CN1706493A - Application of human urokinase-type peptidase in preparing medicine for treating pulmonary hypertension - Google Patents
Application of human urokinase-type peptidase in preparing medicine for treating pulmonary hypertension Download PDFInfo
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- CN1706493A CN1706493A CN 200410088439 CN200410088439A CN1706493A CN 1706493 A CN1706493 A CN 1706493A CN 200410088439 CN200410088439 CN 200410088439 CN 200410088439 A CN200410088439 A CN 200410088439A CN 1706493 A CN1706493 A CN 1706493A
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- urinary kallidinogenase
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Abstract
The present invention relates to the application of human urokinase-type peptidase in preparing medicine for treating pulmonary hypertension and the medicine composition prepared on the method. The human urokinase-type peptidase of the present invention has obvious treating effect on pulmonary hypertension, and the medicine composition is normally compounded into freeze powder for injection or injection liquid.
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, promptly the Human Urinary Kallidinogenase treats and/or prevents application in the pulmonary hypertension disease drug in preparation.
Background technology
(Pulmonary Artery Hypertension PAH) is meant that mean pulmonary arterial pressure is higher than 2.67kPa (20mmHg) or is higher than 4.00kPa (30mmHg) when motion when tranquillization to hypertensive pulmonary vascular disease.But the neonate in birth 2 weeks of back, the comparable above-mentioned numerical value of normal lung arterial pressure is high.Broad sense, pulmonary hypertension not only refer to the rising of pulmonary artery pressure, no matter pulmonary artery pressure surpass normal, still arteriovenous pressure reduction rising, or pulmonary vascular resistance exceeds normal range and all can point out pulmonary hypertension.Pulmonary hypertension comprises the special property sent out pulmonary hypertension, Secondary cases pulmonary hypertension, three kinds of situations of pulmonary veno-occlusive disease.1. the special property pulmonary hypertension of sending out may be owing to due to following several reasons: the lung small artery thromboembolism of congenital lung small artery hypoplasia, multifactor lung blood vessel contracture, outbreak repeatedly, autoimmune, multiple pulmonary infarction, familial pulmonary hypertension etc.2. the Secondary cases pulmonary hypertension can be owing to due to following several reasons: heart disease, respiratory disorders such as obstructive airway disorders, pulmonary parenchyma disease, pulmonary vascular disease, neuromuscular disease.3. pulmonary veno-occlusive disease can be by due to following several reasons: occupying lesion, tuberculosis, sarcoidosis, fibrosis mediastinitis etc.
Hypoxic Pulmonary Hypertension in Rats is that multiple disease such as infantile pneumonia, chronic pulmonary heart disease, respiratory distress syndrome takes place, the important pathophysiological link of development.The alveolar anoxia all can cause pulmonary vascular contractile response due to a variety of causes, increases pulmonary vascular resistance, thereby causes serious pulmonary hypertension.During chronic hypoxia, the lung small artery is in contraction state for a long time, can cause lung tunica media smooth muscle hypertrophy, and sclerosis of blood vessels forms stable pulmonary hypertension.Erythrocytosis due to the anoxia, blood viscosity increase and pulmonary circulation in the formation of microthrombus, also can increase pulmonary vascular resistance.Pulmonary hypertension can increase the resistance that right ventricle is penetrated blood, causes right ventricular hypertrophy, even heart failure.
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.Also be used to improve lower limb circulation clinical research report relevant for the Human Urinary Kallidinogenase.The inventor is through conscientiously research and animal experiment prove that the Human Urinary Kallidinogenase has obvious treatment and/or preventive effect to pulmonary hypertension.
Summary of the invention
The purpose of this invention is to provide that the Human Urinary Kallidinogenase is used for the treatment of and/or the purposes of prophylaxis of pulmonary hypertension disease, promptly be used to prepare the purposes of the medicine that treats and/or prevents pulmonary hypertension.Another object of the present invention provides a kind of being used for the treatment of and/or the pharmaceutical composition that contains the Human Urinary Kallidinogenase of prophylaxis of pulmonary hypertension.
Human Urinary Kallidinogenase of the present invention has the obvious treatment effect to pulmonary hypertension, and tangible preventive effect is also arranged, and 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 and/or prophylaxis of pulmonary hypertension 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, every day 1-2 time.
