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WO2011088715A1 - Utilisation d'albiflorine pour le traitement de la maladie de parkinson - Google Patents

Utilisation d'albiflorine pour le traitement de la maladie de parkinson Download PDF

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WO2011088715A1
WO2011088715A1 PCT/CN2010/079976 CN2010079976W WO2011088715A1 WO 2011088715 A1 WO2011088715 A1 WO 2011088715A1 CN 2010079976 W CN2010079976 W CN 2010079976W WO 2011088715 A1 WO2011088715 A1 WO 2011088715A1
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paeoniflorin
disease
lactone
parkinson
group
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张作光
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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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a medicament or health food for preventing, alleviating and/or treating a neurodegenerative disease, and more particularly to a drug or health food resistant to Parkinson's disease. Background technique
  • Degenerative diseases of the nervous system are a general term for a group of diseases caused by degenerative degeneration of chronic progressive central nervous tissue. Pathologically, neuronal degeneration and loss of brain and/or spinal cord were observed. The main diseases include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington disease (HD) amyotrophic lateral s clerosis (ALS) ) Wait.
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • HD Huntington disease
  • ALS amyotrophic lateral s clerosis
  • Parkinson's Disease also known as 'shock paralysis
  • PD Parkinson's Disease
  • 'shock paralysis is a major type of neurodegenerative disease
  • an age-related neurodegenerative disease with reduced exercise, increased muscle tone, and Tremor is the main symptom.
  • Parkinson's disease is basically a disease of middle and old people; its incidence increases with age; the prevalence of people over 60 years old is 1%. Parkinson's disease is very slow, often with motor symptoms, such as tremors, and the sides are not symmetric. Later, some patients will have psychiatric symptoms such as depression, dementia, personality changes and so on. The survival time of untreated patients is 1 to 30 years, mostly 8 to 10 years.
  • the major lesions in Parkinson's disease are characterized by selective loss of dopaminergic neurons in the melanocytes, decreased dopamine content in the striatum, and the presence of Lewy bodies in the presence of substantia nigra and blue spots. The etiology has not yet been fully understood. At present, most scholars believe that environmental and genetic factors play an important role in the pathogenesis of Parkinson's disease.
  • Parkinson's disease is still dominated by levodopa-type drug replacement therapy, but these preparations have large side effects. Although they can significantly improve the clinical symptoms of patients in a short period of time, they cannot slow down the progress of the disease. And with the prolonged application time, the effect is gradually weakened, and the side effects become more and more serious, which accelerates the death of residual dopaminergic neurons. Therefore, it is necessary to explore and develop new drugs for the treatment of Parkinson's disease.
  • Albiflorin is a monoterpenoid with a molecular formula of C 23 H 28 O u and a molecular weight of 480.46. Its molecular structure is as shown in formula ( I ). It is a natural active substance derived from the genus Ranunculaceae. Paeonia lactiflora Pall or Paeonia veitchii Lynch root, Peony Rsuffrsticosa Andrz Root.
  • Paeoniflorin has a lactone ring structure, but has no hemiacetal structure, which is converted into two products under anaerobic conditions, namely paeoni lactone and paeoni lactone 8 .
  • the structure diagram of paeoni lactone and B is as follows:
  • paeoniflorin has analgesic, sedative, anticonvulsant effects, effects on the immune system, effects on smooth muscle, anti-inflammatory effects, anti-pathogenic microorganisms, liver protection, clinically used mainly for anti-epilepsy, Analgesic, detoxification, vertigo, treatment of rheumatoid arthritis, treatment of bacterial dysentery and enteritis, treatment of viral hepatitis, senile diseases, anti-sulphate flocculation and dissolution of mucus.
  • the use of paeoniflorin for the preparation of a medicament for the prevention, alleviation and treatment of Parkinson's disease has not been reported.
  • the inventors have extracted the paeoniflorin, an active ingredient of Parkinson's disease, from a peony medicinal material by a large amount of modern scientific research, and the content thereof is more than 50%, and the paeoniflorin and its The corresponding pharmaceutical preparations have been used to alleviate and treat the pharmacodynamics and pharmacology of Parkinson's disease.
