WO1986005095A1 - COMPOSITION DE t-PA ET SON PROCEDE D'INTRODUCTION DANS LE COURANT SANGUIN - Google Patents

COMPOSITION DE t-PA ET SON PROCEDE D'INTRODUCTION DANS LE COURANT SANGUIN Download PDF

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Publication number
WO1986005095A1
WO1986005095A1 PCT/US1986/000473 US8600473W WO8605095A1 WO 1986005095 A1 WO1986005095 A1 WO 1986005095A1 US 8600473 W US8600473 W US 8600473W WO 8605095 A1 WO8605095 A1 WO 8605095A1
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Prior art keywords
hydroxylamine
agent
inhibitor
absorption
enhancing agent
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PCT/US1986/000473
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English (en)
Inventor
Stanley Jay Sarnoff
Original Assignee
Survival Technology, Inc.
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Filing date
Publication date
Priority claimed from US06/708,845 external-priority patent/US4661469A/en
Application filed by Survival Technology, Inc. filed Critical Survival Technology, Inc.
Publication of WO1986005095A1 publication Critical patent/WO1986005095A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K38/44—Oxidoreductases (1)
    • A61K38/446—Superoxide dismutase (1.15)
    • 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)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Definitions

  • This invention relates to the treatment of coronary prone individuals in the throes of a suspected myocardial infarction in such a way as to minimize damage to the heart muscle and, more particularly, to improvements in such treatments enabling the same to be commenced at the earliest possible time, even before direct qualified per- sonal care of the individual can be established.
  • a clot forms in a blood vessel, the body organ being supplied with blood by that blood vessel is compromised or totally deprived of blood supply.
  • the threat to the life of the individual is either small or very great as in the circumstances to be addressed by the material below, i.e. certain life threatening circum ⁇ stances. Clot formation in a vessel is described as thrombosis.
  • thrombolytic substances Substances which dissolve thrombi are called thrombolytic substances.
  • thrombolytic substances When a coronary artery clot is dissolved, the resultant establishment of blood flow to the heart is called reperfusion. Examples of life threatening or very serious clot formation in arterial vessels are cerebral thrombosis, renal thrombosis, opthalmic artery thrombosis, and very importantly, throm ⁇ bosis of a coronary artery.
  • cerebral thrombosis cerebral thrombosis
  • renal thrombosis renal thrombosis
  • opthalmic artery thrombosis and very importantly, throm ⁇ bosis of a coronary artery.
  • thrombus In approximately 85% to 90% of cases of acute myocardial infarction (coronary heart attack), a thrombus is found in the coronary artery preventing blood from flowing to the heart muscle (myocardium) and supplying it with essential oxygen and other nutrients.
  • myocardium heart
  • Heart muscle tissue that does the pumping of blood Heart muscle deprived of it's blood supply does not die immediately but does promptly begin the process of becoming dead. The extent of the damage which is done to the heart muscle is, therefore, a function of the time during which the supply of blood to the infarct zone is restricted by the occluding thrombus
  • the procedures undertaken to actually establish reperfusion to the infarct zone have generally been undertaken in a hospital environment or equivalent.
  • the so-called "pre- hospital” treatment was, in general, directed toward keeping the patient alive and getting the patient into the hospital environment as soon as possible so that treatment minimizing the heart muscle damage could be accomplished.
  • the treatment undertaken in the hospital environment involves certain procedures for estab ⁇ lishing reperfusion in the infarct zone of the patient's heart.
  • the establishment of reper- fusion was accomplished by procedures which had the effect of unblocking the occlusion.
  • the available procedures included mechanical cathe- terization and the administration of thrombolytic agents.
  • thrombolytic agents such as strep- tokinase or urokinase required intracoronary infusion or the slow infeed of the agent within the vessel at the site of occlusion by means of a catheter.
  • intravenous infusion of streptokinase has been shown to be effective.
  • tissue- type plasminogen activator or t-PA has been utilized experimentally.
  • t-PA which is found in only small amount in the body— acts specifically on clots and not on other relevant proteins in the blood, when maintained at appropriate and effective levels.
  • tissue-type plasminogen activiator is par ⁇ ticularly exciting because of the clot specific properties of t-PA.
  • coronary thrombolysis its potential advantages include: safety and efficacy of intravenous admin- istration of high doses; effective clot lysis without induction of a systemic lytic state; prompt implementation without the need for extensive characterization of the coagu ⁇ lation and fibrinolytic systems in each patient prior to and during therapy; avoidance of frank allergic reactions or variations in dose-response ⁇ relation due to immune complex formation; ease of minute-by- minute adjustment of dosage and prompt termination of fibrinolysis when needed be ⁇ cause of the short biological half-like of t-PA and the lack of induction of a systemic lytic state.”