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 effect of dog acute anoxia pulmonary hypertension
Experimental technique
Select the common hybrid dog of body weight 10～16kg, anesthesia, is interrupted low dose of intravenous injection again and is kept first in intraperitoneal injection (30mg/kg) with 3% pentobarbital sodium in the test.Circulation of qi promoting cannula in dog anesthesia back connects respirator, and (Gould 5F), joins with pressure monitor and monitor after waiting to reach pulmonary artery to insert the thermodilution method float catheter from right external jugular vein; Again respectively at right strand of arteriovenous inlying catheter and connect the pressure monitor or vein continues infusion normal saline (100ml/h).Employing thermodilution method per injection normal saline 5ml mensuration cardiac output (CO, L/min).
After finishing above-mentioned animal preparation, arterial blood gas and every hemodynamic index when record is ventilated with air earlier contrast as the basis, then fraction of inspired oxygen is adjusted to 10%, ventilation 10min, when 10min, repeat said determination and contrast as anoxia, and from femoral artery and pulmonary artery get respectively blood 4ml (in add EDTA-Na
24mg) be equipped with survey.After this stop anoxia, fraction of inspired oxygen is transferred to 21%, treat that every hemodynamics and vim and vigour index return to base state after, inject medicine from right atrium, after injection at once, carry out hypoxia test 10min during 20min more respectively, each hypoxia test is all with identical and get blood survey fully first.Blood sample medium vessels active substance such as Angiotensin II (AT II) thromboxane TXA
2And prostacyclin PGI
2(measure its stable metabolite TXB
2And 6-Keto-PGF
1a) mensuration adopt the radioimmunity medicine box.With automatic γ calculating instrument and liquid scintillation instrument detection automatically.
Compare between each index is organized and before and after self, judge its significance of difference with the t check.
The experiment grouping: 20 of common hybrid dogs, the male and female dual-purpose is divided into 5 groups at random, 4 every group.
1. model control group
2.L-the arginine group, 3.5g/kg
3. Human Urinary Kallidinogenase I organizes, and the Human Urinary Kallidinogenase 1.5 * 10
-3PNAu
4. Human Urinary Kallidinogenase II organizes, and the Human Urinary Kallidinogenase 3 * 10
-3PNAu
5. Human Urinary Kallidinogenase III organizes, and the Human Urinary Kallidinogenase 6 * 10
-3PNAu
Experimental result
The model control group animal is behind anoxia 10min, and mean pulmonary arterial pressure (mPAP), femoral artery mean pressure (mBP) pulmonary vascular resistance (PVR), systemic vascular resistance (SVR) etc. are all than obviously raise before the anoxia (P＜0.01).MPAP and mBP when the L-arginine can significantly reduce the dog acute anoxia.After the medication 10 and 30min, its mPAP descends 0.61 ± 0.19 or 0.65 ± 0.24kPa respectively; And mBP 30min after medication descends and to reach matched group before 1.85 ± 0.51, two indexs and the medication more all there were significant differences (P＜0.05).Though PVR and SVR decrease not statistically significant before than medication.The cardiac output (CO) of L-arginine during to the dog acute anoxia do not have obviously influence.
Human Urinary Kallidinogenase I, II, III group all can obviously reduce anoxia animal mPAP and mBP level, with before the anoxia and matched group relatively, after the medication 10 and 30min all there were significant differences (P＜0.05), and effect is dose dependent.After the medication of Human Urinary Kallidinogenase II, III group 10 and 30min can also reduce PVR and SVR, and statistical significance (P＜0.05) is arranged more also before the ischemia, cardiac output (CO) has reduction slightly, but not statistically significant (P＞0.05).
Model control group anoxia prerolandic artery Rolando blood AT II content (ng/L) is 72.5 ± 6.9, and raising behind the anoxia 10min is 183.6 ± 31.5; TXB after the anoxia
2Content also significantly rises, and prostacyclin is stablized metabolite 6-Keto-PGF
1aContent but reduces, with more all there were significant differences before the anoxia (P＜0.05).L-arginine treatment group AT II content and TXB
2Content and model control group more all have reduction, but not statistically significant (P＞0.05); 6-Keto-PGF
1aMore then there were significant differences for content and model control group (P＜0.05).
After the medication of Human Urinary Kallidinogenase I, II, III group 10 and 30min all can reduce anoxia animal AT II content and TXB
2Content, but only Human Urinary Kallidinogenase III group relatively there were significant differences (P＜0.05) with model control group.After three dosage medications of Human Urinary Kallidinogenase 10 and the 30min 6-Keto-PGF that all can effectively raise
1aContent, relatively there were significant differences (P＜0.05) with model control group.The result shows, the Human Urinary Kallidinogenase can reduce TXA after the anoxia
2/ PGI
2Ratio, the pulmonary artery that diastole is shunk.
