CN1308035C - Application of human urine kininogenase for preparing medicine to treat acute coronary syndromes - Google Patents
Application of human urine kininogenase for preparing medicine to treat acute coronary syndromes Download PDFInfo
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- CN1308035C CN1308035C CNB2004100884403A CN200410088440A CN1308035C CN 1308035 C CN1308035 C CN 1308035C CN B2004100884403 A CNB2004100884403 A CN B2004100884403A CN 200410088440 A CN200410088440 A CN 200410088440A CN 1308035 C CN1308035 C CN 1308035C
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- 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)
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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Abstract
The present invention relates to a medical purpose of kininogenase of human urine for treating acute coronary artery diseases and a medical composition prepared by the method. The kininogenase of human urine of the present invention has significant curative effect on the acute coronary artery diseases, and the medical composition is usually prepared into freeze-dried powder injections or injection solution to be used.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field.Particularly, the present invention relates to Human Urinary Kallidinogenase's novel medical use, i.e. the application of Human Urinary Kallidinogenase in preparation treatment acute coronary disease medicament.
Background technology
Cardiovascular disease has become the No.1 killer of 21 century human health, and that wherein dangerous is acute coronary syndrome (ACS).ACS comprises unstable angina and acute myocardial infarction.Statistics shows that the whole world has 1,700 ten thousand people to die from cardiovascular disease every year, wherein over halfly dies from acute myocardial infarction.
Human Urinary Kallidinogenase (Human Urinary Kallidinogenase), be from the healthy male Urina Hominis, to extract purified glycoprotein, about 54000 dalton of molecular weight, have and activate the human plasma kininogen and be converted into kassinin kinin, blood vessel dilating blood flow increasing, improve sanguimotor effect, and increase the effect that erythrocytic morphotropism and anticoagulant, prolongation recalcification time improve hyperlipidemia in addition.The applicant's patent application formerly " application of 02116783.4 Human Urinary Kallidinogenase in preparation treatment and prevention of brain infraction medicine " discloses its a kind of medical usage.The inventor is through conscientiously research and animal experiment prove that the Human Urinary Kallidinogenase has the obvious treatment effect to the acute coronary disease.
Unstable angina is rapid temporary transient ischemia and the caused clinical disease of anoxia of cardiac muscle.Acute myocardial infarction is because coronary atherosclerosis, thrombosis or coronary artery continue spasm, makes coronary artery or branch obturation, causes cardiac muscle to necrose because of lasting hypoxic-ischemic.Improve heart blood supply as soon as possible, improve the blood circulation of coronary artery system, improve the oxygen confession of myocardial cell, the load and the myocardial oxygen consumption that reduce heart are present general clinically Therapeutic Principle.Be the buccal nitroglycerine tablets to the most effective Disposal Measures of angina pectoris attacks at present, and nitroglycerin is quick-acting but fugitive feature, can not satisfy anginal treatment.
Summary of the invention
The purpose of this invention is to provide the purposes that the Human Urinary Kallidinogenase is used for the treatment of the acute coronary disease, promptly be used to prepare the purposes of the medicine for the treatment of the acute coronary disease.Another object of the present invention provides a kind of pharmaceutical composition that contains the Human Urinary Kallidinogenase that is used for the treatment of the acute coronary disease.
Human Urinary Kallidinogenase of the present invention has the obvious treatment effect to the acute coronary disease, generally uses with the form of pharmaceutical composition.This compositions contains the Human Urinary Kallidinogenase and the pharmaceutically acceptable auxiliaries as active component for the treatment of effective dose, and main dosage form comprises lyophilized injectable powder and injection liquor, usually with the intravenous injection administration.
Through Human Urinary Kallidinogenase's compositions of intravenous administration, generally be solid sterilization composition form.These compositionss can also contain additive, particularly mannitol, dextran, gelatin hydrolysate, sodium citrate, glycine etc.Be dissolved in use in sterilized water for injection or other injection sterile medium.
