IE65721B1 - Thrombolytically acting combined preparation - Google Patents
Thrombolytically acting combined preparationInfo
- Publication number
- IE65721B1 IE65721B1 IE465490A IE465490A IE65721B1 IE 65721 B1 IE65721 B1 IE 65721B1 IE 465490 A IE465490 A IE 465490A IE 465490 A IE465490 A IE 465490A IE 65721 B1 IE65721 B1 IE 65721B1
- Authority
- IE
- Ireland
- Prior art keywords
- fibrin
- binding
- dspa
- thrombolytically
- molecular
- Prior art date
Links
- 102000009123 Fibrin Human genes 0.000 claims abstract description 24
- 108010073385 Fibrin Proteins 0.000 claims abstract description 24
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229950003499 fibrin Drugs 0.000 claims abstract description 24
- 230000027455 binding Effects 0.000 claims abstract description 14
- 108010001014 Plasminogen Activators Proteins 0.000 claims abstract description 13
- 102000001938 Plasminogen Activators Human genes 0.000 claims abstract description 13
- 229940127126 plasminogen activator Drugs 0.000 claims abstract description 13
- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 6
- 229960000103 thrombolytic agent Drugs 0.000 claims abstract description 6
- ALPWRKFXEOAUDR-GKEJWYBXSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] hydrogen phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)([O-])=O)OC(=O)CCCCCCCCCCCCCCCCC ALPWRKFXEOAUDR-GKEJWYBXSA-M 0.000 claims description 11
- 239000013543 active substance Substances 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 108010073863 saruplase Proteins 0.000 claims description 2
- 230000002537 thrombolytic effect Effects 0.000 abstract description 6
- 208000007536 Thrombosis Diseases 0.000 description 6
- 102000013566 Plasminogen Human genes 0.000 description 5
- 108010051456 Plasminogen Proteins 0.000 description 5
- 229940012957 plasmin Drugs 0.000 description 5
- 241000288921 Desmodus Species 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 206010061216 Infarction Diseases 0.000 description 3
- 208000034158 bleeding Diseases 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 230000007574 infarction Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 241000288673 Chiroptera Species 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 206010047249 Venous thrombosis Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 230000003480 fibrinolytic effect Effects 0.000 description 2
- 239000002657 fibrous material Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 229960005202 streptokinase Drugs 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 1
- 108010057987 Desmodus rotundus salivary plasminogen activator alpha 1 Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 208000002528 coronary thrombosis Diseases 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6456—Plasminogen activators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Compounds Of Unknown Constitution (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention concerns a preparation with thrombolytic action, consisting of a combination of the non-fibrin-binding form of the thrombolytic agent v-PA and a fibrin-binding plasminogen activator.
Description
The present invention relates to novel agents having a thrombolytic action.
Thromboses occur as a result of the formation of a blood clot in blood vessels. A differentiation is made between venous thromboses, including pulmonary embolisms, and arterial thromboses, including acute cardiac infarct.
Pulmonary embolism and cardiac infarct are life-threatening conditions that require immediate medical intervention.
Apart from various invasive methods, in recent years enzymatic thrombolysis using plasminogen activators has been used as a form of therapy for arterial and venous thromboses. These substances, called thrombolytic agents, convert plasminogen, the inactive proenzyme of the fibrinolysis system in the blood, into the active proteolytic enzyme plasmin. Plasmin in turn dissolves the fibrous material fibrin, a basic component of a blood clot, which results in the reopening of the closed vessels and reinstatement of the blood flow. Plasmin, however, is a relatively non-specific protease, that is to say, once formed in the blood it destroys proteolytically components in the blood that are indispensable for an intact haemostasis (e.g. fibrinogen), and as a result may induce serious risks of bleeding.
