WO2011047576A1 - 芍药内酯苷的抗抑郁用途 - Google Patents
芍药内酯苷的抗抑郁用途 Download PDFInfo
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- WO2011047576A1 WO2011047576A1 PCT/CN2010/076279 CN2010076279W WO2011047576A1 WO 2011047576 A1 WO2011047576 A1 WO 2011047576A1 CN 2010076279 W CN2010076279 W CN 2010076279W WO 2011047576 A1 WO2011047576 A1 WO 2011047576A1
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- paeoniflorin
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- depression
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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
- A61K31/70—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- 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
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/24—Antidepressants
Definitions
- the present invention relates to a medicament or a health food for preventing, alleviating and/or treating a neurological disorder of affective disorder, and more particularly to an antidepressant or health food. Background technique
- Depression is the main type of mood disorder, a syndrome characterized by significant and persistent low mood. Depression is a common and frequently-occurring disease that endangers the physical and mental health of human beings. It is a major global mental disorder.
- Depression mainly manifests as depression, low interest, pessimism, slow thinking, lack of initiative, self-blame, poor diet, poor sleep, worry about suffering from various diseases, feeling multiple discomforts in the body, serious suicidal thoughts And behavior.
- Depression is the highest rate of psychiatric suicide.
- the incidence of depression is high, and almost one in every five adults has a depression, so it is called a cold in psychiatry.
- Depression has now become the second most important disease in the world of diseases, causing a serious burden on human beings.
- the suffering caused to patients and their families is unmatched by other diseases.
- society lacks a correct understanding of depression, and prejudice makes patients reluctant to go to the psychiatric department.
- In China only 5% of people with depression have been treated, and a large number of patients have not been diagnosed in time, their condition has deteriorated, and even serious consequences of suicide have occurred.
- the public lacks knowledge about depression those who appear to have depressive symptoms are mistaken for emotions, can not give due understanding and emotional support, cause greater psychological pressure on patients, and further worsen the condition.
- SSRIs selective serotonin reuptake inhibitors
- TCAs tricyclic anti-inhibitors
- MAOIs monoamine oxidase depressants
- SNARI serotonin and norepinephrine reuptake inhibitors
- SSRIs serotonin reuptake inhibitors
- Prozac Prozac
- Serote Serote
- Zoloft reuptake inhibitors
- these drugs have varying degrees of side effects, and studies have shown that "the complex ampoules contained in these drugs have an effect on balancing human skills, but more often they do not calm the patient.”
- these antidepressant drugs have serious social problems and have potential safety hazards. For example, taking Celote leads to an increase in suicidal tendencies among adolescents.
- Depression is a clinical syndrome, which causes many causes. It is the result of various factors. It is often difficult to achieve satisfactory results only when it is treated for a single link (target), while traditional Chinese medicine treatment is particular.
- the comprehensive diagnosis the overall adjustment of the various physiological systems, to achieve the purpose of treatment. For example, a large number of reports have reported that Xiaochaihu Tang, Banxia Houpu Decoction and Baijinsan have been used to treat "Mei Nuclear Gas”, “Depression” and “Depressive Psychiatry”, among which Hu Sirong used Pingxin Forgetting Soup (magnet, limestone, and solid).
- the invention patent of the publication No. CN100509006C discloses a pharmaceutical composition for treating depression, which comprises ginseng, licorice and jujube, or an aqueous extract or an ethanol extract thereof.
- the invention patent of the publication No. CN1256090C discloses a new use of Centella asiatica and its derivatives in the preparation of antidepressants.
- the invention patent application published as CN101385736A discloses the use of paeoniflorin in the prevention and treatment of a medicament for depression and a pharmaceutical composition thereof, the pharmaceutical composition comprising an effective amount of paeoniflorin and a pharmaceutically acceptable carrier,
- the pharmaceutical compositions can be prepared in conventional liquid dosage forms or solid dosage forms.
- the invention patent application with the publication No. 101332205A discloses a medicine for treating depression and a dose thereof which are prepared by using paeoniflorin as a raw material.
- 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. The roots of Paeonia lactiflora Pall or Paeonia veitchii Lynch, the root of Peony Rsuffrsticosa Andrz.
- 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 A paeoni lactone B Modern pharmacological studies have shown that 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 preparation method of paeoniflorin and its application in the preparation of a medicament for preventing and treating depression have not been reported.
- the inventors have used a large number of modern scientific researches to extract the active ingredient of the drug, paeoniflorin, from the peony medicinal materials by using advanced separation and purification techniques, and the content thereof is more than 50%, and the paeoniflorin and its corresponding
- the pharmaceutical preparations have been studied for pharmacodynamics and pharmacology of depression.
- the results show that the paeoniflorin monomer has clear pharmacological effects, strong antidepressant effect, low toxicity and high safety, and can provide a kind of depression for patients. Highly effective and low toxicity drugs. Summary of the invention
- the primary object of the present invention is to provide a paeoniflorin, a paeoni lactone metabolite, a paeoniflorin composition, a paeoniflorin-containing medicinal material or a paeoniflorin-containing medicinal material for the problems of the prior art mentioned above.
- Extracts anti-affective mental disorders, especially anti-depressant properties and efficacy, and in view of the above problems in the prior art, provide paeoniflorin or a pharmaceutically acceptable salt thereof or a solvate thereof or an effective amount of peony
- the present invention provides an aspect of the use of a paeoniflorin for the preparation of a medicament for preventing, ameliorating and/or treating an affective disorder disorder, a health care product.
- the affective disorder disorder described therein is depression.
- paeoniflorin has a strong antidepressant effect in the chemical constituents of paeoniflorin, and two metabolites, paeoni lactone, in the human body of paeoniflorin.
- A paeoni lactone A
- paeoni lactone B also have antidepressant effects.
- peonylide refers to a racemate, a stereoisomer of a paeoniflorin, or a mixture of stereoisomers mixed in an arbitrary ratio.
- peony lactone further includes two metabolites of paeoniflorin, paeoni lactone. A (paeoni lactone A) and Paeoni lactone B.
- 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 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.
- 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.
- 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.
- the paeoniflorin has a purity of 50%, preferably 80%, more preferably 90%.
- the content of the paeoniflorin is 50%, preferably 80%, more preferably 90%.
- Another aspect of the present invention provides a use of a paeoniflorin composition for the preparation of a medicament, a health care product for preventing, alleviating and/or treating an affective disorder.
- the affective disorder disorder described therein is depression.
- 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 an affective disorder or a health care product is provided.
- the affective disorder disorder described therein is depression.
- the medicinal material containing paeoniflorin is selected from the medicinal material paeoniflorin or peony bark, preferably white peony; and the purity of the paeoniflorin in the medicinal material extract containing peony lactone is 10%.
- Another aspect of the present invention provides a use of a paeoniflorin metabolite for the preparation of a medicament, a health care product for preventing, alleviating and/or treating an affective disorder.
- the metabolite of paeoniflorin is paeoni lactone A and paeoni lactone B; and the affective disorder is depression.
- the depression is selected from one or more of endogenous depression, reactive depression, postpartum depression, menopausal depression, occult depression, and depressive neurosis.
- the depression is preferably reactive depression.
- a further aspect of the present invention provides a medicament for preventing, alleviating and/or treating depression comprising a paeoniflorin.
- the paeoniflorin has a purity of 50%, preferably 80%, more preferably
- the drug further comprises a pharmaceutically acceptable carrier
- a medicament for preventing, alleviating and/or treating depression comprises at least one of the following: a paeoniflorin metabolite, a paeoniflorin composition, and a paeoniflorin-containing medicinal material. Or a medicinal extract containing paeoniflorin.
- 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 paeoniflorin-containing medicinal material extract containing the paeoniflorin has a purity of 10%.
- the paeoniflorin-containing extract of the paeoniflorin-containing medicinal material has a purity of 10% to 50%, preferably 20% to 45%, more preferably 30% to 40%.
- the paeoniflorin composition selects a pharmaceutically acceptable salt of paeoniflorin, paeoniflorin Solvate.
- 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 can be prepared into various dosage forms by methods well known in the art, such as tablets, capsules, pills, powders, granules, syrups, solutions, injections, sprays, aerosols, patches, and the like;
- a health food for preventing, alleviating and/or treating a depression disease comprising one of the following: paeoniflorin, paeoniflorin metabolite, paeoniflorin composition, A medicinal material of paeoniflorin or a medicinal material extract containing paeoniflorin.
- the paeoniflorin has a purity of 10%.
- the paeoniflorin-containing extract of the paeoniflorin-containing medicinal material has a purity of 10% to 50%, preferably 20% to 45%, more preferably 30% to 40%.
- the present invention also provides a pharmaceutical composition for the treatment of depression, comprising a pharmaceutical composition comprising a therapeutically effective amount of a paeoniflorin, wherein the therapeutically effective amount is 0.6 to 4 mg/kg ⁇ d, preferably 1 5 ⁇ 3mg/ ⁇ d ⁇ More preferably, it is 1. 5 ⁇ 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. Compared with the prior art, the present invention has the following distinct advantages:
- the present invention excavates a known compound, paeoniflorin or a pharmaceutically acceptable salt thereof or a solvate thereof.
- the new medicinal value which is used for antidepressant (the drug has a significant effect on shortening the time of mouse tail suspension and forced swimming, and can be prepared for prevention, conditioning and/or treatment).
- Depressive drugs or health foods have opened up a new field for the application of medicinal herbs such as peony.
- paeoniflorin has a significant preventive and therapeutic effect on depression, and the main active ingredient of peony and peony extract in the treatment of depression, and the commonly known paeoniflorin is a peony antidepressant.
- paeoniflorin is more significant in shortening the time of suspension and forced swimming in mice, suggesting that the antidepressant effect of paeoniflorin is stronger than that of paeoniflorin.
- the present invention uses paeoniflorin and corresponding pharmaceutical dosage forms, and adopts different animal models, and a large number of animal experiments are carried out by oral and injection routes.
- the test results show that: (1) Paeoniflorin can significantly shorten mice Suspension time and forced swimming time, and a significant dose-effect relationship; (2) can significantly reduce the blood temperature induced by reserpine; (3) can significantly inhibit the weight loss of chronic stress depression rats, The decrease in sucrose consumption significantly reduced the number of jumping errors in depressed rats, and significantly increased the horizontal and vertical movement scores of rat open-box activities; (4) Paeoniflorin significantly increased monoamine-like nerves in the brain of depressed rats The transmitters of norepinephrine and serotonin showed that the glucosides had a strong antidepressant effect.
- the paeoniflorin of the invention has strong pharmacological action, has remarkable effects for preventing, regulating and treating depression, has quick effect, small toxic and side effects, good safety, can be taken for a long time, and can be analyzed by modern pharmacology for antidepressant.
