WO2006047949A1 - Application de la kallidinogénase de l’urine humaine dans la fabrication d’un médicament pour le traitement de syndromes coronariens aggravés - Google Patents

Application de la kallidinogénase de l’urine humaine dans la fabrication d’un médicament pour le traitement de syndromes coronariens aggravés Download PDF

Info

Publication number
WO2006047949A1
WO2006047949A1 PCT/CN2005/001830 CN2005001830W WO2006047949A1 WO 2006047949 A1 WO2006047949 A1 WO 2006047949A1 CN 2005001830 W CN2005001830 W CN 2005001830W WO 2006047949 A1 WO2006047949 A1 WO 2006047949A1
Authority
WO
WIPO (PCT)
Prior art keywords
huk
injection
human urinary
group
urinary kallidinogenase
Prior art date
Application number
PCT/CN2005/001830
Other languages
English (en)
Inventor
Heliang Fu
Piqu Miao
Tie Sun
Yongli Xie
Original Assignee
Techpool Bio-Pharma Co., Ltd.
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 Techpool Bio-Pharma Co., Ltd. filed Critical Techpool Bio-Pharma Co., Ltd.
Publication of WO2006047949A1 publication Critical patent/WO2006047949A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4853—Kallikrein (3.4.21.34 or 3.4.21.35)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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 field of pharmaceutical chemistry. More specifically, the invention relates to a novel pharmaceutical use of human urinary kallidinogenase (HUK) for the manufacture of a medicine for the prevention and/or treatment of acute coronary syndromes.
  • the invention also relates to the pharmaceutical compositions containing HUK as an active ingredient for the management of acute coronary syndromes.
  • the present invention also relates to the method for therapy of acute coronary syndromes.
  • Acute coronary syndromes include unstable angina and acute myocardial infarction. There are 17,000,000 people died of cardiovascular diseases every year and half of them died of acute myocardial infarction.
  • HUK is a glycoprotein purified from the urine of healthy male. Its molecular weight is about 54,000 daltons. HUK can release kinins from human plasma kininogens. Kinins are peptides that are implicated in various physiological and pathological processes, including vasodilation, increase of blood flow and improvement of blood circulation. Kinins are also involved in increasing red cells deformability and inhibiting platelet aggregation, delaying the time of re- calcification, and improving viscousness of blood.
  • Unstable angina is the clinical symptome caused by sudden temporary ischemia and oxygen deficiency in the heart muscle.
  • Acute myocardial infarction is caused by atherosclerosis, thrombosis formation or convulsion of coronary artery. This leads to occlusion of the coronary artery or their branches , and permanent ischemia and oxygen deficiency which eventually cause necrosis of the heart muscle.
  • the therapeutical principles for acute coronary syndromes include improvement of the supply of blood in the heart, the blood circulation of coronary artery system and the supply of oxygen for the heart muscle, and also the decrease of the load of the heart and the oxygen consumption amount of the heart muscle as soon as possible.
  • HUK is effective for the prevention and treatment of acute coronary syndromes, and thus the invention is completed.
  • the object of the present invention is to provide a new use of HUK for manufacture of a medicine for the treatment and/or prevention of acute coronary syndromes.
  • Another object of the present invention is to provide a new use of HUK for management of acute coronary syndromes, this is, to provide a method for therapy of acute coronary syndromes, which comprises administering a therapeutically effective amount of HUK to patients in need of such therapy.
  • Still another object of the invention is to provide the pharmaceutical composition for management of acute coronary syndromes.
  • the composition comprises HUK as active ingredient, and other component(s) as adjuvant, and they can be prepared in a various of formulation forms, preferably the forms of injection, more preferably the forms of intravenous injection, especially dry power for injection and liquid for parenteral injection, for example an aqueous solution.
  • the HUK is notablely effective in the treatment of acute coronary syndromes.
  • composition of the present invention is generally used in drug formulation form .
  • the composition may contain other material(s) as adjuvant.
  • the composition containing HUK is generally administered by intravenous injection of different forms of drug formulation , especially lyophilized powder and solution for injection.