The first-generation thrombolytic agents, streptokinase and urokinase, are substances that, once injected into the circulation, systemically convert plasminogen into plasmin and induce a systemic proteolysis. Thrombolysis therapies using those substances are therefore frequently accompanied by complications of bleeding. The thendeveloped fibrin-specific thrombolysis, in which recombinant plasminogen activators of the tissue type, abbreviated to t-PA, are used, was intended to overcome that dilemma. t-PA has only a low affinity for plasminogen in the blood circulation. In the presence of the fibrous material fibrin, however, with which it reacts by way of specific binding sites, there is a manifold 5 increase in that affinity, resulting in the formation of plasmin at the thrombus surface. It was possible for that concept to be verified in vitro and in animal experiment investigations; clinical studies, however, showed that large amounts of t-PA are necessary to bring 10 about the rapid dissolution of a coronary thrombosis.
If, however, high doses of t-PA are infused in such a manner then, similarly to the case with streptokinase and urokinase, the result is a systemic proteolysis associated with a relative risk of bleeding. Nowadays, tPA is considered to have a relative specificity for fibrin; the reason for that is founded in an important property of t-PA: that molecule is a protease, which under favourable conditions (high enzyme concentration, long exposure time, high substrate concentration, optimum pH and ionic medium) converts plasminogen into plasmin even in the absence of fibrin. All those conditions are met by the current standard clinical therapy with t-PA.
In the search for more specific plasminogen activators that meet the criterium of fibrin specificity, a novel, natural, fibrinolytically active substance called v-Pa (also called DSPA, Desmodus Salivary Plasminogen Activator) (EP-A-0 383 417) was discovered.
The invention relates to a thrombolytical ly active agent consisting of one of the non-fibrin-binding low-molec30 ular-weight forms, DSPA B or DSPA /, with molecular * weights of 46,000 and 42,000 (EP-A-0 383 417), and a fibrin-binding plasminogen activator. t There come into consideration as fibrin-binding plasminogen activators, for example: prourokinase (scu-Pa), t-PA and the high-molecular-weight form of the thrombolytic agent v-PA (DSPA al and DSPA a2, EP-A-0 383 417) having a molecular weight of 52,000.
The thrombolytic active substance v-PA (DSPA) is a novel, naturally occurring plasminogen activator that dissolves blood clots in the human body and is therefore suitable for treating, for example, cardiac infarct (EP-A-0 383 417).
It is found in low concentrations in the saliva of all species of bats of the Desmodus spec, genus and is secreted by the cells of the salivary glands of that genus of animals. Bats of the genus Desmodus spec, include all types of bat of the American continent. The Desmodus genus of Middle America and Mexico has proved especially good.
The invention furthermore relates to medicaments based on the above-mentioned combinations of non-fibrin-binding and f ibrin-binding plasminogen activators and conventional excipients and carriers.
The fibrinolytic activity of v-PA (DSPA) is further strengthened by means of the above-described combination of fibrin-binding and non-fibrin-binding plasminogen activators compared with conventional plasminogen activators. The daily dose administered parenterally to humans is from 5 to 500 mg, preferably from 20 to 200 mg.
EXAMPLE Fibrinogen and plasminogen are caused to clot in a Petri dish by means of the addition of thrombin. There are stamped into the resulting layer of fibrin holes of 3 mm diameter into which v-PA is then introduced in various concentrations and combinations. Both molecular forms of the fibrin-specific plasminogen activator v-PA produce concentration-dependent lysed aureoles after incubation in a humid chamber at 37'c.
If the two different molecular forms of v-PA are then combined, the result is lysed aureoles that are distinctly larger than the lysed aureoles that would have been expected on the basis of a simple additive effect. By means of the combination of high- and low-molecularweight v-PA a synergistic effect on fibrinolysis is thus achieved in vitro. That synergistic effect is attributable to the fact that the low-molecular-weight form of v-PAf which lacks the finger domains, can as a result of its non-fibrin-binding property diffuse better into a fibrin clot, and thus disaggregate the clot as a result of its fibrinolytic activity. The high-molecular-weight fibrin-binding v-PA variant can then completely lyse the already disaggregated fibrin clot.
Assessments of the results of that fibrin plate test have shown that a clearly synergistic effect is achieved as a result of the combination of the two forms of v-PA (Berenbaum, M.C. Clin. exp. Immunol., 28 f 1-18, 1977).