  • a vial is a container for a quantity of liquid medicine or diluent having a rubber stopper capable of being pierced by a hypo ⁇ dermic needle of a syringe to enable the operator of the syringe to withdraw a predetermined dosage of the liquid from the vial.
  • the dosage could then be injected into the mother liquid container of an infusion assembly.
  • the necessity to administer the drug by intravenous infusion or by intravenous injection presents a significant barrier to self-administra ⁇ tion from a practical view point, particularly when considering the disconcerting circumstances of the individual undergoing the symptoms of a myocardial infarction.
  • the invention includes packaging t-PA and an agent enhancing the absorption of t-PA in the blood.
  • the agent preferably is hydroxylamine hydro- chloride, in a known emergency type automatic injector and injecting the two medicament agents 5 into the muscle tissue, e.g. after having received a decision to do so over the telephone from a qualified source and at a time prior to the estab ⁇ lishment of direct contact qualified personal care.
  • t-PA may be regarded as a clot Q selective thrombolytic agent
  • tests thus far performed show that the concentration can be increased to the point that a systemic lytic state can be induced.
  • Intramuscular injection 5 involves the introduction of concentrated dosage of t-PA in an area contiguous to and substantially surrounding the wound caused by the penetration and withdrawal of the injection of the hypodermic needle. Consequently, it would be expected that at Q least a localized lytic state would be induced resulting in hemorrhage from the needle wound. Unexpectedly, tests have shown that no such hemorrhage does in fact occur.
  • t-PA is a large protein, it would _ not be expected that it would be absorbed into the blood stream in discernible quantities.
  • Extra- vascular levels of protein are about 1/10 that of intra-vascular protein. It is thought that this is so because the capillary pores through which trans- port of protein can occur are small relative to the molecular size of protein and limit protein transport because of electrical charge. It was thus highly problematical as to whether a large protein such as t-PA, when given intra-muscularly, i.e. outside the blood vessels, would find its way rapidly into the blood stream in discernible quantities. Application tests have indeed shown that by itself t-PA does not find its way rapidly into the blood stream in therapeutically significant quantities after intramuscular injection.
  • the actual treatment of the system must therefore include intramuscular injection of an absorption enhancing agent simultaneously or sub ⁇ stantially simultaneously with the intramuscular injection of the t-PA so as to produce effective thrombolytic blood levels.
  • the absorption rate of t-PA in the blood is enhanced by utilizing with the t-PA dosage, a dosage of an absorption enhancing agent for t-PA, preferably hydroxylamine hydrochloride.
  • the absorption enhancing agent such as hydroxylamine hydrochloride is mixed in with the t- PA dosage to form a single mixed dosage which is then injected intramuscularly (i.m.).
  • the absorption enhancing agent as a separate dosage within the same site as the separate dosage of t-PA, (e.g. U.S. patent 4,394,863).
  • An example of an amount of absorption enhancing agent, such as hydroxylamine hydrochloride, which is added to the t-PA dosage, as previously described, to form a single mixed dosage is an amount of from 0.1 to 85 e.g. 0.1 to 40 or 1 to 85 milligrams per kilogram of body weight.
  • hydroxylamine is preferably employed in the form of a non-toxic water soluble salt.
  • hydroxylamine salts such as hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroxylamine hydroiodide, hydroxylamine sulfate, hydroxylamine nitrate, hydroxylamine acetate, and hydroxylamine propionate.
  • hydroxylamine hydrochloride Most preferably there is employed hydroxylamine hydrochloride.
  • absorption enhancing agents for t-PA in accordance with the invention compounds such as ammonia (ammonium hydroxide), ammonium carbonate and other ammonium salts, e.g. ammonium chloride, ammonium acetate, ammonium bromide and ammonium sulfate, urea, mono and dialryl ureas, e.g. methyl urea, ethyl urea, propyl urea, butyl urea, N,N-dimethyl urea, N,N- diethyl urea, N,N-diisopropyl urea, mono and dialryl ureas, e.g.
  • ammonia ammonium hydroxide
  • ammonium carbonate and other ammonium salts e.g. ammonium chloride, ammonium acetate, ammonium bromide and ammonium sulfate
  • urea mono and dialryl ureas
  • the sub ⁇ stituted ureas, hydrazines and hydroxylamines likewise can be used in the form of salts, e.g. as hydrochlorides.
  • t-PA and absorption enhancing agent is primarily intended for human use, it is within the scope of the invention that they be administered to other mammals, e.g.
  • hydroxylamine e.g. as the hydrochloride, dissociates t-PA from its naturally occurring inhibitor in tissue culture. Levin. Proc. Natl. Acad. Sci. USA 80, 6804-6808 (1983). It is also known that hydroxylamine inhibits platelet aggregation, see Iizuka, Chem. Pharmacol. Bull. 2_ ⁇ 614-616 (1972) and elicits smooth muscle relaxation potentially enhancing vasodilation and hence absorp ⁇ tion at the injection site, see Diamond, J. Pharmacol, Exp. Therap. 225, 422-426 (1983). These properties may contribute to its success in the present invention.
