WO2006089478A1 - Methode d'utilisation d'isoscutellarine pour fabriquer des medicaments - Google Patents

Methode d'utilisation d'isoscutellarine pour fabriquer des medicaments Download PDF

Info

Publication number
WO2006089478A1
WO2006089478A1 PCT/CN2006/000254 CN2006000254W WO2006089478A1 WO 2006089478 A1 WO2006089478 A1 WO 2006089478A1 CN 2006000254 W CN2006000254 W CN 2006000254W WO 2006089478 A1 WO2006089478 A1 WO 2006089478A1
Authority
WO
WIPO (PCT)
Prior art keywords
isoflavone
medicine
preparation
medicament
cerebral
Prior art date
Application number
PCT/CN2006/000254
Other languages
English (en)
Chinese (zh)
Inventor
Guanzheng Shi
Original Assignee
Guanzheng Shi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guanzheng Shi filed Critical Guanzheng Shi
Publication of WO2006089478A1 publication Critical patent/WO2006089478A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of isoflavone glycosides (ISOSCUTELLARIN 5, 7, 4,-trihydroxyflavone-6-0-glucuronide), in particular to its use in the pharmaceutical field.
  • Astragaloside (SCUTELLARIN 5, 6, 4'-trihydroxyflavone - 7-0-glucuronide) is also known as scutellarin. It has the functions of dilating blood vessels, increasing cerebral blood flow and coronary flow, reducing blood viscosity, and improving microcirculation. It is mainly used for the treatment of cerebral thrombosis, cerebral infarction, post-stroke spasm, coronary heart disease, angina pectoris and other diseases.
  • the existing preparations are ordinary tablets, injections, and powder injection needles. O. 19% ⁇ The oral bioavailability of the ordinary tablets is very low, only 0.4 ⁇ 0.19%. Ordinary injections and powder injections have a short half-life and rapid elimination in the body.
  • the compound has the formula C21 H20 012, a yellow powder, a molecular weight of 464, and is easily soluble in low concentrations of ethanol. According to the literature, it can be extracted from the leaves of the sycamore plant Sterculia foetida or Sterculia colorata.
  • a further object of the present invention is to provide an isoflavone glycoside having an anti-myocardial ischemic effect.
  • Another object of the present invention is to provide an application of isoflavone glycoside in the preparation of a medicament having anti-blood and anti-thrombotic effects, in particular to prepare and treat cerebrovascular diseases such as cerebral vascular diseases such as cerebral thrombosis, cerebral embolism and cerebral hemorrhage.
  • cerebrovascular diseases such as cerebral vascular diseases such as cerebral thrombosis, cerebral embolism and cerebral hemorrhage.
  • the invention establishes a method for determining the blood concentration of the compound in the plasma of the human body (LC/MS/MS); and the pharmacokinetic study of the isoflavone glycoside, the invention adopts the isoflavone glycoside and the jaundice
  • the human kinetic study of the glucoside found that the plasma concentration after oral administration of baicalein was ⁇ 5 ng/ml, and the elimination was fast and irregular.
  • the isoflavone glycoside maintains a higher blood concentration in the human plasma, and the curative effect is superior to baicalein; meanwhile, no clinical adverse reactions are observed in clinical trials.
  • the 20% ethanol layer was chromatographed on silica gel column eluting with chloroform: methanol: water (1: 2: 2); and then eluted with Sephadex LH220, methanol: water (1: 2) to give the compound isoflavin Glycoside 30g.
  • the isolated isoflavone glycoside is extracted as above, and polyethylene glycol 6000 : polyethylene glycol
  • the test protocol is the best test plan; the cooling temperature is 0 ⁇ 5 °C, the inner diameter of the drip is 4. 5/7. 0mm dripper, the drip is 2-6cm from the cooling liquid surface, and the drip speed is 20- Under the dropping conditions of 45 drops/min, pellets containing 10 mg of isoflavone glycoside per pellet were prepared.
  • the animals After intravenous administration, the animals showed symptoms of dose-dependent poisoning, and the mice showed symptoms such as decreased spontaneous activity, flank, convulsions, and struggling. 1185.
