CN101926985A - Lumbrokinase injection for treating thromboembolic disease - Google Patents
Lumbrokinase injection for treating thromboembolic disease Download PDFInfo
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Abstract
The invention relates to a lumbrokinase injection for treating a thromboembolic disease. The lumbrokinase injection can fast hydrolyze fibrinogen and fibrous proteins and fulfill the good effect of treating the thromboembolic disease through the dual actions of defibringening and thrombolysis. The injection can be clinically used for treating (1) acute cerebral infarction, comprising cerebral infarction, cerebral embolism and transient cerebral ischemic attack; (2) myocardial infarction and unstable angina; (3) limb angionosis, comprising thigh artery embolism and thromboangitis obliterans; (4) blood in a high viscosity state, a hypercoagulation state and a prothrombotic state; (5) sudden deafness; and (6) pulmonary embolism and the like.
Description
Technical field
The invention belongs to treatment thrombotic disease drug world.The present invention relates to the purposes of Lumbrukinase injection on treatment of thrombotic disorders and the pharmaceutical dosage of Lumbrukinase injection particularly.
Background technology
Thrombosis (thrombosis) is meant that under certain condition blood formed element forms embolus at blood vessel (majority is little blood vessel), causes vasculature part or obstruction fully, corresponding site blood to supply the pathological process of obstacle.Can be divided into 4 kinds of platelet thrombus, erythrocyte thrombosis, fibrinous thrombus, mixed thrombuss etc. according to thrombosis constituent.Can be divided into arterialness, veins and blood capillary thrombosis by the blood vessel kind.
Thromboembolism (thromboembolism) is that thrombosis comes off by forming the position, in the process that moves with blood flow, partly or entirely stop up some blood vessel, cause respective organization and (or) pathological process of organ ischemia, anoxia, necrosis (arterial thrombus) and blood stasis, edema (phlebothrombosis).
More than two kinds of caused diseases of pathological process, be called thrombotic disease clinically.The thrombotic disease serious threat mankind's life and health, its sickness rate is in first of the various diseases, and also has cumulative gesture in recent years, is one of the emphasis of contemporary medical science research and focus.Now main thrombus disease is described below:
The cerebral thrombosis cerebral thrombosis is modal a kind of in the ischemic cerebrovascular, mainly is on hypertension and atherosclerosis basis, the cerebral artery vessel wall thickening, and luminal stenosis, the coarse injustice of tube wall inner membrance, blood flow rate slows down.When narrow cerebrovascular takes place to stop up fully, just cause pathological changes such as local brain tissue ischemia, softening, necrosis, thereby produce the symptom of a series of delayed ischemic neurological deficits such as hemiplegia, aphasia, sensory disturbance, be called cerebral thrombosis.
Cerebral embolism medically occur in the blood of human body circulation and with mobile some foreign body of blood flow, broken speckle, fatty tissue and bubble etc. as sludged blood, tremulous pulse medicated porridge harden plaque come off are called embolus.When the embolus artery-clogging, cause blood flow to interrupt, the clinical symptoms identical with cerebral thrombosis just appears in local brain tissue ischemia, anoxia even softening, downright bad, is called cerebral embolism.The cerebral embolism pilosity is born in the internal carotid artery system.
Cerebral infarction be by a variety of causes cause cerebral artery vessel inaccessible or block after, make the cerebral tissue hypoxic-ischemic and the cerebral tissue that causes is softening and downright bad.
Coronary heart disease coronary heart disease is the abbreviation of coronary atherosclerotic heart disease.Press clinical classification, coronary heart disease is divided into angina pectoris, myocardial infarction and sudden death.Coronary heart disease is because the blood vessel of supply heart nutrient substance--coronary artery taken place atherosis due to.The a large amount of oxygen of action need consumption of heart; therefore; heart is wanted normal activity; the supply of enough blood and oxygen just must be arranged; coronary artery generation atherosclerotic lesion; tube chamber narrows down gradually; the blood that passes through reduces; heart can not get the oxygen and the energy of capacity, will cause that contraction is unable, and the myocardial metabolism product is piled up; cause angina pectoris symptoms such as uncomfortable in chest, chest pain, suffocated breathing; if coronary artery is stopped up by thrombosis fully, will make the cardiac muscle generation ischemic necrosis that is subjected to its supply section, promptly so-called " myocardial infarction ".