- the mechanism of action has a 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 depression by using a single component of paeoniflorin active ingredient, and can also be used together with other active ingredients (for example, compounds such as ginsenoside Rgl and glycyrrhizic acid GL). Recipe to prepare a multi-target anti-depressant combination drug. Specific embodiment
- test Example 1 Effect of Paeoniflorin on Mouse Suspension Experiment
- mice male, weighing 18-20 g, were provided by the Vitallihua Animal Experimental Center, certificate number: SCXK (Beijing) 2006-0009.
- Paeoniflorin (purity >98%), purchased from WAKO, Japan; Paeoniflorin (purity >98%), purchased from China National Institute for the Control of Pharmaceutical and Biological Products; Positive drug: Fluoxetine hydrochloride capsule (Baiyoujie), ceremony To Suzhou Pharmaceutical Co., Ltd., batch number: A333341-070608.
- mice were randomly divided into 8 groups according to body weight, 20 in each group, namely model group, positive drug fluoxetine hydrochloride capsule (3.5mg/kg/d), paeoniflorin high (14mg/kg/d), Medium (7mg/kg/d), low (3.5mg/kg/d) dose group, paeoniflorin high (14mg/kg/d), medium (7mg/kg/d), low (3.5mg/kg/d) Dosage group. Each group was intragastrically administered at 0.2 ml/10 g body weight for 2 consecutive days.
- the high and middle dose groups of paeoniflorin could significantly shorten the time of mouse tail suspension (compared with the model group, P ⁇ 0.01, P ⁇ 0.05), and showed a significant dose-effect relationship, suggesting paeoniflorin It has a good antidepressant function; the high and medium doses of paeoniflorin are equivalent to the positive drug group, and the high dose group is significantly better than the positive drug group.
- Paeoniflorin (purity >98%), purchased from WAKO, Japan; Paeoniflorin (purity >98%), China National Institute for the Control of Pharmaceutical and Biological Products; Positive drug: Fluoxetine hydrochloride capsule (Baiyoujie), Lilly Suzhou Pharmaceutical Co., Ltd., batch number: A333341-070608.
- mice 160 normal mice were randomly divided into 8 groups according to body weight, 20 in each group, namely model group, positive drug fluoxetine hydrochloride capsule group (3.5mg/kg/d), and paeoniflorin high dose group (14mg/ Kg/d), paeoniflorin middle dose group (7mg/kg/d), paeoniflorin low dose group (3.5mg/kg/d), paeoniflorin high dose group (14mg/kg/d), medium The dose group (7 mg/kg/d) and the low dose group (3.5 mg/kg/d). Each group was intragastrically administered with 0.2 ml/10 g body weight for 2 days, and the blank control group was given deionized water.
- mice After 1 hour of administration on the 2nd day, the mice were individually placed in a water tank of 20 cm in height, 18 cm in diameter, 10 cm in water depth and 23 ⁇ 2 ° C in water temperature. The cells were observed for 6 min, adapted for 2 min, and the cumulative immobility time was recorded within 4 min after recording. ).
- ICR mice male, weighing 18-20 g, were provided by the Viton Lihua Animal Experimental Center.
- Paeoniflorin (purity 96.77%) was purchased from Shanghai Eternal Biotechnology Co., Ltd.
- mice were randomly divided into 3 groups according to body weight, 20 in each group, ie, model group, high in paeoniflorin (14 mg/kg), medium (7 mg/kg) dose group.
- the intraperitoneal administration group was administered for 1 day.
- Each group was administered at a concentration of 0.2 ml/10 g body weight.
- the experiment was carried out 30 minutes after the administration of the intraperitoneal administration group.
- the tail end of the mouse (2 cm from the tip of the tail) was fixed with a tape on the line of the 100 g tension transducer, and the head was placed in an inverted state. The head was about 15 cm away from the test bench, and two animals were tested at the same time. Separated by cardboard.
- the transducer is connected to the Medlab biosignal acquisition and processing system. After 2 min, the results within 4 min are recorded and the immobile state is converted to time (s).
- the experimental data were expressed as ⁇ ⁇ , and the experimental results were analyzed by ANOVA using SPSS 11.5 statistical software (purchased from SPSS, USA). The experimental results are shown in Table 3.
- mice The results showed that: the intraperitoneal injection of paeoniflorin in the high-dose group can significantly shorten the immobility time of the tail-suspended mice (compared with the model group, ⁇ 0.01**), suggesting that the paeoniflorin is administered intraperitoneally. Significant anti-experimental depression.
- Experimental Example 4 Test of induced reserpine induced hypothermia in mice
- ICR mice male, weighing 22.0 ⁇ 2 g, grade 2, were purchased from the Department of Laboratory Animal Science, Capital Medical University, Beijing. Paeoniflorin (purity 96.77%), purchased from Shanghai Eternal Biotechnology Co., Ltd.; Paroxetine (Serite): Sino-US Tianjin Shike Pharmaceutical Co., Ltd.; Li Xueping: Guangdong Bangmin Pharmaceutical Factory Co., Ltd.
- thermometer GM222 type electronic thermometer, stopwatch.
- mice were randomly divided into 5 groups, 10 in each group: 1) high dose group of paeoniflorin (Mmg*! ⁇ 1 ); middle dose group mg kg ); low dose group G mg kg ); control group Paroxetine group (3 mg/kg); model group saline group. Administered for 7 days by intragastric administration.
- the anus temperature of the mice was measured 1 hour after the administration on the 8th day, and then the intraperitoneal injection of reserpine 2 mg/kg was injected.
- the anus temperature of the mice was measured 4 hours after reserpine.
- the depth and time of insertion of the thermometer into the anus of the mouse were consistent at each temperature measurement.
- the experimental data were expressed as ⁇ ⁇ , and the experimental results were analyzed by ANOVA with SPSS 11.5 statistical software (purchased from SPSS, USA). The experimental results are shown in Table 4.
- Paeoniflorin (purity >98%), purchased from WAKO, Japan; Positive drug: Baiyoujie, purchased from Lilly Suzhou Pharmaceutical Co., Ltd., batch number: 20030017.
- Sucrose purchased from Beijing Guohua Chemical Reagent Factory, batch number: 040120.
- mice Ninety rats were normal, and after 24 hours of water ingestion, 1% sucrose water was administered, and the consumption in 1 hour was measured.
- the model was administered by intragastric administration once a day for 21 days. each group They were all administered at a dose of 1.0 ml/lOOg, and the body weight was weighed once a week.
- Modeling ie, using CUMS to create animal models of depression: Electric shock to the sole (36 volts, once every 1 minute, once for 10 seconds, 20 times in total), 4 °C ice water swimming (5 minutes), 45 °C hot drying (5 minutes), tail (1 minute), damp feeding (wet padding), day and night reversal (24 hours), fasting (24 hours), water ban (24 hours), etc. Stirring randomly within 21 days, giving a daily stimulation, All animals except the blank group were housed in single cages, free diet, room temperature (24 ⁇ 1) °C, relative humidity (60 ⁇ 10)%.
- the open box is 40cm high, 80cm long and wide, without cover, the perimeter wall and the bottom of the box are black, and the bottom surface is divided into 25 squares with the same area.
- the number of animals crossing the square is used as the horizontal activity score, and the number of vertical movements is the vertical activity score (the two forelimbs are more than lcm above the ground). Each animal was tested once for 3 minutes each time.
- the experimental device is a 30cmx30cmx30cm plexiglass box with a copper grid on the bottom and a 0.8cm pitch. It can be energized and the voltage is controlled by a transformer.
- a wooden platform with a height of 5 cm and a diameter of 8 cm is placed in the left rear corner of the box.
- the animals were placed in a reaction chamber to acclimate to the environment for 3 minutes, and then immediately passed through 36V AC.
- the animals were shocked and the normal reaction was to jump on the platform to avoid noxious stimulation. Most animals may jump to the copper grid again or again, and after jumping to the platform, they will jump back to the platform. After 5 minutes of training, the number of times the rat is shocked is the wrong number. After 24 hours, the test was repeated and the rats were placed on the platform. When power was applied and recorded, the number of errors within 5 minutes was recorded.
- the measured indicators were tested by means of analysis of variance (ANOVA) using the mean ⁇ standard deviation ( ⁇ , SPSS 12.0 software (purchased from SPSS, USA), p ⁇ 0.05 indicates that the difference was significant.
- ANOVA analysis of variance
- the animal model of depression produced by CUMS has similar behaviors such as simulated behavior and neuroendocrine. It has become a pathogenesis of depression and antidepressant drugs at home and abroad.
- the stress models used in previous studies are mostly single forms of stress, such as restraint and forced swimming.
- this study used a multi-factor chronic stress model, randomly applying different stress stimuli to animals every day, making them unpredictable when and how stress occurs, and humans.
- the mechanisms by which chronic, low-level stressors in depression contribute to the development and progression of depression are closer.
- the horizontal activity and vertical activity scores of the model rats were significantly reduced, and the sucrose solution consumption was significantly reduced, indicating that the animals showed depression, loss of interest, decreased inquiry behavior and lack of pleasure, indicating that the rat depression model was successful.
- Test drug Paeoniflorin (purity >98%), purchased from WAKO, Japan;
- Fluoxetine hydrochloride Fluoxetine, Prozac Prozac
- Lilly Suzhou Pharmaceutical Co., Ltd. batch number: Chinese medicine Zhunji J20030017, rat dosage 2.5mg/kg.
- Norepinephrine E, Serva
- dopamine DA, Fluka
- serotonin 5-HT, Sigma
- DOPAC 4-dihydroxyphenylacetic acid
- DHBA 4- Dihydroxybenzylamine
- DHBA di-n-butylamine
- D-8 ion-pair reagent Teianjin Chemical Reagent 2
- methanol excellent grade, Beijing Chemical Plant
- SD rats after 24 hours of water inadequacy, were given 1% sucrose water and measured the consumption within 1 hour. According to the sucrose water consumption, they were randomly divided into 6 groups, 12 in each group, namely normal control group, model group, positive drug fluoxetine hydrochloride group (2.5 mg/kg/d), and paeoniflorin high (14 mg/kg/ d), medium (7mg/kg/d), low (3.5mg/kg/d) dose group.
- the model was administered by intragastric administration once a day for 21 days. Each group was administered at 1.0 ml/100 g body weight, and the body weight was weighed once a week.
- Ice water swimming The animals were placed in a bucket containing 4 ° C cold water (ice water mixed) at a water depth of 15 cm. The rat's toes just touched the bottom of the bucket, and the animals were taken out after 5 minutes.
- Hot baking The oven temperature was adjusted to 45 ° C, the animals were placed in an oven, and the animals were taken out after 5 minutes.
- Tail Place the rat in a fixed cage to expose the tail, and use a hemostat to clamp the 1cm from the base of the tail (do not use too much force to make the rat wailing), lasting lmin.