  • the dead animals were found in the 4 mg/kg or higher dose group.
  • the LD50 value calculated by the Bliss method was 1509. 9 + 142. 7 mg'/kg, and the 95% confidence limit was 1399. 9 ⁇ 1685. 3mg/kg 0 dead animals and observation At the end of the animal necropsy, no significant abnormal changes were observed. Changes in body weight before and after administration. .
  • the results of the preliminary test showed that the dead animals were not observed for 3 consecutive days after the administration of the test drugs 2500 and 5000 mg/kg. This indicates that the product is less toxic and its LD50 is difficult to measure, so the maximum tolerated dose test is performed.
  • mice in the experimental group had no significant symptoms of spontaneous poisoning except for spontaneous activity, and there was no obvious poisoning symptoms. No animal death was observed after 7 days of continuous observation. Changes in body weight before and after administration. Number of animals Weight change ( g )
  • mice After intravenous administration of the experimental drug to the mice, the symptoms of spontaneous activity, flank, convulsions, and struggling were observed in the mice. The death of the animals was dose-dependent.
  • the LD50 value was calculated by the Miss method.
  • the LD50 value was 1509. 9 ⁇ 142 7mg/kg, 95% confidence limit is 1399. 9 ⁇ : 1685. 3mg/kg.
  • the oral administration of the experimental drug when the dose reached 5000 rag/kg, the animals were generally in good condition except for the reduction of the abdomen and spontaneous activity, and no dead animals were observed. This indicates that the oral administration of LD50 >5000mg/kg o in mice has a therapeutic effect on focal cerebral ischemia-reperfusion in rats.
  • the rats were separated and exposed to the common carotid arteries.
  • the bilateral common carotid arteries were closed with arterial clips to produce bilateral cerebral ischemia. After a certain period of ischemia, the arterial clip can be re-opened for reperfusion of the brain according to the test requirements.
  • the aim is to block the blood vessels that innervate the brain tissue and simulate a pathological model similar to human stroke to evaluate the effectiveness of the drug.
  • mice male and female, 20 soil and 2 g were randomly divided into 4 groups, respectively, and normal saline and baicalein (control group) and isoflavone glycoside (test group) were respectively given at 20 mg/kg.
  • the doses of 40 mg/kg and 60 mg/kg were intragastrically administered for one week.
  • blood was taken from the veins of the mouse in the eye of the eyeballs. The time from the blood inflow into the tube is started. After the blood is filled, the capillary is taken out and placed on the table. The capillary is broken at intervals of about 0.5 cm every 10 s until the appearance of the blood coagulation.
  • the elapsed time is the blood coagulation time, and the average of the data at both ends of the capillary.
  • the value is the blood coagulation time of the mouse. Effect on clotting time in mice (capillary method) (X-soil SD)
  • mice The coagulation test in mice showed that both the baicalein group and the isoflavone group had anticoagulant effects, and the group was particularly effective in the isoflavone group.
  • the venous blood of healthy rabbits was taken, mixed with (38m g /ml) sodium citrate solution 1: 9 for anticoagulation, centrifuged at 3000r/min for 10 minutes, and the supernatant was taken for testing.
  • the mixture was added with rabbit cerebral powder extract solution with different concentrations of baicalein and isoflavone glucoside solution, and the physiological saline solution was 0.1 ml, and then rabbit plasma was added to 0.1 ml, and the mixture was placed in a 37 ° C water bath.
  • Incubate for 30 s add 0. 025raol/L CaC12 solution to 0.1 ml and start timing. Incline the tube once every 5 s to record the time required for fibrin to solidify (liquid level does not move).
  • Xanthosine and isoflavone can significantly prolong clotting time and prothrombin time, which is beneficial to prevent thrombosis.
