control group Another suspension of levodopa was prepared, and 5 SD rats were intragastrically administered at a dose of 150 mg/kg and a volume of 20 mL/kg.
  • UPLC-MS was used to detect the content of active ingredients in blood and brain tissue.
  • Another 40 rats of 6-hydroxydopamine Parkinson's disease model were prepared and divided into 4 groups, 10 rats in each group, respectively, given vehicle physiological saline, YXN10, YXN11 and levodopa.
  • the administration method and dosage were the same as above.
  • the changes of the five indicators such as the slow-moving experiment, the grasping experiment, the tail stiffness, the change of the tonic symptoms, and the tremor experiment were observed.
  • Test Example 1 Application in clinical treatment of ischemic stroke sequelae
  • ginseng total saponin capsules Sixty volunteers with cerebral infarction sequelae were screened and randomly divided into ginseng total saponin capsules, RSSW capsules, and YXN5 capsule treatment groups, 20 in each group.
  • the 20 patients with ginseng total saponin capsule group 13 were male and 7 were female; the age ranged from 38 to 72 (51.6 ⁇ 6.6) years; the course of disease was 37-82 (51.0 ⁇ 7.1) days.
  • the 20 patients in the RSSW capsule group 13 were male and 7 were female; the age ranged from 37 to 74 (51.8 ⁇ 7.0) years; the course of disease was 37-81 (51.8 ⁇ 7.3) days.
  • Ginsenoside saponin capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • RSSW capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • YXN5 capsule group 125 ⁇ 250mg, 3 times / d, according to the condition, individualized administration.
  • Example 6 The composition of the components in each group of capsules is shown in Example 6.
  • ginseng total saponin capsules Three groups of patients were given ginseng total saponin capsules, RSSW capsules and YXN5 capsules. The treatment of each group was started after the treatment, and the treatment was continued for 14 days. The observation time was 4 courses.
  • Observation indicators were used to record the scores of neurological deficits and activities of daily living activities before and after treatment in the two groups.
  • the curative effect criteria were cured: after treatment, the clinical symptoms and signs disappeared or disappeared, the treatment index was 95%; markedly effective: the signs after treatment were significantly improved, 70% ⁇ treatment index ⁇ 95%; effective: signs after treatment improved, 30% ⁇ treatment index ⁇ 70%; invalid: no improvement in signs after treatment, treatment index ⁇ 30%.
  • Total effective rate (healing + effective + effective) / total number of cases
  • NHSS Neurological deficit score
  • the total effective rate of the three groups was higher, and the neurological function was significantly improved after treatment. Compared with the three groups, the effect of ginseng total saponin capsule ⁇ RSSW capsule ⁇ YXN5 capsule, no significant difference, see Table 13.
  • the total effective rate of the three groups was higher, and the curative effect was obvious after treatment.
  • the efficacy of YXN5 capsule group was 90%, which was better than RSSW capsule and ginseng total saponin capsule group. The difference was statistically significant (chi-square test, * P ⁇ 0.05). See Table 15.
  • Test Example 2 Application in clinical treatment of Parkinson's disease
  • All cases from 2010 to 2014 were selected from 100 patients with neurological subjects who met the diagnostic criteria of Parkinson's disease and were diagnosed with Parkinson's disease by clinical examination. They were randomly divided into ginseng total saponin capsule group, RSSW capsule group, YXN5 capsule group, YXN10 capsule group and levodopa group. Among them, there were 20 cases of ginseng total saponin capsule group, 12 males and 8 females; the course of disease was 1-12 years. , an average of 3.7 years; aged 47 to 70 years, an average of 56.4 years.
  • the diagnostic criteria diagnosis based on the 2010 approved Parkinson's disease diagnosis and treatment guidelines (Beijing Union Medical College Hospital. Parkinson's disease diagnosis and treatment guidelines. Chinese clinicians, 2010, 38 (2): 77-79.) Sexual PD patients.
  • Exclusion criteria (a) Parkinson's disease caused by severe heart, lung and kidney dysfunction, secondary to cerebrovascular disease, trauma and other neurological and psychiatric disorders; (b) PD superimposed syndrome; (c) suffering from Malignant tumors, disability, and other serious cases of severe neurological, hematological, and endocrine diseases; (d) Symptomatic Parkinson's syndrome, patients with psychosis, substance abuse, and history of alcohol abuse.
  • the main symptoms of traditional Chinese medicine refer to the guiding principles of clinical research of new Chinese medicine; the guiding principle of clinical research of new Chinese medicine for treating senile dementia.