  • t-PA and the absorption enhancing agent would usually be administered intramuscularly they can also be administered singly or in combina- tion intravenously since hydroxylamine has been shown (see Levin, loc. cit) to disassociate t-PA inhibitor from t-PA, thereby enhancing the effect of the infused exogenous t-PA or the hydroxyl amine and thus reducing the amount of t-PA required to accom- push thrombolysis.
  • the hydroxylamine will usually be administered in the form of a non-toxic salt, preferably the hydrochloride.
  • the dosage of absorption enhancing agent e.g. hydroxylamine hydrochloride can be in 0 the range previously mentioned.
  • t-PA inhibitor disassociating agents In place of hydro ⁇ xylamine in this phase of the invention there can be added other t-PA inhibitor disassociating agents. Electrical stimulation of the muscle at the injection site may be employed in concert with the 5 inclusion of an absorption-enhancing agent, specifically hydroxylamine hydrochloride, in the injectate in a number of the following examples using intramuscular injection. Electrical stimula ⁇ tion augments and enhances the absorption of the o absorption enhancing agent of the invention.
  • an absorption-enhancing agent specifically hydroxylamine hydrochloride
  • an automatic injector device suitable for intramuscular self-administration of t- PA can be employed, the examples set forth below were performed by administering the t-PA and hydroxylamine hydrochloride directly into the muscle with a conventional needle and syringe. Administra ⁇ tion of the agent with an automatic injector, however, it is believed will lead to even higher Q blood levels than those obtainable by manual injection.
  • the volumes used in rabbits were selected to be similar to those planned for use in dogs (1 and 1.5 ml per injection site for rabbits and dogs respectively) even though they represented large volumes with respect to rabbit muscle mass.
  • the same concentration of absorp ⁇ tion-enhancing agent per ml of injectate was used in both species even though they resulted in administration of markedly greater amounts of hydroxylamine per kg of body weight and a 10-fold lower concentration of t-PA in the injectates in rabbits compared with dogs despite administration of comparable proportion of t-PA administered per kg of body weight in the two species.
  • Concentrating the t-PA appreciably with solubilizing agents such as thiocyanate it is believed will permit the volumes to be reduced substantially.
  • t-PA melanoma cell supernatant fractions
  • mt-Pa melanoma cell supernatant fractions
  • Van der Werf Circula ⁇ tion 69_ 605-610 (1984)
  • rt-PA Genentech Corp., lot BH004 DAX
  • Concentrations of 0.5 mg t-PA per ml buffer 0.3 M NaCl, 0.01% Tween 80, 0.01 M potassium phosphate buffer pH 7.5
  • rt-PA Genentech, lot TE031A was concentrated 20-fold with an Amicon membrane filter system.
  • DMSO methyl methoxysulfoxide
  • Hydroxylamine hydrochloride was used in concentrations of 43.75 mg 0 per ml of t-PA solution. This concentration was compatible with a total hydroxylamine hydrochloride dose of approximately 13 mg/kg shown to be well tolerated physiologically.
  • the muscle was stimulated for 2.0 msec at 14 volts with five pulses per second with two 27-gauge, 0.5 inch stainless steel needles. A single negative distal electrode was used as well. A total of 1 mg of t-PA/kg body weight was injected manually divided in 1 ml aliquots in each of 4 sites.
  • Coronary thrombosis was induced in fasted anesthetized dogs weighing approximately 23 kg, see Bergmann Science 220. 1181-1183 (1983). Occlusive thrombus formed within five to 10 minutes and was confirmed angiographically.
  • Serial venous blood samples were obtained through an indwelling inferior vena caval catheter. Electrical field stimulation at the injection site was implemented with three 27- gauge stainless steel, one serving as the negative reference. Parameters were the same as those used in rabbits.
  • t-PA was injected directly into exposed sartorius muscle in 1.5 ml aliquots per site such that the total dose was 3 mg/kg body weight and the total volume of injectate was 6 ml in aggregate for each dog.
  • t-PA activity was determined as well Bergman, loc. cit and Mosenbrunn, Circulation 73., 110-116 (1985).
  • Blood samples were obtained at 0 to 4°C in sodium citrate vacutainer tubes before intramuscular injection of t-PA or vehicle alone, immediately after injection, and at selected intervals from one to 60 minutes subsequently.
  • an additional endpoint was coronary thrombolysis docu ⁇ mented angiographically. Blood pressure, heart rate, the electrocardiogram, arterial blood gases and pH, hemoglobin and hemoglobin oxygen saturation were monitored.
  • t-PA Serial changes in blood levels of t-PA were evaluated in 56 rabbits comprising several groups. Blood levels were assessed before and at selected intervals after intramuscular injection of buffer with or without absorption-enhancing agent alone; or t-PA in buffer, buffer with DMSO, buffer with hydroxylamine (as the hydrochloride), or buffer with DMSO and hydroxylamine (as the hydrochloride).
  • heparin 500 U/kg body weight
  • Statistical comparisons were performed by analysis of variance with Bonferroni critical limits or with Students test for paired data. Values are expressed as means + SE.