  • gerbils Forty-eight healthy gerbils, weighing (54 ⁇ 14) g, were used for both male and female. They were randomly divided into six groups, 8 in each group, respectively: (1) saline control group (NS); (2) isoflavone glycoside Group (50mg/kg), the above groups of animals were injected intraperitoneally, for 2 consecutive days, on the third day, the gerbils were anesthetized; the intravenous administration channel was established, and the drugs and doses of the above groups were intravenously given to each group. The drug was given IS02. 5ug/kg 5 minutes after the last administration, and intravenously injected at a constant rate within 5 minutes.
  • NS saline control group
  • 50mg/kg isoflavone glycoside Group
  • Model control group 0.023 ⁇ 0.032 0.084 + 0.065 0.159 ⁇ 0.046 0.158 ⁇ 0.078 0.025 ⁇ 0.049
  • the test results showed that the first dose of isoflavone injection was administered intraperitoneally for 2 days, the last intravenous administration, and intravenous injection, isoflavone Both have a shorter, milder effect of alleviating ISO-induced acute myocardial ischemia. Its mechanism of anti-myocardial ischemia may be related to its rapid and long-lasting blood pressure reduction, which reduces the burden on the heart and thus reduces the myocardial oxygen consumption.
  • Isoflavone can increase myocardial S0D activity, reduce MDA, reduce the accumulation of free radicals in the myocardium, and reduce the damage of ISO to the myocardium, suggesting that its anti-cardiac ischemia may be related to its anti-lipid peroxidation.
  • Baicalein has the functions of dilating blood vessels, increasing arterial flow, lowering blood viscosity, reducing peripheral resistance, and reducing platelet aggregation. It is mainly used for the treatment of coronary heart disease, angina pectoris, myocardial ischemic injury and cerebral thrombosis.
  • the existing preparations include ordinary tablets, injections, and powder injection needles. Ordinary tablet oral bioavailability is extremely low, only 0.4 ⁇ 0. 19 ° /. . Ordinary injections and powder injections have a short half-life and are rapidly eliminated in the body. The human pharmacokinetic study has not been reported.
  • the Tmax of isoflavone glycoside in plasma was 7.7 ⁇ 1.7 h ; Cmax was 178 ⁇ 142 ng/ml, and tl/2 was 3.26 ⁇ 1.78h; Calculated by the trapezoidal method, AUCO-t was 1195 ⁇ 1136ngh/ml, and AUC0- ⁇ was 1263 ⁇ 127 lng.h/ml.
  • baicalein In the human pharmacokinetic study of baicalein, the plasma concentration of baicalein, the main component of the subject after oral administration of baicalein, was ⁇ 5ng/ml, and the elimination was fast and irregular. It is difficult to perform pharmacokinetic evaluation. And the literature [2] reported that after high-dose baicalin in beagle dogs, the peak plasma concentration was reached between 1 and 3 h, and the absolute bioavailability was between 0.2% and 0.75%, suggesting that baicalein was almost not absorbed orally; The results of the static injection elimination half-life were consistent. ' According to the general pharmacokinetics, isoflavone glycoside has better efficacy than baicalein; at the same time, no clinical adverse reactions have been observed in clinical trials.
  • the present invention has developed a new application field for the known compound isoflavone glycoside, and has opened up a new application field.
  • the isoflavone glycoside of the invention is safe, non-toxic, has strong pharmacological effects, and has good pharmacological effects, indicating that there is a good medicinal prospect.
  • the raw materials of the product of the invention are rich in source and low in cost, and the leaf as the extraction site can be fully resourced, the preparation process is simple, and no toxic side effects are observed. It can be formulated into a solid preparation such as an oral preparation such as a tablet, a dropping pill, or a capsule; or a liquid preparation such as an intravenous preparation such as a powder injection or an intravenous solution.