  • Ginsenoside saponin capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • RSSW capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • YXN5 capsule group 125 ⁇ 250mg, 3 times / d, according to the condition, individualized administration.
  • Example 6 The composition of the components in each group of capsules is shown in Example 6.
  • YXN10 capsule group 250mg/granule, 1 capsule/time, 3 times a day.
  • Levodopa tablet group 200 mg/tablet, 1 tablet/time, 3 times a day.
  • Example 8 The composition of the components in each group of tablets is shown in Example 8.
  • ginseng total saponin capsules Five groups of patients were given ginseng total saponin capsules, RSSC capsules, YXN5 capsules, YXN10 capsules and levodopa tablets. The treatment of each group began after the treatment, and the medication was continued for 15 days, and the drug was shared for 9 months. Use other cerebral vasodilator drugs, brain cell metabolism drugs, neurological function regulating drugs. The efficacy of each group was evaluated after 1, 3, 6, and 9 months of treatment.
  • Efficacy index (pre-treatment score - post-treatment score) / pre-treatment score x 100%.
  • the efficacy index ⁇ 85% is cured; 70-84% is significant; 20%-69% is effective; ⁇ 20% is ineffective.
  • the finger and limbs vibrate, shake, muscle stiffness caused by a certain position of the limb or all limbs can not be autonomous activities and other symptoms are significantly improved, can walk on foot, upper limbs and lower extremity muscle strength recovery level 2 or above.
  • Fingers and limbs vibrate, shake, muscle stiffness caused by a certain multiple of the limbs or all limbs can not be autonomous activities and other symptoms improved, the upper limbs and lower limbs muscle strength recovered to level 1 or above.
  • the severity of motor symptoms was assessed using the PD Unified Rating Scale (UPDRS) Part III and the Hoehn-Yahr Rating Scale. Patients with normal life ability were assessed using the PD Unified Rating Scale (UPDRS) Part II and the Daily Living Ability Questionnaire (ADCS-ADL). The patient's spirit, behavior, and mood were assessed using the PD Unified Rating Scale (UPDRS) Part I.
  • UDRS PD Unified Rating Scale
  • YXN5 capsules containing biloba lactone synergist can significantly improve the mental, behavioral and emotional (UPDRS-I) scores of PD, daily living activities (UPDRS-II), and motor function tests (UPDRS).
  • UDRS-I mental, behavioral and emotional
  • UDRS-II daily living activities
  • UDRS-II motor function tests
  • YXN5 capsule containing biloba lactone synergist can significantly increase the brain of ginseng total saponin and saponin
  • the targeted effect of the department has the effects of relieving muscle tremor and muscle stiffness, and the symptoms such as unfavorable language, insomnia, irritability, irritability, and tongue defects are very obvious, which significantly improves the symptoms of Parkinson's disease.
  • YXN10 capsules containing biloba lactone synergist can significantly improve the mental, behavioral and emotional (UPDRS-I) scores of PD, daily living activities (UPDRS-II), and motor function tests (UPDRS).
  • -III) score score
  • UDRS-IV exercise complication
  • LSIB quality of life score scale
  • Test Example 3 Application in clinical treatment of vascular dementia
  • vascular dementia 110 volunteers with vascular dementia were screened, 60 males and 50 females; aged 58-74 years, mean 63.1 years; the shortest course was 1 year, the longest was 11 years, and the average was 3.6 years.
  • Volunteer patients were randomly divided into ginseng total saponin capsule group, RSSW capsule group, YXN5 capsule group, YXN7 tablet group and vinpocetine tablet group, with 22 people in each group.
  • the diagnostic criteria the diagnostic criteria for vascular dementia in DSM-IV.
  • Exclusion criteria severe neurological, blood, endocrine and other primary diseases and the Haijinsky ischemic index (HIS), total score 18 Points, score ⁇ 7 is divided into senile dementia.
  • HIS Haijinsky ischemic index
  • Scale selection 1. American simple intelligence scale, total score of 30 points, if the score ⁇ 16 points for intelligent obstacles; 2. Japan Hasegawa dementia scale, total score of 30 points, if the score ⁇ 16 points for dementia ; 3. Haijinsky ischemic refers to the number of tables (HIS), a total score of 18 points, if the score is > 7 points for vascular dementia, score ⁇ 7 points for senile dementia.
  • HIS tables
  • the expression is sluggish, the language is unfavorable, or the language is inferior or the language is wrong, forgetting, not swearing, dizziness, headache, and tongue licking.
  • the comprehensive assessment method was adopted to take the changes in the intelligence state and physical signs before and after treatment as the comprehensive review content, with the focus on intelligent change.