  • composition containing HUK for injection is generally formulated into sterilized solid forms, especially lyophilized powder.
  • the composition may contain additive(s) conventionally used in pharmaceutical art, such as mannitol, dextran, hydrolyzed glutin, sodium citrate, glycin and the like.
  • composition of HUK administered by injection can be in form of liquid, especially aqueous solution.
  • the said solution may contain additive(s) conventionally used in pharmaceutical art, for example water, mannitol, sodium chloride, glucose and the like.
  • the invention provides a method for therapy of acute coronary syndromes, which comprises administering a therapeutically effective amount of HUK to patients in need of such therapy.
  • the dosage used for the treatment of acute coronary syndromes can be varied based on many factors, especially the severity of the disease symptoms, the time of beginning the treatment, the age and weight of the patient and so on. Normally, intravenous injection of 0.1 -0.2 PNA unit (PNAU) every time and once or twice daily is advised. The dosage is the same or less than above when it is used for the prevention of acute coronary syndromes.
  • PNAU PNA unit
  • HUK has characteristics of glandular kallidinogenase. It can stimulate the formation of kallidin in blood, and kallidin can be further degraded into bradykinin by kininase. The formation of kinins may account for the longer efficacy of HUK than that of glonoine which is a commonly used drug in ACS but has short half life. Bradykinin can stimulate endothelial cell in blood vessel to release NO, which can interact with heme group of guanylate cyclase (GC) in smooth muscle cell to form NO-heme-GC complex. By this way, GC is activated and a great deal of cellular cGMP is produced, makes the activation of the cGMP-dependent protein kinase.
  • GC guanylate cyclase
  • the calcium-dependant protein phosphorylation occurs and calcium in the cell will be reduced. This leads to the inhibition of phosphorylation of calcium-induced light chain of the muscle globulin and the dilation of blood vessel.
  • NO not only plays an important role for deciding tensile force of blood vessel, but also participates in other mechanisms involved in regulations, such as, inhibiting the adhesion of single nuclear leucocyte and blood platelet, the proliferation of smooth muscle , permeation of blood vessel and inflammation. These regulations can prevent convulsion of blood vessel and formation of thrombus.
  • HUK could be used for therapy of unstable angina and myocardial infarction and the results here indicate that HUK can treat these two forms of ACS.
  • Example 1 Preparation of the lyophilized powder of HUK for injection
  • the components containing 150 PNAU HUK, 7.5 g mannitol, 2g dextran 40, and 5g sodium citrate were mixed and dissolved in water.
  • the pH of the solution was adjusted to neutral and water was added to 500ml of final volume.
  • the solution was then filtered through a 0.22 micron membrane, distributed into 1000 ampule vials as aliquots and freeze-dried ( under sterile conditions. The lyophilized powder for injection was obtained.
  • Example 2 Preparation of the solution of HUK for injection
  • One hundred and fifty PNAU of HUK powder was dissolved in water and adjusted to pH 7.
  • Sodium chloride was added to adjust osmotic pressure, and the solution was made to final volume of 50OmL.
  • the solution was sterilely filtered and distributed to 1000 ampule vials as aliquots.
  • the aqueous solution containing HUK for injection was obtained.
  • Example 3 The effects of HUK on acute myocardial ischemia and oxygen metabolism in experimental dogs
  • the dog models of myocardial ischemia were established by injection of pituitrin to the animals. Among the healthy dogs weighing 10 to 15 kg, half of them are male and another half of them are female. The animals were anesthetized with sodium pentobarbital (30 mg/kg, IP). They were dorsal fixated, intubated endotracheal ⁇ , and ventilated, with a dynamoelectric respirator. Two-lead electrocardiogram (ECG) was recorded. A catheter was inserted into the femoral artery to connect with blood pressure transducer, another catheter was inserted into a femoral vein for drug administration. Heart rate, blood pressure and electrocardiogram were monitored and recorded by eight channel physiological recorder. A catheter was inserted from the left jugular vein into coronary sinus to collect venous blood of heart in specific time; another catheter was inserted into right arteria carotis to collect arterial blood of heart in specific time.
  • ECG electrocardiogram