  • the results show that the pharmacological effects of the paeoniflorin monomer are clear, the efficacy of treating Parkinson's disease is remarkable, the side effects are low, and the safety is high. Provide a highly effective and low-toxic drug for patients with Parkinson's disease. Summary of the invention
  • the primary object of the present invention is to provide a paeoniflorin, a paeoni lactone metabolite, a paeoniflorin composition, Medicament containing paeoniflorin or medicinal extract containing paeoniflorin has the efficacy of preventing, alleviating and treating neurodegenerative diseases, especially the performance and efficacy against Parkinson's disease, and exists in view of the above prior art
  • an aspect of the present invention provides a use of a paeoniflorin for the preparation of a medicament for preventing, ameliorating and/or treating a neurodegenerative disease, a health care product.
  • the neurodegenerative disease is Parkinson's disease.
  • the inventors found that one of the chemical components in the extract of traditional Chinese medicine, the paeoniflorin, has a strong pharmacological effect, and the paeoniflorin is found in the human body.
  • peonylide refers to a racemate, a stereoisomer or a mixture of stereoisomers mixed in an arbitrary ratio of paeoniflorin.
  • the "peiolactone” further includes two metabolites of paeoniflorin, paeoni lactone.
  • the paeoniflorin has a purity of 50%, preferably 80%, more preferably 90%.
  • the content of the paeoniflorin is 50%, preferably 80%, more preferably 90%.
  • the drug consists of paeoniflorin and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of the agent.
  • a compilation of pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical excipients, 2nd edition, edited by A. Wade and P. J. Weller; American Pharmaceutical Association, Washington and The Pharmaceutical
  • the carrier includes excipients such as starch, water, etc.; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; a binder; Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavoring agents, spices, etc.
  • the drug is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an injection, a spray, an aerosol, a patch or the like.
  • the drug is administered by gastrointestinal administration and parenteral administration.
  • parenteral administration route is selected from the group consisting of injectable administration, respiratory administration, dermal administration, mucosal administration or intraluminal administration.
  • non-gastrointestinal administration agents are selected as injections, sprays, aerosols, patches, and the like.
  • the parenteral administration preparation comprises a tablet, a capsule, a powder, a granule, a pill, a solution or a syrup.
  • Another aspect of the present invention provides a use of a paeoniflorin composition for the preparation of a medicament for preventing, ameliorating and/or treating a neurodegenerative disease, a health care product.
  • the neurodegenerative disease described therein is Parkinson's disease.
  • the paeoniflorin composition is a pharmaceutically acceptable salt of paeoniflorin or a solvate of paeoniflorin.
  • the pharmaceutically acceptable salt of the paeoniflorin is a salt which is physiologically acceptable, especially when applied as a medicament to humans and/or mammals.
  • the salt comprises a salt obtained by the addition reaction of paeoniflorin with an acid; and the solvate of the paeoniflorin is a hydrate of paeoniflorin.
  • the acid is selected from one or more of hydrochloric acid, fumaric acid, maleic acid, citric acid or succinic acid, and the acids mentioned are for illustrative purposes only and are not intended to be limiting.
  • a medicinal material containing a peony lactone or a medicinal material extract containing a peony lactone for use in the preparation of a medicament for preventing, alleviating and/or treating a neurodegenerative disease, a health care product.
  • the neurological degeneration described therein is Parkinson's disease.
  • the medicinal material containing paeoniflorin is selected from the group consisting of peony or peony bark.
  • the peony is white or red peony, preferably white peony.
  • the peony lactone glycoside in the medicinal material extract containing the peony lactone has a purity of 6%.
  • the paeoniflorin-containing extract of the paeoniflorin-containing medicinal material has a purity of 6 to 49%, preferably 10 to 40%, more preferably 14 to 24%.
  • Another aspect of the present invention provides a use of a paeoniflorin metabolite for the preparation of a medicament for preventing, ameliorating and/or treating a neurodegenerative disease, a health care product.
  • the neurodegenerative disease is Parkinson's disease.
  • a medicament for preventing, alleviating and/or treating Parkinson's disease comprising a paeoniflorin.
  • the paeoniflorin has a purity of 50%, preferably 80%, more preferably 90%.
  • the medicament further comprises a pharmaceutically acceptable carrier.
  • a further aspect of the present invention provides a medicament for preventing, alleviating and/or treating Parkinson's disease, comprising at least one of the following: a paeoniflorin metabolite, a paeoniflorin composition, and a paeoniflorin-containing Medicinal material or medicinal extract containing peony lactone.
  • the drug consists of one of a paeoniflorin metabolite, a paeoniflorin composition, a paeoniflorin-containing medicinal material or a paeoniflorin-containing medicinal material extract and a pharmaceutically acceptable carrier.