Human Urinary Kallidinogenase's compositions through intravenous administration also can be the aqueous solution form.Compositions can also contain additive, particularly mannitol, sodium chloride, glucose etc.
The dosage of Human Urinary Kallidinogenase's combination treatment acute coronary disease was decided according to the order of severity, the treatment time of the state of an illness, the general each 0.1-0.2PNA unit of intravenous administration, and every day, administration was 1-2 time.
The Human Urinary Kallidinogenase has gland kininogenase feature, promotes kallidins to generate in blood, and the latter is converted into Kallidin I again.Human Urinary Kallidinogenase's effect is longer than the reason of nitroglycerin in following experiment, and conversion process is relevant therewith.Kallidin I can stimulate vascular endothelial cell to discharge NO, NO combines with the heme group (heme) of guanylate cyclase (GC) in the smooth muscle cell, form the NO-heme-GC complex, GC is activated, cause producing a large amount of cGMP in the cell, activate the cGMP deopendent protein kinase, make the intracellular signal transduction protein phosphorylation of many Ca-dependents, intracellular Ca2+ reduces, thereby suppresses the myosin light chain phosphorylation of calcium mediation, makes vasodilation.NO is not only playing a significant role aspect the decision antiotasis, and participates in many other regulatory mechanisms, as inhibition monocyte and platelet adhesion, and the propagation of vascular smooth muscle, vascular permeability and inflammation mechanism etc., thus prevent vasospasm and thrombosis.
The specific embodiment
The invention will be further described by the following examples.
Embodiment 1 preparation Human Urinary Kallidinogenase dry powder pin
Get the Human Urinary Kallidinogenase 150PNA unit of filtration sterilization, add 7.5 gram mannitol, 2 gram Dextran 40s, 5 gram sodium citrate dissolvings, regulate PH to neutral, add injection water to 500 milliliter, aseptic filtration is in 1000 ampoules of packing, lyophilization under the aseptic condition, promptly.
Embodiment 2 preparation Human Urinary Kallidinogenase injection
Get the water-soluble 150PNA unit of Human Urinary Kallidinogenase of filtration sterilization, regulate PH to neutral, add injection water to 500 milliliter, add sodium chloride adjusting etc. and ooze, aseptic filtration is in 1000 ampoules of packing, promptly.
Embodiment 3 Human Urinary Kallidinogenases are to the influence of dog expeirmental myocardial ischemia and myocardium oxygen metabolism
Experimental technique
With injection of pituitrin manufactured myocardial infarction and ischemia model.Select 24 of the healthy domesticated dogs of 10～15kg for use, male and female half and half are divided into 6 groups at random: blank group (normal saline); Pituitrin group (3U/kg); Human Urinary Kallidinogenase I group (1.5 * 10
-3PNAu); Human Urinary Kallidinogenase II group (3 * 10
-3PNAu); Human Urinary Kallidinogenase III group (6 * 10
-3PNAu); Nitroglycerin treatment group (5mg/kg).Pituitrin 3U/kg is slow intravenous injection in 1 minute, the intravenous injection immediately behind injection of pituitrin of each dose drug of Human Urinary Kallidinogenase and nitroglycerin.
With pentobarbital sodium 30mg/kg intravenous injection anesthesia, back of the body position is fixing, and tracheotomy and intubate connect electric pulmotor and practice artificial respiration.Trace two lead electrocardiogram, femoral arteriography connects blood pressure transducer, and femoral venous catheter is used for injection.Blood pressure, heart rate and electrocardiogram connect eight road physiology monitor monitoring and records.From left side external jugular vein intubate to coronary sinus vein, timing acquiring cardiac veins blood; The right carotid intubate, timing acquiring heart arter blood.