  • the drug made by the product of the invention has the ability to reduce brain water content and MDA content, increase SOD, CAT and GSH-Px activity, and protect Na+, K+-ATPase activity. It is suggested that isoflavone can protect the brain tissue from antioxidant enzymes, inhibit lipid peroxidation, and alleviate the damage of free radicals on brain tissue. It can reduce the water content of brain tissue and inhibit Na+, K+-ATPase and Ca2+ in brain tissue. - A decrease in ATPase activity. This drug suggests that the drug can protect against ischemia-reperfusion brain tissue by protecting ATPase activity, which is superior to baicalein.
  • the drug made by the product of the invention can significantly improve the change of TXB2 of platelet aggregation after urinary thrombolysis, and increase the concentration of tissue plasminogen activator and anticoagulant in blood, and reduce plasmin.
  • the concentration of pro-activator inhibitor (PAI) increases the recanalization rate of urinary hormone thrombin therapy in acute coronary thrombosis. It can reduce the number of platelets, reduce platelet aggregation, promote fibrinolytic activity, inhibit thrombin activity, etc., and has anticoagulant and fibrinolysis effects. Its anticoagulant effect is superior to baicalein.
  • the drug produced by the product of the present invention has an anti-ischemic effect. It can improve myocardial SOD activity, reduce MDA, reduce the accumulation of free radicals in the myocardium, and alleviate the damage of ISO to the myocardium, suggesting that its anti-ischemic effect may be related to its anti-lipid peroxidation.
  • the product of the present invention was subjected to a human body dynamics test, and the plasma concentration of plasma in different subjects after oral administration of isoflavone glycoside was determined by liquid chromatography-mass spectrometry-mass spectrometry. - time curve.
  • the AUC value was calculated by the trapezoidal method in a semi-logarithmic plot method, and tl/2 was calculated from the concentration point at the end of the elimination phase, and the main pharmacokinetic parameters were determined. Compared with baicalin, it has better pharmacokinetic parameters. It laid a theoretical foundation for the clinical efficacy of the drug. At the same time, no clinical adverse reactions were observed in clinical trials.
  • FIG. 1 shows the product ion full-scan mass spectrum of baicalein, isoflavone glycoside, baicalin [M+H]+: A, baicalin (B), isoflavinose (ISOSCUTELLARIN) C, baicalin (baicalin)
  • Example 1 Several embodiments of the present invention will be described below, but the content of the present invention is not limited at all.
  • Example 1
  • n-butanol fraction was chromatographed with macroporous adsorption resin, followed by elution with water, 20%, 60%, 80% ethanol to obtain 5 sites, and the 20% ethanol layer was chromatographed on silica gel with chloroform: methanol: water (1) : 2: 2) Elution, followed by Seph a d eX LH220 chromatography, methanol: water (1: 2) elution to obtain the compound isoflavone glycoside.
  • the mixture of polyethylene glycol 6000: polyethylene glycol 4000 (1: 2-4) is used as the substrate, and the coolant is selected from the group consisting of dimethicone: liquid paraffin (3: 2), and the starting isoflavone and the substrate are 1:4. Proportion, the temperature of the liquid is 60-80 ° C, the cooling temperature is 0 ⁇ 5 ⁇ , the drip of the inner diameter of the drip is 4.5/7.0mm, the drip is 3-6cm from the cooling surface, and the drip speed is 25- Under the dropping conditions of 35 drops/min, pellets containing 10 mg of isoflavone glycoside per pellet were prepared.
  • isoflavone glycoside prepared according to the method of Example 1, add an appropriate amount of water for injection, adjust the pH value to 7 with sodium carbonate, stir and dissolve, and add 10-15% of the amount of isoflavone glycoside for injection. Alcohol, sterilized and filtered, determined content, dispensed to 10mg / support, sealed, that is.
  • the isoflavone glycoside prepared by the method of Example 1 is prepared by using an infusion preparation method well known in the art to prepare an isoflavin sodium chloride injection having a specification of 250 ml: isoflavone 20 mg and sodium chloride. 2.25 g; Prepared as an isoflavone glycoside injection, the specification is 250 mh. Isoflavone 20 mg and glucose 12.5 g.