Claims (3)
1. Thrombolytically active agent consisting of a combination of one of the non-fibrin-binding forms of the thrombolytic agent v-PA, DSPA B or DSPA /, with molecular 5 weights of 46,000 and 42,000, and a fibrin-binding plasminogen activator, and also conventional excipients and carriers.
2. Thrombolytically active agent according to claim 1, characterised in that prourokinase (scu-PA), t-PA or the 10 high-molecular-weight forms of the thrombolytic agent v-PA (DSPA al and DSPA a2) having a molecular weight of 52,000 comprise the fibrin-binding plasminogen activator.
3. · A thrombolytically active agent substantially as hereinbefore described with reference to the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3943241A DE3943241A1 (en) | 1989-12-22 | 1989-12-22 | THROMBOLYTICALLY ACTIVE COMBINATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE904654A1 IE904654A1 (en) | 1991-07-17 |
| IE65721B1 true IE65721B1 (en) | 1995-11-15 |
Family
ID=6396574
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE465490A IE65721B1 (en) | 1989-12-22 | 1990-12-21 | Thrombolytically acting combined preparation |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0436261B1 (en) |
| KR (1) | KR927003092A (en) |
| AT (1) | ATE89741T1 (en) |
| AU (1) | AU647763B2 (en) |
| BR (1) | BR9007940A (en) |
| CA (1) | CA2033140A1 (en) |
| DE (2) | DE3943241A1 (en) |
| DK (1) | DK0436261T3 (en) |
| ES (1) | ES2057365T3 (en) |
| HU (1) | HUT65411A (en) |
| IE (1) | IE65721B1 (en) |
| NO (1) | NO922454L (en) |
| WO (1) | WO1991009618A1 (en) |
| ZA (1) | ZA9010367B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5731186A (en) * | 1996-02-05 | 1998-03-24 | Schering Aktiengesellschaft | Method for the production of rDSPA α1 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61112018A (en) * | 1984-11-06 | 1986-05-30 | Mitsubishi Chem Ind Ltd | Agent for promoting fibrinolysis |
| IE69054B1 (en) * | 1988-07-20 | 1996-08-07 | Schering Ag | Vampire bat salivary plasminogen activators |
| CA2046632C (en) * | 1989-02-13 | 1999-05-11 | Schering Aktiengesellschaft | Thrombolytic from vampire bat saliva |
-
1989
- 1989-12-22 DE DE3943241A patent/DE3943241A1/en not_active Withdrawn
-
1990
- 1990-12-21 DE DE9090250330T patent/DE59001558D1/en not_active Expired - Lifetime
- 1990-12-21 BR BR909007940A patent/BR9007940A/en unknown
- 1990-12-21 ES ES90250330T patent/ES2057365T3/en not_active Expired - Lifetime
- 1990-12-21 EP EP90250330A patent/EP0436261B1/en not_active Expired - Lifetime
- 1990-12-21 AU AU69696/91A patent/AU647763B2/en not_active Ceased
- 1990-12-21 KR KR1019920701482A patent/KR927003092A/en not_active Abandoned
- 1990-12-21 ZA ZA9010367A patent/ZA9010367B/en unknown
- 1990-12-21 HU HU9202087A patent/HUT65411A/en unknown
- 1990-12-21 IE IE465490A patent/IE65721B1/en not_active IP Right Cessation
- 1990-12-21 AT AT90250330T patent/ATE89741T1/en not_active IP Right Cessation
- 1990-12-21 DK DK90250330.9T patent/DK0436261T3/en active
- 1990-12-21 WO PCT/DE1990/000995 patent/WO1991009618A1/en not_active Ceased
- 1990-12-24 CA CA002033140A patent/CA2033140A1/en not_active Abandoned
-
1992
- 1992-06-19 NO NO92922454A patent/NO922454L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0436261B1 (en) | 1993-05-26 |
| DE3943241A1 (en) | 1991-06-27 |
| NO922454D0 (en) | 1992-06-19 |
| EP0436261A1 (en) | 1991-07-10 |
| WO1991009618A1 (en) | 1991-07-11 |
| DE59001558D1 (en) | 1993-07-01 |
| ZA9010367B (en) | 1992-08-26 |
| CA2033140A1 (en) | 1991-06-23 |
| DK0436261T3 (en) | 1993-08-16 |