  • the recovery score of the recovery of the Hasegawa dementia scale increased to a normal value, the score of the effective person increased by 5 points or more, and the score of the effective person increased by less than 5 points, and the score of the invalid person not only increased but decreased.
  • Ginsenoside saponin capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • RSSW capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • YXN5 capsule group 125 ⁇ 250mg, 3 times / d, according to the condition, individualized administration.
  • Example 6 The composition of the components in each group of capsules is shown in Example 6.
  • YXN7 tablet group 5 mg/tablet, 1 tablet each morning and evening.
  • Vinpocetine tablet group 3.57 mg/tablet, 1 tablet each morning and evening.
  • Example 7 The composition of the components in each group of tablets is shown in Example 7.
  • the above five groups of patients were given ginseng total saponin capsules, RSSW capsules, YXN5 capsules, YXN7 tablets and vinpocetine tablets.
  • the treatment of each group was started after the treatment, and the drug was administered continuously for 2 months as a course of treatment. During the course of treatment, other cerebral vasodilator drugs, brain cell metabolism drugs, and neuromodulation drugs were discontinued.
  • YXN5 capsules, RSSW capsules and ginseng total saponins capsules have significant effects on the intelligence of vascular dementia.
  • YXN5 capsule containing biloba lactone synergist has the best effect on vascular dementia, indicating that YXN5 capsule containing biloba lactone synergist can significantly improve the brain-targeting effect of drug active molecules and fully exert its vascularity. Therapeutic enhancement of dementia.
  • YXN7 tablets and Vinpocetine tablets have a significant improvement in the intelligence of vascular dementia.
  • YXN7 tablets containing biloba lactone synergist have the best effect on vascular dementia, indicating that YXN7 tablets containing biloba lactone synergist can significantly improve the brain-targeting effect of vinpocetine and fully exert its vascularity.
  • Therapeutic enhancement of dementia is not limited to the above Tables 31-33.
  • Test Example 4 Application in clinical treatment of senile dementia
  • AD Alzheimer's disease
  • HIS Haijinsky Ischemic Index
  • Ginsenoside saponin capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • RSSW capsule group 250mg/granule, 2 capsules/time, 3 times a day.
  • YXN5 capsule group 125 ⁇ 250mg, 3 times / d, according to the condition, individualized administration.
  • Example 6 The composition of the components in each group of capsules is shown in Example 6.
  • YXN5 capsules have the best effect on the treatment of senile dementia, with a total effective rate of 73.33%, which is superior to ginseng total saponin capsules, indicating that YXN5 capsules containing biloba lactone synergist can significantly increase the activity of medicinal molecules.
  • the brain is targeted for efficacy and fully exerts a therapeutic effect on senile dementia.

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Abstract

L'invention concerne une application du bilobalide comme activateur dans la préparation de médicaments ou de produits de soins de santé pour la prévention de maladies de type lésions de nerfs crâniens. Le bilobalide et des dérivés hydroxyle de ce dernier peuvent faciliter la pénétration dans les tissus cérébraux de divers médicaments à fonction thérapeutique ou de soins de santé sur les maladies de type lésions de nerfs crâniens, y compris le ginsénoside, le glucoside de stibène, le resvératrol, la lévodopa, l'édaravone, la vinpocétine, la nicergoline, la citicoline, l'oxiracétam, et analogues. L'efficacité des médicaments peut être améliorée, et les effets indésirables et réactions indésirables des médicaments peuvent être diminués.
