WO2006090557A1 - Preventive or therapeutic agent for stroke or sequelae of stroke comprising as main component salvianolic acid b or the like - Google Patents

Preventive or therapeutic agent for stroke or sequelae of stroke comprising as main component salvianolic acid b or the like Download PDF

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Publication number
WO2006090557A1
WO2006090557A1 PCT/JP2006/301417 JP2006301417W WO2006090557A1 WO 2006090557 A1 WO2006090557 A1 WO 2006090557A1 JP 2006301417 W JP2006301417 W JP 2006301417W WO 2006090557 A1 WO2006090557 A1 WO 2006090557A1
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Prior art keywords
stroke
sal
sequelae
group
control group
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PCT/JP2006/301417
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French (fr)
Japanese (ja)
Inventor
Torao Ishida
Ming Gao
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Juridical Person, Suzuka University Of Medical Science
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Publication of WO2006090557A1 publication Critical patent/WO2006090557A1/en

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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates to a novel agent for preventing or treating stroke or stroke sequelae.
  • Patent Document 1 treatment of thrombotic symptoms in atherosclerotic stroke with thromboxane A2 synthesis inhibitor (Patent Document 1), prevention of recurrence of stroke at a dose that does not lower blood pressure (Patent Document 2), NR2B subtype selective NMDA reception Stroke treatment combining somatic antagonists with various drugs (Patent Document 3), Stroke preventive agent containing phosphatidylcholine as an active ingredient (Patent Document 4), Peroxidation containing phofen as an active ingredient is reduced Preventive stroke (patent document 5), stroke preventive agent containing xanthine as an active ingredient (patent document 6), stroke preventive agent by improving hypertension symptoms containing dioxanecyclo [3, 3, 0] octane derivative as an active ingredient ( Patent literature 7) etc.
  • Patent Document 8 1-aminocyclopropanecarboxylic acid and its prodrugs and their pharmaceutically acceptable salts and their hydrate powers for the prevention of stroke or stroke sequelae based on selected compounds or A therapeutic drug was developed (Patent Document 8) . However, it is still desirable to develop new drugs for the prevention or treatment of stroke or stroke sequelae.
  • Tansan has long been known as a medicine for angina pectoris, myocardial infarction and stroke.
  • an acyl derivative of salvianolic acid A hereinafter abbreviated as Sal'A
  • Sal'A an acyl derivative of salvianolic acid A
  • one of the inventors of the present invention is characterized in that a neural system characterized by proliferating, Z, or differentiating neural stem cells while protecting neural stem cells or neural stem cells and their corresponding neural cells.
  • a neural system characterized by proliferating, Z, or differentiating neural stem cells while protecting neural stem cells or neural stem cells and their corresponding neural cells.
  • An object of the present invention is to provide a new agent for preventing or treating stroke or sequelae of stroke.
  • the present inventors have separated the red ginseng component, and using the separated components, the blood pressure-lowering effect, stroke incidence, severity of stroke sequelae, major organs in stroke-prone rats SHRSP In comparison with the control rats, the effect on the life span was compared with that of the control rats, and it was confirmed that Sal • B was a significant effect in the prevention or treatment of stroke or stroke sequelae in stroke-prone rats SHRSP. As a result of further research based on this, the present invention was completed.
  • Sal ⁇ ⁇ is one of the water-soluble components of Dansang
  • stroke or stroke sequelae is one of the diseases caused by the deterioration or loss of tissue or organ function due to degeneration, decrease, cell death, injury or exclusion of nerve cells.
  • the present invention is based on the preventive or therapeutic action of dansan stroke or sequelae of stroke, and neuronal degeneration, reduction, cell death, injury, exclusion, including Sal ⁇ B described in Japanese Patent Application No. 2004-341367 as an active ingredient. It falls under the selection invention of a therapeutic agent for diseases caused by functional or organ function decline or loss.
  • the present invention provides "a new drug for preventing or treating stroke or sequelae of stroke” ⁇ Sal'B and its prodrugs, and pharmaceutically acceptable salts thereof and their hydrate powers.
  • Prophylactic or therapeutic agents are provided.
  • the drug of the present invention is useful as a drug for preventing or treating stroke or stroke sequelae.
  • the present invention is a novel drug for preventing or treating stroke or sequelae of stroke.
  • the main components of the drug of the present invention are SA and B and prodrugs thereof, and pharmaceutically acceptable salts and hydrate powers thereof.
  • SAL'B may be a natural substance or a synthetic product.
  • Sal'B is one of the plants of the family Lamiaceae (scientific name: Salvia ⁇ miltiorrhiza ⁇ Bunge ;, Antan ('child name: Salvia ⁇ yunnanens IS' CH Wright), blood bonsai (scientific name: Salvia 'cavaleriei' Levl. var. simplicif elia ⁇ Peter-Stibal), Akinotamurasou (scientific name: Salvia 'chinensis' Benth), Salvia' Kava Reliei.
  • Lamiaceae scientific name: Salvia ⁇ miltiorrhiza ⁇ Bunge ;, Antan ('child name: Salvia ⁇ yunnanens IS' CH Wright), blood bonsai (scientific name: Salvia 'cavaleriei' Levl. var. simplicif elia ⁇ Peter-Stibal), Akinotamurasou (scientific
  • TAS ⁇ Dinores (scientific name: Salvia ⁇ flava ⁇ Forrest ⁇ ex ⁇ Diels), Sanorevia ⁇ Bowleyana ⁇ Dunn (scientific name: Salvia ⁇ bowleyana ⁇ Dunn), Sanorevia ⁇ Priotis ⁇ Hanse (scientific name: Salvia-prionitis -Hance) (Non-Patent Document 2), etc., extracted with water, hot water, methanol-water solution, etc., and then purified by column chromatography or counter 'current' chromatography.
  • Ral chromatograph is used to adsorb Sal 'B, and after flowing an aqueous acetate solution such as magnesium acetate or calcium acetate, the fraction eluted with methanol solution is collected and further purified.
  • aqueous acetate solution such as magnesium acetate or calcium acetate
  • the fraction eluted with methanol solution is collected and further purified.
  • Patent Document 10 hot water extract of Tansan is adsorbed on a rosin column and eluted with 50% -95% ethanol
  • Patent Document 11 the ethanol / aqueous solution extract of Dansan is extracted with normal-hexane.
  • Non-patent Document 3 It is obtained by purifying with a high-speed counter 'current' chromatography of a two-layer solvent system consisting of 'ethyl acetate' ethanol 'water (3: 7: 1: 9 volume Z volume) (Non-patent Document 3).
  • the quality control of Sal'B can be carried out by adsorbing the Sal'B sample to an analytical DS column (ODS ⁇ column) and methanol ⁇ 5% acetic acid solution (35: 65 volumes).
  • Non-patent document 4 High-pressure liquid chromatography (HPLC) eluting at 281 nanometer wavelength is detected (Non-patent document 4), and 20 microliters of Sal'B sample is analyzed using C18 (Discovery'C18, 4.6 (Millimeter x 25cm) adsorbed on a column and detected in methanol-water-glacial acetic acid (40: 60: 2, volume Z volume) at a flow rate of 0.5 ml Z min. Non-patent document 5). However, if there are Sal'B-containing plants other than these plants, they can be synthesized if they can be separated from the plants and synthesized.
  • Sal ⁇ B is currently marketed in China (Jingtian Biological Process Co., Ltd.) and the United States (Ivy ⁇ Fine ⁇ Chemicals' Corporation). Sal'B is the main component of this product, even if other compounds such as isolated but not sufficiently purified, unpurified and unisolated compounds coexist in addition to the isolated and purified product.
  • the mixed compound can be used as long as the object of the present invention is not impaired.
  • the prodrug of SAL'B may be any prodrug as long as it is pharmaceutically acceptable as long as it undergoes hydrolysis or the like and becomes SAB.
  • examples of such prodrugs include, but are not limited to, methyl ester derivatives or ethyl ester derivatives at the carboxyl group in the SAL • B molecule and acetyl derivatives at the amino group in the SAL • B molecule. It may be synthesized in the future.
  • the salts of SAL'B and the prodrugs of SA and B are limited to pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and ammonia such as ammonium and tetramethylammonium. Salts, organic acid salts such as triethylamine, lysine and arginine, and acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, but are not limited thereto. Any salt that can be synthesized in the future may be used as long as it is pharmaceutically acceptable as long as it is pharmaceutically acceptable. Hydrates of SAL'B and prodrugs thereof, pharmaceutically acceptable salts of SAL'B and prodrug salts thereof can also be used as the main component of the present invention.
  • the agent for preventing or treating stroke or sequelae of stroke according to the present invention is relatively stable in the absence of oxygen and moisture. However, it has an antioxidant effect and is relatively unstable in the air and in aqueous solutions. Sal'B in aqueous solution is unstable at high temperatures, 72 at 80 degrees Celsius 35% change over time, partially changed even with addition of sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, cystine hydrochloride, EDTA disodium salt, 80 degrees Celsius only when vitamin C is added And stable for 72 hours (Non-patent Document 6).
  • antioxidants include alpha 'carotene, beta' carotene, lycopene, rutin, flavonoids, catechins, resaveratrol, isoflavones, vitamin A, vitamin E, selenium, zinc, coenzyme Q10, Examples include dartathione and enzogenol. These antioxidants suppress Sal'B changes in hot aqueous solutions.
  • Nitrite does not completely suppress Sal'B changes. Therefore, nitrite alone is insufficient as a stabilizer. Vitamin Suppresses Sal'B changes. Therefore, vitamin C can be used as a stabilizer such as Sal'B, but vitamin C itself is relatively unstable in the air and in aqueous solution, and it can add a large amount of vitamin C to other antioxidants. Need to be used together.
  • the main component of the medicament for preventing or treating stroke or sequelae of stroke of the present invention is a non-high molecular weight molecule, it is administered orally or parenterally (suppository, intramuscular, subcutaneous, intravenous, intracerebral, etc. ) Can be administered. Even in the case of a prodrug whose main component is SAL'B, since the prodrug is activated in the body, it is not necessary to activate the prodrug in advance.
  • binder for example, polyvinylenoreconole, polyvinylinoatenole, ethinoresenorelose, methinorescenellose, arabica gum, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl starch, polybutylpyrrolidone Etc.
  • disintegrant include starch, agar, ungelatinized, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextran, and pectin.
  • lubricant include magnesium stearate, talc, polyethylene darcol, silica, hydrogenated vegetable oil, and the like.
  • colorant those permitted to be added to pharmaceuticals can be used.
  • a flavoring agent cocoa powder, coconut powder, coconut brain, aromatic acid, heart power oil, dragon brain, cinnamon powder and the like can be used. These tablets may be appropriately coated on the granules by sugar coating, gelatin coating, etc. if necessary.
  • an isotonic solution such as glucose or physiological saline, a pH adjuster, a buffer, the above-mentioned antioxidant and other stabilizers, a preservative, etc. are added.
  • an isotonic solution such as glucose or physiological saline, a pH adjuster, a buffer, the above-mentioned antioxidant and other stabilizers, a preservative, etc.
  • the injection may be a solid preparation or a preparation prepared for daily use by lyophilization after storing the solution in a container.
  • One dose may be stored in a container, or multiple doses may be stored in the same container.
  • a known method may be used.
  • the dose of the agent for preventing or treating stroke or sequelae of the present invention varies depending on the dosage form such as oral preparation, suppository, subcutaneous injection, intramuscular injection, intravenous injection, intracerebral injection and the like.
  • the dosage form such as oral preparation, suppository, subcutaneous injection, intramuscular injection, intravenous injection, intracerebral injection and the like.
  • adults are usually administered in daily doses of 0.01 to: LOOO milligrams, preferably 0.1 to 100 milligrams, and 1 dose is given in 1 to 1 doses or divided into 2 to 4 doses. .
  • the dose may be adjusted according to age and symptoms.
  • toxicity tests and medicinal effects tests acute toxicity tests, subacute toxicity tests, teratogenic toxicity tests, mutagenicity tests, leukocytes, lymphoid, neutrophils, reproductive tests, hemoglobin, GOT, serum total protein, albumin , Triglyceride, Cholesterol, Glucose, Urea, Micronucleus rate, Sperm malformation rate, Revertant bacteria, Fetal death rate, Fetal weight / Height, Tail length, Sternum deletion rate, etc.
  • the company outsources the routine analysis to routine N02ZN03, creatine, Na, K, Ca, Cl, Mg, blood albumin, globulin, GOT, GTP, gamma-daltamyl transpeptidase, urea nitrogen, Analyzes of reatune, Na, K, Ca, Cl, Mg, angiotensin 1 convertase, angiotensin 2, etc. are routinely outsourced by clinical laboratory contractors such as Shionogi 'Biomedical' Laboratories.