  • the peony lactone glycoside in the medicinal material extract containing the peony lactone has a purity of 6%.
  • the paeoniflorin-containing extract of the paeoniflorin-containing saccharide has a purity of 6% to 49%, preferably 10% to 40%, more preferably 14% to 24%.
  • the paeoniflorin composition selects a pharmaceutically acceptable salt of paeoniflorin and a solvate of paeoniflorin.
  • the pharmaceutically acceptable salt of the paeoniflorin is a salt which is physiologically acceptable, especially when applied as a medicament to humans and/or mammals.
  • the salt comprises a salt obtained by the addition reaction of paeoniflorin with an acid.
  • the acid is selected from one or more of hydrochloric acid, fumaric acid, maleic acid, citric acid or succinic acid, and the acids mentioned are for illustrative purposes only and are not intended to be limiting.
  • solvate of the paeoniflorin is a hydrate of paeoniflorin
  • the medicinal material containing paeoniflorin is selected from the group consisting of paeoniflorin or peony bark, preferably white peony.
  • the carrier includes an excipient such as starch, water or the like; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; a binder; Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavoring agents, spices, etc.
  • the medicament may be formulated into various dosage forms such as tablets, capsules, pills, powders, granules, syrups, solutions, injections, sprays, aerosols, patches, and the like, by methods well known in the art.
  • a health food for preventing, alleviating and/or treating Parkinson's disease which comprises one of the following: paeoniflorin, paeoniflorin metabolite, paeoniflorin composition, ⁇ A medicinal material of a drug lactone or a medicinal material extract containing a peony lactone.
  • the paeoniflorin has a purity of 6%.
  • the paeoniflorin-containing extract of the paeoniflorin-containing medicinal material has a purity of 6% to 49%, preferably 10% to 40%, more preferably 14% to 24%.
  • the present invention also provides a method of treating a Parkinson's disease, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of the paeoniflorin, wherein the therapeutically effective amount is 0.6 to 4 mg/kg ⁇ d, preferably 1 ⁇ 3. 5 ⁇ 3mg/kg ⁇ d. More preferably, it is 1. 2 ⁇ 3mg/kg ⁇ d.
  • therapeutically effective amount is the amount of the drug in need of an effective effect; “therapeutically effective amount” is adjusted and varied, and is ultimately determined by the medical personnel, the factors considered including the route of administration. And the nature of the preparation, the recipient's weight, age, etc., as well as the nature and severity of the condition being treated.
  • the present invention has discovered a new medicinal value for the known compound paeoniflorin or a pharmaceutically acceptable salt thereof or a solvate thereof, and is used for anti-Parkinson's disease (peoside lactone glycoside)
  • the DA content of the striatum, the number of rotations of the 6-0HDA model rats, and the shortening of the climbing time of the MPTP model mice are significant, and can be prepared as a medicine or health food for preventing, regulating and/or treating Parkinson's disease.
  • it has opened up a new field for the application of medicinal herbs such as peony.
  • paeoniflorin has a significant preventive and therapeutic effect on Parkinson's disease, and the main active ingredients of paeoniflorin and paeoniflorin extract are more effective than paeoniflorin. .
  • the anti-Parkinson's disease mechanism of the present invention has clear action mechanism, remarkable curative effect, small toxic and side effects, good safety, long-term use, high drug-forming property and good medicinal prospect.
  • the raw materials of the invention have rich sources, low cost, safe clinical use, simple preparation process, can be made into various dosage forms, and have small dosage and convenient use, so it is easy to promote.
  • the invention can be used for preparing a medicament for preventing and treating Parkinson's disease by using a single component of paeoniflorin active ingredient, and also using paeoniflorin and other active ingredients (for example, paeoniflorin, schisandrol or other antioxidants, etc. Compound)
  • paeoniflorin active ingredient for example, paeoniflorin, schisandrol or other antioxidants, etc.
  • Compound A combination of multiple targets for the preparation of a compound drug against Parkinson's disease.
  • Specific embodiment The invention is further illustrated below in conjunction with specific embodiments. However, the examples are intended to be illustrative only and not to limit the scope of the invention.
  • the experimental methods in which the specific experimental conditions are not indicated in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer.
  • Wistar rats Male, weighing 210 ⁇ 20 g, were provided by the Viton Lihua Animal Experimental Center.