Observation index
Animal surgery is finished and is observed each physical signs and promptly begins experiment after steadily.Before injectable drug and injection after 30 seconds, 45 seconds, 1 minute, 1 minute 30 seconds, 2 minutes, traced electrocardiogram in 2 minutes 30 seconds, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, measure the variation of T ripple, with its standard as the judgement myocardial ischemia.Simultaneously, before injectable drug, gathered heart arteriovenous blood in 1 minute, 3 minutes, 5 minutes, 10 minutes, 15 minutes and 30 minutes after the injection and carry out blood gas analysis.Compare between each index is organized and before and after self, judge its significance of difference with the t check.
Experimental result
1. the Human Urinary Kallidinogenase is to the therapeutical effect of domesticated dog acute myocardial ischemia
Trace 30 minutes electrocardiograms behind the intravenous injection pituitrin continuously.The result shows, injection back T ripple promptly obviously increases and lasts till always and still was higher than matched group in 30 minutes, illustrates that this model is reliable.Adopt the Human Urinary Kallidinogenase to carry out observation of curative effect then, and contrast with nitroglycerin, as seen the pituitrin group was injected back 5 minutes, ECG T wave wave amplitude obviously raise (is 100% to calculate with T wave number before the administration), with the matched group ratio highly significant difference (P＜0.01) is arranged, inject back 30 minutes T wave numbers still raise (P＜0.05).Four treatment group injectable drug amplitudes that the T ripple raises after 5 minutes all obviously reduce (P＜0.05), especially reduce the most obvious with Human Urinary Kallidinogenase III group.After the vein injection 30 minutes, the T ripple of pituitrin group still than raising (P＜0.05) before the injection, as seen still is in myocardial ischemia.Human Urinary Kallidinogenase I, II, III group compare with the pituitrin group, and the T wave number descends to some extent, and all there were significant differences (P＜0.05).Though and nitroglycerin group T wave number descends, and does not relatively have significant difference (P＞0.05) with the pituitrin group.
2. the Human Urinary Kallidinogenase is to the influence of acute myocardial ischemia dog heart arteriovenous vim and vigour and myocardium oxygen metabolism
Experimental dog is gathered heart arteriovenous blood in required time before and after injection, observe the variation of vim and vigour and myocardium oxygen metabolism.Behind the injection of pituitrin, the oxygen uptake rate of heart significantly improves than matched group, illustrates that pituitrin group myocardial oxygen consumption significantly increases, and proves that this model is successful.Utilize this model injection Human Urinary Kallidinogenase I, three dosage of II, III group and nitroglycerin 5 minutes,, relatively significantly reduce with the pituitrin group though the myocardial oxygen consumption of each treatment group fails to drop to the oxygen consumption level before the matched group injection.Human Urinary Kallidinogenase's group is similar with nitroglycerin treatment group, the effect (P＜0.05) of remarkable reduction myocardial oxygen consumption is arranged, and action effect is very close.Human Urinary Kallidinogenase I, II, III group reduce than pituitrin group to some extent at the myocardial oxygen consumption of injection after 30 minutes, and statistical significance (P＜0.05) is arranged, and nitroglycerin relatively there is not significant difference (P＞0.05) in the myocardial oxygen consumption and the pituitrin group of injection after 30 minutes.
This experiment shows that the Human Urinary Kallidinogenase has protective effect to expeirmental myocardial ischemia, can reduce the oxygen consumption of ischemic myocardium.
Embodiment 4 Human Urinary Kallidinogenases are to the influence of rat experiment myocardial ischemia
Experimental technique
1. the Human Urinary Kallidinogenase is to the influence of Acute Myocardial Ischemia in Rats due to the pituitrin
Select 60 of healthy rats for use, be divided into 6 groups at random: blank group (normal saline) by body weight; Pituitrin group (6.5U/kg); Human Urinary Kallidinogenase I group (3.85 * 10
-3PNAu); Human Urinary Kallidinogenase II group (8.75 * 10
-3PNAu); Human Urinary Kallidinogenase III group (17.5 * 10
-3PNAu); Nitroglycerin group (25mg/kg).Each dose drug tail vein injection immediately behind injection of pituitrin.Rats by intraperitoneal injection 10% chloral hydrate 3ml/kg anesthesia, it is fixing to lie on the back, it is subcutaneous that needle electrode is inserted extremity, and regulate electrocardiogram sensitivity to 1mv=15mm, chart speed is 50mm/s, record II leads electrocardiogram, select the electrocardiogram intact animal to carry out tongue intravenous injection pituitrin (6.5U/kg) and cause myocardial infarction and ischemia model, injection speed is 1min, carries out 15s, 30s, 1min, 2min, 5min, 10min duplicate record electrocardiogram (can write down at any time according to oscillograph finding abnormal conditions) after the injection immediately.After experiment finishes, measure the variation of comparing administration forward and backward stipulated time S-T section and T wave height and heart rate.