  • Patent Document 1 Japanese Patent Laid-Open No. 2003-26660
  • Patent Document 2 Japanese Patent Laid-Open No. 2002-370981
  • Patent Document 3 Japanese Patent Laid-Open No. 2002-332095
  • Patent Document 4 Japanese Unexamined Patent Publication No. 2000-239168
  • Patent Document 5 Japanese Patent Laid-Open No. 11-228396
  • Patent Document 6 Japanese Patent Laid-Open No. 10-182469
  • Patent Document 7 JP-A-8-268887
  • Patent Document 8 # 112005— No. 025806
  • Patent Document 9 Japanese Patent Application No. 2004-341367
  • Patent Document 10 Japanese Patent Laid-Open No. 1268682
  • Patent Document 11 US Patent 2001, 299, 910
  • Non-Patent Document 1 J. C. Dong et al., Yao'Xue'Bao, 31 ⁇ 6, p. 1996
  • Non-Patent Document 2 L. N. Li et al., J. Chinese-Pharmaceutical-Sciences, 1997 6-2, 57-64
  • Non-Patent Document 3 HB Li et al., J. Chromatogr. A. 2002 943-2 2 235-239
  • Non-Patent Document 4 QW Zhang et al., Zhongguo-Zhong-Yao-Za-Zhi, 2001 26 ⁇ 1 2 pages 848-849
  • Non-Patent Document 5 Kyokutake et al., Http: Z / www.ndc enter, com.cnZ tongxun / 2 / q uguiwul.pdf.
  • Non-patent document 6 Katsura Take et al., Http: Z / www.ndc enter, com.cnZ tongxun / 2 / q uguiwu2.pdf.
  • Toshimoto Tenkaido's 20 g of medical dandelion was filled with 150 ml of water and extracted at 30 ° C for 30 minutes while warming to 100 ° C. After filtration, add 150 ml of water again to the residue. 10 While heating at 0 ° C., extraction was further performed for 30 minutes, and then the filtrate obtained by two extractions was collected. The liquid volume decreased due to water evaporation during the extraction, and 170 ml of Tansan extract was obtained. Water was adjusted so that the amount of this solution was 222 ml. This is referred to as Tansan extract.
  • the room temperature is 22 ⁇ 1 degrees Celsius
  • the humidity is 60 ⁇ 10%
  • the lighting time is from 6 o'clock to 18 o'clock 12 hours
  • Preliminary breeding for 1 week in the breeding room set up in. Measure blood pressure and body weight of 60 rats with normal weight gain and no abnormalities in the general condition, so that 10 rats of 60 rats were divided into 6 groups so that there was no difference in blood pressure and body weight between groups. divided.
  • the B-control group was used as the group for measuring the value. During the experiment, they were fed with solid SP feed and tap water. Regarding the handling of animal experiments, we followed the “Basic Guidelines for Animal Experiments in the Physiological Field” established by the Physiological Society of Japan.
  • Example 1 rats were warmed for 10 minutes in a 38 degrees Celsius warmer before and after drug administration from 11:00 am to 5:00 pm in the above-mentioned temperature and humidity room once a week. After that, the systolic blood pressure was measured using the Softron non-invasive automatic blood pressure measurement device (BP-98A) (manufactured by Softron Co., Ltd.) by the tail-cuff method without anesthesia. The diastolic blood pressure and heart rate were measured three times, and the average and standard deviation were calculated and expressed as mean standard error. The presence or absence of significant difference was examined by t-test.
  • BP-98A Softron non-invasive automatic blood pressure measurement device
  • the systolic blood pressure immediately before the start of administration of Dansang or SAl ⁇ B, 1 week, 2 weeks, 3 weeks, and 4 weeks after the start of administration was 164. 76 ⁇ 12. 98, 186. 74 ⁇ 10 respectively. 3, 206.29 ⁇ 15.36, 212.87 ⁇ 13.17, 228.54 ⁇ 10.46 (mm Hg), Dansang group force S 165.75 ⁇ 6.87, 187.37 respectively ⁇ 10. 2 203. 28 ⁇ 13. 35, 210. 6 4 ⁇ 10. 23, 218.
  • Example 2 after measuring blood pressure and heart rate 4 weeks after starting Dansang or SAL'B administration, the rats were placed in a metabolic cage, and urine was collected for 24 hours.
  • N02ZN03 in the control group, Dansang group, and SAL'B group are 8.68 ⁇ 3.26 and 8.02 ⁇ 1.58 and 6.96 ⁇ 1.32 (*) (micromonore), creatinine 38. 75 people 7. 92 and 36.
  • ACC 1-aminocyclopropanecarboxylic acid
  • ACC 1-aminocyclopropanecarboxylic acid
  • the mechanism of action of SA and B seems to be due to the difference in the mechanism of action of preventive or therapeutic agents for stroke or sequelae of stroke mainly composed of ACC.
  • Tansan also has a low force effect that shows the same tendency as Sal 'B.
  • Example 3 urine was collected for 24 hours, then fasted for 24 hours, ether anesthetized, and blood was collected from the abdominal artery.
  • Blood albumin by BCG method, albumin / globin ratio by calculation, GOT and GPT by UV method, gamma-daltamyl transpeptidase by colorimetric method, urea nitrogen by UV method, and Creathun by alkaline picrin method Na and K by ion electrode method, Ca by OCPC method, C1 by ion electrode method, Mg by xylidyl-blue method, angiotensin 1 transferase by Kasahara method, and angiotensin 2 by RIA 'Measured by DCC method.
  • the blood albumins in order were 2. 31 ⁇ 0.18 and 2.30 ⁇ 0.17 and 2.23 ⁇ 0.10 (grams / decirit nore), and anolebumin / globin it was In the river page 0. 61 ⁇ 0. 02 and 0. 61 ⁇ 0. 08 and 0.64 ⁇ 0.03 (* 2) (calculated value), GOT is in the j jet 476. 9 ⁇ 178.1 and 472. 6 ⁇ 186.2 and 455.3 3 ⁇ 139.0 (units / liter), GPT is Kawasaki 115.
  • Example 2 the incidence of stroke on the 100th day after administration of Dansang or SAL'B, the severity of the sequelae of stroke, and the survival status were observed and analyzed. Rats that died were dissected on the day and examined for the presence of stroke lesions. The experimental data were expressed as mean value standard error. The presence or absence of significant difference was examined by t-test.
  • Example 5 the severity was determined based on the behavioral neurological symptoms of the rat, and the score was evaluated. The following evaluation criteria were used. Sensation (painfulness, etc.) 1 point of hypersensitivity, one-limbed paralysis 1S Voluntary walking, 2 points to be able to eat food on the cage lid, one-limbed paralysis is present, and voluntary walking is difficult, Three points were given to eat only the food in the cage, and four points were given to death. Compared to the control group, the Dansang group scored 36 points and the SAL'B group scored 4 points, and the SA or B group significantly reduced the sequelae of stroke compared to the control group. The Tansan group also showed a tendency to reduce the sequelae of stroke, but the difference was not significant compared to the control group.
  • Example 1 on the 30th day after drug administration, continuous measurement of cerebral blood flow was performed using the laser-Doppler method on the rats in the B-SAL'B group and the B-control group. Two-dimensional measurement was performed. As the measurement method, the rat scalp was incised under anesthesia, the skull was exposed, and the cerebral blood flow of the rat was measured using the laser power imaging device PiM2 (Risu Power Company, Sweden) manufactured by Rishiki. . The presence or absence of significant difference was examined by t-test. Using laser Doppler method, continuous measurement and two-dimensional measurement were performed to obtain values of SAL 'B group 1.414 ⁇ 0.24 and control group 1.144 ⁇ 0.31 (P ⁇ 0.05). It was. This result shows that cerebral blood flow in SAL'B group rats This is an improvement over the rats. The cerebral blood flow of the Dansang group is 1.199 ⁇ 0.43, which is not as good as that of the SAL'B group, but improved cerebral blood flow was observed.
  • High risk factors for stroke such as hypertension, diabetes, hyperlipidemia, heart disease, transient ischemic attack, effects that may be obtained by this trial for patients who want to participate in the trial Give a written statement that you can withdraw your trial participation at any time and that you can withdraw from the trial at any time.
  • SAL'B group which receives SAL'B on top of the basic treatment
  • control group which performs only basic treatment.
  • the patient's symptoms are scored according to the Japan 'Stroke' scale questionnaire every day, the score is calculated, and the onset of the stroke is diagnosed with the calculated value according to the rules written in the questionnaire. Strokes in the control group and SAL • B group
  • the stroke prevention effect of SAL'B can be measured from the difference in incidence.
  • the contents of the Japan 'Stroke' scale questionnaire are as follows.
  • Japan ' Koma' scale [Awakened without stimulating] 9 points for normality, clearness for general consciousness, 8 points for unclearness, 7 6 points for a person's name, their name and date of birth, 5 points for easy eye-opening with a normal call, 5 points for opening with a loud voice or body shake 4 points, pain ⁇ Repeating the call while applying stimuli, barely 3 points to open eyes, [not awakening even if stimulated, state] 2 points to move away from pain stimuli, pain Stimulate the limbs or grimacing a little with a stimulus, 1 point, 0 points not responding to painful stimulation, 9 points as A, 8-3 points as B, 2-points as C.
  • 10-2.Arm Normal A, arm can be raised with elbows extended, or arm can be raised by bending elbows B, arms move to some extent but cannot be lifted or do not move at all
  • the stroke prevention or treatment effect of SAL'B can be measured from the difference in the frequency of stroke onset between the control group and SAL'B group.
  • the contents of the Stroke Motor Dysfunction Severity Scale are as follows.
  • a constant of 14.60 is added to the cumulative value of each category above, and if the value is positive, it is determined that there is sequelae of stroke. From the difference in the severity of stroke motor dysfunction between the control group and SAL'B group, it is possible to measure the effect of SA or B in preventing or treating stroke sequelae.
  • the drug of the present invention can be used as a preventive or therapeutic agent for stroke or stroke sequelae.

Abstract

[PROBLEMS] To provide a novel preventive or therapeutic agent for stroke or sequelae of stroke. [MEANS FOR SOLVING PROBLEMS] A preventive or therapeutic agent for stroke or sequelae of stroke comprising as a main component, a compound selected from salvianolic acid B, its prodrugs, and their pharmaceutically acceptable salts and hydrates has been developed. For example, by being administered at a dose of 22.5 mg/kg once daily five times a week, salvianolic acid B reduces the occurrence of stroke by 30% and even in the case where stroke occurs, the sequelae are mild.

Description

明 細 書  Specification
サルビアノール酸 B等を主成分とする脳卒中又は脳卒中後遺症の予防用 又は治療用薬剤  Drugs for the prevention or treatment of stroke or sequelae of stroke with salvianolic acid B as the main component
技術分野  Technical field
[0001] 本発明は、新しい脳卒中又は脳卒中後遺症の予防用又は治療用薬剤に関する。  [0001] The present invention relates to a novel agent for preventing or treating stroke or stroke sequelae.