  • HUK group I injection of HUK(1 .5X10 "3 PNAU) immediately after injection of pituitrin
  • HUK group II injection of HUK(3.0X10 ⁇ 3 PNAU) immediately after injection of pituitrin 5)
  • HUK group III injection of HUK(6.0X10 ⁇ 3 RWAU) immediately after injection of pituitrin
  • Nitroglycerin treatment group injection of nitroglycerin(5mg/kg) immediately after injection of pituitrin
  • the experiment data were started to collect.
  • the electrocardiogram was recorded at the time before the injection and at the following time points: 30 s, 45 s, and 1 , 1 .5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 min after the injection, and simultaneously monitored the change of T waves which had been considered as the standard criteria for measuring myocardial ischemia.
  • the oxygen metabolism was analyzed after the venous and arterial blood of heart were collected at the time before the injection and at 1 , 3, 5, 10, 15 and 30 min after the injection.
  • the statistic analysis was carried out by comparing the data of the same group before and after drug treatment and comparing the results of different animal groups. The statistic difference was determined by t-test.
  • the electrocardiogram was continuously recorded with 30 min of window period after venous injection of pituitrin.
  • the electrocardiogram indicated that T wave increased obviously after injection of pituitrin and the wave of the pituitrin group was notably higher than that of the control group even at 30 min after injection, indicating the animal model of myocardial ischemia were successfully established.
  • the T wave in the pituitrin group was obviously increased at 5 minutes after injection of pitu ⁇ trin( the T wave before administrating drug was considered as 100% ).
  • the T wave was increased even at 30 min after injection of pituitrin (p ⁇ 0.05) , indicating the animals was still in myocardial ischemic state.
  • the venous and arterial blood of the heart were collected at the specific time points before and after drug administration, and the change of oxygen metabolism of myocardium was assayed.
  • the rate of oxygen uptake of animals was significantly increased and the rate of the pituitrin group was higher than that of the control group. This result indicated that the oxygen consumption amount of the pituitrin group was obviously increased and thus the myocardial ischemic model was valid.
  • the oxygen consumption amount of myocardium in the dogs of HUK group I 1 II, III and nitroglycerin treatment group was much lower than that of the dogs of the pituitrin group even though it was not decrease to the level before drug administration.
  • the HUK groups and the nitroglycerin treatment group had similar effect in the decrease of oxygen consumption amount of myocardium (p ⁇ 0.05) .
  • the oxygen consumption amount of myocardium in HUK group I 1 II, III was lower than that of the pituitrin group, and there was statistically significant difference (p ⁇ 0.05) between the kallidinogenase treatment groups and the pituitrin group.
  • the above results showed that HUK can reduce the oxygen consumption amount in the experimental dogs of myocardial ischemia.
  • HUK group I injection of the enzyme (3.85 x 10 ⁇ 3 PNAU) immediately after injection of pituitrin
  • HUK group II injection of the enzyme (8.75 X 1 CT 3 PNAU) immediately after injection of pituitrin
  • HUK group III injection of the enzyme (17.5 X 1 CT 3 PNAU) immediately after injection of pituitrin
  • Nitroglycerin treatment group injection of nitroglycerin (25mg/kg) immediately after injection of pituitrin
  • the drug treatment (the HUK groups and the nitroglycerin treatment group) was injected into the caudal vein immediately after the injection of pituitrin.
  • the rats were anesthetized with 10% chloral hydrate (3m I/kg b. wt, i.p.) and dorsal fixated.
  • the needle electrode was inserted into the rats' limb hypoderm and the sensitivity of cardiograph was adjusted to 1 mv/1 5mm with paper speed 50mm/s to record ECGs.
  • the rats with normal ECGs were selected and sublingual intravenously injected with pituitrin(6.5U/kg) in one minute to create rat models of acute myocardial ischemia.
  • the ECGs were repeatedly recorded at 15s, 30s, 1 min, 2min, 5min and 10min after injection(or recorded at any moment according to abnormal condition of the oscillograph) .
  • the change of S-T segment, T wave level and he " art rate before and after drug administration were measured and compared.
  • HUK group I injection of the enzyme (3.85X10 "3 PNAU)
  • HUK group II injection of the enzyme (8.75X10 "3 PNAU)
  • HUK group III injection of the enzyme (17.5X10 "3 PNAU)