  • Paeoniflorin (purity 96.77%) was purchased from Shanghai Eternal Biotechnology Co., Ltd.
  • DA Dopamine
  • Rats were randomly divided into 5 groups, 5 rats in each group, namely saline control group, high dose of paeoniflorin (12 mg/kg), divided into 2 groups (ie 30 min group, 60 min group), paeoniflorin
  • the low dose (6 mg/kg) group was divided into 2 groups (gp30min group, 60min group).
  • each group of rats was intraperitoneally injected with 10% urethane for anesthesia.
  • 0.5 mL/lOOg body weight
  • 0.5 mL/lOOg body weight
  • 5 rats at each time point 30 min, 60 min after administration, take the brain, remove the cerebellum and brain stem, filter paper Blood was removed, and the bilateral striatum was carefully separated on ice, weighed, and immediately frozen in liquid nitrogen.
  • the method of perchloric acid (HC104) solution is prepared by adding 1 mg of striatum to each gram of striatum and pre-cooling to 0 to 4 ° C for a concentration of 0. 2moI / L perchloric acid (HC104) solution. Contains lg/mL of dihydroxybenzoic acid (DHBA).
  • DHBA dihydroxybenzoic acid
  • the striatum was homogenized by MSE150 ultrasonic pulverizer. The homogenate was centrifuged at 02000 °C for 12000 rpm for 10 min. The supernatant was injected for 20 ⁇ , and the liquid chromatographic determination was carried out. The internal standard method was used to calculate the sample.
  • the content of dopamine (DA) is shown in Table 1.
  • Parkinson's disease patients with Parkinson's disease have pathological changes in the substantia nigra cells in the midbrain, resulting in a significant decrease in dopamine (DA) content in the striatum, resulting in a decrease in the function of inhibiting acetylcholine and abnormal globus pallidus in the brain. Active, causing Parkinson's disease. In addition, due to the decrease in DA content, extrapyramidal dysfunction is caused, resulting in a Parkinson's disease. By increasing the content of dopamine (DA) in the striatum, it can replace the therapeutic effect and maintain the normal function of the body.
  • DA dopamine
  • the paeoniflorin has the medicinal effect of preventing, alleviating or treating Parkinson's disease, and can be used for Prevention and treatment of Parkinson's disease.
  • Experimental Example 2 Effect of paeoniflorin on rotational behavior of striatum 6-OHDA induced damage model rats
  • cytochrome in the substantia nigra is the main pathological change of Parkinson's disease (PD), and 6-hydroxydopamine (6-0HDA) has selective damage to dopaminergic neurons.
  • the damage caused by unilateral injection of 6-hydroxydopamine in the nigral striatum of the rat brain can cause asymmetry in the hemispheres of the animal and dopamine receptor (DA-R) hypersensitivity.
  • Apomorphine is a post-synaptic membrane D2 receptor agonist.
  • the number of rotations is inversely related to the number of tyrosine hydroxylase positive neurons in the SNpc.
  • Paeoniflorin can increase the DA content of the nigrostria and has anti-free kinase activity. In this experiment, the paeoniflorin can significantly reduce the number of rotations of the model animals.
  • Apomorphine purchased from EHSY Western Region China Product Service Center, purity 98. 5%; Lot number: L6170132. Paeoniflorin (96.77%), purchased from Shanghai Eternal Biotechnology Co., Ltd.
  • SD rats were placed on the locator with 10% chloral hydrate solution and intraperitoneal injection of 450 mg/kg (body weight).
  • the tooth rod was 2 mm higher than the ear rod, and the injection site was on the right side of the substantia nigra and midbrain abdomen.
  • Rats with successful modeling were randomly divided into three groups, namely, paeoniflorin group, metoprolol group and model group, with 6 rats in each group. Animals were observed for 1, 2, 3, and 4 weeks of behavioral changes.
  • the paeoniflorin group began to receive paeoniflorin (12 mg/kg) at 8 and 20 o'clock every day.
  • the model control group was intragastrically administered with normal saline.
  • the Medopa group was 10 mg/kg.
  • Dopa solution is administered by stomach. For two weeks in a row, the dose was increased to 10 times after two weeks for 2 consecutive weeks.
  • Parkinson's (PD) rats were intraperitoneally injected with apomorphine at a dose of 0.5 mg/kg for 4 weeks. The rats were induced to rotate and the behavioral changes were observed. The observation time was 40. minute. The results are shown in Table 2.