  • the isoflavone glycoside prepared by the method of Example 1 260 g, lactose 460 g, starch 420 g, talcum powder
  • Example 5 100 g of isoflavone glycoside prepared by the method of Example 1 and 32 ml of 10% hydroxypropylmethylcellulose were used. A capsule preparation method known in the art is used to prepare 1000 capsules having a specification of 20 mg/granule.
  • Example 6 A review of related literatures at home and abroad revealed no reports of human kinetic tests of isoflavone glycosides.
  • the invention conducts human pharmacokinetics research, and uses liquid chromatography-tandem mass spectrometry (LC/MS/MS) to determine the plasma concentration of isoflavone glycoside in human body, and uses the pharmacokinetic behavior of isoflavone glycoside The preparation was evaluated for efficacy.
  • LC/MS/MS liquid chromatography-tandem mass spectrometry
  • Plasma sample treatment Add 100 ⁇ M methanol, 100 ⁇ ⁇ internal standard solution ( baicalin 400 ng/ml) and 200 ⁇ l water to 500 ⁇ M ⁇ plasma, mix well; force n3 ml extraction solvent ethyl acetate, vortex mixing lmin Reciprocating oscillation lOmin (240 times / min), centrifugation for 5 min (3500 rpm), separate the upper organic phase in another tube, blow dry under a nitrogen flow at 40 ° C, the residue was added to 150 ⁇ ⁇ mobile phase to dissolve, vortex mixing, Take 20 ⁇ l for LC/MS/MS analysis.
  • Chromatographic conditions The mobile phase was methanol: water: formic acid (70: 30: 0.5, ⁇ / ⁇ / ⁇ ), flow rate 0.50 ml/min, column temperature: 25 ° C.
  • Mass spectrometry conditions ion source is ESI source; source spray voltage is 4kV; heating capillary temperature is 320° C; sheath gas (N2) pressure is 25 ⁇ ; auxiliary gas (N2) flow rate is 3Arb; collision gas (Ar) pressure is 1.OmTorr; collision The induced dissociation (CID) voltage is 25 eV; positive ion mode detection; the scanning mode is selective reaction monitoring (SRM), and the ion reactions for quantitative analysis are m/z 463 ⁇ m/z 287 (SCUTELLARIN and ISOSCUTELLARIN) and m/, respectively. Z447 ⁇ m/z271 (xanthine); scan time is 0.3s. The corresponding secondary full scan mass spectrum is shown in Figure 1.
  • baicalein and baicalin mainly produced [M+H]+ excimer ion peaks in the ESI ionization mode, which were m/z 463 and m/z 447, respectively.
  • [M+H]+ excimer ion peaks in the ESI ionization mode which were m/z 463 and m/z 447, respectively.
  • the Tmax of isoflavone glycoside in plasma was 7.7 ⁇ 1.7 h; Cmax score Not 178 ⁇ 142 ng / ml, tl / 2 was 3.26 ⁇ 1.78h; calculated by the trapezoidal method, AUCO-t was 1195 ⁇ 1136 ng 'h / ml, AUC0 - ⁇ were 1263 ⁇ 1271 ng. h / ml.
  • the plasma concentration of baicalein was ⁇ 5 ng/ml, and the elimination was fast and irregular.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle méthode d'utilisation d'isoscutellarine (5, 7, 4 ?-tri-hydroxylflavone-6-O-glucoronide) pour fabriquer un médicament. L'invention concerne l'utilisation d'isoscutellarine pour fabriquer un médicament destiné à une ischémie antimyocardique, en particulier une maladie cardio-vasculaire, une maladie cardiaque coronaire ou une angine de poitrine. L'invention concerne également l'utilisation d'isoscutellarine pour fabriquer un médicament destiné à du sang anticoagulé, à une thrombolyse, en particulier pour le traitement et pour la prophylaxie de maladies liées à des accidents cérébraux, notamment une thrombose cérébrale, un embolisme cérébral, une hémorragie cérébrale, etc. L'invention concerne également un médicament contenant de l'isoscutellarine. Ce médicament présente un effet vasodilatateur, permettant d'élever la circulation artérielle, de diminuer la viscosité sanguine et la résistance périphérique, de réduire les plaquettes et l'agglutination de plaquettes etc.
PCT/CN2006/000254 2005-02-22 2006-02-22 Methode d'utilisation d'isoscutellarine pour fabriquer des medicaments WO2006089478A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2005100074646A CN1823798A (zh) 2005-02-22 2005-02-22 异黄芩素苷在制药中的应用
CN200510007464.6 2005-02-22