背景技術  Background art
[0002] 平成 13年度の厚生労働省の統計によれば、介護を要する 65歳以上の高齢者 94,75 0人に対し、介護が必要になった主な原因の 1位は脳卒中等脳血管疾患 24,749人、 2位は骨折 11,744人、 3位は痴呆 10,659人であり、脳卒中等脳血管疾患が飛びぬけ て多い。脳卒中又は脳卒中後遺症の予防用又は治療用薬剤の開発が強く望まれる 高齢者の高血圧症患者、糖尿病患者、高脂血症患者は脳卒中を起こしやすい。そ こで、脳卒中又は脳卒中後遺症の予防として、脳卒中又は脳卒中後遺症の原因たる 高血圧症を降圧剤で、糖尿病を抗糖尿病剤で、高脂血症を抗脂血剤で管理する方 法が取られて 、るが、脳卒中又は脳卒中後遺症の発生を十分には防 ヽで 、な 、。 そこで、種々のアプローチに脳卒中又は脳卒中後遺症の予防用又は治療用薬剤 の開発研究が行われている。例えば、トロンボキサン A2合成阻害剤によるァテローム 動脈硬化性脳卒中の血栓症状の治療 (特許文献 1)、血圧を低下させない用量で脳 卒中の再発防止剤（特許文献 2)、 NR2Bサブタイプ選択的 NMDA受容体アンタゴ 二ストを種々の薬剤と組み合わせる脳卒中治療法 (特許文献 3)、ホスファチジルコリ ンを有効成分とする脳卒中予防剤 (特許文献 4)、ァホェンを有効成分とする過酸ィ匕 物を減少させることによる脳卒中予防剤 (特許文献 5)、キサンチンを有効成分とする 脳卒中予防剤 (特許文献 6)、ジォキサンシクロ [3, 3, 0]オクタン誘導体を有効成分 とする高血圧症状の改善による脳卒中予防剤 (特許文献 7)等が公表されている。極 最近、 1 -アミノシクロプロパンカルボン酸及びそのプロドラッグ、ならびに薬学的に許 容することのできるそれらの塩およびそれらの水和物力 選ばれる化合物を主成分と する脳卒中又は脳卒中後遺症の予防用又は治療用薬剤が開発された (特許文献 8) 。しかし、未だ、新しい脳卒中又は脳卒中後遺症の予防用又は治療用薬剤の開発が 望まれる。 [0002] According to statistics from the Ministry of Health, Labor and Welfare in 2001, the number one cause of the need for nursing care for 94,75 0 elderly people aged 65 years or older is the cerebrovascular disease such as stroke. There are 24,749 people, 2nd place is 11,744 fractures, 3rd place is dementia 10,659 people, stroke and other cerebrovascular diseases are overwhelming. Development of drugs for preventing or treating stroke or sequelae of stroke is strongly desired. Elderly hypertensive patients, diabetic patients, and hyperlipidemia patients are prone to stroke. Therefore, as a prevention of stroke or stroke sequelae, a method of managing hypertension that causes stroke or stroke sequelae with antihypertensive agents, diabetes with antidiabetic agents, and hyperlipidemia with antilipidemic agents is adopted. However, it is sufficient to prevent the occurrence of stroke or stroke sequelae. Accordingly, research and development of drugs for preventing or treating stroke or sequelae of stroke are being conducted in various approaches. For example, treatment of thrombotic symptoms in atherosclerotic stroke with thromboxane A2 synthesis inhibitor (Patent Document 1), prevention of recurrence of stroke at a dose that does not lower blood pressure (Patent Document 2), NR2B subtype selective NMDA reception Stroke treatment combining somatic antagonists with various drugs (Patent Document 3), Stroke preventive agent containing phosphatidylcholine as an active ingredient (Patent Document 4), Peroxidation containing phofen as an active ingredient is reduced Preventive stroke (patent document 5), stroke preventive agent containing xanthine as an active ingredient (patent document 6), stroke preventive agent by improving hypertension symptoms containing dioxanecyclo [3, 3, 0] octane derivative as an active ingredient ( Patent literature 7) etc. are published. Very recently, 1-aminocyclopropanecarboxylic acid and its prodrugs and their pharmaceutically acceptable salts and their hydrate powers for the prevention of stroke or stroke sequelae based on selected compounds or A therapeutic drug was developed (Patent Document 8) . However, it is still desirable to develop new drugs for the prevention or treatment of stroke or stroke sequelae.
[0003] 一方、丹参は、狭心症、心筋梗塞および脳卒中の薬として古くから知られている。し かし、丹参成分の一つであるサルビアノール酸 A (以下、 Sal'Aと略称する。）のァシル 誘導体が抗スロンボティック作用により脳卒中に有効であるという報告があるのみで（ 非特許文献 1)、丹参のどの成分が脳卒中に有効かは知られていない。  On the other hand, Tansan has long been known as a medicine for angina pectoris, myocardial infarction and stroke. However, there is only a report that an acyl derivative of salvianolic acid A (hereinafter abbreviated as Sal'A), which is one of the Dansang components, is effective for stroke due to its antithrombotic action (Non-patented) It is not known which component of reference 1), Tansan is effective for stroke.
[0004] しかし、本発明者の一人は神経幹細胞又は神経幹細胞及びその分ィ匕細胞力 な る神経系細胞を保護しつつ、神経幹細胞を増殖及び Z又は分化することを特徴とす る神経系細胞の作用剤を探索し、 Sal-Bにその作用を発見し、種々研究した結果、 S al'B等を有効成分とする神経細胞の退化、減少、細胞死、傷害、除外による組織や 臓器の機能低下又は喪失により発症する疾病の治療剤を開発した (特許文献 9)。 発明の開示 However, one of the inventors of the present invention is characterized in that a neural system characterized by proliferating, Z, or differentiating neural stem cells while protecting neural stem cells or neural stem cells and their corresponding neural cells. As a result of exploring cell agents, discovering their effects on Sal-B, and conducting various studies, tissues and organs caused by degeneration, decrease, cell death, injury, or exclusion of nerve cells containing Sal'B as an active ingredient Has developed a therapeutic agent for diseases caused by functional loss or loss (Patent Document 9). Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0005] 本発明の目的は、新しい脳卒中又は脳卒中後遺症の予防用又は治療用薬剤を提 供することにある。 [0005] An object of the present invention is to provide a new agent for preventing or treating stroke or sequelae of stroke.
課題を解決するための手段  Means for solving the problem
[0006] そこで、今回、発明者等は丹参成分を分離し、分離した種々の成分を用いて脳卒 中易発症ラット SHRSPにおける血圧の降圧作用、脳卒中発症率、脳卒中後遺症の 重傷度、主要臓器及び寿命への影響を対照ラットと比較検討し、丹参成分の中で Sal • Bが脳卒中易発症ラット SHRSPの脳卒中又は脳卒中後遺症の予防又は治療に著 しい効果があることを確認し、この結果を基に更に種々研究した結果、本発明を完成 した。 Sal ·Βは丹参の水溶成分の一つであり、脳卒中又は脳卒中後遺症は神経細胞 の退化、減少、細胞死、傷害、除外による組織や臓器の機能低下又は喪失により発 症する疾病の一つである。従って、本発明は丹参の脳卒中又は脳卒中後遺症の予 防又は治療作用及び特願 2004— 341367に記載された Sal · B等を有効成分とする 神経細胞の退化、減少、細胞死、傷害、除外による組織や臓器の機能低下又は喪 失により発症する疾病の治療剤の選択発明に該当する。  [0006] In view of this, the present inventors have separated the red ginseng component, and using the separated components, the blood pressure-lowering effect, stroke incidence, severity of stroke sequelae, major organs in stroke-prone rats SHRSP In comparison with the control rats, the effect on the life span was compared with that of the control rats, and it was confirmed that Sal • B was a significant effect in the prevention or treatment of stroke or stroke sequelae in stroke-prone rats SHRSP. As a result of further research based on this, the present invention was completed. Sal · Β is one of the water-soluble components of Dansang, and stroke or stroke sequelae is one of the diseases caused by the deterioration or loss of tissue or organ function due to degeneration, decrease, cell death, injury or exclusion of nerve cells. is there. Therefore, the present invention is based on the preventive or therapeutic action of dansan stroke or sequelae of stroke, and neuronal degeneration, reduction, cell death, injury, exclusion, including Sal · B described in Japanese Patent Application No. 2004-341367 as an active ingredient. It falls under the selection invention of a therapeutic agent for diseases caused by functional or organ function decline or loss.
[0007] すなわち、本発明は、「新しい脳卒中又は脳卒中後遺症の予防用又は治療用薬剤 を提供する」という課題に対し、「Sal'B及びそのプロドラッグ、ならびに薬学的に許容 することのできるそれらの塩およびそれらの水和物力 選ばれる化合物を主成分とす る脳卒中又は脳卒中後遺症の予防用又は治療用薬剤」を提供する。 [0007] That is, the present invention provides "a new drug for preventing or treating stroke or sequelae of stroke" `` Sal'B and its prodrugs, and pharmaceutically acceptable salts thereof and their hydrate powers. Prophylactic or therapeutic agents "are provided.
発明の効果  The invention's effect
[0008] 本発明の薬剤は、脳卒中又は脳卒中後遺症の予防用又は治療用薬剤として有用 である。  [0008] The drug of the present invention is useful as a drug for preventing or treating stroke or stroke sequelae.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0009] 本発明は新しい脳卒中又は脳卒中後遺症の予防用又は治療用薬剤の発明である 。本発明の薬剤の主成分は SAい B及びそのプロドラッグ、ならびに薬学的に許容す ることのできるそれらの塩およびそれらの水和物力 選ばれる化合物である。  [0009] The present invention is a novel drug for preventing or treating stroke or sequelae of stroke. The main components of the drug of the present invention are SA and B and prodrugs thereof, and pharmaceutically acceptable salts and hydrate powers thereof.
[0010] SAL'Bは、天然物質も合成品も使用可能である。 Sal'Bは、シソ科の植物の 1種であ る丹参 (学名： Salvia · miltiorrhiza · Bunge;、アン丹多 ('子名： Salvia · yunnanens IS ' C. H. Wright)、血盆草 (学名： Salvia'cavaleriei'Levl. var. simplicif elia · P eter-Stibal)、アキノタムラソゥ（学名： Salvia 'chinensis 'Benth)、サルビア 'カバ レリエイ .レブル（学名： Salvia · cavaleriei · Levi. )、サノレビア ·フラバ ·フォレスト ·ェ タス ·ディーノレス（学名： Salvia · flava · Forrest · ex · Diels)、サノレビア ·ボウレャナ ·ド ゥン（学名： Salvia · bowleyana · Dunn)、サノレビア ·プリオ-ティス ·ハンセ（学名： Sa lvia-prionitis -Hance) (非特許文献 2)等から水、熱湯、メタノール-水溶液等で抽 出後、カラムクロマトグラフィーやカウンター 'カレント 'クロマトグラフィーで精製される 。例えば、丹参の抽出液を pH2— 4に調整した後、これをカラムクロマトグラフィーに かけて Sal' Bを吸着させ、これに酢酸マグネシウム、又は酢酸カルシウム等の酢酸塩 水溶液を流した後、メタノール溶液を用いて溶出した区分を分取し、さらにこれを精 製する（特許文献 10)か、丹参の熱湯抽出物を榭脂カラムに吸着させ、 50%-95% エタノールで溶離する（特許文献 11)か、抽出液丹参のエタノール ·水溶液抽出物を ノルマル-へキサン'ェチル酢酸'エタノール '水（3 : 7 : 1 : 9容量 Z容量）からなる二 層溶媒系の高速カウンター'カレント'クロマトグラフィーで精製する（非特許文献 3) 等して得られる。取得した Sal'Bの品質管理は、例えば、 Sal'B試料を分析用ォー 'デ ィ ·エス.カラム（ODS · column)に吸着させ、メタノール · 5%酢酸溶液 (35： 65容量 Z容量)で溶離する高圧液体クロマトグラフィー (HPLC)を 281ナノメーターの波長 で検出する（非特許文献 4) 、 Sal'B試料 20マイクロリットルをデイスカノくリー C18 (D iscovery'C18、 4. 6ミリメーター X25センチメーター）カラムに吸着させ、メタノール- 水-氷酢酸 (40 : 60 : 2、容量 Z容量)で流速 0. 5ミリリットル Z分で溶離する HPLCを 286ナノメーターの波長で検出する（非特許文献 5)等して行う。しかし、これらの植物 以外の Sal'B含有植物があれば、その植物から分離してもよぐ合成が可能な場合は 合成品でもよ ヽ。現在 Sal · Bは中国（景天生物工程有限公司）と米国 (Ivy · Fine · Ch emicals' Corporation社)等で市販されている。 Sal'Bは単離精製物の他、単離した が精製が十分でないもの、単離未精製物、未単離物等他の化合物が混在する場合 でも、本剤が主成分で、かつ、その混在する化合物が、本発明の目的を阻害しない 限り、用いることができる。 [0010] SAL'B may be a natural substance or a synthetic product. Sal'B is one of the plants of the family Lamiaceae (scientific name: Salvia · miltiorrhiza · Bunge ;, Antan ('child name: Salvia · yunnanens IS' CH Wright), blood bonsai (scientific name: Salvia 'cavaleriei' Levl. var. simplicif elia · Peter-Stibal), Akinotamurasou (scientific name: Salvia 'chinensis' Benth), Salvia' Kava Reliei. TAS · Dinores (scientific name: Salvia · flava · Forrest · ex · Diels), Sanorevia · Bowleyana · Dunn (scientific name: Salvia · bowleyana · Dunn), Sanorevia · Priotis · Hanse (scientific name: Salvia-prionitis -Hance) (Non-Patent Document 2), etc., extracted with water, hot water, methanol-water solution, etc., and then purified by column chromatography or counter 'current' chromatography. After adjustment, Ral chromatograph is used to adsorb Sal 'B, and after flowing an aqueous acetate solution such as magnesium acetate or calcium acetate, the fraction eluted with methanol solution is collected and further purified. (Patent Document 10), or hot water extract of Tansan is adsorbed on a rosin column and eluted with 50% -95% ethanol (Patent Document 11), or the ethanol / aqueous solution extract of Dansan is extracted with normal-hexane. It is obtained by purifying with a high-speed counter 'current' chromatography of a two-layer solvent system consisting of 'ethyl acetate' ethanol 'water (3: 7: 1: 9 volume Z volume) (Non-patent Document 3). For example, the quality control of Sal'B can be carried out by adsorbing the Sal'B sample to an analytical DS column (ODS · column) and methanol · 5% acetic acid solution (35: 65 volumes). High-pressure liquid chromatography (HPLC) eluting at 281 nanometer wavelength is detected (Non-patent document 4), and 20 microliters of Sal'B sample is analyzed using C18 (Discovery'C18, 4.6 (Millimeter x 25cm) adsorbed on a column and detected in methanol-water-glacial acetic acid (40: 60: 2, volume Z volume) at a flow rate of 0.5 ml Z min. Non-patent document 5). However, if there are Sal'B-containing plants other than these plants, they can be synthesized if they can be separated from the plants and synthesized. Sal · B is currently marketed in China (Jingtian Biological Process Co., Ltd.) and the United States (Ivy · Fine · Chemicals' Corporation). Sal'B is the main component of this product, even if other compounds such as isolated but not sufficiently purified, unpurified and unisolated compounds coexist in addition to the isolated and purified product. The mixed compound can be used as long as the object of the present invention is not impaired.