The sudden deafness sudden deafness be because narrow, hemorrhage in the vasospasm, thromboembolism, thrombosis, blood vessel pressurized, blood vessel, blood coagulation increases, arteriotony fluctuate and other angiopathy, feels structure generation degeneration because of anoxia makes spiral organ of Corti.Mucocutaneous microscope can be observed and have " silting up " phenomenon in the blood vessel in the sudden deafness case, thinks that this phenomenon may cause the internal ear microcirculation disturbance and cause sudden deafness.Its pathophysiological mechanism is red blood cell condensation in the pathologic vessels → blood viscosity increase → blood flow rate decline → anoxia → permeability increase, tissue edema, concentrated, the [formation → tissue injury of blood.
Above-mentioned thrombotic disease is all directly related with Fibrinogen, Fibrinogen be a kind of measure easily directly be involved in thrombotic acute phase protein, its rising is relevant with the bad clinical consequences of coronary heart disease, also be main coagulation albumen in the blood plasma, in blood, play hemostasis, increase the blood viscosity effect, also can increase the incidence rate of thrombosis.Fibrinogen promotes that the generation of cardiovascular event may be relevant with following reason: (1) fibrinogen molecule amount is big, and three dimensional structure is asymmetric, very easily forms network structure albumen, makes plasma viscosity, whole blood viscosity all raise; (2) Fibrinogen is a composition of the inductive platelet agent of ADP aggreation, promotes the formation of thrombosis; (3) Fibrinogen activates tissue plasminogen activator's inhibitor, further influences vascular endothelial function.
Lumbrukinase is that a class of extracting from Lumbricus can the former and fibrinous enzyme of hydrolysis of fibrin.Lumbrukinase is not single a kind of enzyme, but has the general name of the multiple protein hydrolytic enzyme of identical function.Therefore, " Lumbrukinase " this term comprises various isozymes of Lumbrukinase and reactive derivative thereof.In addition, term " Lumbrukinase " had both comprised natural Lumbrukinase, also comprised Lumbrukinase reorganization or synthetic.
Experimental result shows, Lumbrukinase has dual-use function, except energy direct hydrolysis Fibrinogen and fibrin, can also activate plasminogen (plasminogen) and form plasmin (plasmin), make Lumbrukinase have the effect of indirect hydrolysis fibrin simultaneously.In addition, Lumbrukinase can stimulate vascular endothelial cell to discharge tPA, i.e. tissue plasminogen activator, thus strengthen intravital fibrinolytic effect.
At present, the Lumbrukinase that uses on the domestic and international market has only enteric coated capsule, the molecular weight ranges broad of Lumbrukinase wherein, and between 10000-60000, purity is lower, only is not less than 20000u/mg than vigor, does not meet the requirement of injection, is only applicable to oral formulations.Though the content of everyone each oral Lumbrukinase enteric coated capsule is up to 600000u, the speed that is absorbed into blood owing to oral formulations is slow, and bioavailability is low, and therefore, the Lumbrukinase oral formulations falls fine effect slowly, and acute cerebral infarction is only had preventive effect.
The Lumbrukinase injection that the present invention relates to, its Lumbrukinase molecular weight ranges is narrower only between 10000-35000.Purity is higher, is not less than 140000u/mg than vigor, meets the requirement of intravenous injection.Therefore, the Lumbrukinase injection can adopt the method administration of intravenous drip and intravenous injection, improve clinical effect speed, not only can realize falling the purpose that fine method is treated acute thrombotic disease, also can treat the purpose of acute thrombotic disease by adjusting dosage and administration time realization thrombolytic method.
But yet there are no research report so far, the description of also not seeing the Lumbrukinase injection of treatment thrombotic disease with Lumbrukinase injection treatment thrombotic disease.