Publications (1)

Publication Number Publication Date
WO2006089478A1 true WO2006089478A1 (fr) 2006-08-31

Family

ID=36927029

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/000254 WO2006089478A1 (fr) 2005-02-22 2006-02-22 Methode d'utilisation d'isoscutellarine pour fabriquer des medicaments

Country Status (2)

Country Link
CN (1) CN1823798A (fr)
WO (1) WO2006089478A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1318373A (zh) * 2000-10-09 2001-10-24 朱邦豪 灯盏花素在制药中的应用
RU2228673C1 (ru) * 2003-06-20 2004-05-20 Московский государственный университет прикладной биотехнологии Пищевой продукт, содержащий антиоксидант из экстракта шлемника байкальского
CN1502337A (zh) * 2002-11-20 2004-06-09 成都力思特制药股份有限公司 一种治疗心脑血管疾病的口服药物制剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1318373A (zh) * 2000-10-09 2001-10-24 朱邦豪 灯盏花素在制药中的应用
CN1502337A (zh) * 2002-11-20 2004-06-09 成都力思特制药股份有限公司 一种治疗心脑血管疾病的口服药物制剂及其制备方法
RU2228673C1 (ru) * 2003-06-20 2004-05-20 Московский государственный университет прикладной биотехнологии Пищевой продукт, содержащий антиоксидант из экстракта шлемника байкальского

Also Published As

Publication number Publication date
CN1823798A (zh) 2006-08-30

Similar Documents

Publication Publication Date Title
KR100281679B1 (ko) 염증 치료용 신규 약제학적 조성물 및 그 제조방법
Cobb et al. The effect of fluconazole on the clinical pharmacokinetics of methadone
IE60773B1 (en) Drug compositions stabilized against oxidation and discoloration
WO2006056129A1 (fr) Compositions d'alcaloides d'huperzia serrata comportant de l'huperzine a et de l'huperzine b et preparation de ces compositions
JP2013529654A (ja) レボカルニチン及びドベシレートを含む医薬組成物
CA2767833A1 (fr) Compositions de n-acetyl cysteine et procedes pour ameliorer l'efficacite therapeutique de l'acetaminophene
EP2292242A1 (fr) Dérivé de scutellarine, procédé d'élaboration, composition pharmaceutique, et utilisation correspondante
EP2262501B1 (fr) Traitement d' une septicémie avec 5-éthyl-1-phényl-2(1h)-pyridone
US4576951A (en) Proglumide, pharmaceutical preparations and compositions including it for use in human pain relief
US4952564A (en) Antiallergic agent
WO2006089478A1 (fr) Methode d'utilisation d'isoscutellarine pour fabriquer des medicaments
CN1278433A (zh) 一种溶栓药物,其制备方法及其用途
JPH02149515A (ja) アルドースリダクターゼ阻害剤
AU2004204804B2 (en) Carbohydrate conjugates to prevent abuse of controlled substances
KR100394329B1 (ko) 성기능장애 및 혈관계질환의 치료용 약제학적 조성물
Wells et al. Significance of histamine in trypsin shock as determined by benadryl.
EP2292241A1 (fr) Dérivé de scutellarine, procédé d'élaboration, composition pharmaceutique, et utilisation correspondante
CN101181259B (zh) 硝酸异山梨酯缓释剂及其制备方法
JPH045231A (ja) 慢性痛用鎮痛剤
EP0324212A1 (fr) Dérivés de l'acide glucuronique des antagonistes d'opiöides
JPS6213927B2 (fr)
US6139863A (en) Suppositories
US6916845B2 (en) Method for prevention and treatment of male and female sexual dysfunction
Green et al. Locomotor stimulant effects of nornicotine: role of dopamine
RU2780646C1 (ru) Новая кристаллическая форма 7-бром-1-(гидразинокарбонил)метил-5-фенил-1,2-дигидро-3h-1,4-бензодиазепин-2-она и ее фармацевтическое применение

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06705675

Country of ref document: EP

Kind code of ref document: A1

WWW Wipo information: withdrawn in national office

Ref document number: 6705675

Country of ref document: EP