  • Paeoniflorin can significantly reduce the number of rotations in model rats, indicating that paeoniflorin can increase the number of dopaminergic neurons in SNpc, while Parkinson's disease is mainly caused by the loss of dopaminergic neurons in the substantia nigra.
  • the central nervous system is dysfunctional, so the paeoniflorin can be used to prevent and treat Parkinson's disease.
  • Experimental Example 3 Effect of paeoniflorin on climbing time and spontaneous activity of MPTP-induced Parkinson's disease model mice
  • MPTP is an inhibitor of mitochondrial respiratory chain complex I. After injection into the body, it can be catalyzed by midbrain monoamine oxidase B to produce MPP + , which is a selective neurotoxin that specifically damages dopaminergic neurons in the substantia nigra.
  • C57BL mice can produce pathological and neurophysiological changes similar to those of clinical PD patients after application of larger doses of MPTP, which is a better animal model.
  • the crawl time reflects the animal's ability to coordinate movement. If the animal's movement coordination is good, the time required for the climbing of the rod is short, and the poor coordination is long.
  • the number of autonomous activities reflects the animal's ability to exercise at will. Parkinson's disease mice reduced the number of autonomous activities due to muscle stiffness and tremors.
  • mice Male, weighing 20 ⁇ 2 g, were provided by the Viton Lihua Animal Experimental Center.
  • MPTP i-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Medoc purchased from Shanghai Roche Pharmaceutical Co., Ltd.
  • Stainless steel measuring rod Take a stainless steel tube with a length of 0.5m and a diameter of lcm, wrapped with tape, and place a wooden ball with a diameter of 2.5cm at the top of the rod;
  • MPTP was directly dissolved in 0.9% sterile physiological saline to prepare an MPTP solution at a concentration of 2 mg/ml.
  • C57BL mice were intraperitoneally injected with MPTP 20 mg/kg/day for 8 consecutive days to establish a MPTP-induced Parkinson's disease mouse model.
  • model mice were randomly divided into 4 groups, 15 in each group, namely the model group, the blank control group, the paeoniflorin group, and the positive drug control group.
  • mice in the model group were intraperitoneally injected with MPTP 20 mg/kg/day for 8 consecutive days to prepare model mice.
  • the blank control group was injected intraperitoneally with the model group for the same dose of normal saline for 8 days.
  • the paeoniflorin group was used for the abdominal cavity of mice. Injection of MPTP 20mg/kg/day, continuous injection for 8 days, and intragastric administration of paeoniflorin (12mg/kg); positive drug control group mice were injected with MPTP 20mg/kg/day, continuous injection for 8 days, simultaneous gavage Metopbar (65 mg/kg) was given.
  • the mouse climbing time was determined by the experimental method of Nobutaka Arai:
  • the experimental tool was a self-made stainless steel rod with a length of 0.5 m, a diameter of lcm (which was wrapped with a tape), and a wooden ball of 2.5 cm in diameter at the top.
  • the day before the animal was given MPTP the pole training was carried out first, and the animals were guided to climb from the top of the pole to the sole of the rod within 10 seconds, each training 4 times.
  • the first climbing time of the mouse before the application of MPTP was first determined, and the second climbing time of the animal was measured within 1 to 2 hours after the last MPTP administration.
  • the model group, the blank control group, the paeoniflorin group, and the positive drug control group were each subjected to a mouse climbing rod experiment.
  • the specific determination methods are as follows:
  • the time difference between the two groups in the model group was significantly longer than that in the normal control group ( ⁇ 0.01), but relative In the model group, the time difference between the two groups of mice in the paeoniflorin group and the positive drug (Medopa) group was significantly shorter (P ⁇ 0.05), and the time difference between the two rods in the paeoniflorin group was more positive.
  • the drug metoprol is short, indicating that the effect of paeoniflorin is superior to the positive drug metoprolol.
  • Paeoniflorin can significantly shorten the climbing time of model mice, indicating that it can strongly inhibit the damage of MPTP on dopaminergic neurons in the substantia nigra, and help restore the motor coordination of mice, thus effectively Prevent, alleviate and/or treat Parkinson's disease.
  • the model group, the blank control group, the paeoniflorin group, and the positive drug control group mice were each taken for 15 spontaneous activity experiments.