- the animals were killed by decapitation, and the brain was quickly dissected on the ice.
- the forehead cortex was taken. After weighing, the tissue was frozen in a freezer tube and then frozen in liquid nitrogen. The sample was stored in a -70 °C refrigerator until the measurement.
- DHBA formulated into 800 ⁇ l, ultrasonic homogenate, centrifuged at llOOO rpm for 10 min, and the supernatant was used for neurotransmitter determination.
- HPLC-ECD HPLC-electrochemical detector system
- the chromatographic conditions were: 4xl50mm, Nova-pakC18, 5 ⁇ (Dalian chromatographic center filling); mobile phase was 50mM citric acid-sodium acetate Buffer pH 3.5 (containing 1.0mMB-8 ion pair reagent, 1.8mM di-n-butylamine, 0.3mM EDTA disodium, 4% methanol), flow rate 1.0mL/min, glassy carbon working electrode, detection cell voltage is + 0.75V; 3, 4-dihydroxybenzylamine DHBA is the internal standard, and the main components in the sample are quantified by internal standard method.
- test data is expressed in ⁇ s, processed by SPSS 13.0 software, and the results are shown in Tables 9 and 10 using the One-Way ANOVA method.
- Table 9 Effect of paeoniflorin on norepinephrine in the brain of chronically stressed rats ( ⁇ s)
- Blank group - 12 398.47 ⁇ 51.11* model group - 10 159.20 ⁇ 49.31 positive group 2.5mg/kg/d 11 440.88 ⁇ 62.58* low dose group 3.5mg/kg/d 11 174.59 ⁇ 60.35
- the experimental data in Tables 9 and 10 showed that after 21 days of continuous administration, the levels of monoamine neurotransmitter norepinephrine and 5-hydroxytryptamine in the brain of the model group were significantly lower than those in the blank group (P ⁇ 0.05).
- the model group compared the content of monoamine neurotransmitter norepinephrine and 5-hydroxytryptamine in the brain of the middle and high dose groups of paeoniflorin and the positive drug fluoxetine hydrochloride group (P ⁇ 0.05).
- ICR mice male, weighing 18-22 g. Provided by Vitallihua Animal Experimental Center, certificate number: 2007-0001.
- Test drug Baizhi extract containing 31. 16% paeoniflorin, provided by Beijing O'Neill Bioengineering Technology Co., Ltd.;
- mice Fluoxetine hydrochloride (Prozac Prozac), Lilly Suzhou Pharmaceutical Co., Ltd., batch number: National Pharmaceutical Standard J20030017, the amount of mice used is 3.5mg/kg.
- the contents of the capsules were removed and formulated into solutions using deionized water.
- Medlab Biosignal Acquisition System Nemlab Biosignal Acquisition System (Nanjing Yimei Technology Co., Ltd.), JZ100 type lOOg tension transducer
- mice were randomly divided into 5 groups, namely the blank control group and the positive drug fluoxetine hydrochloride group.
- the SFP grade ICR mice were intragastrically administered with paeoniflorin at a dose of 8.4 g/kg and 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 in the drug-administered group After 14 days of administration, no abnormal symptoms were found and no death occurred.
- the body weight of the mice in the drug-administered group was weighed on the 7th day and the 14th day, and there was no significant difference compared with the control group (P>0.05).
- the mixture After pulverizing the chalk, the mixture is heated and refluxed three times with a 70% aqueous solution of ethanol, and the weight of the solvent of the solvent of 70% of the ethanol solution is 5 times, 4 times, and 3 times the weight of the chalk, respectively (for example, 1 kg of chalk, added 5 kg of 70% aqueous ethanol solution, recover ethanol, dilute the extract to 4 volumes (for example, 1 kg of chalk, dilute the extract volume of 4 liters), filter to clear liquid A, and use.
- a 70% aqueous solution of ethanol for example, 1 kg of chalk, added 5 kg of 70% aqueous ethanol solution, recover ethanol, dilute the extract to 4 volumes (for example, 1 kg of chalk, dilute the extract volume of 4 liters), filter to clear liquid A, and use.
- 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 eluent, concentrate and dry ( Temperature ⁇ 70 ° C, 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 D-101 type macroporous resin adsorption column on the percolate A is used.
- the specific adsorption amount is the ratio of the amount of the drug to the amount of the resin: 1.5:1, the flow rate is 0.033 ml/g.min, and the effluent is discarded.
- the resin column was rinsed with 3 times the amount of resin, the flow rate was 0.033 ml/g.min, and the effluent was discarded.
- the resin column was washed with a 4 times resin amount of 50% ethanol at a flow rate of 0.033 ml/g.min, and a 4 times resin amount of the effluent was collected and used.