PCT/CN2016/113602 2016-12-22 2016-12-30 Application du bilobalide comme activateur dans la préparation de médicaments pour la prévention de maladies de type lésions de nerfs crâniens WO2018113027A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111494390A (zh) * 2020-05-18 2020-08-07 南通大学 白桦醇衍生物在制备修复神经损伤药物中的新用途
IT201900018089A1 (it) * 2019-10-07 2021-04-07 Dymalife Res S R L Associazione per l’uso nel trattamento e prevenzione di ischemia cerebrale e successiva riperfusione

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117159535A (zh) * 2018-05-25 2023-12-05 成都百裕制药股份有限公司 一种预防和/或治疗震颤的组合物、药物、保健品
CN109528782A (zh) * 2018-12-30 2019-03-29 广东药科大学 银杏叶提取物作为增效剂在制备对睡眠障碍疾病具有治疗或保健的药物的应用
CN109833320B (zh) * 2019-03-19 2021-05-25 河北工业大学 人参皂苷在制备激活tmem16a离子通道的产品中的应用、激活剂、试剂盒和药物
CN111329853A (zh) * 2020-04-21 2020-06-26 遵义医科大学 一种治疗帕金森病的药物组合物及其应用和治疗帕金森病的药物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1660224A (zh) * 2004-12-24 2005-08-31 陕西爱波卓科技有限责任公司 一种植物提取的高效抗氧化组合物
CN101011405A (zh) * 2007-01-09 2007-08-08 贵州信邦远东药业有限公司 一种治疗缺血性脑血管疾病的药物组合物
CN102233009A (zh) * 2011-06-21 2011-11-09 广东药学院 一种促进神经再生的中药组合物及其制备方法和应用
US20160038550A1 (en) * 2014-07-22 2016-02-11 Craig E. Kinzer Methods and compositions for treating conditions associated with memory loss
CN105853473A (zh) * 2016-03-31 2016-08-17 海南合瑞制药股份有限公司 一种奥拉西坦的药物组合物及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103285051A (zh) * 2012-03-01 2013-09-11 郑州锦宏瑞达医药科技有限公司 银杏提取物和长春西汀的复合制剂及用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1660224A (zh) * 2004-12-24 2005-08-31 陕西爱波卓科技有限责任公司 一种植物提取的高效抗氧化组合物
CN101011405A (zh) * 2007-01-09 2007-08-08 贵州信邦远东药业有限公司 一种治疗缺血性脑血管疾病的药物组合物
CN102233009A (zh) * 2011-06-21 2011-11-09 广东药学院 一种促进神经再生的中药组合物及其制备方法和应用
US20160038550A1 (en) * 2014-07-22 2016-02-11 Craig E. Kinzer Methods and compositions for treating conditions associated with memory loss
CN105853473A (zh) * 2016-03-31 2016-08-17 海南合瑞制药股份有限公司 一种奥拉西坦的药物组合物及其制备方法

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CEN, CHUAN ET AL.: "The Side Effects of LD and the Progress of the Prevention and Treatment of TCM for Parkinson's Disease", CHINESE ARCHIVES OF TRADITIONAL CHINESE MEDICINE, vol. 27, no. 12, 31 December 2009 (2009-12-31), pages 2530 - 2532 *
CHEN, ZANLI: "Observation on Effect of Vinpocetine Combined With Shuxuening on treatingVertebro-Basilar Artery Insufficiency Vertigo", CHINESE JOURNAL OF CLINICAL RATIONAL DRUG USE, vol. 5, no. 9B, 30 September 2012 (2012-09-30), pages 91 and 92 *
HOU ET AL.: "Effect of Ginkgo Biloba Extract Combined with Edaravone on Cell Apoptosis and bcl-2/bax Expression in Rats with Qi Deficiency and Blood Stasis Type Ischemia Reperfusion", ACTA ACADEMIAE MEDICINAE WANNAN, vol. 30, no. 4, 31 December 2011 (2011-12-31), pages 264 - 267 *
LIU, XIUPING ET AL.: "Ginkgolide and bilobalide Play a Protective Role in Cerebral Ischem ia by Down-regulating PAK1-PP2A Pathway and Inhibiting Cx43 Dephosphorylation", THE 15TH CONGRESS OF CHINESE CEREBROVASCULAR DISEASE ABSTRACTS, 10 April 2015 (2015-04-10) *
YUAN, HUILI ET AL.: "Mechanism and Research Progress of Chinese Traditional Medicine in The Prevention and Treatment of Parkinsons Disease", ACTA PHYSIOLOGICA SINICA, vol. 62, no. 1, 18 October 2010 (2010-10-18), pages 166 and 167 *
ZHANG, CHENHONG ET AL.: "Observation on curative effect of ginkgo biloba leaf and citicoline on treating vascular dementia", MODERN MEDICINE & HEALTH, vol. 27, no. 22, 31 December 2011 (2011-12-31), pages 3393 and 3394 *
ZHAO, YING ET AL.: "Observation on Curative Effect of Ginkgo Biloba Leaf and Citicoline on Treating Vascular Dementia", MODERN JOURNAL OF INTEGRATED TRADITIONAL CHINESE AND WESTERN MEDICINE, vol. 20, no. 34, 31 December 2011 (2011-12-31), pages 4351 and 4352. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201900018089A1 (it) * 2019-10-07 2021-04-07 Dymalife Res S R L Associazione per l’uso nel trattamento e prevenzione di ischemia cerebrale e successiva riperfusione
CN111494390A (zh) * 2020-05-18 2020-08-07 南通大学 白桦醇衍生物在制备修复神经损伤药物中的新用途
CN111494390B (zh) * 2020-05-18 2022-08-19 南通大学 白桦醇衍生物在制备修复神经损伤药物中的新用途

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