One of purpose of the present invention provides a kind of Lumbrukinase injection of new treatment thrombotic disease; Two provide a kind of purposes that the Lumbrukinase injection is used for the fine and quick acute thrombotic disease of thromboembolism treatment of fast prompt drop; Three provide the safe and effective amount of Lumbrukinase injection treatment thrombotic disease, comprising: (1) Lumbrukinase be used for safe and effective amount that fine treatment falls in multiple dosing be 20000-100000u/ people/time.(2) Lumbrukinase be used for the safe and effective amount of single-dose thromboembolism treatment be 150000-600000u/ people/time.
The mechanism of action that falls fine treatment is former by hydrolysis of fibrin for the Lumbrukinase injection, reduce fibrinogenic content, thereby show anti-blood coagulation effect, naturally interrupt the thrombosis process, and reduction blood samples of patients viscosity, improve the blood samples of patients circulation and comprise brain microcirculation and internal ear microcirculation, increase blood oxygen saturation, reach the purpose of treatment thrombotic disease.Its treatment characteristics are repeatedly intravenous drips of low dose.
The mechanism of action of thromboembolism treatment passes through directly and the indirect action hydrolysis of fibrin for the Lumbrukinase injection, make it be degraded to soluble polypeptide, make the thromboembolism of formation, the cardiovascular and cerebrovascular vessel of thromboembolism are logical again, recover blood circulation and oxygen supply, reach the purpose of treatment thrombotic disease.Its treatment characteristics are heavy dose of single intravenous injections.
Description of drawings
Fig. 1 is that electrophoresis technique determining Lumbrukinase injection is to fibrinogenic hydrolysis.Wherein the molecular weight of standard protein is 14400,20100,31000,43000,66200,97400.Fine former is that Fibrinogen does not dilute the blended sample of liquid phase with Lumbrukinase.0,1/3,1/2,1,2,3,4,5,10,20,30,60 minute (response time) was represented Fibrinogen and Lumbrukinase dilution liquid-phase mixing, 37 ℃ of samples that are incubated behind the different time respectively.
Term as used herein " Lumbrukinase injection " refers to extract the former and fibrinous Lumbrukinase isozyme of class energy hydrolysis of fibrin of purification from Lumbricus, its molecular weight is between 10000-35000, purity is higher, be not less than 140000u/mg than vigor, quality control indexs such as bacterial endotoxin, anaphylaxis and undue toxicity all meet the requirement of intravenous injection.Injection comprises injectable powder and aqueous injection.
Process for separating worm kinase adopts the inventor in application on November 14th, 2000 and obtain method in the patent of invention patent certificate, and its patent of invention number is: 00132716.X.The document is incorporated herein by reference.
As for the kind of Lumbricus, without any special restriction.From all Lumbricus kinds, all can extract Lumbrukinase.Suitable Lumbricus kind comprises (but being not limited to): Lumbricidae Bimostos, Eisenia foetida, Amythas dancatala, LUMBRICUS.
Summary of the invention
The safe and effective amount of Lumbrokinase capsulae enterosolubilis be 600000u/ people/time, because the speed of oral formulations absorbed into serum is slow, bioavilability is low, can only produce prevention effect to Patients With Acute Cerebral Infarction by falling fine effect, can not reach the effect of the fine treatment of fast prompt drop and thromboembolism treatment. Yet, the safe and effective amount of the fine treatment of the fast prompt drop of lumbrokinase injection thrombotic diseases be 20000-100000u/ people/time, only be the 1/30-1/6 of oral capsule. And lumbrokinase injection 150000-600000u/ people/time condition under can produce fast thromboembolism treatment effect. Show: the safe and effective amount of lumbrokinase injection is low, and clinical effect is rapid, and determined curative effect has remarkable advantage and novelty.
The clinical scope of application of Lumbrokinase capsulae enterosolubilis only is the prevention of Patients With Acute Cerebral Infarction; And the clinical treatment scope of lumbrokinase injection is including, but not limited to following content: (1) Patients With Acute Cerebral Infarction comprises cerebral thrombus, cerebral embolism, transient ischemic attack; (2) miocardial infarction, unstable angina; (3) limb angiopathy comprises femoral artery embolism, Buerger's disease etc.; (4) blood is high viscosity and high coagulant state, hypercoagulative state, Pre-thrombosis State; (5) sudden deafness; (6) pulmonary embolism etc.