Conclusion
This experimental result shows, the mean pulmonary arterial pressure when L-arginine and Human Urinary Kallidinogenase can significantly reduce the anesthetized dog acute anoxia, and prompting NO participates in regulating the acute anoxia compressive reaction of whole animal, and the generation of NO increases can suppress HPV.The Human Urinary Kallidinogenase can promote the generation of the NO of pulmonary, therefore can reduce the lung antiotasis, reduces pulmonary artery pressure.The Human Urinary Kallidinogenase has the good curing effect to the acute anoxia pulmonary hypertension.
Embodiment 4 Human Urinary Kallidinogenases are interrupted the effect of Hypoxic Pulmonary Hypertension in Rats to rat chronic
Experimental technique
Use the hypoxia cabin and set up anaerobic environment.Inflated with nitrogen in the cabin, and regulate nitrogen flow and wake air mass flow makes that oxygen concentration remains on 10 ± 0.5% in the cabin, and the cabin internal gas pressure equates with atmospheric pressure.Other that will be except that the normal control group respectively organized rat and placed in the normal pressure low oxygen cabin, continues anoxia 8h every day, and 6 days weekly, totally 5 weeks.Each medication group rat advances tail vein injection relative medicine before the cabin every day.The normal control group places the air of same chamber.
The mensuration of the every index of 5 week back row, behind the weighing animal, with 10% urethane (10ml/kg) anesthetized rat, separate the rat external jugular vein, the row pulmonary artery catheter is inserted, to pulmonary artery, determine catheter proximal end position by waveform through jugular vein, superior vena cava, right atrium, right ventricle, the record right ventricle presses pulmonary artery pressure.After the pressure measurement, get blood, survey erythrocyte hematocrit (HCT) with the capillary tube centrifuging from pulmonary artery intubate in-position.Open breast then, win heart and inferior lobe of right lung.Lobe of the lung formalin fixed gives over to histological examination.Separate right ventricle, left ventricle and interventricular septum, natural drying is after half an hour, and the weighing right ventricle is heavy, left ventricle+interventricular septum is heavy.So that the right ventricle weight/(left ventricle+interventricular septum is heavy) (%), right ventricle weight/body weight (mg/100g) reflects the variation of right ventricle weight.
Will be through the fixing embedded section (4 μ m thickness) of the lobe of the lung of formalin fixed dehydration, and add Mayer-esin with the Gomori elastic fibers and redye, carry out histological observation after the film-making.25 of random observationes possess the lung small artery of following 3 conditions: a. diameter 30-100 μ m (average 58 μ m); B. the elastic fibers film is complete; C. the position is near the lung acinus.And record wherein contains the lung small artery quantity of flesh layer.
Compare between each index is organized and before and after self, measurement data is checked with t, and enumeration data is checked with X2, carries out statistical analysis.
Experiment grouping: every group of 8 rats, body weight 150-200g, male and female dual-purpose.
1. normal control group
2. hypoxia matched group
3. nitrendipine group, 8mg/kg
4. Human Urinary Kallidinogenase I organizes, and the Human Urinary Kallidinogenase 3.85 * 10
-3PNAu
5. Human Urinary Kallidinogenase II organizes, and the Human Urinary Kallidinogenase 8.75 * 10
-3PNAu
6. Human Urinary Kallidinogenase III organizes, and the Human Urinary Kallidinogenase 17.5 * 10
-3PNAu
Experimental result
The rat of respectively organizing of low-oxygen environment is total to dead 13 in 5 weeks, and none death of normal control group of in room air, raising, and its weight increase (116.9 ± 26.8g) apparently higher than the hypoxia matched group (87.2 ± 31.3g), the nitrendipine group (86.9 ± 25.4g) and Human Urinary Kallidinogenase I II III group (P＜0.05), and hypoxia organize respectively that body weight increases no significant difference (P＞0.05) between rat.
After the chronic hypoxia, right ventricular pressure and pulmonary artery pressure and normal control group significantly raise (P＜0.05).The right ventricular pressure of nitrendipine treatment group and pulmonary artery pressure all significantly reduce (P＜0.05) than the hypoxia matched group.Human Urinary Kallidinogenase I II III group can obviously reduce anoxia animal right ventricular pressure and pulmonary artery pressure, compares with hypoxia group, and all there were significant differences (P＜0.05), and effect is dose dependent.