  • the specific measurement method is as follows:
  • Paeoniflorin can increase the number of spontaneous activities of mice, which is beneficial to improve the ability of mice to exercise at random, thus effectively alleviating symptoms such as muscle stiffness and tremor in Parkinson's disease model mice. It has prevention, relief and/or treatment. The role of Parkinson's disease.
  • Experimental Example 4 Effect of peony extract containing paeoniflorin on climbing time of MPTP-induced Parkinson's disease model mice 4.1
  • mice Male, weighing 20 ⁇ 2 g, were provided by the Viton Lihua Animal Experimental Center.
  • a white peony extract containing paeoniflorin (purity of 45%) was purchased from Shanghai Eternal Biotechnology Co., Ltd.
  • Medoc purchased from Shanghai Roche Pharmaceutical Co., Ltd.
  • Stainless steel measuring rod Take a stainless steel tube with a length of 0.5m and a diameter of lcm, wrapped with tape, and place a wooden ball with a diameter of 2.5cm at the top of the rod;
  • MPTP was directly dissolved in 0.9% sterile physiological saline to prepare an MPTP solution at a concentration of 2 mg/ml.
  • C57BL mice were intraperitoneally injected with MPTP 20 mg/kg/day for 8 consecutive days to establish a MPTP-induced Parkinson's disease mouse model.
  • the model mice were randomly divided into 4 groups, 15 in each group, namely the model group, the blank control group, the paeoniflorin extract group, and the positive drug control group.
  • mice in the model group were intragastrically injected with distilled water for 3 weeks, and then injected intraperitoneally with MPTP 20 mg/kg/day for 8 days to prepare model mice.
  • the blank control mice were intragastrically administered with distilled water for 3 weeks.
  • the rats in the peony extract group were given an equal dose of normal saline for 8 days; the peony extract group was intragastrically administered with the extract of Radix Paeoniae Alba (24 mg/kg, wherein the purity of the paeoniflorin in the extract was 45%). After 3 weeks, the intraperitoneal injection was performed.
  • MPTP 20mg/kg/day continuous injection for 8 days
  • positive drug control group mice were treated with distilled water for 3 weeks, intraperitoneal injection of MPTP 20mg/kg/day, continuous injection for 8 days, and intragastric administration of Madopar ( 65mg/kg).
  • the mouse climbing time was determined by the experimental method of Nobutaka Arai:
  • the experimental tool was a self-made stainless steel rod with a length of 0.5 m, a diameter of lcm (which was wrapped with a tape), and a wooden ball of 2.5 cm in diameter at the top.
  • the day before the animal was given MPTP the pole training was carried out first, and the animals were guided to climb from the top of the pole to the sole of the rod within 10 seconds, each training 4 times.
  • the first climbing time of the mouse before the application of MPTP was first determined, and the second climbing time of the animal was measured within 1 to 2 hours after the last MPTP administration.
  • the time difference between the two groups in the model group was significantly longer than that in the normal control group (P ⁇ 0.01), while in the model group, the purity was 55% in the paeoniflorin extract group and the positive drug Madopar.
  • the time difference between the two groups was significantly shortened (P ⁇ 0.05), and the effect of paeoniflorin extract was slightly better than that of the positive drug.
  • the peony-containing lactone extract can significantly shorten the mouse climbing time, indicating that it can better avoid the damage of MPTP on dopaminergic neurons in the substantia nigra, and help restore the motor coordination of the mouse, thus It can effectively prevent, alleviate and/or treat Parkinson's disease.
  • Experimental Example 5 Acute Toxicity Test of Paeoniflorin
  • the SFP-grade ICR mice (provided by the Vital River Animal Experimental Center) were intragastrically administered with paeoniflorin (purity > 98%, purchased from WAKO, Japan) at a dose of 8.4 g/kg.
  • the administration time was 14 days.
  • mice Observe the respiratory properties and rate, behavior of the mice (especially including vomiting), movement, fur color tension, abdominal shape, stool hardness, body weight, etc.
  • mice were intragastrically administered with paeoniflorin.
  • the drug had no acute toxicity damage to the traditional Chinese medicine tissues and organs of the animals, and the administration of the medicament of the present invention was still safe.
  • Example 1 Preparation of an extract of paeoniflorin
  • the mixture was heated and refluxed three times with a 70% by volume aqueous solution of ethanol, and the weight of the ethanol solution having a solvent concentration of 70% for three times was 5 times, 4 times, and 3 times the weight of the chalk.