Be enough to obtain the result for the treatment of of needs when herein, term " safe and effective amount " refers to use by mode of the present invention and do not have a significant bad reaction (such as irritated, pyrogen and hemorrhage bad reaction).
General Lumbrokinase be used for safe and effective amount that fine treatment falls in multiple dosing be 20000-100000u/ people/time. Best safe and effective amount be 40000-60000u/ people/time. The disease of falling fine treatment mainly comprises: Patients With Acute Cerebral Infarction, unstable angina, blood are high viscosity and high coagulant state, hypercoagulative state, Pre-thrombosis State and sudden deafness etc. Its effect and scope of falling fine treatment is that Lumbrokinase capsulae enterosolubilis institute is inaccessiable.
The safe and effective amount that general Lumbrukinase is used for the single-dose thromboembolism treatment be 150000-600000u/ people/time.Best safe and effective amount be 250000-500000u/ people/time.The disease of thromboembolism treatment mainly comprises: acute myocardial infarction, femoral artery thromboembolism, thromboangiitis obliterans and pulmonary infarction etc.The effect of its thromboembolism treatment and scope also are that the Lumbrukinase enteric coated capsule is not available.
The advantage of Lumbrukinase injection is among the present invention: the Lumbrukinase injection can adopt intravenous drip or intravenous injection method to make Lumbrukinase directly enter blood, powerful hydrolysis of fibrin and the fibrinogenic effect of performance fast, thereby be applicable to fine treatment of falling of thrombotic disease and thromboembolism treatment, and its safe and effective amount is low.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to normal condition.
Embodiment 1 Lumbrukinase injection is to fibrinogenic hydrolysis
With making its concentration after the dilution of Lumbrukinase injection is 1250u/ml, mix (1: 1) back again with fibrinogen solution (concentration is 2mg/ml) in 37 ℃ of insulations, take out the 0.1ml reactant liquor and do not participate in the fine former of reaction respectively at different time, cessation reaction is observed the Lumbrukinase diluent to fibrinogenic Degradation with the SDS-polyacrylamide gel electrophoresis then.
The results are shown in Figure 1.Fig. 1 is that electrophoresis technique determining Lumbrukinase diluent is to fibrinogenic hydrolysis.Wherein the molecular weight of standard protein is 14400,20100,31000,43000,66200,97400.Fine former is that Fibrinogen does not dilute the blended sample of liquid phase with Lumbrukinase.0,1/3,1/2,1,2,3,4,5,10,20,30,60 minute (response time) was represented Fibrinogen and Lumbrukinase dilution liquid-phase mixing, 37 ℃ of samples that are incubated behind the different time respectively.
The result shows: Fibrinogen is divided into three district's bands behind the SDS-polyacrylamide gel electrophoresis, distinguish called after α, β, γ chain from top to bottom.The Lumbrukinase diluent all has Degradation to fibrinogenic three peptide chains, but the speed difference of degraded.The α chain degradation is fastest, and degraded fully in 1 minute; The β chain was degraded fully in 3 minutes.γ chain degradation speed is slow, and degraded in 60 minutes fully.Therefore, the Lumbrukinase injection has the former effect of fibrin degradation.Fibrin degradation is former to be the main mechanism of treatment thrombotic disease.
Embodiment 2 injection Lumbrukinases are to the cerebral infarction effect
Get 40 rats, male and female half and half, body weight 250-310g.Be divided into five groups at random, every group eight, each is organized administering mode and is the dorsal lingual veins injection: the ischemia model group gives with the volume dextran, and positive controls gives urokinase injection 12500u/kg, three dosage of administration component are respectively: 1250u/kg, 5000u/kg, 150000u/kg
After chloral hydrate (350mg/kg) anesthesia, preparation intraluminal middle cerebral artery occlusion in rats blocking-up model, method with reference to Bederson etc. is carried out behavior scoring, its behavior scoring is the result show: the rat of high, medium and low dosage group of injection Lumbrukinase and urokinase group is 24h after surgery, its nervous symptoms all has improvement in various degree, and relatively there were significant differences (P＜0.01) with model group.The results are shown in Table 1.