| NO922454L (en) | 1992-06-19 |
| HU9202087D0 (en) | 1992-10-28 |
| ATE89741T1 (en) | 1993-06-15 |
| IE904654A1 (en) | 1991-07-17 |
| ES2057365T3 (en) | 1994-10-16 |
| AU647763B2 (en) | 1994-03-31 |
| AU6969691A (en) | 1991-07-24 |
| BR9007940A (en) | 1992-11-10 |
| KR927003092A (en) | 1992-12-17 |
| HUT65411A (en) | 1994-06-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Stump et al. | Urokinase-related proteins in human urine. Isolation and characterization of single-chain urokinase (pro-urokinase) and urokinase-inhibitor complex. | |
| Collen et al. | Synergism of thrombolytic agents in vivo | |
| Zamarron et al. | Biological and thrombolytic properties of proenzyme and active forms of human urokinase–I. Fibrinolytic and fibrinogenolytic properties in human plasma in vitro of urokinases obtained from human urine or by recombinant DNA technology | |
| Kluft et al. | Role of the contact system in fibrinolysis | |
| Collen et al. | Biological and thrombolytic properties of proenzyme and active forms of human urokinase–III. Thrombolytic properties of natural and recombinant urokinase in rabbits with experimental jugular vein thrombosis | |
| HUT58812A (en) | Process for producing tissue plasminogen activator (t-pa) zimogenes and compositions containing them as active components | |
| US5776452A (en) | Thrombosis agent | |
| Sakuragawa et al. | Studies on the effect of PEG-modified urokinase on coagulation-fibrinolysis using beagles | |
| Menashi et al. | 2 Endothelial cell proteases: physiological role and regulation | |
| Gao et al. | Differential effect of platelets on plasminogen activation by tissue plasminogen activator, urokinase, and streptokinase | |
| Aoki et al. | Influence of α2-plasmin inhibitor on adsorption of plasminogen to fibrin | |
| de Serrano et al. | Influence of various structural domains of fibrinogen and fibrin on the potentiation of plasminogen activation by recombinant tissue plasminogen activator | |
| EP0324597A2 (en) | Fibrin selective two-chain plasminogen activator | |
| Rijken et al. | Specific fibrinolytic properties of different molecular forms of pro-urokinase from a monkey kidney cell culture | |
| Soeda et al. | Rapid and high-yield purification of porcine heart tissue-type plasminogen activator by heparin-sepharose choromatography | |
| Dunn et al. | Importance of the interaction between plasminogen and fibrin for plasminogen activation by tissue-type plasminogen activator | |
| Nakayama et al. | The plasmin heavy chain-urokinase conjugate: a specific thrombolytic agent | |
| Menshikov et al. | Plasmin-independent gelatinase B (matrix metalloproteinase-9) release by monocytes under the influence of urokinase | |
| Lenich et al. | The effect of the carboxy-terminal lysine of urokinase on the catalysis of plasminogen activation | |
| Sugiyama et al. | Effects of kringles derived from human plasminogen on fibrinolysis in vitro | |
| Nieuwenhuizen et al. | Species specificity in the acceleration of tissue-type plasminogen activator-mediated activation of plasminogens, by fibrinogen cyanogen bromide fragments | |
| IE904654A1 (en) | "Thrombolytically acting combined preparation" | |
| Abercrombie et al. | Fibrin specific thrombolysis by two-chain urokinase-type plasminogen activator cleaved after arginine 156 by thrombin | |
| EP0381640B1 (en) | New thrombolytic compositions | |
| Gaffney et al. | Roles for chloride ion and fibrinogen in the activation of [Glu1] plasminogen in human plasma. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |