CA2111644A1 - Use of thrombin inhibitors for the inhibition of ocular fibrin formation - Google Patents
Use of thrombin inhibitors for the inhibition of ocular fibrin formationInfo
- Publication number
- CA2111644A1 CA2111644A1 CA002111644A CA2111644A CA2111644A1 CA 2111644 A1 CA2111644 A1 CA 2111644A1 CA 002111644 A CA002111644 A CA 002111644A CA 2111644 A CA2111644 A CA 2111644A CA 2111644 A1 CA2111644 A1 CA 2111644A1
- Authority
- CA
- Canada
- Prior art keywords
- thrombin
- inhibitor
- body weight
- fibrin
- inhibition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
- A61K38/55—Protease inhibitors
-
- 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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
- A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Tropical Medicine & Parasitology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Abstract of the disclosure The use of thrombin inhibitors for the inhibition of ocular fibrin formation The use of substances which are able to inhibit the activity of soluble and fibrin- and cell-bound thrombin, in particular hirudin, its derivatives, peptides derived therefrom and low molecular weight thrombin inhibitors in a process for the preparation of a pharmaceutical for the inhibition of ocular fibrin formation and deposition is described.
Description
2 ~ ~ 1 & ~ ~
B~HRI~GW~RRE ARTI~GESE~LSC~AFT HO~ 92/B 029 - Ma 967 Auslandstext THE USE OF THROMBIN I~IBITORS FOR T~E IN~IBITIO~
OF OCULAR FIBRI~ FORMATIO~
The invention relates to the use of substances which are able to inhibit the activity of solubie and fibrin- and cell-bound thrombin, in particular hirudin, its deriva-tives, peptide~ derived therefrom and low molecular weight thrombin inhibitors in a process for the prepara-tion of a pharmaceutical for the inhibition of ocularfibrin formation and deposition.
The activation of fibrinogen to fibrin represents the central reaction in the production of a primary wound closure~ This process which is so important after injury to the vascular system may, if there is uncontrolled fibrin formation and deposition Ithrombus), considerably impair physiological functions.
The crucial contribution to fibrinogen activation is provided by thrombin,the central protease in blood coagulation. Fibrin formation and deposition occur at sites of vascular injury and also extend into extravascular regions when plasma components, including fibrinogen, leave the vascular system ~for exampls when endothelial permeability is increased) as, ~or example, during the course of certain diseases or during or afker surgical interventions. The endogenous fibrinolytic system i.s able after some time to dissolve these fibrin deposits or thrombi. The situation is usually diferent with certain eye diseases or after operations on the eye during the course of which or postoperatively there may be considerable impairments of vision by fibrin tfor example dimness, opalescence, starburst effect), in somP
cases associated with pain~ However, the intraocular activit~ of endogenous fibrinolysis is zero or only very ' ~ 2 --low, which means that the impairments frequently last a long time and may lead to blindness.
The fibrin/thrombus breakdown can be therapeutically initiated or accelerated by administration of substances with fibrinolytic activity, such as tissue plasminogen activator (t-PA). However, treatment of this type may have disadvantageous effects on wound healing processes.
Moreover, it is known that fibrin degradation products liberated during these breakdown processes have chemotactic effects on macrophages and granulocytes and thus considerably increasP the risk of intraocular inflammation~
It is therefore expedient to take prophylactic measures against fibrin formation and deposition. The initial activation of fibrinogen can be substantially suppressed by inhibiting the activity of soluble thrombin, as described in EP-A-0 353 018 for the plasma inhibitor antithrombin III (AT III ) . AT III displays its complete activity only in combination with its cofactor heparinO
The efficacy of these substances is, however, limited by the fact that they are able adequately to inhibit only soluble thrombin. By contrast, thrombin molecules which are bound to fibrin or cell surfaces are poorly inhibited by A~ III/heparin. It is known that such surface-bound thrombin activities represent a considerable problem because they cause further fibrin deposits. In addition, they activate other coagulation factors and thus increa~;e the risk of ocular thrombi in eye diseases and operatiorls on the eye.
The object therefoxe was to develop an ocular thrombosis prophylaxis with ~ubstances which are able to inhibit not only soluble but also fibrin- and cell-bound throm~in.