Table 1 injection Lumbrukinase is to the influence of middle cerebral artery thrombus model rat behavior defect level
Annotate: compare with the saline group: * P＜0.05; * P＜0.01; * * P＜0.001
After giving above-mentioned scoring processing, broken end is got brain, separate and remove olfactory bulb, behind cerebellum and the low brain stem, keep the brain position, cut four blade, be cut into five brain tissue slices along crown line etc., rapidly it being inserted 5ml then contains in 4%TTC and the 1mol/L dipotassium hydrogen phosphate 0.1ml solution, under the lucifuge condition, hatch 30min for 37 ℃, dyed after, normal cerebral tissue is rose, blocking tissue is white in color, and behind the cellophane cover parcel, traces the naked eyes morphological change of specimen with scanner, according to image analytical method, calculate the percentage ratio that the infarct area area accounts for the cerebral hemisphere area.
The results are shown in Table 2, visible basic, normal, high three the dosage groups of injection Lumbrukinase are compared with the ischemia model group with urokinase positive control treated animal, and cerebral infarct size significantly descends, and obvious statistical significance (P＜0.05, P＜0.05, P＜0.01 and P＜0.01) is arranged.
Table 2 injection Lumbrukinase is to the influence of middle cerebral artery thrombus model rat cerebral ischemia area
Annotate: compare with the saline group: * P＜0.05; * P＜0.01; * * P＜0.001
The effect of embodiment 3 Lumbrukinase injection dissolving plasma fibrin
Rabbit carotid artery blood sampling, with the anticoagulant of an amount of Disodium oxalate. powder, centrifuging and taking blood plasma adds the Tris buffer by a certain percentage, shakes to be layered on rapidly on the glass plate after mixing, because of the effect of the calcium fibrin plate that congeals into.Each medicinal liquid is all got 10 μ L and is dripped on specific surface location, puts 22h in 37 ℃ of calorstats, and instrumentation respectively adds the area that dissolves of snack made with traditional Chinese medicines.
Test sees Table 3.As seen the Lumbrukinase injection has fibrinolytic effect under isolated condition, and certain concentration effect relation is arranged, and the meaning (P＜0.01) of highly significant is arranged statistically through the t check.The positive drug urokinase is also like this.This explanation Lumbrukinase injection has fibrinolysis.Therefore, the Lumbrukinase injection has the effect of hydrolysis of fibrin.Hydrolysis of fibrin also is the main mechanism of treatment thrombotic disease.
Each group of table 3 dissolve area (mm
2)
The effect of the anti-arteriovenous shut thrombosis of embodiment 4 injection Lumbrukinases
Male rat anesthesia exposes one section carotid artery and other side external jugular vein, clamp arteriovenous and connect a polyethylene tube bypass between the two, manage the silk thread of a built-in 5cm and be full of heparin liquid (50u/mL), the tail cava vein is injected corresponding medicinal liquid, the pipe clamp of dehematizing behind the 2min makes bypass inner blood circulation 15min, reclamps blood vessel, take out silk thread weighing, deduct the silk thread weight in wet base and then get wet weight of thrombus with thrombosis.
The results are shown in Table 4.As seen the injection Lumbrukinase can reduce wet weight of thrombus, and dose-effect relationship is arranged, and the meaning (P＜0.01) of highly significant is arranged statistically through the t check.The positive drug urokinase also has this effect.
The wet weight of thrombus (mg) of each group of table 4
The effect of embodiment 5 Lumbrukinase injection dissolving lung thrombosis
Get fixing the exposure and free carotid artery and jugular vein in rabbit back of the body position, clamp vein blood vessel at a distance of 1cm, extract blood out with two vascular clamps.By carotid artery extraction arterial blood and with certain density an amount of thrombin with I
125The Fibrinogen of labelling mixes mutually, injects aforesaid vein cavity rapidly and makes the formation sludged blood.Decontrol behind the certain hour vascular clamp then sludged blood return the heart and go into lung and form the lung thrombosis.