  • t-PA Prior to intramuscular injection of t-PA, no human t-PA was detectable by immunoradiometric assay in plasma from any of the rabbits. No detectable endogenous t-PA activity was evident in plasma samples assayed with the fibrin plate functional assay despite the minor surgical proce ⁇ dure performed and the imposed electrical stimulation of muscle for 60 minutes in any of four rabbits tested. No human t-PA was detectable after injection of any of the combinations of vehicles tested when exogenous t-PA was not included in the injectate.
  • No immunoradiometrically detectable t-PA was present in plasma samples from sham operated dogs during a 60 minute sampling interval with or without intramuscular injection of a total of 262 g/ml of hydroxylamine as the hydrochloride administered in multiple sites.
  • Fibrin plate assayable functional activity in sham operated dogs ranged from 10 to 53 IU/ml and did not increase in any of four animals tested during the 60 minute sampling interval after electrical stimulation and intramuscular injection of hydroxylamine hydrochloride in buffer without t-PA.
  • Figure 2 is a graph showing the dependence of the peak concentration plasma of immunoradiometrically detectable t-PA on the concen ⁇ tration of hydroxylamine in the injectate. Conditions were the same as those indicated in the legend to figure 1 except that the amounts of hydroxylamine hydrochloride in the 4 ml aggregate volume of injectate were varied as indicated in the figure.
  • Figure 4 is a graph showing early changes in plasma t-PA concentrations after facilitated absorption of intramuscularly administered t-PA in each of three rabbits. Conditions were the same as those indicated in the legend to figure 1.
  • Figure 5 a graph of serial changes in plasma t-PA assayed immunoradiometrically in a dog which had been subjected to coronary thrombosis.
  • Thrombosis was induced with a thrombogenic coil advanced into the left anterior descending coronary artery at the tip of a coronary arterial catheter.
  • Coronary thrombolysis was induced by facilitated absorption of intramuscularly administered t-PA.
  • thrombogenic coil elicited formation of a clot evident by lack of distal fill with angiographic dye as well as by lack of opacification of the vessel proximal to the coil that appears as a bright rectangle.
  • t-PA 3 mg/kg in a total injectate volume of 6 ml divided among four sites
  • electrical stimulation of muscle at the injection site lysis of the clot proximal and distal to the coil was evident with angiographically demonstrable restoration of patency.
  • plasma t-PA activity peaked soon after facilitated absorption of intramuscularly administered t-PA. Elevated levels persisted throughout the sampling interval. A secondary peak was seen in each of the three dogs studied.
  • t-PA and other activators of the fibrinolytic system have been given only by direct injection into the blood stream.
  • This invention provides an alternative means of administration of t-PA potentially amendable to prompt implementation by paramedical personnel or by telephonically super ⁇ vised patients at high risk previously instructed in self-medication procedures.
  • Hydroxylamine was employed after numerous attempts with other absorption-enhancing media for other compounds failed to yield the desired results with t-PA. Its major side effect, induction of methemoglobinemia does not prohibitively limit tissue oxygenation with the doses used. If the concentration of the hydroxylamine in the injectate is the critical determinant of absorption of t-PA as appears likely judging from the present results, the total dose of hydroxylamine required in human subjects is likely to be so low that induced methemoglobinemia would be of only trivial extent even for patients with ischemic heart disease especially if the injectate volume can be reduced further by increasing the concentration of t-PA.
  • Blood levels of t-PA comparable to those obtained in the present investigation induce coronary thrombolysis in experimental animals and patients without inducing a systemic lytic state predisposing to bleeding.
  • the time course of eleva ⁇ tion of plasma t-PA after facilitated intramuscular absorption is particuarly favorable because of its sharp peak.
  • subjects would be under direct medical care soon after self-medication with an automatic injector or treatment by relatives of paramedical personnel.
  • intravenous infusions could be initiated along with anticoagulants or other measures taken to prevent reocclusion while definitive diagnostic information was being obtained.
  • thromboxane A *thromboxane A2) with a thromboxane synthetase inhibitor, e.g. an imidazole such as 4-(2-[lH- imidazol-l-yl]ethoxy)-benzoic acid hydrochloride (dazoxiben)
  • a thromboxane synthetase inhibitor e.g. an imidazole such as 4-(2-[lH- imidazol-l-yl]ethoxy)-benzoic acid hydrochloride (dazoxiben)
  • thromboxane A2 an antagonist for the receptor of the thromboxane A (thromboxane A2) such as [l ⁇ , 2s (5Z), 3 ⁇ (IE), 4o]-7-[3-(3-cyclohexyl-3- hydroxy-1-propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic acid)(SQ 27,427)
  • the agent for the prevention of reocclusions or platelet aggregations could be administered simultaneously or sequentially in either order with reference to the t-PA and absorption enhancing agent, e.g. hydroxylamine hydrochloride.
  • the agent for the prevention of reocclusions or platelet aggregations can be administered in conventional manner, e.g. intra ⁇ muscularly, intravenously, or even orally.
  • the receptor antagonist or other agent-for prevention of platelet reocclusions can be administered for example in an amount of 0.1-10 mg/kg body weight.