  • a 70% by volume aqueous solution of ethanol e.g 1 kg of chalk, add 5 kg of 70% aqueous ethanol
  • recover the ethanol dilute the extract to 4 volumes (eg 1 kg of chalk, dilute the extract volume of 4 liters), filter to clear solution A, stand-by.
  • D-101 type macroporous resin was soaked in 95% ethanol overnight, wet packed, steamed and washed to near alcohol-free, and then clear liquid A on D-101 type macroporous resin adsorption column, 1 column volume / hour ( BV/H) Flow rate adsorption, first rinse with 4 column volumes of water, then rinse with 10% ethanol, then elute with 30% ethanol, collect the 2-5 column volume of ethanol eluent, concentrate and dry (Temperature ⁇ 70 ° C, relative vacuum ⁇ -0.06 Mpa), after smashing through 80 mesh sieve, the content of 30 ⁇ 35% of the paeoniflorin extract, the creaming rate is about 3 to 3.5%.
  • D-101 macroporous resin was soaked in 95% ethanol overnight, packed in a wet manner, washed with steam and washed until nearly alcohol-free, and set aside.
  • the effluent is concentrated under reduced pressure (temperature ⁇ 70 ° C, relative vacuum ⁇ -0.06 MPa), to a relative density of 1.30 1.35 (60 ° C measured) thick paste, dried, crushed through 80 mesh sieve, that is, the content For the 15 ⁇ 303 ⁇ 4 paeoniflorin extract, the creaming rate is about 4 ⁇ 5%.

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Abstract

L'invention porte sur l'utilisation d'albiflorine dans la préparation de médicaments ou de produits de soins de santé pour la prévention, l'atténuation et/ou le traitement de la maladie de Parkinson. Les essais de la présente invention prouvent que l'albiflorine a un net effet contre les tremblements, une faible toxicité et de faibles effets secondaires.
PCT/CN2010/079976 2010-01-19 2010-12-20 Utilisation d'albiflorine pour le traitement de la maladie de parkinson Ceased WO2011088715A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107412244A (zh) * 2016-10-11 2017-12-01 张作光 芍药内酯苷在制备改善褪黑素系统功能的产品中的用途
US20190336519A1 (en) * 2017-01-06 2019-11-07 Zuoguang Zhang Application of albiflorin as indoleamine 2,3-dioxygenase (ido) inhibitor

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012068958A1 (fr) * 2010-11-25 2012-05-31 Zhang Zuoguang Utilisation de l'albiflorine ou d'un métabolite de celle-ci dans la lutte contre l'anxiété et pour l'amélioration de troubles du sommeil
CN102643316B (zh) * 2011-11-28 2017-06-13 宁波立华制药有限公司 一种酰化苷类化合物及其制法和应用
CN106565802B (zh) * 2016-09-26 2020-05-15 中国人民解放军北部战区总医院 白芍醇提物、4-o-没食子酰基白芍苷及其制备和应用
CN107184591A (zh) * 2017-06-07 2017-09-22 南京晶云化工有限公司 一种促进术后伤口愈合软膏剂
WO2020168760A1 (fr) * 2019-02-21 2020-08-27 张作光 Utilisation d'albiflorine dans la préparation de médicaments pour le traitement rapide de la dépression

Citations (2)

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CN1833668A (zh) * 2005-12-06 2006-09-20 深圳市生物谷科技有限公司 一种具有协同作用的药物组合物
WO2007038610A2 (fr) * 2005-09-26 2007-04-05 President & Fellows Of Harvard College Utilisation de produits naturels pour le traitement de troubles neurologiques

Patent Citations (2)

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WO2007038610A2 (fr) * 2005-09-26 2007-04-05 President & Fellows Of Harvard College Utilisation de produits naturels pour le traitement de troubles neurologiques
CN1833668A (zh) * 2005-12-06 2006-09-20 深圳市生物谷科技有限公司 一种具有协同作用的药物组合物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107412244A (zh) * 2016-10-11 2017-12-01 张作光 芍药内酯苷在制备改善褪黑素系统功能的产品中的用途
WO2018068565A1 (fr) * 2016-10-11 2018-04-19 张作光 Application d'albiflorine dans la production de produits destinés à améliorer la fonction du système mélatonine
US20190336519A1 (en) * 2017-01-06 2019-11-07 Zuoguang Zhang Application of albiflorin as indoleamine 2,3-dioxygenase (ido) inhibitor

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