- the effluent is concentrated under reduced pressure (temperature ⁇ 70 ° C, vacuum ⁇ 0.016 MPa), to a thick paste with a relative density of 1.30 to 1.35 (measured at 60 ° C), concentrated under reduced pressure (temperature ⁇ 70 ° C, vacuum) Degree ⁇ - 0.06Mpa), crushed through 80 mesh sieve, that is, the content of Paeoniflorin extract of 30 ⁇ 55% is obtained.
- the paste rate is about 4 to 5%.
- the above-mentioned extract of paeoniflorin (white peony root or red peony) which is the main active ingredient of anti-depressant with peony lactone glucoside, and if necessary, after adding auxiliary materials, filling or preparing tablets, the preferred oral administration of the present invention is carried out.
- a pharmaceutical preparation or the above-mentioned extract of a peony (white or red peony) containing a higher purity paeoniflorin, together with other antidepressant active ingredients (for example, ginsenoside, glycyrrhizic acid, glycyrrhetinic acid, etc.)
- antidepressant active ingredients for example, ginsenoside, glycyrrhizic acid, glycyrrhetinic acid, etc.
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Description
芍药内酯苷的抗抑郁用途 技术领域
本发明涉及一种预防、 缓解和 /或治疗情感性精神障碍神经系统疾病的药物或保 健食品, 特别涉及一种抗抑郁药物或保健食品。 背景技术
抑郁症 (depression ) 是情感性精神障碍 (mood disorders) 的主要类型, 是一 种以显著而持久的心境低落为主要特征的综合症。 抑郁症是危害人类身心健康的常 见病、 多发病, 是一个全球性的主要精神疾患。
抑郁症主要表现为情绪低落, 兴趣减低, 悲观, 思维迟缓, 缺乏主动性, 自责自罪, 饮食、 睡眠差, 担心自己患有各种疾病, 感到全身多处不适, 严重 者可出现自杀念头和行为。
抑郁症是精神科自杀率最高的疾病。 抑郁症发病率很高, 几乎每 5个成年 人中就有 1个抑郁症患者, 因此它被称为精神病学中的感冒。 抑郁症目前已成 为全球疾病中给人类造成严重负担的第二位重要疾病, 对患者及其家属造成的 痛苦, 对社会造成的损失是其他疾病所无法比拟的。 造成这种局面的主要原因 是社会对抑郁症缺乏正确的认识, 偏见使患者不愿到精神科就诊。 在中国, 仅 有 5%的抑郁症患者接受过治疗, 大量的病人得不到及时的诊治, 病情恶化, 甚至出现自杀的严重后果。 另一方面, 由于民众缺乏有关抑郁症的知识, 对出 现抑郁症状者误认为是闹情绪, 不能给予应有的理解和情感支持, 对患者造成 更大的心理压力, 使病情进一步恶化。
抑郁症流行趋势的日益严重性, 患者因精神障碍所致心理素质的下降和对社会 功能的损害, 己引起世界各国的普遍重视。 世界范围内对抗抑郁药品的需求量日益 增大, 近年来该类药品全球市场销售量每年以 16.2%的速度增长。 抑郁症的防治和 抗抑郁新药的研制, 己成为当今国际医药界前沿热点研究课题之一。
抑郁症的治疗方法很多, 如心理治疗、 睡眠剥夺治疗、 光疗和电痉挛治疗等, 但目 前仍以药物治疗为主, 同时辅以心理治疗。 目前的抗抑郁主流药物基本有五大类: 选择性的五羟色胺再摄取抑制剂(SSRIs ) ,去甲肾上腺素与特定五羟色胺再摄取抑
制剂(NaSSA) , 三环类抗抑制剂(TCAs ) , 单胺氧化酶抑郁剂(MAOIs)和五羟 色胺与去甲肾上腺素再摄取抑制剂 (SNARI)。 这些药物均有不同程度的不良反应, 如嗜睡、 视物模糊、 高血压、 惊厥和性欲低下等, 影响其广泛推广使用, 而且这些 药物由于其自身缺陷所限, 存在抗抑郁谱较窄、 毒副作用较大、 价格高昂、 停药后 易复发、 不适宜进行调理性治疗等问题, 故严重影响了它们的临床使用。
例如, 目前国内外市场上的抗抑郁症的药物百忧解、 赛洛特、 左洛复等 5-羟色 胺再摄取抑制剂 (SSRIs), 其作用机理是通过增加人体神经介质内 5-羟色胺成分含 量来缓解抑郁症状。 这类药物都有不同程度的副作用, 研究表明 "这些药品中含有 的复安栓对平衡人体技能有作用, 但更多的时候, 它们还是无法使患者平静下来"。 而且这些抗抑郁症的药物存在严重的社会问题, 具有安全隐患, 例如服用赛洛特导 致青少年自杀倾向增高。
抑郁症是一种临床综合症, 其诱发原因多, 是各种因素共同作用的结果, 仅仅 针对某个单一环节 (靶点) 进行治疗, 往往难以取得满意的效果, 而传统的中医中 药治疗讲究的是综合诊断, 整体上调节各生理系统, 达到治疗的目的。 例如大量文 献报道小柴胡汤、 半夏厚朴汤及白金散等方剂治疗 "梅核气"、 "抑郁症" 、 "抑郁性 精神病" , 其中胡思荣用平心忘忧汤 (磁石、 檬石、 积实、 黄柏、 半夏、 厚朴、 朱 获荃、 神肉、 肉桂、 苏叶、 营蒲、 生姜) 治疗抑郁症 470 例, 痊愈 70.2 % , 好转 20.2 % , 总有效率 90.4 % ; 赵志升自拟中药"抑虑康 "胶囊治疗抑郁, 总体疗效优 于西药对照组; 马云枝等人用舒郁调神汤 (柴胡、 郁金、 菖蒲、 积实、 桃仁、 红花、 柏子仁、 远志、 锻龙牡、 丹参) 治疗中风后抑郁症, 其治愈率为 39.06 % , 显效率 为 30.40 % , 有效率为 21.09 % , 无效率为 9.45 % , 并明显改善主要及伴随症状; 日本尾崎哲发现小建中汤 (桂枝、 生姜、 芍药、 甘草、 大枣、 怡糖末) 对抑郁性神 经症患者情绪具有调节作用。 如此临床案例很多。 但是, 复方中药方剂也存在起效 慢, 药效不够显著, 组份比较复杂, 功效成分不明确等问题, 故其质量可控性受到 制约, 也难以用现代药理学分析它们的作用机理。
近年来从传统药中提取具有高效抗抑郁的单体药物研究日益增多, 而且已经成 为国际制药业开发抗抑郁药物的趋势,例如在德国, 以贯叶连翘的提取物金丝桃素治 疗抑郁症, 不仅疗效显著, 而且副作用小, 现已列入欧美等国家的抗抑郁主流药物。
对传统复方中药以及中药提取成分中单体药物抗抑郁的研究众多, 例如:
授权公告号为 CN100509006C的发明专利公开了一种治疗抑郁症药物组合物, 该组合物包括人参、 甘草和大枣, 或是它们的水提取物或是乙醇提取物。
授权公告号为 CN1256090C的发明专利公开了一种积雪草及其衍生物在制备抗 抑郁药物中的新用途。
公开号为 CN101385736A的发明专利申请公开了涉及芍药苷在预防和治疗抑郁 症药物中的应用及其药物组合物, 所述药物组合物含有有效剂量的芍药苷和药学上 可接受的载体, 所述药物组合物可以制备成常规的液体剂型或固体剂型。
公开号为 101332205A 的发明专利申请公开了一种以芍药甙为原料制成的用于 治疗抑郁症的药物及其服用量。
芍药内酯苷 (Albiflorin) 为单萜类化合物, 其分子式为 C23H28Ou, 分子量为 480.46, 分子结构如式 ( I ) 所示, 是一种天然活性物质, 来源于毛莨科植物白芍 Paeonia lactiflora Pall或川赤苟 Paeonia veitchii Lynch的根、 牡丹 Rsuffrsticosa Andrz 的根。
( I )
芍药内酯苷具有内酯环结构, 但是没有半缩醛结构, 其在厌氧条件下转化 成两种产物, 分别为芍药内酯 、 芍药内酯 8。 芍药内酯 、 B的结构示意图 如下:
芍药内酯 A 芍药内酯 B
现代药理研究表明芍药内酯苷具有镇痛、 镇静、 抗惊厥作用, 对免疫系统 的作用, 对平滑肌的作用, 抗炎作用, 抗病原微生物, 护肝作用, 临床上主要 用于抗癫痫, 镇痛、 戒毒, 止眩暈, 治疗类风湿性关节炎, 治疗细菌性痢疾及 肠炎, 治疗病毒性肝炎, 老年性疾病, 抗硫酸钡絮凝和溶解粘液的作用。 有关 芍药内酯苷的制备方法以及其在制备预防和治疗抑郁症药物中的应用还未见 报道。
本发明人通过大量的现代科学研究, 采用先进的分离纯化技术从芍药药材 中提取其治疗抑郁症的有效成分芍药内酯苷, 使其含量达到 50%以上, 并对芍 药内酯苷及其相应的药物制剂进行了治疗抑郁症的药效学、 药理学研究, 结果 表明芍药内酯苷单体药理作用清楚, 抗抑郁功效强, 毒副作用低, 安全性高, 可以为抑郁症患者提供一种高效低毒的药物。 发明内容
本发明的首要目的是针对上述现有技术存在的问题, 提供芍药内酯苷、 芍药内 酯苷代谢物、 芍药内酯苷组合物、 含芍药内酯苷的药材或含芍药内酯苷的药材提取 物抗情感性精神障碍, 特别是抗抑郁的性能和功效, 并针对上述现有技术存在的问 题, 提供芍药内酯苷或其药学上可接受的盐或其溶剂化物或是含有效量芍药内酯苷 的芍药提取物新的药用用途, 即在治疗、 调理和预防抑郁症的药物或保健食品中的 新应用。
为实现上述目的, 本发明一方面提供一种芍药内酯苷在制备预防、 缓解和 /或治 疗情感性精神障碍疾病药物、 保健品中的应用。
其中所述的情感性精神障碍疾病为抑郁症。
在筛选具有抗抑郁作用的天然活性成分的过程中, 发明人发现芍药的化学成分 中芍药内酯苷具有强烈的抗抑郁作用, 同时发现芍药内酯苷的人体内的两个代谢产 物芍药内酯 A (paeoni lactoneA)和芍药内酯 B (paeoni lactoneB)也具有抗抑郁作 用。
其中, 所述的 "芍药内酯苷"是指芍药内酯苷的外消旋体、 立体异构体, 或 以任意比例混合的立体异构体混合物。
特别是, 所述的 "芍药内酯苷"还包括芍药内酯苷的两个代谢产物芍药内酯
A (paeoni lactoneA)禾口苟药内酉旨 B (paeoni lactoneB)。
其中, 所述药物由芍药内酯苷和药学上可接受的载体组成。
特别是, 药学上可接受的载体通常被保健专家认可用于这一目的且作为药剂 的非活性成分。 有关药学上可接受的载体的汇编可以在 《药物赋形剂手册》 (Handbook of Pharmaceutical excipients,第 2 版, 由 A . Wade 禾口 P . J . Weller 编 辑; American Pharmaceutical Association 出片反, Washington and The Pharmaceutical