[0011] SAL'Bのプロドラッグは加水分解等分解を受けて SAい Bに成るものであれば、薬学 的に許容することのできる限り、どのようなものでもよい。当該プロドラッグの一つとし て SAL · B分子中のカルボキシル基でのメチルエステル誘導体又はェチルエステル誘 導体や SAL · B分子中のアミノ基でのァセチル誘導体等が挙げられるが、それらに限 らない。将来合成されるものでも差し支えない。  [0011] The prodrug of SAL'B may be any prodrug as long as it is pharmaceutically acceptable as long as it undergoes hydrolysis or the like and becomes SAB. Examples of such prodrugs include, but are not limited to, methyl ester derivatives or ethyl ester derivatives at the carboxyl group in the SAL • B molecule and acetyl derivatives at the amino group in the SAL • B molecule. It may be synthesized in the future.
[0012] SAL'Bの塩及び SAい Bのプロドラッグの塩は薬学的に許容することのできる塩に限 られる。薬学的に許容することのできる塩としては、例えば、ナトリウム、カリウム等のァ ルカリ金属塩、マグネシウム、カルシウム等のアルカリ土類金属塩、アンモ-ゥム、テト ラメチルアンモ -ゥム等のアンモ-ゥム塩、トリエチルァミン、リジン、アルギニン等の 有機ァミンの塩、塩酸、臭化水素酸、硫酸等鉱酸との酸付加塩等が挙げられるが、そ れらに限らない。薬学的に許容することのできる塩であればよぐ薬学的に許容する ことのできる限り、将来合成される有機化合物との塩でも差し支えない。 SAL'B及び そのプロドラッグの水和物、薬学的に許容することのできる SAL'Bの塩及びそのプロ ドラッグの塩の水和物も本発明の主成分として用いることができる。  [0012] The salts of SAL'B and the prodrugs of SA and B are limited to pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and ammonia such as ammonium and tetramethylammonium. Salts, organic acid salts such as triethylamine, lysine and arginine, and acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, but are not limited thereto. Any salt that can be synthesized in the future may be used as long as it is pharmaceutically acceptable as long as it is pharmaceutically acceptable. Hydrates of SAL'B and prodrugs thereof, pharmaceutically acceptable salts of SAL'B and prodrug salts thereof can also be used as the main component of the present invention.
[0013] 本発明の脳卒中又は脳卒中後遺症の予防用又は治療用薬剤は酸素及び湿気の ない状態では比較的安定である。しかし、抗酸化作用を有するので、空中及び水溶 液中で比較的不安定である。水溶液中の Sal'Bは高温で不安定で、摂氏 80度で 72 時間加温すると 35%変化し、チォ硫酸ナトリウム、硫酸ナトリウム、亜硫酸ナトリウム、 ヒドロ亜硫酸ナトリウム、システィン塩酸塩、 EDTA2ナトリウム塩を添加しても一部変 化し、ビタミン Cを添加した時のみ摂氏 80度で 72時間加温しても安定である（非特許 文献 6)。 [0013] The agent for preventing or treating stroke or sequelae of stroke according to the present invention is relatively stable in the absence of oxygen and moisture. However, it has an antioxidant effect and is relatively unstable in the air and in aqueous solutions. Sal'B in aqueous solution is unstable at high temperatures, 72 at 80 degrees Celsius 35% change over time, partially changed even with addition of sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, cystine hydrochloride, EDTA disodium salt, 80 degrees Celsius only when vitamin C is added And stable for 72 hours (Non-patent Document 6).
Sal · Bを保存する時は酸素や湿気の無!ヽ状態で保存することが好ま ヽ。長期保存 を考慮に入れると、本発明の脳卒中又は脳卒中後遺症の予防用又は治療用薬剤に は有効成分の安定のため、他の抗酸化剤を添加することが好ましい。抗酸化剤とし ては薬学的に許容することのできる抗酸化剤に限られる。薬学的に許容することので きる抗酸化剤としては、アルファ 'カロチン、ベータ'カロチン、リコペン、ルティン、フラ ボノイド、カテキン、リザベラトール、イソフラボン、ビタミン A、ビタミン E、セレン、亜鉛 、補酵素 Q10、ダルタチオン、ェンゾジノール等が挙げられる。これらの抗酸化剤は 高温の水溶液中の Sal'Bの変化を抑える。亜硝酸塩は Sal'Bの変化を完全には抑え ない。したがって、亜硝酸塩は、単独では安定剤としては不十分である。ビタミン ま Sal'Bの変化を抑える。したがって、ビタミン Cは Sal'B等の安定剤として使用は可能で あるが、ビタミン C自体が空中及び水溶液中で比較的不安定であり、ビタミン Cを多量 に添加する力他の抗酸化剤との併用が必要になる。  When storing Sal · B, it is preferable to store it without oxygen or moisture. In consideration of long-term storage, it is preferable to add another antioxidant to the agent for preventing or treating stroke or sequelae of stroke according to the present invention in order to stabilize the active ingredient. Antioxidants are limited to pharmaceutically acceptable antioxidants. Pharmaceutically acceptable antioxidants include alpha 'carotene, beta' carotene, lycopene, rutin, flavonoids, catechins, resaveratrol, isoflavones, vitamin A, vitamin E, selenium, zinc, coenzyme Q10, Examples include dartathione and enzogenol. These antioxidants suppress Sal'B changes in hot aqueous solutions. Nitrite does not completely suppress Sal'B changes. Therefore, nitrite alone is insufficient as a stabilizer. Vitamin Suppresses Sal'B changes. Therefore, vitamin C can be used as a stabilizer such as Sal'B, but vitamin C itself is relatively unstable in the air and in aqueous solution, and it can add a large amount of vitamin C to other antioxidants. Need to be used together.
[0014] 本発明の脳卒中又は脳卒中後遺症の予防用又は治療用薬剤は、主成分が非高 分子であることから、経口投与又は非経口投与 (坐薬、筋肉内、皮下、静脈内、脳内 など）のいずれでも投与できる。主成分が SAL'Bのプロドラッグの場合も、体内で当該 プロドラッグが活性ィ匕するので、当該プロドラッグを予め活性ィ匕しておく必要はな 、。 [0014] Since the main component of the medicament for preventing or treating stroke or sequelae of stroke of the present invention is a non-high molecular weight molecule, it is administered orally or parenterally (suppository, intramuscular, subcutaneous, intravenous, intracerebral, etc. ) Can be administered. Even in the case of a prodrug whose main component is SAL'B, since the prodrug is activated in the body, it is not necessary to activate the prodrug in advance.
[0015] 経口用製剤を調製する場合、賦形剤、さらに必要に応じて、結合剤、崩壊剤、滑沢 剤、着色剤、矯味矯臭剤及び前述の抗酸化剤などを加えた後、常法により、錠剤、 被服錠剤、顆粒剤、カプセル剤、溶液剤、シロップ剤、エリキシル剤、油性又は水性 の懸濁液剤などとする。賦形剤としては、例えば、乳糖、コーンスターチ、白糖、ブド ゥ糖、ソルビット、結晶セル一ロスなどが挙げられる。結合剤としては、例えば、ポリビ ニノレアノレコーノレ、ポリビニノレエーテノレ、ェチノレセノレロース、メチノレセノレロース、ァラビ ァゴム、トラガント、ゼラチン、シェラック、ヒドロキシプロピルセルロース、ヒドロキシプロ ピルスターチ、ポリビュルピロリドンなどが挙げられる。 [0016] 崩壊剤としては、例えば、デンプン、寒天、ゼラチン未、結晶セルロース、炭酸カル シゥム、炭酸水素ナトリウム、クェン酸カルシウム、デキストラン、ぺクチンなどが挙げ られる。滑沢剤としては、例えば、ステアリン酸マグネシウム、タルク、ポリエチレンダリ コール、シリカ、硬化植物油などが挙げられる。着色剤としては、医薬品に添加するこ とが許可されているものが使用できる。矯味矯臭剤としては、ココア末、ノ、ッカ脳、芳 香酸、ハツ力油、竜脳、桂皮末などが使用できる。これらの錠剤は、顆粒剤には、糖 衣、ゼラチン衣、その他必要により適宜コーティングしてもよい。 [0015] When preparing an oral preparation, after adding an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the above-mentioned antioxidant, etc. According to the method, tablets, coated tablets, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, etc. are used. Examples of the excipient include lactose, corn starch, sucrose, bud sugar, sorbitol, crystal cell loss, and the like. As the binder, for example, polyvinylenoreconole, polyvinylinoatenole, ethinoresenorelose, methinorescenellose, arabica gum, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl starch, polybutylpyrrolidone Etc. [0016] Examples of the disintegrant include starch, agar, ungelatinized, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextran, and pectin. Examples of the lubricant include magnesium stearate, talc, polyethylene darcol, silica, hydrogenated vegetable oil, and the like. As the colorant, those permitted to be added to pharmaceuticals can be used. As a flavoring agent, cocoa powder, coconut powder, coconut brain, aromatic acid, heart power oil, dragon brain, cinnamon powder and the like can be used. These tablets may be appropriately coated on the granules by sugar coating, gelatin coating, etc. if necessary.
[0017] 注射剤を調製する場合、必要により、グルコースや生理的食塩水等の等調液、 pH 調整剤、緩衝剤、前述の抗酸化剤及びその他の安定化剤、保存剤などを添加し、常 法により、皮下、筋肉内、静脈内、脳内注射剤とする。注射剤は、溶液を容器に収納 後、凍結乾燥などによって、固形製剤として、用事調製の製剤としてもよい。また、一 投与量を容器に収納してもよぐまた、多投与量を同一の容器に収納してもよい。溶 液の場合、酸素や湿気を遮断する方がよい。そのため、場合によってはアンプル型 の容器に入れ、空気を抜くか、窒素ガス等で空気を置換しておく方がよい。公知の方 法でよい。  [0017] When preparing an injection, if necessary, an isotonic solution such as glucose or physiological saline, a pH adjuster, a buffer, the above-mentioned antioxidant and other stabilizers, a preservative, etc. are added. In the usual manner, use subcutaneous, intramuscular, intravenous, or intracerebral injections. The injection may be a solid preparation or a preparation prepared for daily use by lyophilization after storing the solution in a container. One dose may be stored in a container, or multiple doses may be stored in the same container. In the case of a solution, it is better to shut off oxygen and moisture. Therefore, in some cases, it is better to put it in an ampoule type container and evacuate it or replace it with nitrogen gas. A known method may be used.
[0018] 本発明の脳卒中又は脳卒中後遺症の予防用又は治療用薬剤の投与量は、経口 剤、坐薬、皮下注射剤、筋肉内注射剤、静脈内注射剤、脳内注射剤等剤型によって 異なるが、ヒトの場合、成人 1日当たり通常 0. 01〜： LOOOミリグラム、好ましくは、 0. 1 〜 100ミリグラムの範囲で、 1曰量を 1曰 1回、あるいは 2〜4回に分けて投与する。な お、年齢、症状により適宜増減する。  [0018] The dose of the agent for preventing or treating stroke or sequelae of the present invention varies depending on the dosage form such as oral preparation, suppository, subcutaneous injection, intramuscular injection, intravenous injection, intracerebral injection and the like. However, in the case of humans, adults are usually administered in daily doses of 0.01 to: LOOO milligrams, preferably 0.1 to 100 milligrams, and 1 dose is given in 1 to 1 doses or divided into 2 to 4 doses. . The dose may be adjusted according to age and symptoms.