2. the Human Urinary Kallidinogenase is to the influence of Acute Myocardial Ischemia in Rats due to the ligation coronary artery
Get 50 of the female Sexual health Wistar rats of body weight 200g ± 40g, be divided into 5 groups at random by body weight: ischemic control group (normal saline); Propranolol group (5mg/kg); Human Urinary Kallidinogenase I group (3.85 * 10
-3PNAu); Human Urinary Kallidinogenase II group (8.75 * 10
-3PNAu); Human Urinary Kallidinogenase III group (17.5 * 10
-3PNAu).1h lumbar injection 10% chloral hydrate 3ml/kg anesthesia after administration, the record normal ECG.Along left mid-clavicular line stringer otch, open the thoracic cavity, behind ligation left coronary artery in Coronary vein place between right side of heart circular cone and the left auricle, heart is put back to the thoracic cavity, stitching is closed, the respirator assisted respiartion.After the ligation at once, 1h, 24h, 48h trace one section electrocardiogram respectively, and respectively organize medicine and normal saline in 24h, 48h intravenous injection.Broken end is got blood behind coronary ligation 50h, measures serum CPK, LDH, and takes out heart rapidly after broken end is got blood, uses normal saline flushing, removes blood stains, rejects non-cardiac muscular tissues such as blood vessel, fat, inhales the branch that anhydrates with absorbent paper, claims weight in wet base whole-heartedly.Along coronary sulcus excision atrium, stay ventricle, weigh, along coronary sulcus from the apex of the heart to heart base portion 4 of parallel myocardium sheets with ventricular muscles crosscut Cheng Houyue 0.1cm, clean with normal saline flushing, myocardium sheet is placed in 0.1% the N-BT solution, 15min, water flush away excess dyestuff immediately dye under 37 ℃ of water bath condition.Infarcted region is not painted, and non-infarcted region is dyed blueness by N-BT solution.Cut off infarcted myocardium, claim weight in wet base, account for whole-heartedly the percentage ratio of weight in wet base with the infarcted region weight in wet base and represent myocardial infarct size.
Experimental result
1. the Human Urinary Kallidinogenase causes the influence that S-T section, T ripple change to pituitrin
Matched group involves the ST section in injection of pituitrin 15S left and right sides T to be raised the most obviously, and the T ripple reaches as high as 0.45mv, the S-T section reaches as high as 0.29mv, shows that Model Rats with Acute Myocardial Ischemia is successful.Human Urinary Kallidinogenase I, II, III group and nitroglycerin group T ripple, S-T section are raised amplitude and significantly are lower than matched group level (P＜0.01); Human Urinary Kallidinogenase I group act as poor (P＜0.05) than nitroglycerin, and Human Urinary Kallidinogenase II, III group similar to the effect of nitroglycerin group (P＞0.05).
2. the Human Urinary Kallidinogenase is to the Electrocardiographic influence of coronary artery ligation rats with myocardial ischemia
The ligation rat coronary artery causes ischemia model, lifts on the visible ST section back of a bow, and the T ripple is towering gradually; Lift on again after minority animal foreknowledge ST section moves down, whole ischemic stage ischemic ST-T change highly significant.Propranolol group, Human Urinary Kallidinogenase I, II, III group ST section are raised and significantly are lower than model group (P＜0.01), but do not have significant difference (P＞0.05) between each group.