The invention relates to the use of substances which are able to inhibit the activity of soluble and fibrin- and cell bound thrombin in a process for the preparation of . .
a pharmaceutical for the inhibition of ocular fibrin formation and deposition.
Substances of this type which are preferred ar~ hirudin, its derivatives, peptides derived therefrom or low S molecular weight thrombin inhibitors.
Hirudin is a speci~ic thrombin inhibitor which is 7 kDa in size and is derived from the leech Hirudo medicinalis and can be prepared by genetic manipulation and which efficiently inhibits both soluble and surface-associated thrombin independently of cofactors. Likewise suitable are derivatives of hirudin, for example those which contain part sequences from the amino-acid sequence of hirudin or variants of this sequence, an analog or generally functional equivalents of hirudin or low molecular weight thrombin inhibitors with the properties described above, such as ~2R,4R)-4-methyl-1-[N-~3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidine and substances described in EP-A-0 097 630 or 0 468 231.
Where ocular fibrin deposits already exist, the use of these substances is likewise worthwhile because the QppOSing processes of fibrin deposition and endogenous thrombus disintegration are shifted in favor of fibrino-lysis. Therapeutic administration of the corresponding thrombin inhibi-tors with substances with fibrinolytic activity, for example intraocularly with t-PA, i~ lik~-wise used for the said reasons.
These inhibitors are used, for axample, during/after cataract, glaucoma operations, vitrectomies and la~er-surgical interventions (for example photocoagulation,laser ablation) during the course of which hyphemas ~hemorrhages in chambers of the eye) with subsequent fibrin deposition/thrombus formation ara a frequen-t occurrence. This ~avors inter alia the development of glaucomas ~interference with the outflow of ~luid). The ,~. . ..
; ' i--' described inhibitors are also used after lens implanta-tions because the resulting fibrin deposits ~caused inter alia by the artificial surfaces) may cause iridocyclitis, inflammation of the iris and of the ciliary body. Also not uncommon ~re retinal arterial or venous thromhoses (for example during the course of diabetes mellitus, autoimmune diseases or after operations), which can be prevented by the inhibitors. These inhibitors can be used in combination with volume replacers such as, for example, hyaluronic acid, for example in surgical inter-ventions. Suitable for the prophylaxis or therapy of infl~mmatory or infectious irritations or diseases of the eye are, correspondingly, combinations with steroidal or non-steroidal antiinflammatory drugs or antibiotics.
It is additionally possible to use together with the thrombin inhibitor inhibitors of plasmin as well as plasminogen activator inhibitors (examples: PAI-1 and PAI-2), especially inhibitors of urokinase (proteins and low molecular weight substances).
,.
A pharmaceutical which contains these thrombin inhibitors and, where appropriate, others of the indicated active substances can be administered intravenously, orally, intraocularly or topically (eye drops) before, during or after operations. It can contain a thrombin inhibitor in an amount of 0.01 to 20 mg/kg of body weight ~oral or i.v. administration), preferably 0.05 to 5 mg/kg of body weight, and of G.01 to 100 ~g/kg o~ body weight ~intra-ocular, topical), pre~erably 0.1 to 10 ~g/kg of body weight.
The active sobstances as for example inhibitors of plasmin and/or plasminogen activator inhibitors which can be administered in addition to the thrombin inhibitors can be used in an amount of 0.001 to 50 mg/kg (oral/i.v.), preferably 0.01 to 10 mg/kg~ and of 0.001 to 100 ~g/kg, preferably 0.01 to 10 ~g/kg (in-traocular, topical).
; . -~.:
.". ~ .
:"'~ '`' .. .
:~
..:..
i :
.,.,:
B~HRI~GW~RRE ARTI~GESE~LSC~AFT HO~ 92/B 029 - Ma 967 Auslandstext THE USE OF THROMBIN I~IBITORS FOR T~E IN~IBITIO~
OF OCULAR FIBRI~ FORMATIO~
The invention relates to the use of substances which are able to inhibit the activity of solubie and fibrin- and cell-bound thrombin, in particular hirudin, its deriva-tives, peptide~ derived therefrom and low molecular weight thrombin inhibitors in a process for the prepara-tion of a pharmaceutical for the inhibition of ocularfibrin formation and deposition.