  • the normal ECGs of the rats were recorded one hour after they were anesthetized with 10% chloral hydrate (3m I/kg b. wt, i.p.) .
  • the animal models were prepared by coronary artery ligation using the following procedures. The rats were incised along their left midclavicular middle-line, thorax was opened, and the left coronary artery was ligated in the site of coronary vein between right cone and left atria. The heart was replaced back to the thorax, the incision was stitched, and a respirator was used to assist animal breathe. ECGs were recorded immediately after ligation, and at 1 h, 24h, 48h after ligation.
  • Drugs and physiological saline were intravenously injected to the rat at 24h and 48h after ligation.
  • the brain was removed for blood collection at 5Oh after ligation, the activities of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) in serum were determined.
  • the heart was removed as soon as possible after the brain removal, and it was washed with physiological saline.
  • the blood vessel, fat and other non- myocardial tissues were removed, water was sopped up with clean papers and the wet weight of the entire heart was weighed.
  • Ventricle was separated along coronary channel from atrium and was weighed.
  • Serial ventricular muscle sections ( ⁇ 1 mm thick) were obtained by transversely cutting ventricle myocardium from apex to base alone atrioventricular groove and washed with physiological saline before they were immersed and stained in normal saline containing 0.1 % N-BT solution for 15 minutes at 37 ° C. Water wash was followed up to remove superfluous stain. Whereas the infracted areas were not stained, the areas without infarction were stained with blue, lnfarcted portion was cut off and weighed. The level of myocardial infarct was expressed as the percentage of the wet weight of the infarcted portion to the wet weight of the entire heart. The statistic analysis was performed.
  • T wave and S-T segment in the control group were obviously observed at about 1 5 seconds after injection of pituitrin.
  • the level of T wave and S- T segment in the control group was reached up to 0.45mv and 0.29mv, respectively.
  • the increase of T wave and S-T segment in the HUK group HII and the nitroglycerin treatment group was much lower than that in the control group (p ⁇ 0.01 ).
  • Rats made by coronary artery ligation were used as myocardial ischemic model.
  • the elevation of T wave and S-T segment was significant in the rats of myocardial ischemia. A few of them had slightly different pattern of elevation of T- wave and S-T segment. Their S-T segment initially decreased before it increased. However, their overall pattern of S-T segment and T wave fitted the pattern of ischmia.
  • the elevation of S-T segment in the propranolol group and HUK group I 1 II, III was significantly lower than that of the control group (p ⁇ 0.01 ), but there was no significant difference among the four treatment groups with drug(p>0.05) in term of the elevation of change of S-T segment.
  • arrhythmia After coronary artery ligation, there were animals occurring arrhythmia in every group.
  • the main arrhythmia was ectopic ventricular rhythm , including ventricular premature beats, paroxysmal ventricular tachycardia, and fibrillation. The incidence was higher and the symptom was more severe in the control group than those in other groups.
  • Arrhythmia occurred in 8 out of 10 rats in the control group.
  • Four of eight rats had ventricular fibrillation, and among them , three rats died of ventricular fibrillation and the other one survived after sinus rhythm recovery.
  • P>0.05 the probability of arrhythmia is remarkably lower than that of the control group (p ⁇ 0.01 ).
  • ECGs can reflect the change of myocardial ischemia, particularly the elevation of T wave and S-T segment. After coronary artery ligation, the elevation of S-T segment in animals can be detected . Such change of S-T segment is an important indication for diagnostics of acute myocardial infraction. If a drug can prevent the change of myocardial ischemia, it would be valuable for having the effect of anti- myocardial ischemia.
  • HUK could significantly reduce the elevation of T wave and S-T segment induced by pituitrin or coronary artery ligation, and thus HUK had effect to antagonize myocardial ischemia.
  • the mechanism could be that HUK could dilate blood vessel and increase blood flow.
  • fast heart beating could remarkably decrease the perfusion amount of coronary artery, and this leaded to the reduction of blood flow amount and the increase of myocardial oxygen consumption.