3. the Human Urinary Kallidinogenase is to the influence of coronary artery ligation rats with myocardial ischemia arrhythmia and survival rate
Each treated animal all has arrhythmia person behind the ligation arteria coronaria, based on chamber property ectopic cardiac rhythm, comprises ventricular premature contraction, paroxysmal ventricular tachycardia and Fibrillation, and is wherein high and serious with blank group incidence rate.There are 8 arrhythmia takes place in 10 animals of blank group.Wherein have 4 chambers of appearance to quiver, have only 1 to recover sinus rhythm and continue survival, all the other 3 all the chamber of dying from quiver, 4 treated animal incidence of arrhythmia are starkly lower than blank group (P＜0.01) in addition.Each group of its survival rate is compared no significant difference (P＞0.05).
4. the Human Urinary Kallidinogenase is to the influence of coronary artery ligation rats with myocardial ischemia myocardial infarct size
Propranolol group, Human Urinary Kallidinogenase I, II, III group all can obviously be dwindled rat myocardium block scope (P＜0.05), wherein the Propranolol group is better than Human Urinary Kallidinogenase I, II group (P＜0.05), with Human Urinary Kallidinogenase III group no significant difference (P＞0.05).
5. the Human Urinary Kallidinogenase is to the influence of serum paraoxonase creatine acid creatase (CPK) and lactic acid dehydrogenase (LDH)
Propranolol group, Human Urinary Kallidinogenase I, II, III organize behind rat ligation arteria coronaria, and its serum CPK and LDH all are starkly lower than matched group (P＜0.01), but no significant difference (P＞0.05) between each group.
Discuss
Creatine phosphokinase in the cardiac muscle (CPK) and lactic acid dehydrogenase (LDH) when myocardial infarction because of ischemia after membrane damage discharge human blood, can be used as the index of observing myocardial ischemia.Originally experiment showed, that serum CPK and LDH content that the Human Urinary Kallidinogenase organizes behind the rat ligation arteria coronaria are starkly lower than model group, but prompter's urinary kallidinogenase protecting myocardial cell; increase its anti-hypoxic-ischemic ability; improve the stability of film, CPK, the LDH minimizing of overflowing, myocardial infarct size dwindles.
Pituitrin can make coronary vasospasm, causes acute blood supply insufficiency; In addition Peripheral resistance increases, and causes cardiac load to increase the weight of, and can see myocardial ischemia and change on electrocardiogram, is mainly that the T ripple is raised, the S-T section is lifted high or low flat.When ligation animal arteria coronaria, electrocardiogram S-T section is raised and also is an important indicator of diagnosing acute myocardial infarction.Medicine just is considered to the value that resists myocardial ischemia if can prevent this myocardial ischemia changes.Experiment showed, that originally but the T ripple that Human Urinary Kallidinogenase's antagonism pituitrin causes is raised, the S-T section is raised, the ST section that raises behind the ligation rat arteria coronaria is obviously reduced, thereby function of resisting myocardial ischemia is arranged.Its mechanism may be by coronary artery dilator, and increase coronary flow etc. plays a role.
Dwindle that infarction size is a leading indicator of estimating the medicaments for resisting myocardial ischemia curative effect after the myocardial infarction.This experiment NBT substantially specimen staining measures the heart infarction scope, and confirmer's urinary kallidinogenase can obviously dwindle the myocardial infarct size of acute myocardial ischemia due to the ligation rat arteria coronaria, shows that the Human Urinary Kallidinogenase has function of resisting myocardial ischemia.
Claims (6)
1. the Human Urinary Kallidinogenase is preparing the purposes for the treatment of in the acute coronary disease medicament.
2. purposes according to claim 1, the dosage of wherein said medicine are administration every day 1-2 times, each 0.1-0.2PNA unit.
3. purposes according to claim 2, wherein said medicine is a lyophilized injectable powder.
4. purposes according to claim 2, wherein said medicine is an injection.