Press , London , 1994 ) 等工具书中找到。
尤其是, 所述的载体包括赋形剂, 如淀粉、 水等; 润滑剂, 如硬脂酸镁等; 崩解剂, 如微晶纤维素等; 填充剂, 如乳糖等; 粘结剂, 如预胶化淀粉、 糊精等; 甜味剂; 抗氧化剂; 防腐剂、 矫味剂、 香料等;
其中, 所述药物是通过经胃肠道给药和非经胃肠道给药途径给药。
特别是, 所述的非经胃肠道给药途径选择注射给药、 呼吸道给药、 皮肤给药、 粘膜给药或腔道给药。
其中, 所述药物以片剂、 胶囊剂、 丸剂、 散剂、 颗粒剂、 糖浆剂、 溶液剂、 注射剂、 喷雾剂、 气雾剂、 贴剂等形式存在。
其中, 非经胃肠道给药药剂选择注射剂、 喷雾剂、 气雾剂、 贴剂等。
特别是, 所述的经胃肠道给药制剂选择片剂、 胶囊剂、 散剂、 颗粒剂、 丸剂、 溶液剂或糖浆剂等。
其中, 所述的芍药内酯苷的纯度 50%, 优选为 80%, 进一步优选为 90%。 其中, 所述的芍药内酯苷的含量 50%, 优选为 80%, 进一步优选为 90%。 本发明另一方面提供一种芍药内酯苷组合物在制备预防、缓解和 /或治疗情感性 精神障碍疾病药物、 保健品中的应用。
其中所述的情感性精神障碍疾病为抑郁症。
其中, 所述的芍药内酯苷组合物选择芍药内酯苷药学上可接受的盐、 芍药内酯 苷的溶剂化物。
特别是, 所述的芍药内酯苷药学上可接受的盐为具有生理学上一一尤其在作 为药物施加至人类和 /或哺乳动物时可接受的盐。
其中, 所述的盐包括芍药内酯苷与酸加成反应得到的盐; 所述的芍药内酯苷 的溶剂化物为芍药内酯苷的水合物。
特别是, 所述的酸选择盐酸、 富马酸、 马来酸、 柠檬酸或琥珀酸中的一种或 多种, 所提及的这些酸仅作为说明的目的而不用来起限定作用。
本发明又一方面提供一种含芍药内酯苷的药材或含芍药内酯苷的药材提取物在 制备预防、 缓解和 /或治疗情感性精神障碍疾病药物、 保健品中的应用。
其中所述的情感性精神障碍疾病为抑郁症。
其中, 所述的含有芍药内酯苷的药材选择药材芍药或牡丹皮, 优选为白芍; 所 述的含芍药内酯苷的药材提取物中芍药内酯苷的纯度 10%。
本发明另一方面提供一种芍药内酯苷代谢物在制备预防、缓解和 /或治疗情感性 精神障碍疾病药物、 保健品中的应用。
其中, 所述的芍药内酯苷代谢物为芍药内酯 A、 芍药内酯 B; 所述的情感性精 神障碍疾病为抑郁症。
特别是, 所述的抑郁症选择为内源性抑郁症、 反应性抑郁症、 产后抑郁症、 更 年期忧郁症、 隐匿性抑郁症、 抑郁性神经症中的一种或多种。
尤其是, 所述的抑郁症优选为反应性抑郁症。
本发明再一方面提供一种用于预防、 缓解和 /或治疗抑郁症的药物, 包含芍药 内酯苷。
其中, 所述药物中芍药内酯苷的纯度 50%, 优选为 80%, 进一步优选为
90%。
其中, 所述的药物还含有药学上可接受的载体;
本发明再一方面提供一种预防、缓解和 /或治疗抑郁症的药物, 含有以下物质 中的至少一种: 芍药内酯苷代谢物、 芍药内酯苷组合物、 含芍药内酯苷的药材或含 芍药内酯苷的药材提取物。
其中, 所述药物由芍药内酯苷代谢物、芍药内酯苷组合物、含芍药内酯苷的药 材或含芍药内酯苷的药材提取物中的一种与药学上可接受的载体组成。
特别是, 所述的含芍药内酯苷的药材提取物中芍药内酯苷的纯度 10%。 尤其是, 所述含芍药内酯苷的药材提取物中芍药内酯苷的纯度为 10%〜50%, 优选为 20%〜45%, 进一步优选为 30%〜40%。
其中, 所述的芍药内酯苷代谢物为芍药内酯 、 芍药内酯^
其中, 芍药内酯苷组合物选择芍药内酯苷药学上可接受的盐、 芍药内酯苷的
溶剂化物。
特别是, 所述的芍药内酯苷药学上可接受的盐为具有生理学上一一尤其在作 为药物施加至人类和 /或哺乳动物时可接受的盐。
其中, 所述的盐包括芍药内酯苷与酸加成反应得到的盐。
特别是, 所述的酸选择盐酸、 富马酸、 马来酸、 柠檬酸或琥珀酸中的一种或 多种, 所提及的这些酸仅作为说明的目的而不用来起限定作用。
其中, 所述的芍药内酯苷的溶剂化物为芍药内酯苷的水合物
其中, 所述的含有芍药内酯苷的药材选择芍药或牡丹皮, 优选为白芍。
特别是, 所述的载体包括赋形剂, 如淀粉、 水等; 润滑剂, 如硬脂酸镁等; 崩解剂, 如微晶纤维素等; 填充剂, 如乳糖等; 粘结剂, 如预胶化淀粉、 糊精等; 甜味剂; 抗氧化剂; 防腐剂、 矫味剂、 香料等;
所述药物可以采用本领域公知的方法制成各种剂型, 如片剂、胶囊剂、 丸剂、 散剂、 颗粒剂、 糖浆剂、 溶液剂、 注射剂、 喷雾剂、 气雾剂、 贴剂等;
本发明再一方面提供一种预防、 缓解和 /或治疗抑郁症疾病的保健食品, 含有 以下物质中的一种: 芍药内酯苷、 芍药内酯苷代谢物、 芍药内酯苷组合物、 含芍药 内酯苷的药材或含芍药内酯苷的药材提取物。
其中, 所述的芍药内酯苷的纯度 10%。
特别是, 所述含芍药内酯苷的药材提取物中芍药内酯苷的纯度为 10%〜50%, 优选为 20%〜45%, 进一步优选为 30%〜40%。
本发明还提供了一种治疗抑郁症的方法, 包括向受试者给予治疗有效量的芍药 内酯苷的药物组合物, 其治疗有效量为 0. 6~4mg/kg · d, 优选为 1~3. 5mg/kg · d, 进 一步优选为 1. 5~3mg/kg · d。
除非另外说明, 本文所用的术语 "治疗有效量"为需要产生有效作用的药物的 用量; "治疗有效量"是可以调整和变化的, 最终由医务人员确定, 其所考虑的因 素包括给药途径和制剂的性质、 接受者的体重、 年龄等一般情况以及所治疗疾病的 性质和严重程度。 与现有技术相比, 本发明具有如下的明显优点:
1、本发明对已知化合物芍药内酯苷或其药学上可接受的盐或其溶剂化物发掘了
新的药用价值, 将其用于抗抑郁症 (芍药内酯苷对缩短小鼠悬尾不动时间、 强迫游 泳不动时间均具有显著性), 并可制备成预防、 调理和 /或治疗抑郁症的药物或保健 食品, 从而为芍药等药材的应用开拓了一个新的领域。
2、 本发明的系列试验研究证明芍药内酯苷具有显著的预防和治疗抑郁症的作 用, 系芍药以及芍药提取物治疗抑郁症的主要有效成分, 与通常认为的芍药苷为芍 药抗抑郁症的有效成分相比, 芍药内酯苷对缩短小鼠悬尾不动时间和强迫游泳不动 时间更具有显著性, 提示芍药内酯苷的抗抑郁功效要强于芍药苷。
3、本发明使用芍药内酯苷及相应的药物剂型, 采用了不同的动物模型, 通过口 服和注射途径进行了大量的动物试验, 试验结果表明: (1 ) 芍药内酯苷能显著缩短 小鼠悬尾不动时间和强迫游泳不动时间, 并且呈明显的量效关系; (2) 能显著降低 利血平诱导的体温下降; (3) 能显著抑制慢性应激抑郁大鼠的体重下降、 对蔗糖消 耗量的下降, 显著降低抑郁大鼠跳台错误次数, 显著增加大鼠敞箱活动的水平和垂 直运动得分; (4) 芍药内酯苷能显著增加抑郁大鼠脑内的单胺类神经递质去甲肾上 腺素、 5-羟色胺含量, 表明芍苷内酯苷具有较强的抗抑郁作用。
4、本发明的芍药内酯苷药理作用强,用于预防、调理和治疗抑郁症的功效显著, 见效快、 毒副作用小、 安全性好, 能够长期服用, 且可用现代药理学分析其抗抑郁 的作用机理, 具有良好的药用前景。
5、 本发明的产品原料来源丰富、 价廉、 临床使用安全, 制备工艺简单, 可制成 各种剂型, 且服量小, 使用方便, 因此易于推广。
6、本发明既可采用单一成分的芍药内酯苷活性成分制备预防和治疗抑郁症的药 物, 又可采用芍药内酯苷与其它活性成分 (例如与人参皂甙 Rgl、 甘草酸 GL等化合 物) 共同组方, 制备多靶点抗抑郁的复方药物。 具体实施例方式
下面结合具体实施例, 进一步阐述本发明。 但这些实施例仅限于说明本发明而 不用于限制本发明的范围。 下列实施例中未注明具体实验条件的实验方法, 通常按 照常规条件, 或按照厂商所建议的条件。
以下通过试验例来进一步阐述本发明所述药物的有益效果, 这些试验例包括了 本发明药物的药效学试验。
试验例 1 芍药内酯苷对小鼠悬尾实验的影响
1.1 实验材料
ICR小鼠, 雄性, 体重 18~20g, 由维通利华动物实验中心提供, 合格证编号: SCXK (京) 2006-0009。
芍药内酯苷 (纯度 >98%), 购自日本 WAKO公司; 芍药苷 (纯度 >98%), 购 自中国药品生物制品检定所; 阳性药物: 盐酸氟西汀胶囊(百优解), 礼来苏州制药 有限公司, 批号: A333341-070608。
JZ型 300g张力换能器(高碑店市新航积淀设备有限公司), Medlab生物信号采 集处理系统 (南京易美)
1.2 实验方法及结果
将正常小鼠按体重随机分成 8个组, 每组 20只, 即模型组、 阳性药盐酸氟西汀胶 囊 (3.5mg/kg/d), 芍药内酯苷高 (14mg/kg/d)、 中 (7mg/kg/d)、 低 (3.5mg/kg/d) 剂 量组, 芍药苷高 (14mg/kg/d)、 中 (7mg/kg/d)、 低 (3.5mg/kg/d) 剂量组。 各组均按 0.2ml/10g体重灌胃给药, 连续给药 2天。
于第 2天给药 lh之后将小鼠尾端 (在距尾尖 2cm处)用胶布固定在 100g张力换能 器的连线上, 使其呈倒悬状态, 头部离实验台约 15cm, 每次同时测试 2只动物, 相 互之间用纸板隔开。 换能器连接到 Medlab生物信号采集处理系统, 适应 2min后, 记 录 4min之内的结果, 将不动状态换算成时间 (s)。 实验数据用 ± ^表示, 实验结果用 SPSS11.5统计软件 (购自美国 SPSS公 司) 进行方差分析。 实验结果见表 1。 表 1 芍药内酯苷对小鼠悬尾不动时间的影响 ( ±s)
组别 剂量 (mg/kg) 样本数 不动时间 (S ) 模型组 20 93.47±38.678 阳性组 3.5 20 66.21±33.253* 芍药内酯苷高剂隨 14 20 48.32±32.756** 芍药内酯苷中剂隨 7 20 65.12±36.452* 芍药内酯苷低剂隨 3.5 20 83.82±35.099 芍药苷高剂量组 14 20 81.32±32.756
芍药苷中剂量组 7 20 76.83±36.452 芍药苷低剂量组 3.5 20 85.62±31.225
注: 与模型组比较, * P<0.05, ** P<0.01
实验结果表明:
1、 芍药内酯苷高、 中剂量组均能显著缩短小鼠悬尾不动时间 (与模型组比较, P<0.01, P<0.05 ), 且呈明显的量效关系, 提示芍药内酯苷具有良好的抗抑郁功能; 芍药内酯苷高、 中剂量与阳性药组效果相当, 高剂量组效果则明显优于阳性药组。
2、 芍药苷高、 中、 低剂量虽也能在一定程度上缩短小鼠悬尾不动时间, 但与模 型组相比不具有明显性差异, 提示芍药苷的抗抑郁作用能力较弱;
3、芍药提取物中芍药内酯苷的抗抑郁作用明显强于芍药苷, 是芍药抗抑郁的主 要活性有效成分。 实验例 2、 芍药内酯苷对小鼠强迫游泳实验的影响
2.1实验材料