以下、実施例により本発明を更に詳細に説明するが、本発明はこれらの実施例に 限定されるものではない。なお、毒性試験、薬効試験に関し、急性毒性試験、亜急性 毒性試験、催奇性毒性試験、変異原性試験、繁殖性試験中の白血球、リンパ、好中 数、ヘモグロビン、 GOT,血清総蛋白、アルブミン、トリグリセリド、コレステロール、グ ルコース、尿素、小核率、***奇形率、復帰変異菌、死胎率、胎児体重 ·身長，尾長 、胸骨欠失率等の分析は株式会社日本実権医学研究等毒性試験受託会社がルー チンに受託分析し、尿中 N02ZN03、クレアチュン、 Na、 K、 Ca、 Cl、 Mg、血中アルブ ミン、グロブリン、 GOT, GTP、ガンマ-ダルタミルトランスぺプチダーゼ、尿素窒素、ク レアチュン、 Na、 K、 Ca、 Cl、 Mg、アンギオテンシン 1転換酵素、アンギオテンシン 2等 の分析はシオノギ 'バイオメディカル'ラボラトリーズ等臨床検査受託会社がルーチン に受託分析している。 EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Regarding toxicity tests and medicinal effects tests, acute toxicity tests, subacute toxicity tests, teratogenic toxicity tests, mutagenicity tests, leukocytes, lymphoid, neutrophils, reproductive tests, hemoglobin, GOT, serum total protein, albumin , Triglyceride, Cholesterol, Glucose, Urea, Micronucleus rate, Sperm malformation rate, Revertant bacteria, Fetal death rate, Fetal weight / Height, Tail length, Sternum deletion rate, etc. The company outsources the routine analysis to routine N02ZN03, creatine, Na, K, Ca, Cl, Mg, blood albumin, globulin, GOT, GTP, gamma-daltamyl transpeptidase, urea nitrogen, Analyzes of reatune, Na, K, Ca, Cl, Mg, angiotensin 1 convertase, angiotensin 2, etc. are routinely outsourced by clinical laboratory contractors such as Shionogi 'Biomedical' Laboratories.
以下に先行文献を特許文献と非特許文献に分けて表示する。  In the following, prior documents are displayed separately for patent documents and non-patent documents.
特許文献 1：特開 2003 - 26660号公報 Patent Document 1: Japanese Patent Laid-Open No. 2003-26660
特許文献 2 :特開 2002— 370981号公報 Patent Document 2: Japanese Patent Laid-Open No. 2002-370981
特許文献 3：特開 2002— 322095号公報 Patent Document 3: Japanese Patent Laid-Open No. 2002-332095
特許文献 4:特開 2000— 239168号公報 Patent Document 4: Japanese Unexamined Patent Publication No. 2000-239168
特許文献 5：特開平 11― 228396号公報 Patent Document 5: Japanese Patent Laid-Open No. 11-228396
特許文献 6：特開平 10— 182469号公報 Patent Document 6: Japanese Patent Laid-Open No. 10-182469
特許文献 7：特開平 8 - 268887号公報 Patent Document 7: JP-A-8-268887
特許文献 8： #112005— 025806号 Patent Document 8: # 112005— No. 025806
特許文献 9：特願 2004— 341367号 Patent Document 9: Japanese Patent Application No. 2004-341367
特許文献 10：特開平 1 268682号公報 Patent Document 10: Japanese Patent Laid-Open No. 1268682
特許文献 11 :米国特許 2001年 6, 299, 910号公報 Patent Document 11: US Patent 2001, 299, 910
非特許文献 1 :J. C. Dongら、 Yao'Xue'Bao, 31卷 6頁 1996年 Non-Patent Document 1: J. C. Dong et al., Yao'Xue'Bao, 31 卷 6, p. 1996
非特許文献 2 :L. N. Liら、 J. Chinese - Pharmaceutical - Sciences, 1997年 6卷 2号 57頁- 64頁 Non-Patent Document 2: L. N. Li et al., J. Chinese-Pharmaceutical-Sciences, 1997 6-2, 57-64
非特許文献 3 : H. B. Liら、 J. Chromatogr. A. 2002年 943卷 2号 235頁- 239頁 非特許文献 4: Q. W. Zhangら、 Zhongguo - Zhong - Yao - Za - Zhi, 2001年 26卷 1 2号 848頁- 849頁 Non-Patent Document 3: HB Li et al., J. Chromatogr. A. 2002 943-2 2 235-239 Non-Patent Document 4: QW Zhang et al., Zhongguo-Zhong-Yao-Za-Zhi, 2001 26 卷 1 2 pages 848-849
非特許文献 5 :曲桂武ら、 http : Z / www. ndc enter, com. cnZ tongxun/ 2/ q uguiwul. pdf. Non-Patent Document 5: Kyokutake et al., Http: Z / www.ndc enter, com.cnZ tongxun / 2 / q uguiwul.pdf.
非特許文献 6 :曲桂武ら、 http : Z / www. ndc enter, com. cnZ tongxun/ 2/ q uguiwu2. pdf. Non-patent document 6: Katsura Take et al., Http: Z / www.ndc enter, com.cnZ tongxun / 2 / q uguiwu2.pdf.
実施例 1 Example 1
栃本天海堂の医療用の丹参 20グラムに 150ミリリットルの水をカ卩えて、 100°Cに加 温しながら、 30分抽出を行った。濾過後、残渣に再び 150ミリリットルの水をカ卩え、 10 0°Cに加温しながら、更に 30分抽出後、 2回の抽出で得られた濾液を集めた。抽出 中の水分蒸発により液量が減少し、丹参抽出液を 170ミリリットル得た。この溶液量が 222ミリリットルになるように水をカ卩えて調整した。これを丹参抽出液とする。 4週齢雄 SHR-SPZlzmラットを京都にある SHR等疾患モデル動物利用研究会より入手後、 室温を摂氏 22± 1度、湿度を 60± 10%、照明時間を 6時から 18時まで 12時間に設 定した飼育室で 1週間予備飼育した。体重増加が順調で、一般状態に異常の認めら れなかったラット 60匹の血圧及び体重を測定し、このラット 60匹を 10匹ずつ 6群に群 間で血圧、体重の差のないように分けた。以下、毎日 1回、週 5回、前述の丹参抽出 液を 10ミリリットル (丹参 901ミリグラム相当量) Zキログラム体重の割合でラットの腹腔 内に注射で投与する群を丹参群、 1. 125%の SAL'B (中国の天津中一製薬有限公 司製)溶液を 22. 5ミリグラム Zキログラム体重の割合でラットの腹腔内に注射で投与 する群を SAL'B群、同じ投与条件でラットの脳血流量等を測定する群を B-丹参群、 B -SAL'B群、同量の蒸留水をラットの腹腔内に注射で投与する群を対照群、同じ投与 条件でラットの脳血流量等を測定する群を B-対照群とした。実験期間は固体 SP飼料 と水道水を自由に摂取させて飼育した。動物実験の取扱いに関しては、日本生理学 会の定める「生理学領域における動物実験に関する基本指針」に従った。 Toshimoto Tenkaido's 20 g of medical dandelion was filled with 150 ml of water and extracted at 30 ° C for 30 minutes while warming to 100 ° C. After filtration, add 150 ml of water again to the residue. 10 While heating at 0 ° C., extraction was further performed for 30 minutes, and then the filtrate obtained by two extractions was collected. The liquid volume decreased due to water evaporation during the extraction, and 170 ml of Tansan extract was obtained. Water was adjusted so that the amount of this solution was 222 ml. This is referred to as Tansan extract. After obtaining a 4-week-old male SHR-SPZlzm rat from the SHR and other disease model animal utilization study group in Kyoto, the room temperature is 22 ± 1 degrees Celsius, the humidity is 60 ± 10%, the lighting time is from 6 o'clock to 18 o'clock 12 hours Preliminary breeding for 1 week in the breeding room set up in. Measure blood pressure and body weight of 60 rats with normal weight gain and no abnormalities in the general condition, so that 10 rats of 60 rats were divided into 6 groups so that there was no difference in blood pressure and body weight between groups. divided. In the following, once a day, 5 times a week, 10 ml of the above mentioned Dansang extract (equivalent to 901 milligrams of Dansang) was administered to the rats by intraperitoneal injection at a rate of Z kilogram body weight. SAL'B (manufactured by Tianjin Zhongichi Pharmaceutical Co., Ltd., China) solution is administered by intraperitoneal injection of rats at a rate of 22.5 mg Z kilogram body weight. The groups that measure blood flow, such as the B-Tansan group and the B-SAL'B group, the group that administers the same amount of distilled water by intraperitoneal injection into rats, the control group, the cerebral blood flow of rats under the same administration conditions, etc. The B-control group was used as the group for measuring the value. During the experiment, they were fed with solid SP feed and tap water. Regarding the handling of animal experiments, we followed the “Basic Guidelines for Animal Experiments in the Physiological Field” established by the Physiological Society of Japan.
実施例 2 Example 2
実施例 1において、毎週 1回、前述の温度'湿度の部屋で午前 11時から午後 5時ま でで、薬剤投与前後にラットを摂氏 38度の加温器中で 10分間加温させ、順応した後 、無麻酔下でティル-カット（tail-cuff)法によりソフトロン（Softron)非観血式自動血 圧測定装置 (BP-98A) (株式会社ソフトロン製)を用いて、収縮期血圧、拡張期血圧 と心拍数を 3回測定し、平均値と標準偏差を計算し、平均値士標準誤差で表した。有 意差の有無を t-検定により調べた。  In Example 1, rats were warmed for 10 minutes in a 38 degrees Celsius warmer before and after drug administration from 11:00 am to 5:00 pm in the above-mentioned temperature and humidity room once a week. After that, the systolic blood pressure was measured using the Softron non-invasive automatic blood pressure measurement device (BP-98A) (manufactured by Softron Co., Ltd.) by the tail-cuff method without anesthesia. The diastolic blood pressure and heart rate were measured three times, and the average and standard deviation were calculated and expressed as mean standard error. The presence or absence of significant difference was examined by t-test.
丹参又は SAl^Bの投与開始直前、投与開始 1週間後、 2週間後、 3週間後、 4週間 後の収縮期血圧は、対照群力それぞれ 164. 76± 12. 98, 186. 74± 10. 3、 206 . 29± 15. 36、 212. 87± 13. 17、 228. 54± 10. 46 (ミリメートル Hg)であり、丹 参群力 Sそれぞれ 165. 75±6. 87、 187. 37± 10. 2 203. 28± 13. 35, 210. 6 4± 10. 23、 218. 63±8. 46 (ミリメートル Hg)であり、 SAL'B群力それぞれ 166. 2 0±5.84、 188.33±10.01、 197.07±10.34、 200.25±9.89(水）、 209. 72±6.35(*3) (ミリメートル Hg)であり、弛緩期血圧は、対照群がそれぞれ 120. 40±11.1、 147.37±12.68、 170.33±17.6、 172. 16±10.70、 189.04 ±11.5 (ミリメートル Hg)であり、丹参群力それぞれ 120.33±9.45、 144.67±1 1.66、 162.42±16.7、 164.76±10.78、 176. 16±11.8(ミリメートル Hg)で あり、 SAい B群力それぞれ 120.03±8.73、 135.95±10.91、 141.74±15.3 3(*2)、 144.59±10.97(*3)、 152.96±12.8(*3) (ミリメートル Hg)であり 、心拍数は、対照群力 Sそれぞれ 388.40±28.8、 393.25±27.90、 372.33士 33.16、 357.83 ±34.62、 380.20±30.9 (回数 Z分）であり、丹参群力 sそれぞ れ 385.60±28.3、 383.46±29.84、 369.45±32.87、 350.66±29.67、 361.31±30.6 (回数 Z分）であり、 SAL' B群力それぞれ 381.83±26.2、 377. 62±31.64、 345.70±31.93、 333.22±24.98、 338.20±30.6(*2) (回 数 Z分）であった。なお、対照群と比較して P<0.05、 P<0.01、 P<0.001の範 囲で有意差があった SAL ·Β群の値はそれぞれ（*)、（*2)、（* 3)印で示した。 収縮期血圧は SAL' Β群と丹参群と対照群ともに投与 4週目まで上昇したが、 SAL-B 群では、対照群と比較して投与開始後 3、 4週目において血圧が有意な低値を示し、 血圧上昇抑制効果を示した (それぞれ Pく 0.01、 0.001)。丹参群では、対照群と 比較して投与開始後 3、 4週目において血圧が低値を示す傾向が認められた力 統 計的有意差はな力つた。拡張期血圧について投与開始後 2、 3, 4週目において SAL •B群は対照群に比べ有意に低値を示した (それぞれ P<0.01、 0.001、 0.001)。 丹参群は対照群に比べ低値を示す傾向が見られたが有意差はな力つた。心拍数に ついては、投与開始後 4週目までは SAL'B群と対照群の間に有意な差が認められな かったが、 4週目に Pく 0.01の範囲で有意差に低力つた。 SAい Bの心筋保護作用 が働いたと思われる。丹参群も対照群に比べ低値を示す傾向が見られたが有意差 はなかった。 The systolic blood pressure immediately before the start of administration of Dansang or SAl ^ B, 1 week, 2 weeks, 3 weeks, and 4 weeks after the start of administration was 164. 76 ± 12. 98, 186. 74 ± 10 respectively. 3, 206.29 ± 15.36, 212.87 ± 13.17, 228.54 ± 10.46 (mm Hg), Dansang group force S 165.75 ± 6.87, 187.37 respectively ± 10. 2 203. 28 ± 13. 35, 210. 6 4 ± 10. 23, 218. 63 ± 8.46 (mm Hg), SAL'B group force 166.2 respectively 0 ± 5.84, 188.33 ± 10.01, 197.07 ± 10.34, 200.25 ± 9.89 (water), 209.72 ± 6.35 (* 3) (millimeter Hg), and the diastolic blood pressure is 120.40 ± 11.1 in the control group, 147.37 ± 12.68, 170.33 ± 17.6, 172.16 ± 10.70, 189.04 ± 11.5 (mm Hg), Tandan group force 120.33 ± 9.45, 144.67 ± 1 1.66, 162.42 ± 16.7, 164.76 ± 10.78, 176.16 ± 11.8 (Millimeter Hg) and SA group B forces 120.03 ± 8.73, 135.95 ± 10.91, 141.74 ± 15.3 3 (* 2), 144.59 ± 10.97 (* 3), 152.96 ± 12.8 (* 3) (mm Hg) Yes, heart rate, the control group force s, respectively 388.40 ± 28.8, 393.25 ± 27.90, 372.33 mechanic 33.16, 357.83 ± 34.62, a 380.20 ± 30.9 (number of times Z min), Danshen group force s it respectively 385.60 ± 28.3, 383.46 ± 29.84, 369.45 ± 32.87, 350.66 ± 29.67, 361.31 ± 30.6 (number of times Z), SAL 'B group force 381.83 ± 26.2, 377. 62 ± 31.64, 345.70 ± 31.93, 333.22 ± 24.98, 338.20 ± 30.6 ( * 2) (Number of times Z) It was. The values in the SAL • Β group that were significantly different in the range of P <0.05, P <0.01, and P <0.001 compared to the control group are marked with (*), (* 2), and (* 3), respectively. It showed in. Systolic blood pressure increased in the SAL 'と も に group, Dansang group, and the control group until the 4th week of administration, but in the SAL-B group, the blood pressure was significantly lower at 3 and 4 weeks after the start of administration compared to the control group. Value, and blood pressure increase suppression effect (P 0.01 and 0.001, respectively). In the Tansan group, compared to the control group, there was no significant statistical difference in the blood pressure tended to be low at 3 and 4 weeks after the start of administration. Regarding diastolic blood pressure, the SAL • B group was significantly lower than the control group at 2, 3, and 4 weeks after the start of administration (P <0.01, 0.001, 0.001 respectively). The Tansan group tended to show a lower value than the control group, but the difference was not significant. As for heart rate, there was no significant difference between the SAL'B group and the control group until 4 weeks after the start of treatment, but at 4 weeks, P showed a significant difference within a range of 0.01. . The myocardial protection of SA B seems to have worked. The Tansan group tended to show a lower value than the control group, but there was no significant difference.