5. purposes according to claim 3, wherein said medicine also contains the additive that is selected from mannitol, dextran, gelatin hydrolysate, sodium citrate or glycine.
6. the described purposes of claim 4, wherein said medicine also contains the additive that is selected from mannitol, sodium chloride or glucose.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100884403A CN1308035C (en) | 2004-11-03 | 2004-11-03 | Application of human urine kininogenase for preparing medicine to treat acute coronary syndromes |
| PCT/CN2005/001830 WO2006047949A1 (en) | 2004-11-03 | 2005-11-02 | The use of human urinary kallidinogenase for the manufacture of a medicine for the treatment of acute coronary syndromes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100884403A CN1308035C (en) | 2004-11-03 | 2004-11-03 | Application of human urine kininogenase for preparing medicine to treat acute coronary syndromes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634575A CN1634575A (en) | 2005-07-06 |
| CN1308035C true CN1308035C (en) | 2007-04-04 |
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| CNB2004100884403A Active CN1308035C (en) | 2004-11-03 | 2004-11-03 | Application of human urine kininogenase for preparing medicine to treat acute coronary syndromes |
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| CN (1) | CN1308035C (en) |
| WO (1) | WO2006047949A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108969758B (en) * | 2018-09-07 | 2020-03-24 | 广东天普生化医药股份有限公司 | Application of human urinary kallidinogenase in preparing medicine for treating thromboangiitis obliterans |
| CN110935015A (en) * | 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 | Function of ulirelilin in promoting survival of ischemic overlong random skin flap |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07149661A (en) * | 1993-11-26 | 1995-06-13 | Rooman Kogyo:Kk | Kallidinogenase-containing external preparation |
| CN1384199A (en) * | 2001-02-20 | 2002-12-11 | 深圳市人民医院 | Recombinant expression vector expressing human pancreatic tissue kallikrein gene and prepn of human pancreatic tissue kallikrein |
| CN1403156A (en) * | 2002-05-13 | 2003-03-19 | 广东天普生化医药股份有限公司 | Application of human urokininogenase in preparing medicine for preventing and treating cerebral infraction |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294256C (en) * | 2002-10-11 | 2007-01-10 | 中国科学院大连化学物理研究所 | Gene-expressed human tissue kallikrein protein separating and purifying method |
-
2004
- 2004-11-03 CN CNB2004100884403A patent/CN1308035C/en active Active
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2005
- 2005-11-02 WO PCT/CN2005/001830 patent/WO2006047949A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07149661A (en) * | 1993-11-26 | 1995-06-13 | Rooman Kogyo:Kk | Kallidinogenase-containing external preparation |
| CN1384199A (en) * | 2001-02-20 | 2002-12-11 | 深圳市人民医院 | Recombinant expression vector expressing human pancreatic tissue kallikrein gene and prepn of human pancreatic tissue kallikrein |
| CN1403156A (en) * | 2002-05-13 | 2003-03-19 | 广东天普生化医药股份有限公司 | Application of human urokininogenase in preparing medicine for preventing and treating cerebral infraction |
Non-Patent Citations (4)
| Title |
|---|
| 人尿激肽原酶的纯化与鉴定 汪炬，生物化学与生物物理进展，第30卷第5期 2003 * |
| 人尿激肽原酶的纯化与鉴定 汪炬，生物化学与生物物理进展，第30卷第5期 2003;人尿激肽原酶的纯化与鉴定 汪炬等，生物化学与生物进展，第30卷第5期 2003;心绞痛发生机制的新看法 刘凡，国外医学生理，病理科学与临床分册，第20卷第1期 2000 * |
| 人尿激肽原酶的纯化与鉴定 汪炬等，生物化学与生物进展，第30卷第5期 2003 * |
| 心绞痛发生机制的新看法 刘凡，国外医学生理，病理科学与临床分册，第20卷第1期 2000 * |
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| Publication number | Publication date |
|---|---|
| WO2006047949A1 (en) | 2006-05-11 |
| CN1634575A (en) | 2005-07-06 |
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