After the chronic hypoxia, right ventricle weight/body weight right ventricle weighs/(left ventricle+interventricular septum is heavy) (%) significantly rising, compares with rats in normal control group, and statistical significance (P＜0.05) is arranged.Each medication group all can alleviate right ventricle's hypertrophy (P＜0.05) that anoxia causes, wherein the most remarkable with the effect of Human Urinary Kallidinogenase III group inhibition anoxia right ventricle hypertrophy, relatively there were significant differences (P＜0.01) with hypoxia group.
The erythrocyte hematocrit (HCT) of each hypoxia group is all than normal group significantly raise (P＜0.01).But medication group and hypoxia matched group relatively do not have significant difference (P＞0.05).
Behind the chronic interruption hypoxia, contain flesh lung small artery quantity and normal group in the hypoxia matched group lobe of the lung and significantly increase (P＜0.01).Compare with hypoxia group, each medication group all can significantly suppress the arteriolar fleshization of lung (P＜0.05).
Discuss
A large amount of experiment confirms, pulmonary hypertension and right ventricular hypertrophy all can take place in rat pig and people under the situation of chronic intermittent hypoxia.Discover Ca in the arteria pulmonalis smooth muscle cells of Chronic Hypoxic Rats
2+Concentration raises, and increases the Ca in the perfusate
2+Concentration also can increase the lung vasoconstriction reaction (HPV) of Hypoxic Rats, thinks that therefore calcium ion antagonist antagonism HPV has good action.
Discovery methylene blues such as Rodman can strengthen the contraction of the induced lung artery segment with complete endothelium that anoxia causes, and methylene blue is brought into play pharmacological action by blocking-up endothelium-dependent relaxation vascular relaxing factor (NO), and this just points out EDRF may participate in the lung antiotasis indirectly and regulates.The Human Urinary Kallidinogenase can promote the generation of Kallidin I, and then promotes pulmonary vascular endothelial cell to discharge NO, causes a series of biological effects, comprising Ca in blood vessel dilating and the reduction cell
2+Concentration.
Hypoxia causes that the lung vasoconstriction is to keep a most important adjusting compensatory mechanism of suitable ventilation/perfusion ratio in the lung.Nagasaka proves the lung small artery of the main position of hypoxic pulmonary vascular contraction at 30-40 μ m with blood vessel micropuncture technique under the pleura.But thereby the anoxia stimulating growth factor produce to promote the propagation of endotheliocyte and smooth muscle cell, makes the non-muscular artery generation of part fleshization just often, becomes muscular artery, makes the quantity showed increased of muscular artery.So chronic hypoxia after a couple of days, is promptly found the flesh increase of the non-flesh blood vessel of alveolar region.In the alveolar tunica media of artery to thicken that fleshization, lumen of vessels with blood vessel narrow down be the important morphological basis that pulmonary hypertension forms.This experiment reflects lung small artery flesh situation with the flesh lung small artery quantity that contains that calculating meets three conditions, the arteriolar fleshization of lung when discovery nitrendipine and Human Urinary Kallidinogenase all can suppress hypoxia.
Conclusion
The pulmonary hypertension that the Human Urinary Kallidinogenase can effectively prevent chronic interruption hypoxia to cause.
Claims (6)
1. the Human Urinary Kallidinogenase treats and/or prevents purposes in the pulmonary hypertension disease drug in preparation.
2. the described hypertensive pulmonary vascular disease of claim 1 is the hypertensive pulmonary vascular disease that acute anoxia causes.
3. the described hypertensive pulmonary vascular disease of claim 1 is the hypertensive pulmonary vascular disease that chronic interruption hypoxia causes.
4. one kind is used for the treatment of and/or the pharmaceutical composition of prophylaxis of pulmonary hypertension disease, and it contains the Human Urinary Kallidinogenase and the pharmaceutically acceptable auxiliaries as active component for the treatment of effective dose.
5. the described pharmaceutical composition of claim 4 is a lyophilized injectable powder.
6. the described pharmaceutical composition of claim 4 is an aqueous solution injection.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134106B (en) * | 2007-07-02 | 2012-01-11 | 广东天普生化医药股份有限公司 | Pharmaceutical composition containing human urine kininogenase for treating cerebral infarction |
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2004
- 2004-11-03 CN CN 200410088439 patent/CN1706493A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134106B (en) * | 2007-07-02 | 2012-01-11 | 广东天普生化医药股份有限公司 | Pharmaceutical composition containing human urine kininogenase for treating cerebral infarction |
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