After causing the lung thrombosis, each organizes the corresponding medicinal liquid of intravenous injection, and medication is 0.5 and 1 hour arterial blood drawing before and after, and cut open inspection pulmonary then and take out the lung thrombosis, be index with counting of the isotope radioactivity in the blood and lung wet weight of thrombus.Instrument is that the FT-613 that the Beijing Nuclear Instrument Factory produces calculates automatically
125I is put and is exempted from measuring instrument, well type probe.
Each rabbit blood radioactivity counting is general in the scope of 700-900cpm/g before the medication, with this as 100%.The results are shown in Table 5.As seen increase because of thrombolytic can make the blood radioactivity during dosage in the Lumbrukinase injection, and certain dose-effect relationship is arranged, the meaning (P＜0.01) of highly significant is arranged statistically through the t check.The positive drug urokinase is also like this.
Table 5 is respectively organized before the medication and blood radioactivity percentage ratio after the medication
The lung wet weight of thrombus of each group the results are shown in Table 6.The Lumbrukinase injection alleviates because of thrombolytic can make the lung wet weight of thrombus as can be known, and certain dose-effect relationship is arranged. and the positive drug urokinase is also like this.
The lung wet weight of thrombus of each group of table 6
The effect of embodiment 6 Lumbrukinase injection dissolving femoral artery thrombosis
Canis familiaris L. anesthesia exposes femoral artery, is close to the steel wire that blood vessel is put a diameter 1.5mm, takes out steel wire after pricking with toe-in, and then vessel diameter narrows down.Clamp a 2cm vessel segment at the proximal part of ligation, the blood of finding time, and the mixture of injection arterial blood and certain density an amount of thrombin, this place can form thrombosis behind the certain hour.Decontrol vascular clamp and make blood circulation.Blood flow volume (using electromagnetic flowmeter) and blood vessel surface temperature (measuring temperature with ST-1 digital clinical thermometer (Shanghai Medical Instrument and Meter Factory)) with moulding place distal end are index.Looked moulding forward and backward 30 minutes and the intravenous injection medicinal liquid after the variation of 15,30,60 minutes indexs.
The results are shown in Table 7.As seen: 1. moulding is successful, and each index lowers to some extent after the moulding, and the minimizing of femoral artery blood flow has the meaning (P＜0.01) of highly significant statistically through the t check; 2. the Lumbrukinase injection really improves because of thrombolytic can make each index, and certain dose-effect relationship is arranged, and the increase of femoral artery blood flow has the meaning (P＜0.01) of highly significant statistically through the t check.3. the positive drug urokinase is also effective.
The variation of each index of femoral artery in 60 minutes behind forward and backward 0.5h of table 7 moulding and the intravenous injection medicinal liquid.
* P＜0.01 (with comparing after the moulding)
The effect of embodiment 7 injection Lumbrukinases dissolving coronary artery thrombosis
Canis familiaris L. anesthesia exposes heart, the branch of looking for a coronary artery descending branch, and the blood of finding time, and the mixture of injection arterial blood and certain density an amount of thrombin, this place can form thrombosis behind the certain hour.(according to getting the point that 5 S-T sections are appreciated at random with traveling electrode behind the type 0.5h, obtain at 5 with the surface ECG ∑ S-T section of moulding place distal end
Desired value, each dog pole location basically identical) and heart surface temperature and myocardial necrosis district size be index.Look the variation of 0.5h index behind forward and backward 0.5h of moulding and the intravenous injection medicinal liquid.
Result of the test sees Table 8.As seen: 1. moulding is successful, and each index changes to some extent after the moulding, and the increase of surface ECG ∑ S-T has the meaning (P＜0.01) of highly significant statistically through the t check; 2. the injection Lumbrukinase really improves because of thrombolytic can make each index, and certain dose-effect relationship is arranged, and the minimizing of surface ECG ∑ S-T has significant meaning (P＜0.05) statistically through the t check; 3. the positive drug urokinase is also effective.