実施例 3 Example 3
実施例 2において、丹参又は SAL'B投与開始 4週間後の血圧と心拍数測定後に、 ラットを代謝ケージに入れ、 24時間採尿を行った。対照群と丹参群と SAL'B群の 24 時間***量に関し、 N02ZN03を Griess法により、クレアチュンをアルカリピクリン法 により、 Naと Kと C1をイオン電極法により、 Mgをキシリジル -ブルー法により、 Caを OCP C法により測定した。対照群と丹参群と SAL'B群の N02ZN03は順に 8. 68± 3. 26 と 8. 02± 1. 58と 6. 96± 1. 32 ( * ) (マイクロモノレ）、クレアチニンは j噴に 38. 75士 7. 92と 36. 77± 9. 95と 31. 77± 12. 88 (ミリグラム/デシリットノレ）、 Naは川頁に 0. 267±0. 086と 0. 298±0. 084と 0. 356±0. 08 (ミリ等量）、 Kは川頁に 0. 590±0 . 17と 0. 599±0. 19と 0. 624±0. 22 (ミリ等量）、 C1は j噴に 0. 222±0. 07と 0. 2 23 ±0. 08と 0. 229±0. 10 (ミリ等量）、 Mgは j噴に 1. 61 ±0. 80と 1. 58±0. 64と 1. 45±0. 38 (ミリ等量）、 Caは川頁に 0. 20±0. 08と 0. 20±0. 08と 0. 22±0. 08 (ミリ等量）の値を得た。 SAL'B群は対照群に比べ、尿中の N02ZN03が Pく 0. 05 ( * )の範囲ないで、有意に高値を示した力 尿中クレアチン、 Na、 Cl、 K、 Mg、 Caは、対 照群に比べ有意な差は無力つた。丹参群は対照群に比べ、尿中の N02ZN03、タレ ァチン、 Na、 Cl、 K、 Mg、 Caは、対照群に比べ有意な差は無かった。特願 2005— 02 5806に記載の 1 -アミノシクロプロパンカルボン酸（以下、 ACCと略称する。）投与に よる結果と非常に異なる。 SAい Bの作用機序は ACCを主成分とする脳卒中又は脳卒 中後遺症の予防用又は治療用薬剤の作用機序が異なる力 であると思われる。丹参 も Sal' Bと同様の傾向を示す力 作用が低い。 In Example 2, after measuring blood pressure and heart rate 4 weeks after starting Dansang or SAL'B administration, the rats were placed in a metabolic cage, and urine was collected for 24 hours. 24 in the control group, Tansan group and SAL'B group Regarding time excretion, N02ZN03 was measured by Griess method, Creathun by alkaline picrin method, Na, K and C1 by ion electrode method, Mg by xylidyl-blue method, and Ca by OCPC method. N02ZN03 in the control group, Dansang group, and SAL'B group are 8.68 ± 3.26 and 8.02 ± 1.58 and 6.96 ± 1.32 (*) (micromonore), creatinine 38. 75 people 7. 92 and 36. 77 ± 9. 95 and 31. 77 ± 12. 88 (milligrams / Decilit Nore), Na on the river page 0.267 ± 0.086 and 0.298 ± 0.084 0. 356 ± 0.08 (millimeter equivalent), K on the river page 0. 590 ± 0.17 and 0.599 ± 0.19 and 0.624 ± 0.22 (millimeter equivalent), C1 is j 0.222 ± 0.07 and 0.23 ± 0.08 and 0.222 ± 0.10 (milli-equivalent) in the jet, Mg is 1.61 ± 0.80 and 1.58 ± 0 in the j jet 64 and 1. 45 ± 0.38 (mm equivalent), Ca on the river page 0.20 ± 0.08 and 0.20 ± 0.08 and 0.22 ± 0.08 (mm equivalent) Got the value. Compared with the control group, the SAL'B group showed significantly higher levels of urinary creatine, Na, Cl, K, Mg, and Ca, with N02ZN03 in the urine being in the range of P and 0.05 (*). There was no significant difference compared to the control group. Compared with the control group, the Tansan group had no significant differences in the urine N02ZN03, taleatin, Na, Cl, K, Mg, and Ca compared with the control group. The result of administration of 1-aminocyclopropanecarboxylic acid (hereinafter abbreviated as ACC) described in Japanese Patent Application No. 2005-02 5806 is very different. The mechanism of action of SA and B seems to be due to the difference in the mechanism of action of preventive or therapeutic agents for stroke or sequelae of stroke mainly composed of ACC. Tansan also has a low force effect that shows the same tendency as Sal 'B.
実施例 4 Example 4
実施例 3にお 、て 24時間採尿後、 24時間絶食させ、エーテル麻酔し、腹動脈より 採血を行った。血中アルブミンは BCG法により、アルブミン/グロビン比は計算により 、 GOTと GPTは UV法により、ガンマ-ダルタミルトランスぺプチダーゼは比色法により 、尿素窒素は UV法により、クレアチュンはアルカリピクリン法により、 Naと Kはイオン電 極法により、 Caは OCPC法により、 C1はイオン電極法により、 Mgはキシリジル -ブルー 法により、アンジォテンシン 1転移酵素は笠原法により、アンジォテンシン 2は RIA' DC C法により測定した。対照群と対照群と SAい B群の血中アルブミンは順に 2. 31 ±0. 18と 2. 30±0. 17と 2. 23±0. 10 (グラム/デシリットノレ）、 ァノレブミン/グロビン it は川頁に 0. 61 ±0. 02と 0. 61 ±0. 08と 0. 64±0. 03 ( * 2) (計算値）、 GOTは j噴に 476. 9± 178. 1と 472. 6± 186. 2と 455. 3± 139. 0 (単位/リットノレ）、 GPTは川頁 に 115. 6±43. 9と 115. 9±46. 4と 113. 3± 18. 4 (単位/リットノレ）、ガンマ-グ ノレタミノレトランスぺプチダーゼは j噴に 1. 86±0. 90と 1. 85±0. 87と 1. 83±0. 98 (単位/リツ卜ノレ）、尿素窒素は川頁に 20. 43± 2. 82と 20. 44± 2. 97と 19. 00± 1. 78 (ミリグラム/デシリットノレ）、クレアチニンは j噴に 0. 37±0. 08と 0. 36±0. 11と 0 . 33±0. 05 (ミリグラム/デシリットノレ）、 Naは川頁に 148. 0± 7. 02と 148. 5± 7. 72 と 146. 8± 2. 56 (ミリ等量/リットノレ）、 Kは j噴に 6. 36± 1. 37と 6. 33± 1. 42と 5. 75 ±0. 91 (ミリ等量/リットノレ）、 Caは j噴に 10. 95± 1. 00と 10. 99± 1. 10と 10. 5 8±0. 57 (ミリグラム/デシリットノレ）、 C1は j噴に 104. 0± 5. 90と 103. 9± 5. 85と 1 02. 5± 2. 58 (ミリ等量/リットノレ）、 Mgは j噴に 3. 34±0. 45と 3. 30±0. 48と 3. 2 5±0. 30 (ミリグラム Zデシリットル）、アンジォテンシン 1転移酵素は順に 28. 47± 1 0. 3と 27. 57± 9. 9と 21. 82± 3. 2 (単位/リットノレ）、アンジ才テンシン 2は j噴位 20 7. 2± 210. 4と 187. 2± 223. 5と 115. 6±42. 2 (ピコグラム/ミリリットノレ）の値を 得た。栄養状態を反映する血中アルブミン及び、肝、腎機能を表す GOT、 GPTや尿 素窒素、クレアチニンは全て対照群と丹参群と SAL · B群の間に有意な差が無力つた ため、丹参と SAL' Bの栄養状態、肝腎機能への影響が少ないと考えられる。アルブミ ン /ゴロブリン比にっ 、て SAL · B群が対照群より P〈0. 001 ( * 2)の範囲内で有意に 高値を示した力 正常範囲内であるので、 SAL'Bの副作用と考えにくい。また、血中 Na、 Cl、 K、 Ca、 Mg値について、丹参群又は SAL'B群と対照群の間に有意な差が示 されなかったことは、丹参群及び SAL'Bが血中電解質のバランスに影響が無いことを 示す。対照群に比べ、丹参群及び SAL'B群のアンジォテンシン 1転移酵素、アンジ ォテンシン 2値が低下の傾向が見られた。これは SAい Bの降血圧の一因の可能性が ある。丹参は SAい Bと同様の薬効を示すが作用が低力つた。 In Example 3, urine was collected for 24 hours, then fasted for 24 hours, ether anesthetized, and blood was collected from the abdominal artery. Blood albumin by BCG method, albumin / globin ratio by calculation, GOT and GPT by UV method, gamma-daltamyl transpeptidase by colorimetric method, urea nitrogen by UV method, and Creathun by alkaline picrin method Na and K by ion electrode method, Ca by OCPC method, C1 by ion electrode method, Mg by xylidyl-blue method, angiotensin 1 transferase by Kasahara method, and angiotensin 2 by RIA 'Measured by DCC method. In the control group, the control group, and the SA group B, the blood albumins in order were 2. 31 ± 0.18 and 2.30 ± 0.17 and 2.23 ± 0.10 (grams / decirit nore), and anolebumin / globin it was In the river page 0. 61 ± 0. 02 and 0. 61 ± 0. 08 and 0.64 ± 0.03 (* 2) (calculated value), GOT is in the j jet 476. 9 ± 178.1 and 472. 6 ± 186.2 and 455.3 3 ± 139.0 (units / liter), GPT is Kawasaki 115. 6 ± 43.9 and 115.9 ± 46.4 and 113.3 ± 18.4 (units / liter), gamma-gnoretaminoretranspeptidase is 1.86 ± 0.90 And 1.85 ± 0.87 and 1.83 ± 0.98 (units / liter), urea nitrogen in the river page 20.43 ± 2.82 and 20.44 ± 2.97 and 19.00 ± 1.78 (milligrams / decirit nore), creatinine is 0.37 ± 0.08 and 0.36 ± 0.11 and 0.33 ± 0.05 (milligram / decirit nore) in the jet, Na is 148. 0 ± 7.02 and 148. 5 ± 7.72 and 146.8 8 ± 2.56 (mm equivalent / Lit Nore), K is j jet 6.36 ± 1.37 and 6.33 ± 1.42 5. 75 ± 0.91 (milli equivalent / Little Nore), Ca 10.95 ± 1.00 and 10.99 ± 1.10 and 10.5 8 ± 0.57 (Milligram / Desirit Nore), C1 is in the j jet 104. 0 ± 5. 90 and 103.9 9 ± 5. 85 and 1 02.5 ± 2. 58 (mm equivalent / Lit Nore), Mg is in the j jet 3. 34 ± 0.45 3. 30 ± 0.48 and 3.2 ± 5 ± 0.30 (milligram Z deciliter), angiote Nsyn 1 transferase is 28. 47 ± 1 0. 3 and 27. 57 ± 9. 9 and 21. 82 ± 3.2 (units / Lit Nore) in order, and Anzi Tenshin 2 is j-jet position 20 7. 2 ± 210 Values of 4 and 187.2 ± 23.5. 5 and 115. ± 6 ± 42.2 (picogram / millilitre) were obtained. Blood albumin reflecting nutritional status and GOT, GPT, urinary nitrogen, and creatinine, which represent liver and kidney functions, all had significant differences between the control group, the Dansang group, and the SALB group. SAL'B is thought to have little effect on the nutritional status and liver and kidney function. Since the SAL B group has a significantly higher force within the range of P <0.001 (* 2) than the control group, the SAL'B side effects Very Hard to think. In addition, regarding blood Na, Cl, K, Ca, and Mg levels, there was no significant difference between the Tanzan group or SAL'B group and the control group. Indicates that there is no effect on the balance. Compared to the control group, the angiotensin 1 transferase and angiotensin 2 levels in the Tanzan and SAL'B groups tended to decrease. This may contribute to SA or B's blood pressure drop. Tansan has the same medicinal effect as SA B, but its action was low.