ICR小鼠, 雄性, 体重 18-20g, 由维通利华动物实验中心提供。 合格证编号: SCX (京) 2006-0009。
芍药内酯苷 (纯度 >98%), 购自日本 WAKO公司; 芍药苷 (纯度 >98%), 中 国药品生物制品检定所; 阳性药物: 盐酸氟西汀胶囊(百优解), 礼来苏州制药有限 公司, 批号: A333341-070608。
温度计, 秒表, 玻璃缸, 柏拉图数码摄像头, 笔记本电脑。
2.2实验方法
正常小鼠 160只, 按体重随机分成 8个组, 每组 20只, 即模型组、 阳性药盐酸氟 西汀胶囊组 (3.5mg/kg/d)、 芍药内酯苷高剂量组 (14mg/kg/d)、 芍药内酯苷中剂量 组 (7mg/kg/d)、 芍药内酯苷低剂量组 (3.5mg/kg/d), 芍药苷高剂量组 (14mg/kg/d)、 中剂量组 (7mg/kg/d)、 低剂量组 (3.5mg/kg/d)。 各组均按 0.2ml/10g体重灌胃给药, 连续给药 2天, 空白对照组给去离子水。
于第 2天给药 lh之后将小鼠单个放入高 20cm、直径 18cm、水深 10cm、水温 23±2°C 的水缸中, 观察 6min, 适应 2min, 记录后 4min内累计不动时间 (s)。
数据以 x ±s表示, 以 SPSS13.0统计软件处理, 用 One-Way ANOVA方法, 方
差齐性用 LSD和 SNK检验。 实验结果见表 2。 表 2 芍药内酯苷对小鼠强迫游泳不动时间的影响 ( ±s)
组别 剂量 (mg/kg) 样本数 不动时间 (s)
20 64.90±34.620
模型组
阳性组 3.5 20 30.05±28.888* 芍药内酯苷高剂隨 14 20 17.20±24.230** 芍药内酯苷中剂隨 7 20 33.65±26.362* 芍药内酯苷低剂隨 3.5 20 44.85±29.695 芍药苷高剂量组 14 20 50.39±31.257 芍药苷中剂量组 7 20 43.94±38.341 芍药苷低剂量组 3.5 20 58.60±32.320
注: 与模型组比较, * P<0.05, ** P<0.01
实验结果表明:
1、芍药内酯苷高、 中剂量组均能明显缩短小鼠强迫游泳不动时间(与模型组比 较, P<0.01, P<0.05 ) , 显示芍药内酯苷具有较强的抗抑郁作用, 且呈明显量效关 系; 芍药内酯苷中剂量组效果与阳性药组相当, 高剂量组效果明显优于阳性药组。
2、 芍药苷高、 中、 低剂量虽也能在一定程度上缩短小鼠强迫游泳不动时间, 但 与模型组相比不具有明显差异 (P>0.05 ), 提示芍药苷的抗抑郁作用能力较弱;
3、芍药提取物中芍药内酯苷的抗抑郁作用明显强于芍药苷, 是芍药抗抑郁的主 要活性有效成分。 实验例 3 芍药内酯苷腹腔注射给药对小鼠悬尾不动时间的影响
3. 1 实验材料
ICR小鼠, 雄性, 体重 18-20g, 由维通利华动物实验中心提供。
芍药内酯苷 (纯度 96.77%), 购自上海永恒生物科技有限公司。
JZ型 300g张力换能器(高碑店市新航积淀设备有限公司), Medlab生物信号采集 处理系统 (南京易美)。
3. 2 实验方法
将正常小鼠按体重随机分成 3个组, 每组 20只, 即模型组、 芍药内酯苷高
(14mg/kg)、 中 (7mg/kg)剂量组。 腹腔注射给药组给药 1天。 各组均按 0. 2ml/10g体 重给药。
腹腔注射给药组给药后 30min进行实验。 将小鼠尾端 (在距尾尖 2cm处) 用胶布 固定在 100g张力换能器的连线上, 使其呈倒悬状态, 头部离实验台约 15cm, 每次同 时测试 2只动物,相互之间用纸板隔开。换能器连接到 Medlab生物信号采集处理系统, 适应 2min后, 记录 4min之内的结果, 将不动状态换算成时间 (s)。 实验数据用 ± ^表示, 实验结果用 SPSS11.5统计软件 (购自美国 SPSS公 司) 进行方差分析。 实验结果见表 3。 表 3 腹腔注射芍药内酯苷对小鼠悬尾不动时间的影响 ( ±s) 组别 剂量 (mg/kg) 样本数 不动时间 (s) 模型组 20 107. 775 ± 53· 3934 芍药内酯苷高剂量组 20 62. 550 ± 40. 1303** 芍药内酯苷中剂量组 20 82. 350 ± 52· 5132 注: 与空白组相比, Ρ<0. 01**„
试验结果表明: 芍药内酯苷腹腔注射给药高剂量组可明显缩短悬尾小鼠的不动 时间 (与模型组相比, Ρ<0.01** ), 提示芍药内酯苷腹腔注射给药具有明显的抗试验 性抑郁作用。 实验例 4 芍药内酯苷对小鼠利血平诱导体温下降试验
4.1 实验材料
ICR小鼠,雄性,体重 22.0±2g,二级,购自北京首都医科大学实验动物科学部。 芍药内酯苷 (纯度 96.77%), 购自上海永恒生物科技有限公司; 帕罗西汀 (赛 乐特): 中美天津史克制药有限公司产品; 利血平: 广东邦民制药厂有限公司。
GM222型电子温度计, 秒表。
4.2 实验方法
将 50只小鼠随机分为 5组, 每组 10只: 1 )芍药内酯苷大剂量组(Mmg*!^1 ); 中剂量组 mg kg ); 小剂量组 G mg kg ); 对照组帕罗西汀组 (3mg/kg); 模 型组生理盐水组。 灌胃给药 7天。
在第 8天给药后 1小时测定小鼠肛温,然后经腹腔注射利血平 2 mg/kg, 于注射
利血平后 4小时再测定小鼠肛温。 每次测温时温度计插入小鼠肛门的深度及时间均 一致。 实验数据用 ± ^表示,实验结果用 SPSS11.5统计软件 (购自美国 SPSS公司 ) 进行方差分析, 实验结果见表 4。
表 4 芍药内酯苷对小鼠利血平诱导体温下降的影响
动物数 (只) 体温下降值 rc)
生理盐水组 (模型组) 10 3.65±0.77
帕罗西汀组 (对照组) 10 2.38±0.69**
芍药内酯苷大剂量组 10 0.97±0.92**
10 2.34±0.91 **
10 2.57±0.67**
注: 与模型组比较 * P<0.05 **P<0.01
试验结果表明:
芍药内酯苷大、 中、 小剂量组和阳性药对照组 (帕罗西汀组) 均可明显减少利 血平诱导的体温下降, 具有显著性差异 (与模型组比较, 均为 P<0.01 ), 提示其抗 试验性抑郁作用可能与影响单胺递质含量有关。 实验例 5、 芍药内酯苷对慢性应激抑郁大鼠体重及行为的影响
5.1 实验材料
SD 雄性大鼠, 体重 240g〜260g, 购自北京维通利华公司, 合格证号: SCXK (京) 2002— 0003。
芍药内酯苷 (纯度 >98%), 购自日本 WAKO公司; 阳性药物: 百优解, 购自礼 来苏州制药有限公司, 批号: 20030017。
蔗糖, 购自北京国华化学试剂厂, 批号: 040120。
烘箱, 大鼠固定笼, 止血钳, 水桶, 温度计, 足底电击箱, 1/100秒表, 大鼠行 为观察敞箱, 大鼠跳台反应箱。
5.2 实验方法
正常大鼠 90只, 24小时禁水不禁食后, 给予 1 %蔗糖水, 测定 1小时内的消耗 量。随机分成 6个组,每组 15只,即空白组、模型组、芍药内酯苷高剂量组( 14mg/kg/ 天)、 芍药内酯苷中剂量组 (7mg/kg/天)、 芍药内酯苷低剂量组 (3.5mg/kg/天)、 阳 性药百优解组 (3mg/kg/天)。 造模同时灌胃给药, 每日一次, 连续给药 21天。 各组
均按 l .Oml/lOOg体重给药, 每周称一次体重。
参照文献方法 (许晶, 李晓秋, 慢性应激抑郁模型的建立及其评价, 中国行为 医学科学, 2003, 12 ( 1 ) : 14〜16 )进行造模(即采用 CUMS法造抑郁症动物模型): 将电击足底(36伏电压, 每隔 1分钟电击一次, 一次持续 10秒, 共 20次)、 4°C冰水游 泳 (5分钟)、 45 °C热烘 (5分钟)、 夹尾 (1分钟)、 潮湿饲养 (潮湿垫料)、 昼夜颠倒 ( 24小时)、 禁食(24小时)、 禁水 (24小时)等剌激随机安排到 21天内, 每日给予 1 种剌激,除空白组外其余动物均单笼饲养,自由饮食,室温 (24±1) °C,相对湿度 (60±10) %。
5.2.1 行为学观察
5.2.1.1 蔗糖水消耗量
每次禁水后, 测定每组动物 1小时内的 1 %蔗糖水消耗量。
5.2.1.2 敞箱实验 (open-field)
敞箱高 40cm、 长和宽均为 80cm, 无盖, 周壁和箱底均为黑色, 底面划分为面 积相等的 25块方格。 以动物穿越方格数作为水平活动得分, 以直立次数为垂直活动 得分 (两前肢离地 lcm以上)。 每只动物进行 1次测定, 每次 3分钟。
5.2.1.3 跳台实验
实验装置为一个 30cmx30cmx30cm的有机玻璃箱, 底面是铜栅, 间距为 0.8cm, 可以通电, 电压由一变压器控制。箱子左后角置一高 5cm、直径为 8cm的木头平台。 将动物放入反应箱内适应环境 3分钟, 然后立即通 36V交流电, 动物受到电击, 正 常反应是跳上平台以躲避伤害性剌激。 多数动物可能会再次或多次跳至铜栅上, 受 到电击后又迅速跳回平台, 如此训练 5分钟, 大鼠受到电击的次数为错误次数。 24 小时后重做测验, 将大鼠置于平台上, 通电并记时, 记录 5分钟内的错误次数。
所测定指标均采用均数±标准差( ± 表示,使用 SPSS 12.0软件(购自美国 SPSS 公司) 中的方差分析 (ANOVA) 进行检验, p <0.05表示差异具有显著性。
5.3 结果
5.3.1芍药内酯苷对慢性应激抑郁大鼠体重的影响
结果表明, 实验第 0天 、 7天各组动物体重无明显差异 P>0.05 实验第 14 天与空白组比较模型组大鼠体重显著降低 P<0.01 , 与模型组相比芍药内酯苷中、 高剂量组和阳性药百优解组大鼠体重显著增加 实验第 21天与空白组比
较模型组大鼠体重显著降低 P<0.01,与模型组相比芍药内酯苷中、 高剂量组和阳 性药百优解组大鼠体重显著增加 P<0.01。 实验结果见表 5。
表 5 对慢性应激抑郁大鼠体重的影响 ( ±s, g)
第 0天 第 7天 第 14天 第 21天 空白组 249.72±8.69 268.35±11.95 313.08±9.39** 342.94±11.56** 模型组 255.02±10.43 261.88±13.23 259.48±12.25 265.48±16.01 阳性药物组 257.19±9.90 265.90±13.94 280.64±12.32** 291.00±11.31 ** 低剂量组 256.83±11.49 265.65±11.23 270.75±18.15 271.07±19.06 中剂量组 250.18±13.45 265.65±12.44 279.61±15.99** 294.01±21.23 ** 高剂量组 255.84±11.69 268.11±17.50 277.05±20.65** 290.24±19.11 ** 注: 与模型组比较, *P〈0.05, **P<0.01 , ***P<0.00J。
5.3.2 芍药内酯苷对慢性应激抑郁大鼠蔗糖水消耗量的影响