The variation of each index of 0.5h heart behind forward and backward 0.5h of table 8 moulding and the intravenous injection medicinal liquid.
* P＜0.05 (with comparing after the moulding)
The coagulation of YIN-cold in ZANG-organ of coring after the test is pricked and is cut into slices below the position with 0.1% nitro tetrazole orchid (pH 7.4 phosphate buffers) dyeing (about 25 ℃, about 1 minute).Non-orchid is dyed the district and shows the myocardial ischaemia necrosis.
Result of the test is listed in table 9.As seen: 1. moulding is successful, causes the myocardial ischaemia damage after the moulding really; 2. the injection Lumbrukinase really reduces to some extent because of thrombolytic can make downright bad percentage ratio, and certain dose-effect relationship is arranged, and through the t check significant meaning (P＜0.05) is arranged statistically; 3. the positive drug urokinase is also like this.
Table 9 is respectively organized myocardial necrosis percentage ratio
*P＜0.05
Embodiment 8 injection Lumbrukinase human tolerances test
24 healthy volunteers are divided into 4 groups at random, every group 6 people, and the injection Lumbrukinase of single intravenous drip 20000u, 40000u, 60000u and 80000u is observed the maximum tolerated dose of healthy volunteer to medicine respectively.
Result: all nervous system, cardiovascular, blood pressure, hepatic and renal function, heart rate and no abnormal variations of breathing before and after experimenter's medication, with the fine relevant with thrombolytic variation that goes out coagulation indexes (prothrombin time, partial thromboplastin soak time, thrombin time) there are no significant is fallen, hematuria routine, electrolyte, fasting glucose do not have significance yet and change, and do not have irritated and hemorrhagic untoward reaction.Find that simultaneously experimenter's plasma fibrinogen, endogenic blood coagulation activity and platelet aggregation rate have the effect that reduces or suppress.
Conclusion: the healthy volunteer is good to the toleration of injection Lumbrukinase.Lumbrukinase be used for safe and effective amount that fine treatment falls in multiple dosing be 20000-80000u/ people/time, its optimal dose be 40000-60000u/ people/time.
Claims (6)
1. the purposes of a Lumbrukinase is characterized in that, it is used to prepare the injection for the treatment of thrombotic disease.
2. Lumbrukinase as claimed in claim 1 is characterized in that, the multi-component Lumbrukinase isozyme of molecular weight between 10000-35000.
3. Lumbrukinase injection as claimed in claim 1 is characterized in that this injection comprises injectable powder and aqueous injection.
4. the purposes of Lumbrukinase as claimed in claim 1 is characterized in that, described Lumbrukinase is used for the treatment of following disease after making injection: (1) acute cerebral infarction comprises cerebral thrombosis, cerebral embolism, transient ischemic attack; (2) myocardial infarction, unstable angina pectoris; (3) limb angiopathy comprises femoral artery thromboembolism, thromboangiitis obliterans etc.; (4) blood is high viscosity and high coagulant state, hypercoagulability, the preceding state of thrombosis; (5) sudden deafness; (6) pulmonary infarction etc.
5. Lumbrukinase injection as claimed in claim 1 is characterized in that, Lumbrukinase be used for safe and effective amount that fine treatment falls in multiple dosing be 20000-100000u/ people/time.
6. Lumbrukinase injection as claimed in claim 1 is characterized in that, the safe and effective amount that Lumbrukinase is used for the single-dose thromboembolism treatment be 150000-600000u/ people/time.
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| CN106680470A (en) * | 2016-06-12 | 2017-05-17 | 北京儒展生化药物研究中心 | Method for determining maximum tolerated dose of defibringen medicine in human body |
| CN106680470B (en) * | 2016-06-12 | 2018-12-21 | 北京儒展生化药物研究中心 | A method of fine drug maximum tolerated dose in human body drops in measurement |
| CN115125228A (en) * | 2022-06-24 | 2022-09-30 | 北京农学院 | Maggot kinase and use thereof |
| CN115125228B (en) * | 2022-06-24 | 2023-09-19 | 北京农学院 | Maggot kinase and application thereof |
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