実施例 5 Example 5
実施例 2において、丹参又は SAL'B投与後 100日目の脳卒中の発症率と脳卒中 後遺症の重傷度及び生存状況を観察し、分析した。死亡したラットを当日に解剖し、 脳卒中病変の有無を病理検査した。実験データは平均値士標準誤差で表した。有 意差の有無を t-検定により調べた。  In Example 2, the incidence of stroke on the 100th day after administration of Dansang or SAL'B, the severity of the sequelae of stroke, and the survival status were observed and analyzed. Rats that died were dissected on the day and examined for the presence of stroke lesions. The experimental data were expressed as mean value standard error. The presence or absence of significant difference was examined by t-test.
投与 100日まで、行動神経症状 (過敏性、痛覚過敏性、四肢の麻痺等)の観察から 脳卒中症状を示していた個体数はそれぞれ SAL'B群 7匹、丹参群 9匹、対照群 10匹 であった。丹参投与によっても脳卒中発症を抑制するが、 SAL'B投与により脳卒中 発症を 3倍も効率よく抑制することが示された。投与 100日までの生存個体数に関し て ίま、 SAL'B群 ίま 67日目に 3匹、 68日目、 73日目、 77日目、 85日目に各 1匹ずつ 死亡した。これ〖こ対して丹参群〖ま 70日目〖こ 3匹、 75日目〖こ 2匹、 80日目〖こ 1匹、 82 日目に 3匹、計 9匹の死亡が認められた。これに対して対照群は 70日目に 3匹、 75 曰目に 2匹、 80曰目に 1匹、 82曰目に 3匹、 85曰目に 1匹、計 10匹の死亡力 ^認めら れた。 SAL'B又は丹参投与による延命効果が確認できた (Ρく 0.01)。死亡した個体に ついての解剖肉眼的所見は対照群の全例に大脳皮質下と大脳基底核に梗塞巣とそ の周囲の瀰漫性脳浮腫および出血巣を認めたのに対し、 SAL · B群ではこの病理変 化が軽力つた。丹参群での病理変化は対照群と比較し、やや良好の傾向が見られる 1S ほとんど変わらな力つた。 From the observation of behavioral neurological symptoms (hypersensitivity, hyperalgesia, paralysis of limbs, etc.) up to 100 days after administration The number of individuals who showed stroke symptoms was 7 in the SAL'B group, 9 in the Tansan group, and 10 in the control group, respectively. It has been shown that administration of dansan suppresses the onset of stroke, but administration of SAL'B effectively suppresses the onset of stroke three times. Regarding the number of surviving animals up to 100 days after administration, 3 animals were killed on the 67th day, and one animal each died on the 68th, 73rd, 77th and 85th days. On the other hand, there were 9 deaths in total, 3 animals from the Tansan group, 2 animals from the 70th day, 2 animals from the 75th day, 1 animal from the 80th day, and 3 animals on the 82nd day. In contrast, the control group had 3 mortality on day 70, 2 in 75th, 1 in 80th, 3 in 82th, 1 in 85th, total 10 mortality ^ It was. A life-prolonging effect by administration of SAL'B or Dansang was confirmed (0.01). The anatomical macroscopic findings of the deceased individuals showed infarcts and surrounding diffuse cerebral edema and hemorrhagic lesions in the subcortical and basal ganglia in all cases in the control group. Then, this pathological change was minor. The pathological changes in the Dansang group were slightly different from those in the control group.
実施例 6  Example 6
[0024] 実施例 5にお 、て、ラットの行動神経症状により重症度の判定を行 、、点数を付き て評価した。以下の評価基準を用いた。感覚 (痛覚等)過敏を 1点、片肢体マヒがある 1S 自主的に歩け、ケージ蓋上の餌が自主的に食べられるを 2点、片肢体マヒが存 在し、自主的歩きが困難、ケージ内の餌しかを食べられないを 3点、死亡を 4点とした 。対照群 40点に対し、丹参群は 36点、 SAL'B群は 4点であり、対照群に比較して SA い B群は有意に脳卒中後遺症を軽減した。丹参群も脳卒中後遺症を軽減の傾向は 見られたが対照群と比較して有意差はな力つた。  [0024] In Example 5, the severity was determined based on the behavioral neurological symptoms of the rat, and the score was evaluated. The following evaluation criteria were used. Sensation (painfulness, etc.) 1 point of hypersensitivity, one-limbed paralysis 1S Voluntary walking, 2 points to be able to eat food on the cage lid, one-limbed paralysis is present, and voluntary walking is difficult, Three points were given to eat only the food in the cage, and four points were given to death. Compared to the control group, the Dansang group scored 36 points and the SAL'B group scored 4 points, and the SA or B group significantly reduced the sequelae of stroke compared to the control group. The Tansan group also showed a tendency to reduce the sequelae of stroke, but the difference was not significant compared to the control group.
実施例 7  Example 7
[0025] 実施例 1において、薬剤投与後の 30日目に、 B-SAL'B群と B-対照群の 2群のラッ トにレーザー ·ドッブラ法を用いて脳血流量の連続的測定と 2次元的測定を行なった 。測定方法としては麻酔下においてラット頭皮を切開し、頭蓋骨を露出させ、リス力社 のレーザ一.トップラー血流画像装置 PiM2 (リス力社、スウェーデン)を用いてラットの 脳血流量を測定した。有意差の有無を t-検定により調べた。レーザードッブラ法を用 いて連続的測定と二次元的測定を行い、 SAL' B群 1. 414±0. 24、対照群 1. 144 ±0. 31 (P< 0. 05)の値を得た。この結果は SAL' B群ラットの脳血流状況が対照群 のラットより改善されたことを示している。丹参群の脳血流量は 1. 199±0. 43であり 、 SAL'B群ほどではないが、脳血流の改善が認められた。 [0025] In Example 1, on the 30th day after drug administration, continuous measurement of cerebral blood flow was performed using the laser-Doppler method on the rats in the B-SAL'B group and the B-control group. Two-dimensional measurement was performed. As the measurement method, the rat scalp was incised under anesthesia, the skull was exposed, and the cerebral blood flow of the rat was measured using the laser power imaging device PiM2 (Risu Power Company, Sweden) manufactured by Rishiki. . The presence or absence of significant difference was examined by t-test. Using laser Doppler method, continuous measurement and two-dimensional measurement were performed to obtain values of SAL 'B group 1.414 ± 0.24 and control group 1.144 ± 0.31 (P <0.05). It was. This result shows that cerebral blood flow in SAL'B group rats This is an improvement over the rats. The cerebral blood flow of the Dansang group is 1.199 ± 0.43, which is not as good as that of the SAL'B group, but improved cerebral blood flow was observed.
実施例 8 Example 8
高血圧症、糖尿病、高脂血症、心疾患、一過性能虚血発作等脳卒中発症の危険 因子の大き 、患者で治験に参加を希望する人に対し、本治験により得られる可能性 のある効果と危険性、及びいつでも治験参加を撤回でき、撤回により不利に扱わな い旨が書かれた文書を渡して、かつ口頭でも説明した上で、それでも参加を希望す る患者に対し、事前に治験倫理委員会の承認を得る治験プロトコールに従い、基礎 治療の上に SAL'B投与を行う SAL'B群と基礎治療だけを行う対照群に 2群する。患 者の症状を毎日ジャパン 'ストローク 'スケール調査票に従い、点数を記入し、調査票 に書かれた規則に従って計算された計算値で脳卒中の発症を診断し、対照群と SAL • B群の脳卒中発症率の差から、 SAL'Bの脳卒中予防効果を測定できる。  High risk factors for stroke, such as hypertension, diabetes, hyperlipidemia, heart disease, transient ischemic attack, effects that may be obtained by this trial for patients who want to participate in the trial Give a written statement that you can withdraw your trial participation at any time and that you can withdraw from the trial at any time. In accordance with the clinical trial protocol approved by the Ethics Committee, two groups are included: the SAL'B group, which receives SAL'B on top of the basic treatment, and the control group, which performs only basic treatment. The patient's symptoms are scored according to the Japan 'Stroke' scale questionnaire every day, the score is calculated, and the onset of the stroke is diagnosed with the calculated value according to the rules written in the questionnaire. Strokes in the control group and SAL • B group The stroke prevention effect of SAL'B can be measured from the difference in incidence.
ジャパン 'ストローク 'スケール調査票の内容は以下の通りである。  The contents of the Japan 'Stroke' scale questionnaire are as follows.
1.意識: a)または b)  1. Consciousness: a) or b)
a)グラスゴゥ ·コマ ·スケール： [開眼]自発的に開眼するを 4点、呼びかけにより開眼 するを 3点、痛み刺激により開眼するを 2点、全く開眼しないを 1点、 [言語]見当識良 好を 5点、混乱した会話を 4点、不適切な言葉を 3点、理解不能の応答を 2点、反応 なしを 1点、 [運動]命令に従うを 6点、疼痛に適切に反応を 5点、屈曲逃避を 4点、異 常屈曲反応を 3点、伸展反応を 2点、反応なしを 1点とし、 [開眼]と [言語]と [運動]の 合計が 15点を A、 14— 7点を B、 6— 3点を Cと分類する。  a) Glasgow · Koma · Scale: [Open eyes] 4 points for spontaneously opening eyes, 3 points for opening eyes by calling, 2 points for opening eyes by pain stimulation, 1 point for not opening eyes at all, [Language] 5 points for good, 4 points for confused conversations, 3 points for inappropriate words, 2 points for incomprehensible responses, 1 point for no response, 6 points for following [exercise] commands, 5 for proper response to pain 4 points for flexion escape, 3 points for abnormal flexion response, 2 points for extension response, 1 point for no response, and a total of 15 points for [open eye], [language] and [movement] is A, 14— Classify 7 points as B and 6-3 points as C.
b)ジャパン 'コマ 'スケール： [刺激しなくても覚醒している状態]全く正常を 9点、大 体意識清明だが、今一つはっきりしないを 8点、時 '人'場所がわ力もないを 7点、自 分の名前、生年月日が言えないを 6点、 [刺激すると覚醒している状態]普通の呼び 力けで容易に開眼するを 5点、大きな声または体を揺さぶることにより開眼するを 4点 、痛み ·刺激を加えつつ呼びかけを繰り返すとかろうじて開眼するを 3点、 [刺激しても 覚醒しな 、状態]痛み刺激に対しはら 、のける様な動作をするを 2点、痛み刺激で少 し手足を動力したり顔をしかめるを 1点、痛み刺激に全く反応しないを 0点とし、 9点を A、 8-3点を B、 2-点を Cと分類する。 分類の値 (A= 7. 74、B= 15. 47、 = 23. 21)を累計に用いる。 b) Japan 'Koma' scale: [Awakened without stimulating] 9 points for normality, clearness for general consciousness, 8 points for unclearness, 7 6 points for a person's name, their name and date of birth, 5 points for easy eye-opening with a normal call, 5 points for opening with a loud voice or body shake 4 points, pain · Repeating the call while applying stimuli, barely 3 points to open eyes, [not awakening even if stimulated, state] 2 points to move away from pain stimuli, pain Stimulate the limbs or grimacing a little with a stimulus, 1 point, 0 points not responding to painful stimulation, 9 points as A, 8-3 points as B, 2-points as C. The classification values (A = 7.74, B = 15.47, = 23.21) are used for the total.