结果表明, 实验第 0天 、 7天各组动物蔗糖水消耗量无显著差异 Ρ>0· 05 ; 实 验第 14天与模型组相比, 芍药内酯苷中剂量组和阳性药组 (百优解组) 大鼠蔗糖水 消耗量显著增加 Ρ<0.05 ·, 实验第 21天与空白组比较, 模型组大鼠蔗糖水消耗量显 著降低 Ρ<0· 05, 与模型组相比芍药内酯苷中、 高剂量组和阳性药组 (百优解组) 大鼠蔗糖水消耗量显著增加 Ρ<0.0ί 实验结果见表 6。
表 6 芍药内酯苷对慢性应激抑郁大鼠蔗糖水消耗量的影响 ( ±s, ml)
实验第 0天 实验第 7天 实验第 14天 实验第 21天
** 空白组 13.17±6.97 11.17±3.80 17.41±7.30" 16.91±5.20 模型组 13.17±6.67 13.17±7.21 10.00±4.61 10.00±2.76
** 阳性药组 12.67±5.53 10.00±4.24 15.00±2.22* 14.91±2.68 低剂量组 12.75±5.24 12.67±5.42 11.83±5.15 11.92±3.96
** 中剂量组 12.67±5.37 13.42±5.37 14.25±6.03* 14.75±5.14 高剂量组 12.50±5.32 14.08±3.65 13.00±3.74 14.50±3.48" 注: 与模型组比较, *P<0.05, **P<0.01 , ***P<0.00J。
5.3.3 芍药内酯苷对慢性应激抑郁大鼠敞箱活动行为的影响
结果表明, 与空白组相比, 模型组大鼠水平运动得分、 垂直运动得分显著降低 (P<0.05) ; 与模型组相比, 芍药内酯苷中、 高剂量组和阳性药百优解组大鼠水平运 动得分、 垂直运动得分均显著增加 P<0.05 , 见表 7。
表 7 芍药内酯苷对慢性应激抑郁大鼠敞箱活动行为的影响 (x±s)
水平运动得分 垂直运动得分 空白组 45.91±33.37 14.75±11.50 模型组 6.75±2.49 1.75±2.42 阳性药组 28.09±18.55: 7.00±3.90*
低剂量组 21.42±20.38 4.67±6.87 中剂量组 28.33±18.63* 6.50±3.1 l" 高剂量组 29.25士 16.42" 6.50士 3.37* 注: 与模型组比较, *P<0.05, * *P<0.01 , * * *P〈0.00J。
5.3.4 芍药内酯苷对慢性应激抑郁大鼠跳台行为的影响
结果表明, 模型组大鼠训练期错误次数和测试期错误次数比空白组显著增加 ( P<0.0J ) ; 芍药内酯苷中、 高剂量组和阳性药百优解组与模型组相比显著减少 (P<0.05 ) o 实验结果见表 8。
表 8 芍药内酯苷对慢性应激抑郁大鼠跳台错误次数的影响 ( ±
组别 训练期错误次数 测试期错误次数
**
空白组 1.83±1.11 0.58±0.67* 模型组 5.08±1.83 3.16±1.95
**
阳性药组 2.09±1.22 0.72±1.19*
低剂量组 2.25±1.42 2.08±1.31
**
中剂量组 2.33±1.37 0.67±0.78*
**
高剂量组 2.33±1.23 0.83±0.94*
注: 与模型组比较, *P<0.05, * *P<0.01 , * * *P<0.00J。
5.4 结论:
应激是抑郁症的发病因素之一, 应用 CUMS制造的抑郁症动物模型, 其模拟行 为学以及神经内分泌等变化与人类抑郁症相类似, 已成为国内外探讨抑郁症的发病 机制及抗抑郁药物作用机制而广泛应用的动物模型之一。 但以往研究中所采用的应 激模型多为单一形式的应激, 如束缚、 强迫游泳等。 为避免动物对同一应激原产生 适应, 本研究采用了多因素的慢性应激模型, 每天随机将不同的应激剌激作用于动 物, 使其不可预测应激的发生时间和类型, 与人类抑郁症中慢性、 低水平的应激源 促进抑郁症的发生及发展的机制更为接近。 在此基础上结合孤养, 改变群居动物生 活环境, 更保证模型的成功。 模型大鼠水平活动和垂直活动得分显著降低, 蔗糖溶 液消耗量明显减少, 说明动物表现出抑郁状态, 兴趣丧失、 探究行为降低和快感缺 乏, 表明大鼠抑郁模型造模成功。
从敞箱探究活动、 跳台行为、 体重和对糖水消耗量试验结果显示, 芍药内酯苷 能有效改善抑郁模型大鼠的抑郁行为, 对抑郁症具有治疗作用, 作用效果与阳性药 百优解相当。
实验例 6 芍药内酯苷对慢性应激大鼠脑内单胺类神经递质的影响 6.1 实验材料
受试药: 芍药内酯苷 (纯度 >98%), 购自日本 WAKO公司;
阳性药: 盐酸氟西汀 (Fluoxetine, Prozac百忧解), 礼来苏州制药有限公司, 批 号: 国药准字 J20030017, 大鼠用量为 2.5mg/kg。
去甲肾上腺素( E, Serva公司); 多巴胺(DA, Fluka公司); 5-羟色胺(5-HT, Sigma公司); 3, 4-二羟基苯乙酸(DOPAC, Sigma公司); 3, 4-二羟苄胺(DHBA, Sigma公司), 二正丁胺(上海化学试剂厂), D-8离子对试剂(天津化学试剂二厂), 甲醇 (优级纯, 北京化工厂), 其它试剂均为国产分析纯。
SD大鼠, 雄性, 体重 220~240g。 由维通利华动物实验中心提供, 合格证编号: 2007-0001。
Waters510泵, M464电化学检测器 DL-822色谱工作站(大连化物所色谱中心), MSE150型超声粉碎器
6.2 实验方法
6.2.1 分组和给药
SD大鼠, 24h禁水不禁食后, 给予 1%蔗糖水, 测定 lh内的消耗量。 根据蔗糖 水消耗量随机分成 6个组, 每组 12只, 即正常对照组、 模型组、 阳性药盐酸氟西汀 组 (2.5mg/kg/d)、 芍药内酯苷高 (14mg/kg/d)、 中 (7mg/kg/d)、 低 (3.5mg/kg/d) 剂量组。 造模同时灌胃给药, 每日一次, 连续给药 21天。 各组均按 1.0ml/100g体重 给药, 每周称一次体重。
6.2.2 造模
正常对照组 6只 /笼饲养, 正常饮食饮水, 不给任何剌激。
其他五个组, 1只 /笼饲养, 并接受 21天的不可预知的应激剌激, 包括: 冰水游 泳, 热烘, 夹尾, 潮湿饲养, 昼夜颠倒, 禁食, 禁水等。 每组每天随机给予一种剌 激。
每种应激的具体操作方法:
( 1 ) 冰水游泳: 将动物放入盛有 4°C冷水 (冰水混合) 的桶中, 水深 15cm, 大鼠的足尖刚能触及桶底, 5min后将动物取出。
(2)热烘: 烘箱温度调至 45°C固定, 将动物放入烘箱中, 5min后将动物取出。
(3)夹尾:将大鼠放入固定笼中,露出尾巴,用止血钳夹住距尾根部 1cm处 (用 力不要过大, 使大鼠发出哀号即可), 持续 lmin。
(4) 潮湿饲养: 早上 8点, 往鼠笼中加入 200ml水, 至次日早 8点换掉。
(5)昼夜颠倒: 早上 8点, 将大鼠放入黑暗箱中, 晚上 8点打开灯照明, 至次 日早 8点。
(6) 禁食: 24h断料。
(7) 禁水: 24h断水。
6.2.3 样品制备及检测
动物断头处死, 迅速在冰上剥离大脑, 取前额皮质, 称重后置组织冷冻管中用 液氮快速冷冻后, 放入 -70°C冰箱保存至测定。
根据脑组织的重量, 加入预冷的 0.1mol/L过氯酸 (内含 0.3mM EDTA二钠和 0.5mM亚硫酸钠),
DHBA, 配制成 800μ1, 超声匀浆, llOOOrpm离心 10min, 上清液用于神经递质测定。
采用高效液相色谱一电化学检测器系统(HPLC— ECD)进行测定,色谱条件为: 色谱柱为 4xl50mm, Nova-pakC18, 5μιη (大连色谱中心填装); 流动相为 50mM柠 檬酸-乙酸钠缓冲液 PH3.5 (内含 1.0mMB-8离子对试剂, 1.8mM二正丁胺, 0.3mM EDTA二钠, 4%甲醇), 流速 1.0mL/min, 玻璃碳工作电极, 检测池电压为 +0.75V; 3, 4-二羟苄胺 DHBA为内标物, 样品中各主要组分用内标法进行定量。 检测数据以 ±s表示, 以 SPSS 13.0软件处理, 用 One-Way ANOVA方法, 检 测结果见表 9、 10。 表 9 芍药内酯苷对慢性应激大鼠脑内去甲肾上腺素的影响 ( ±s)
组别 剂量 (mg/kg) 样本数 NA
空白组 - 12 398.47±51.11* 模型组 - 10 159.20±49.31 阳性组 2.5mg/kg/d 11 440.88±62.58* 低剂量组 3.5mg/kg/d 11 174.59±60.35
中剂量组 7mg/kg/d 11 345.19±53.43* 高剂量组 14mg/kg/d 11 430.48±52.50*
注: 与模型组比较, *P<0.05, **P<0.01。 表 10 芍药内酯苷对慢性应激大鼠脑内五羟色胺的影响 ( ±s) 组别 剂量 (mg/kg) 样本数 5-HT 空白组 - 12 340.11±75.88* 模型组 - 10 158.27±60.34 阳性组 2.5mg/kg/d 11 272.19±63.42* 低剂量组 3.5mg/kg/d 11 188.43±67.91 中剂量组 7mg/kg/d 11 270.77±56.43* 高剂量组 14mg/kg/d 11 288.86±61.55* 注: 与模型组比较, *P<0.05, **P<0.01。
表 9、 10中的实验数据表明, 连续给药 21天后, 与空白组比较模型组大鼠脑内 单胺类神经递质去甲肾上腺素、 5-羟色胺含量明显降低 (P<0.05 ); 与模型组比较芍 药内酯苷中、 高剂量组和阳性药盐酸氟西汀组大鼠脑内单胺类神经递质去甲肾上腺 素、 5-羟色胺含量明显升高 (P<0.05 )。
脑内单胺类递质, 如去甲肾上腺素、 5-羟色胺 和多巴胺等功能不足, 导致抑郁 症发病。 利血平降压的同时引发抑郁症的原因就是由于利血平使突触前膜囊泡中的 去甲肾上腺素耗竭所致。 本实验研究显示慢性应激大鼠脑内 5-羟色胺、 去甲肾上腺 素含量明显降低, 芍药内酯苷能显著提高脑内 5-羟色胺、 去甲肾上腺素的含量。 提 示以上作用可能是芍药内酯苷的抗抑郁作用的重要机制之一。 实验例 7 含芍药内酯苷的白芍提取物对小鼠悬尾不动时间的影响
7.1 实验材料
ICR小鼠, 雄性, 体重 18-22g。 由维通利华动物实验中心提供, 合格证编号: 2007-0001。
受试药物: 含 31. 16%苟药内酯苷的白芍提取物, 北京欧纳尔生物工程技术有限 公司提供;
阳性药物: 盐酸氟西汀 (Fluoxetine, Prozac百忧解), 礼来苏州制药有限公司, 批号: 国药准字 J20030017, 小鼠用量为 3.5mg/kg。 取出胶囊内容物, 用去离子水配 制成溶液。
Medlab生物信号采集系统(南京易美科技有限公司), JZ100型 lOOg 张力换能器
(高碑店市新航机电设备有限公司)。
7.2 实验方法与结果
正常 ICR小鼠, 随机分为 5组, 即空白对照组、 阳性药物盐酸氟西汀组