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)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention a pour objet une nouvelle application pharmaceutique de la kallidinogénase de l'urine humaine dans la fabrication d’un médicament pour le traitement prophylactique et/ou thérapeutique de syndromes coronariens aggravés. La présente invention a également pour objet les préparations pharmaceutiques comprenant la kallidinogénase de l’urine humaine au titre de principe actif. Ladite kallidinogénase ainsi que les préparations pharmaceutiques la contenant peuvent être employées efficacement dans le traitement de syndromes coronariens aggravés. Lesdites préparations de kallidinogénase peuvent être employées sous diverses formes galéniques pharmaceutiques, préférentiellement sous forme de poudre sèche ou de solution aqueuse pour injection.
PCT/CN2005/001830 2004-11-03 2005-11-02 Application de la kallidinogénase de l’urine humaine dans la fabrication d’un médicament pour le traitement de syndromes coronariens aggravés WO2006047949A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2004100884403A CN1308035C (zh) 2004-11-03 2004-11-03 人尿激肽原酶在制备急性冠脉疾病药物中的应用
CN200410088440.3 2004-11-03

Publications (1)

Publication Number Publication Date
WO2006047949A1 true WO2006047949A1 (fr) 2006-05-11

Family

ID=34847502

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2005/001830 WO2006047949A1 (fr) 2004-11-03 2005-11-02 Application de la kallidinogénase de l’urine humaine dans la fabrication d’un médicament pour le traitement de syndromes coronariens aggravés

Country Status (2)

Country Link
CN (1) CN1308035C (fr)
WO (1) WO2006047949A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110935015A (zh) * 2019-07-16 2020-03-31 温州医科大学附属第二医院温州医科大学附属育英儿童医院 尤瑞克林在促进缺血超长随意皮瓣存活的作用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108969758B (zh) * 2018-09-07 2020-03-24 广东天普生化医药股份有限公司 人尿激肽原酶在制备治疗血栓闭塞性脉管炎药物中的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1403156A (zh) * 2002-05-13 2003-03-19 广东天普生化医药股份有限公司 人尿激肽原酶在制备治疗和预防脑梗塞药物中的应用
CN1488753A (zh) * 2002-10-11 2004-04-14 中国科学院大连化学物理研究所 一种基因表达人组织激肽释放酶蛋白的分离纯化方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07149661A (ja) * 1993-11-26 1995-06-13 Rooman Kogyo:Kk カリジノゲナーゼ含有外用剤
CN1228447C (zh) * 2001-02-20 2005-11-23 深圳市人民医院 一种含有人胰腺组织激肽释放酶成熟蛋白基因的重组表达载体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1403156A (zh) * 2002-05-13 2003-03-19 广东天普生化医药股份有限公司 人尿激肽原酶在制备治疗和预防脑梗塞药物中的应用
CN1488753A (zh) * 2002-10-11 2004-04-14 中国科学院大连化学物理研究所 一种基因表达人组织激肽释放酶蛋白的分离纯化方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
LI H. ET AL: "Kallikrein and its Clinical Applications", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 24, no. 5, 1993, pages 283 - 286 *
WANG F. ET AL: "A Novel Method for Isolation of Human Urinary Kallikrein", JOURNAL OF YUNNAN INSTITUTE OF THE NATIONALITIES (NATURAL SCIENCE EDITION), vol. 5, no. 2, October 1996 (1996-10-01), pages 40 - 42 *
WANG J. ET AL: "The Purification and Identification of Human Urinary Kallikrein", PROG. BIOCHEM. BIOPHYS., vol. 30, no. 5, 2003, pages 772 - 777 *
WANG T. ET AL: "Advances in research on kallikrein-kinin system in cardiovascular system", CHIN J PHARMACOL TOXICOL, vol. 17, no. 6, December 2003 (2003-12-01), pages 466 - 470 *
ZHAN J.: "Character and Clinical Practice of Kallikrein", JOURNAL OF HANSHAN TEACHERS COLLEGE, no. 3, August 1996 (1996-08-01), pages 109 - 113 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110935015A (zh) * 2019-07-16 2020-03-31 温州医科大学附属第二医院温州医科大学附属育英儿童医院 尤瑞克林在促进缺血超长随意皮瓣存活的作用