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Abstract

Le taux d'absorption de t-PA (activateur plasminogène de type tissulaire) par le sang augmente si l'on l'administre avec un agent d'augmentation de l'absorption, de préférence l'hydroxylamine ou un de ses sels, surtout l'hydrochlorure d'hydroxylamine.
PCT/US1986/000473 1985-03-06 1986-03-06 COMPOSITION DE t-PA ET SON PROCEDE D'INTRODUCTION DANS LE COURANT SANGUIN WO1986005095A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/708,845 US4661469A (en) 1984-08-08 1985-03-06 t-PA composition capable of being absorbed into the blood stream and method of administration
US708,845 1985-03-06

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WO1986005095A1 true WO1986005095A1 (fr) 1986-09-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0292908A1 (fr) * 1987-05-28 1988-11-30 Survival Technology, Inc. Agents modifiant l'absorption des protéines
EP0419252A1 (fr) * 1989-09-21 1991-03-27 MITSUI TOATSU CHEMICALS, Inc. Composition thrombolytique contenant activateur plasminogène de type tissulaire ou un de ses dérivés

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Vol. 77, Published 1972, (Columbus, Ohio, USA) Iizuka et al:, 17315W *
Chemical Abstracts, Vol. 92, Published 1980, (Columbus, Ohio, USA) Belousov et al:, 39285W *
Chemical Abstracts, Vol. 95, Published 1981, (Columbus, Ohio, USA) Collen 197,233U *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0292908A1 (fr) * 1987-05-28 1988-11-30 Survival Technology, Inc. Agents modifiant l'absorption des protéines
EP0419252A1 (fr) * 1989-09-21 1991-03-27 MITSUI TOATSU CHEMICALS, Inc. Composition thrombolytique contenant activateur plasminogène de type tissulaire ou un de ses dérivés

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ZA861695B (en) 1986-10-29
JPS62502195A (ja) 1987-08-27
GR860624B (en) 1986-07-08

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