( 3.5mg/kg/d)、 受试药物高剂量组 (90mg/kg/d)、 中剂量组 (45mg/kg/d)、 低剂量 组 (22.5mg/kg/d)。 各组均按 0.2ml/10g体重给药。 每日一次, 空白对照组给去离子 水, 连续灌胃给药 2天, 于末次给药后 1小时进行实验。 将小鼠尾端 (在距尾尖 2cm 处) 用胶布固定在 lOOg张力换能器的连线上, 使其呈倒悬状态, 头部离实验台约 15cm, 换能器连接到 Medlab生物信号采集系统, 适应 2min后, 记录 4min之内的不动 时间 (秒)。 试验数据以 士 s表示, 以 SPSS 13.0统计软件处理, 采用 One-Way ANOVA方差 分析。 实验结果见表 11。
表 11 对小鼠悬尾不动时间的影响 组别 剂量 (mg/kg/d) 样本数 不动时间( ± 3) 空白组 - 10 105.05 ± 8.91 阳性药物组 3.5 11 32.41 ±4.54* 受试药物低剂量组 22.5 10 91.10 ± 16.03 受试药物中剂量组 45 10 30.80±4.92* 受试药物高剂量组 90 10 60.90± 11.26* 注: 与空白组比较, * P<0.05 试验结果表明, 灌胃给药 2天, 受试药物高、 中剂量组与阳性药组均能明显缩短 小鼠悬尾不动时间, 与空白组比较差异显著 (P<0.05)。说明含 31. 16%苟药内酯苷的白 芍提取物具有显著的抗抑郁作用。 实验例 8 芍药内酯苷的急性毒性实验
对 SFP级 ICR小鼠灌胃给芍药内酯苷, 给药剂量为 8.4g/kg, 给药观察时间为 14天。
观察小鼠的呼吸性质和速率、 行为 (特别包括是否有致呕吐现象)、 动作、 皮毛 颜色张力、 腹型、 粪便硬度、 体重等。
经过 14天给药观察, 均未发现动物有任何异常症状, 也未出现死亡; 分别于第
7天和第 14天称量给药组小鼠体重, 与对照组相比无显著性差异 (P>0.05 )。
急性毒性试验的结果表明, 小鼠灌胃给予芍药内酯苷, 在给药剂量高达 8.4g/kg 体重时 (约为临床拟用量的近 600倍), 服用本发明的药物仍然是安全的。 实施例 1 制备芍药内酯苷的提取物
将白芍粉碎后, 用 70%的乙醇水溶液加热回流 3次, 3次的溶剂 70%的乙醇水 溶液的重量分别为白芍重量的 5倍、 4倍、 3倍 (例如 1公斤白芍, 添加 5公斤的 70%乙醇水溶液), 回收乙醇, 稀释浸膏至 4倍体积 (例如 1公斤白芍, 稀释浸膏的 体积为 4升), 过滤得澄清液 A, 待用。
将 D-101型大孔树脂用 95%的乙醇浸泡过夜,湿法装柱,蒸熘水洗至近无醇后, 将澄清液 A上 D-101型大孔树脂吸附柱, 1柱体积 /小时(BV/H)流速吸附, 先用 4 倍柱体积的水冲洗, 然后用 10%的乙醇冲洗, 再用 30%的乙醇洗脱, 收集第 2-5个 柱体积的洗脱液, 浓缩干燥 (温度≤70°C, 真空度≤—0.06Mpa), 粉碎后过 80目筛, 得含量为 30~35%的芍药内酯苷提取物, 出膏率约为 3~3.5%。
实施例 2 水渗漉法制备芍药内酯苷提取物
1) 将白芍破碎成粗颗粒 (≤10mm), 用 4倍量的水为溶剂 (例如 1公斤白芍, 用 4 公斤水浸泡), 浸渍 2 小时, 装入渗漉器内, 浸泡 1 小时, 进行渗漉, 流速 0.03ml/g.min,收集 10倍药材量的渗漉液(例如 1公斤白芍,收集 10公斤的渗漉液), 取渗漉液常压浓缩至浓缩液与药材的重量之比为 2: 1 (70°C测量), 得渗漉液 。
2) 将 D-101型大孔树脂用 95%的乙醇浸泡过夜,湿法装柱, 蒸熘水洗至近无醇 后, 备用。
3) 将渗漉液 A上 D-101型大孔树脂吸附柱, 比吸附量为芍药药材量比树脂量 为 1.5: 1, 流速 0.033ml/g.min, 弃去流出液。 用 3倍树脂量的水冲洗树脂柱, 流速 0.033ml/g.min,弃去流出液。用 4倍树脂量 50%乙醇冲洗树脂柱,流速 0.033ml/g.min, 收集 4倍树脂量的流出液, 备用。 以水冲洗至流出液乙醇含量为 0%, 取 50%乙醇 洗脱流出液 (上柱液) 重复上样。 对流出液进行减压浓缩 (温度≤70°C, 真空度≤一 0.06Mpa) ,至相对密度为 1.30~1.35 (60°C测) 的稠膏, 减压浓缩 (温度≤70°C, 真 空度≤— 0.06Mpa), 粉碎过 80 目筛, 即得含量为 30~55%的芍药内酯苷提取物, 出
膏率约为 4~5%。
将上述以芍药内酯苷为抗抑郁主要活性有效成分的芍药(白芍或赤芍)提取物, 按需要添加辅料后灌胶囊或是制片,即得本发明优选的以口服形式给药的药物制剂; 或是将上述含有较高纯度芍药内酯苷的芍药 (白芍或赤芍) 提取物与其它的抗抑郁 活性有效成分(例如人参皂甙、 甘草酸、 甘草次酸等), 一起组方制备治疗抑郁症的 复方药物。 实施例 3、 芍药内酯苷胶囊剂的制备
将 100g纯度为 96.77%的芍药内酯苷加入到 80g淀粉和 20g淀粉硅胶中, 混匀 后直接灌入明胶硬胶囊中, 制成每粒含 lOmg芍药内酯苷的胶囊剂。 实施例 4 芍药内酯苷片剂的制备
将 100g纯度为 96.77%的芍药内酯苷, 粉碎过 100目筛后与过 100目筛的 700g 淀粉混匀后, 加入适量的淀粉浆搅拌均匀, 经 16目铁筛丝网制粒, 60°C以下干燥, 整粒, 加入适量的硬脂酸镁混匀, 送入压片机内进行压片, 制成每片含 lOmg芍药 内酯苷的片剂。 实施例 5 芍药内酯苷氯化钠输液的制备
取纯度为 98.5%芍药内酯苷 10g, 加入氯化钠 90g, 加入注射用水, 搅拌使其溶 解, 加注射用水至 1000ml , 然后用 0. 22 μ πι微孔滤膜过滤, 分装灌封, 灭菌即可。 实施例 6 药内酯苷混悬剂的制备
将实施例 2制备的芍药内酯苷含量为 50%的芍药提取物 200g粉碎至 200目,加 入到 100g已经溶胀的羧甲基纤维素钠 (CMC) 中, 搅拌均匀, 加入蒸熘水至 10L, 搅拌制成混悬液, 每毫升混悬液含芍药内酯苷 10mg。
Claims
1、 芍药内酯苷在制备用于预防、 缓解和 /或治疗情感性精神障碍疾病或症状的药物 中的应用。
2、 芍药内酯苷在制备用于预防、 缓解和 /或治疗情感性精神障碍疾病或症状的保健 品中的应用。
3、 根据权利要求 1或 2所述的应用, 其特征是所述的精神疾病为抑郁症。
4、 根据权利要求 1或 2所述的应用, 其特征是所述的芍药内酯苷的纯度为 50%。
5、根据权利要求 1所述的应用,其特征是所述药物由芍药内酯苷和药学上可接受的 载体组成。
6、 根据权利要求 1或 2所述的应用, 其特征是所述药物或保健品以片剂、 胶囊剂、 丸剂、 散剂、 颗粒剂、 糖浆剂、 溶液剂、 注射剂、 喷雾剂、 气雾剂、 贴剂形式存 在。
7、 一种预防、 缓解和 /或治疗抑郁症疾病的药物, 其特征是至少含有以下物质中的 一种: 芍药内酯苷、 芍药内酯苷代谢物、 芍药内酯苷组合物、 含芍药内酯苷的药材 或含芍药内酯苷的药材提取物。
8、根据权利要求 7所述的含芍药内酯苷的药材提取物,其特征是所述含芍药内酯苷 的药材提取物中芍药内酯苷的纯度 10%。
9、 根据权利要求 7所述的药物, 其特征是所述的芍药内酯苷组合物选择芍药内酯 苷药学上可接受的盐、 芍药内酯苷的溶剂化物。
10、 根据权利要求 7所述的药物, 其特征是所述的含有芍药内酯苷的药材选择芍药 或牡丹皮。
11、 根据权利要求 7所述的药物, 其特征是所述的芍药内酯苷代谢物选择芍药内酯 A、 芍药内酯8。
12、 一种预防、 缓解和 /或治疗抑郁症疾病的保健品, 其特征是至少含有以下物质中 的一种: 芍药内酯苷、 芍药内酯苷代谢物、 芍药内酯苷组合物、 含芍药内酯苷的药 材或含芍药内酯苷的药材提取物。
13、根据权利要求 12所述的保健品,其特征是所述含芍药内酯苷的药材提取物中芍 药内酯苷的纯度 10%。
14、 根据权利要求 12 所述的药物, 其特征是所述的芍药内酯苷组合物选择芍药内 酯苷药学上可接受的盐、 芍药内酯苷的溶剂化物。
15、根据权利要求 12所述的药物,其特征是所述的含有芍药内酯苷的药材选择芍药 或牡丹皮。
16、根据权利要求 12所述的药物,其特征是所述的芍药内酯苷代谢物选择芍药内酯 A、 芍药内酯8。
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DK10824417.9T DK2491934T3 (en) | 2009-10-20 | 2010-08-24 | Use of albiflorin against depression |
ES10824417.9T ES2574663T3 (es) | 2009-10-20 | 2010-08-24 | Utilización de albiflorina contra la depresión |
EP10824417.9A EP2491934B1 (en) | 2009-10-20 | 2010-08-24 | Use of albiflorin for anti-depression |
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CN102670752A (zh) * | 2012-06-11 | 2012-09-19 | 河南中医学院 | 牡丹皮提取物在制备治疗抑郁症药物中的应用 |
KR101672274B1 (ko) * | 2013-10-28 | 2016-11-04 | 한국 한의학 연구원 | 자화지정 추출물 또는 자화지정, 도인, 계지, 및 감초 복합 추출물을 포함하는 지질 관련 심혈관 질환 및 비만의 예방 또는 치료용 조성물 |
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EP2644198A4 (en) * | 2010-11-25 | 2014-05-07 | Zuoguang Zhang | USE OF ALBIFLORIN OR A METABOLITE THEREOF IN THE FIGHT AGAINST ANXIETY AND FOR THE IMPROVEMENT OF SLEEP DISORDERS |
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US20120270820A1 (en) | 2012-10-25 |
EP2491934A1 (en) | 2012-08-29 |
US9023817B2 (en) | 2015-05-05 |
DK2491934T3 (en) | 2016-06-20 |
ES2574663T3 (es) | 2016-06-21 |
EP2491934A4 (en) | 2013-04-03 |
EP2491934B1 (en) | 2016-03-09 |
CN102038701B (zh) | 2012-06-27 |
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