Also Published As

Publication number Publication date
CN1308035C (zh) 2007-04-04
CN1634575A (zh) 2005-07-06

Similar Documents

Publication Publication Date Title
US5760081A (en) Omega 3 fatty acids in the prevention of ventricular fibrillation
TWI508726B (zh) 治療心房纖維性顫動之方法
CA2061270C (fr) Methode et appareil pour traiter les blessures de reperfusion
JP2002540144A (ja) 心血管及び関連病理学治療のためのピリドキシン化合物の使用
US5280038A (en) Histidine as a protective agent in cardiac surgery and myocardial ischemic syndrome
WO2006002549A1 (fr) Polytherapies faisant intervenir des inhibiteurs d'agregation plaquettaire
KR0156597B1 (ko) 허혈 및 재관류로 인한 조직 손상 개선용 조성물
SU1183112A1 (ru) Способ лечени острой ишемии миокарда
AU2012340670B2 (en) Cysteamine and/or cystamine for treating ischemic injury
US4978668A (en) Treatment to reduce ischemic tissue injury
JPH09501946A (ja) 急性心筋梗塞中の心筋傷害の低減方法
WO1993006833A1 (fr) Utilisation de composes de aica ribosides pour le traitement et la prevention de dommages de tissus dus a une diminution de l'ecoulement sanguin
JPS60109524A (ja) 抗血栓剤
WO2006047949A1 (fr) Application de la kallidinogénase de l’urine humaine dans la fabrication d’un médicament pour le traitement de syndromes coronariens aggravés
EP0483614B1 (fr) Utilisation des amino acides pour la protection et le rétablissement métabolique du tissu cardiaque ischémique
Conen et al. Pharmacologic profile of trandolapril, a new angiotensin-converting enzyme inhibitor
JP2535504B2 (ja) 選択的冠血管拡張剤
EP2837380A1 (fr) Préparation composée constituée de chlorhydrate de lercanidipine et de losartan potassique et son procédé de préparation
KANEKO et al. New Theory on the Pathogenesis of Acute Myocardial Infarction: SYMPOSIUM ON PATHOGENESIS OF MYOCARDIAL INFARCTION: 49th Annual Scientific Session of Japanese Circulation Society
Griffith et al. Heparin versus heparin-bishydroxycoumarin anticoagulant therapy: comparison in patients with acute complicated myocardial infarction
MacLennan et al. High dose intravenous streptokinase in acute myocardial infarction--short and long term prognosis.
CA2402645A1 (fr) Modulation de lesion cardio-vasculaire
Johansson et al. Adrenaline-induced changes in serum electrolytes, ECG, and blood pressure, with Ca-blockade pretreatment
JPS6379831A (ja) １，４−ジビドロピリジン誘導体およびアシル化１，２，３，４−テトラヒドロイソキノリン−３−カルボン酸を含有する医薬組成物
Wizemann et al. Cardiac arrhythmias in end-stage renal disease: Prevalence, risk factors, and management

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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: 05801913

Country of ref document: EP

Kind code of ref document: A1