2.言語：口頭命令で拳をつくる、時計を見せて時計といえる、サクラを繰り返して言 える、住所'家族の名前が上手に言える: 4Z4を A、 3Z4又は 2Z4を B、 1/4又は 0 Z4を Cと分類し、分類の値 (A= l. 74、 B = 2. 95、 C=4. 42)を累計に用いる。  2. Language: Make a fist by verbal command, show the clock, say a clock, repeat the cherry, say the address' family name well: 4Z4 A, 3Z4 or 2Z4 B, 1/4 or 0 Classify Z4 as C, and use the classification values (A = l. 74, B = 2.95, C = 4.42) for the total.
3.無視:線分二等分試験正常を A、線分二等分試験で半側空間無視を B、麻痺に 気が付力な!、ある！/、は一側の空間を無視した行動をするを Cと分類し、分類の値 (A =0. 42、 B = 0. 85、 C = l. 27)を累計【こ用!ヽる。  3. Ignore: A normal bisector test is A, a half-line ignorance is B in a bisector test, and I am aware of paralysis! /, Classifies actions that ignore the space on one side as C, and accumulates the classification values (A = 0.42, B = 0.85, C = l. 27).
4.視野欠損または半盲：同名性の視野欠損または半盲なしを A、同名性の視野欠 損または半盲ありを Bと分類し、分類の値 (A=0. 45、 B=0. 91)を累計に用いる。  4. Visual field loss or semi-blindness: A homozygous visual field defect or no half-blind is classified as A, homogeneous visual field defect or semi-blind is classified as B, and classification values (A = 0.45, B = 0. 91) is used for the total.
5.眼球運動障害:なしを A、側方視が自由にできないを B、眼球に偏位したままで 反対側へ側方視できないを Cと分類し、分類の値 (A=0. 84、 B= l. 68、 C = 2. 53 )を累計に用いる。  5.Eye movement disorder: Classify A as none, B as side view cannot be freely controlled, and C as unable to laterally view the other side without shifting to the eyeball, and the classification value (A = 0.84, B = l. 68, C = 2.53) is used for the total.
6.瞳孔異常:瞳孔異常なしを A、片側の瞳孔異常ありを B、両側の瞳孔異常ありを C と分類し、分類の値 (A= l. 03、 B = 2. 06、 C = 3. 09)を累計に用いる。  6.Pupil abnormalities: Class A with no pupil abnormalities, B with pupil abnormalities on one side, C with abnormal pupils on both sides, and classification values (A = l. 03, B = 2.06, C = 3. 09) is used for the total.
7.顔面麻痺:なしを A、片側の鼻唇が浅いを B、安静時に口角が下垂しているをじと 分類し、分類の値 (A=0. 31、 B = 0. 62, C = 0. 93)を累計【こ用 ヽる。  7.Facial paralysis: Classify none as A, shallow nose lips as B, resting mouth angle as the rest, and the classification values (A = 0.31, B = 0.62, C = 0.93) is accumulated.
8.足底反射:正常を A、いずれとも言えないを B、病的反射ありを Cと分類し、分類 の値 (A=0. 08、B = 0. 15、C = 0. 23)を累計【こ用!ヽる。  8. Plantar reflexes: Normal is A, B is not normal, C is pathological reflex, and classification values (A = 0.08, B = 0.15, C = 0.23) Cumulative [for use!
9.感覚系：正常を A、何らかの軽い感覚障害があるを B,はっきりした感覚障害があ るを Cと分類し、分類の値 (A=— 0. 15、B=— 0. 29、C= 0. 44)を累計に用いる  9. Sensory system: Normal is classified as A, mild sensory impairment is classified as B, distinct sensory impairment is classified as C, and classification values (A = —0.15, B = —0.29, C = 0. 44) is used for the total
10.運動系： 10. Motor system:
10- 1.手:正常を A、親指と小指で輪をつくる、またはそばに置いたコップが持てる を B、指は動くが物がつかめない、または全く動かないを Cと分類し、分類の値 (A=0 . 33、 B = 0. 66、 C = 0. 99)を累計【こ用!ヽる。  10- 1. Hand: Classify A as normal, make a ring with thumb and little finger, or hold a cup placed beside B, finger move but can't catch things or move at all, and classify as C Accumulate the values (A = 0.33, B = 0.66, C = 0.99).
10-2.腕:正常を A、肘を伸ばしたまま腕を挙上できる、または肘を屈曲すれば腕 を挙上できるを B、腕はある程度動くが持ち上げられない、または全く動かないをじと 分類し、分類の値 (A=0. 66、B= 1. 31、C = 1. 97)を累計に用いる。 10-3.下肢手:正常を A、膝を伸ばしたまま下肢を挙上できる、または自力で膝立 てが可能を B、下肢は動くが膝立てはできない、または全く動力ないを Cと分類し、分 類の値 (A= l. 15、B = 2. 31、C = 3. 46)を累計に用いる。 10-2.Arm: Normal A, arm can be raised with elbows extended, or arm can be raised by bending elbows B, arms move to some extent but cannot be lifted or do not move at all The classification values (A = 0.66, B = 1.31, C = 1.97) are used for the total. 10-3.Lower limb hand: Class A is normal, B can be lifted with the knees stretched, or can stand on its own, B, Climbs can move but cannot stand, or no power at all The classification values (A = l. 15, B = 2.31, C = 3.46) are used for the total.
上記各分類の値の累計から定数 14. 71を差引いた値がプラスの場合は脳卒中発 症と判断する。対照群と SAL'B群の脳卒中発症の頻度の差から、 SAL'Bの脳卒中予 防または治療効果を測定できる。  If the value obtained by subtracting the constant 14.71 from the cumulative value of each category above is positive, it is determined that the stroke has occurred. The stroke prevention or treatment effect of SAL'B can be measured from the difference in the frequency of stroke onset between the control group and SAL'B group.
実施例 9 Example 9
脳卒中後遺症がある患者を脳卒中運動機能障害重傷度スケールに従い、診断し、 重傷度別に群分けをする。一つの群を SAL · Bを投与する SAL · B群と投与しな 、対照 群に 2群する。両群とも重傷度に合わせた同じリハビリを行い、定期的に脳卒中運動 機能障害重傷度スケール採点を行う。対照群と SAL，B群の脳卒中運動機能障害重 傷度の差から、 SAL'Bの脳卒中後遺症予防または治療効果を測定する。  Patients with sequelae of stroke are diagnosed according to the stroke motor dysfunction severity scale and grouped by severity. Do not administer one group with SAL • B group, which is administered SAL • B, and 2 groups with control group. Both groups will undergo the same rehabilitation according to the severity of the injury, and will be regularly scored for stroke motor dysfunction severity. Measure the effect of SAL'B on preventing or treating stroke sequelae from the difference in the severity of stroke motor dysfunction between the control group and SAL and B groups.
脳卒中運動機能障害重傷度スケールの内容は以下の通りである。  The contents of the Stroke Motor Dysfunction Severity Scale are as follows.
1.顔面麻痺:なしを A、ありを Bと分類し、分類の値 (A=— 1. 27、 B= l. 27)を累 計に用いる。  1. Facial paralysis: Classify A as “A” and “B” as “B”, and use the classification values (A = —1.27, B = l. 27) for the accumulation.
2.嚥下障害：なしを A、時にむせることがあるを B、チューブ 'フィーディングが必要 を Cと分類し、分類の値 (A=—4. 93、 B= -0. 89、 C = 5. 82)を累計に用 、る。  2. Dysphagia: none is A, sometimes it can be broken B, tube 'feeding required is classified as C, classification values (A = —4.93, B = -0. 89, C = 5 82) is used for accumulation.
3.腕:肘を伸ばしたまま腕を挙上できるを A、肘を屈曲すれば腕を挙上できるを B、 重力に抗して運動できないを Cと分類し、分類の値 (A=— 0. 97、 B=— 0. 09、 C = 1. 06)を累計に用いる。  3.Arm: Class A can lift the arm with the elbow extended, B can lift the arm if the elbow is bent, C can not move against gravity, and the classification value (A = — 0.97, B = —0.09, C = 1.06) are used for the total.
4.手:正常を A、そばに置いたコップが持てるを B、物がつかめないを Cと分類し、 分類の値 (A=— 1. 26、B=—0. 16、C = 1. 42)を累計に用いる。  4.Hand: Classify A as normal, B to hold a cup placed beside, B as unpossible, C as classification value (A = —1.26, B = —0.16, C = 1. 42) is used for the total.
5.下肢近位筋：臥位で検査し正常を A、膝立て可能を B、膝立て不能を Cと分類し 、分類の値 (A=— 1. 04、 B = 0. 14、 C = 0. 89)を累計に用いる。  5. Proximal muscles of the lower limbs: Examined in the supine position, classifying normal as A, knee-capable as B, and non-capable as C, classification values (A = —1.04, B = 0.14, C = 0. 89) is used for the total.
6.足関節:座位で検査し、座位がとれない場合は臥位の筋力から推定し、爪先を 上げられるを A、爪先を上げられないを Bと分類し、分類の値 (A=— 0. 52、 B = 0. 5 2)を累計に用いる。  6.Ankle joint: Examined in the sitting position, and if the sitting position cannot be estimated, it is estimated from the muscle strength in the supine position, classifying the toe up as A and classifying out the toe as B, the classification value (A =-0 52, B = 0.5 2) is used for the total.
7.複合運動：ベッド上仰臥位力 ベッド脇で立位になるまでの一連の動作で、べッ ド脇に立てるを A、ベッドに座れるを B、座れないを Cと分類し、分類の値 (A=— 1. 2 4、B=—0. 39、C = 1. 63)を累計【こ用!ヽる。 7. Combined exercise: supine position on the bed. Classify A as standing on the side of the door, B as sitting on the bed, C as unable to sit on the bed, and cumulative values (A = —1.24, B = —0.39, C = 1.63) are accumulated. For!
8.歩行:補助具なしに歩けるを A、補助具ないしは介護者があれば歩けるを B、自 力では歩けないを Cと分類し、分類の値 (A=— 3. 63、 B=— 0. 45、 C=4. 08)を 累計に用いる。  8.Walking: Classify as A (can walk without assistive devices, B as walkable with assistive devices or caregivers, C as unable to walk on their own, and classification values (A = —3.63, B = —0) 45, C = 4.08) is used for the total.
上記各分類の値の累計に定数 14. 60を加え値がプラスの場合は脳卒中後遺症あ りと判断する。対照群と SAL'B群の脳卒中運動機能障害重傷度の差から、 SAい Bの 脳卒中後遺症予防または治療効果を測定できる。  A constant of 14.60 is added to the cumulative value of each category above, and if the value is positive, it is determined that there is sequelae of stroke. From the difference in the severity of stroke motor dysfunction between the control group and SAL'B group, it is possible to measure the effect of SA or B in preventing or treating stroke sequelae.
産業上の利用可能性 Industrial applicability
本発明の薬剤は、脳卒中又は脳卒中後遺症の予防剤又は治療剤として、利用可 能性がある。  The drug of the present invention can be used as a preventive or therapeutic agent for stroke or stroke sequelae.

Claims

請求の範囲 The scope of the claims
サルビアノール酸 B及びそのプロドラッグ、ならびに薬学的に許容することのできる それらの塩およびそれらの水和物力 選ばれる化合物を主成分とする脳卒中又は脳 卒中後遺症の予防用又は治療用薬剤。  Salvianolic acid B and prodrugs thereof, and pharmaceutically acceptable salts and hydrates thereof A drug for preventing or treating stroke or stroke sequelae comprising a selected compound as a main component.
請求項 1に記載する脳卒中後遺症予防用又は治療用薬剤。  The agent for preventing or treating sequelae of stroke according to claim 1.
PCT/JP2006/301417 2005-02-23 2006-01-30 Preventive or therapeutic agent for stroke or sequelae of stroke comprising as main component salvianolic acid b or the like WO2006090557A1 (en)

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CN105218495B (en) * 2014-05-27 2019-01-29 天津天士力之骄药业有限公司 A kind of red sage root water soluble ingredient noval chemical compound, preparation method and applications

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