The activation of fibrinogen to fibrin represents the central reaction in the production of a primary wound closure~ This process which is so important after injury to the vascular system may, if there is uncontrolled fibrin formation and deposition Ithrombus), considerably impair physiological functions.
The crucial contribution to fibrinogen activation is provided by thrombin,the central protease in blood coagulation. Fibrin formation and deposition occur at sites of vascular injury and also extend into extravascular regions when plasma components, including fibrinogen, leave the vascular system ~for exampls when endothelial permeability is increased) as, ~or example, during the course of certain diseases or during or afker surgical interventions. The endogenous fibrinolytic system i.s able after some time to dissolve these fibrin deposits or thrombi. The situation is usually diferent with certain eye diseases or after operations on the eye during the course of which or postoperatively there may be considerable impairments of vision by fibrin tfor example dimness, opalescence, starburst effect), in somP
cases associated with pain~ However, the intraocular activit~ of endogenous fibrinolysis is zero or only very ' ~ 2 --low, which means that the impairments frequently last a long time and may lead to blindness.
The fibrin/thrombus breakdown can be therapeutically initiated or accelerated by administration of substances with fibrinolytic activity, such as tissue plasminogen activator (t-PA). However, treatment of this type may have disadvantageous effects on wound healing processes.
Moreover, it is known that fibrin degradation products liberated during these breakdown processes have chemotactic effects on macrophages and granulocytes and thus considerably increasP the risk of intraocular inflammation~
It is therefore expedient to take prophylactic measures against fibrin formation and deposition. The initial activation of fibrinogen can be substantially suppressed by inhibiting the activity of soluble thrombin, as described in EP-A-0 353 018 for the plasma inhibitor antithrombin III (AT III ) . AT III displays its complete activity only in combination with its cofactor heparinO
The efficacy of these substances is, however, limited by the fact that they are able adequately to inhibit only soluble thrombin. By contrast, thrombin molecules which are bound to fibrin or cell surfaces are poorly inhibited by A~ III/heparin. It is known that such surface-bound thrombin activities represent a considerable problem because they cause further fibrin deposits. In addition, they activate other coagulation factors and thus increa~;e the risk of ocular thrombi in eye diseases and operatiorls on the eye.
The object therefoxe was to develop an ocular thrombosis prophylaxis with ~ubstances which are able to inhibit not only soluble but also fibrin- and cell-bound throm~in.
The invention relates to the use of substances which are able to inhibit the activity of soluble and fibrin- and cell bound thrombin in a process for the preparation of . .
a pharmaceutical for the inhibition of ocular fibrin formation and deposition.
Substances of this type which are preferred ar~ hirudin, its derivatives, peptides derived therefrom or low S molecular weight thrombin inhibitors.
Hirudin is a speci~ic thrombin inhibitor which is 7 kDa in size and is derived from the leech Hirudo medicinalis and can be prepared by genetic manipulation and which efficiently inhibits both soluble and surface-associated thrombin independently of cofactors. Likewise suitable are derivatives of hirudin, for example those which contain part sequences from the amino-acid sequence of hirudin or variants of this sequence, an analog or generally functional equivalents of hirudin or low molecular weight thrombin inhibitors with the properties described above, such as ~2R,4R)-4-methyl-1-[N-~3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]-2-piperidine and substances described in EP-A-0 097 630 or 0 468 231.
Where ocular fibrin deposits already exist, the use of these substances is likewise worthwhile because the QppOSing processes of fibrin deposition and endogenous thrombus disintegration are shifted in favor of fibrino-lysis. Therapeutic administration of the corresponding thrombin inhibi-tors with substances with fibrinolytic activity, for example intraocularly with t-PA, i~ lik~-wise used for the said reasons.
These inhibitors are used, for axample, during/after cataract, glaucoma operations, vitrectomies and la~er-surgical interventions (for example photocoagulation,laser ablation) during the course of which hyphemas ~hemorrhages in chambers of the eye) with subsequent fibrin deposition/thrombus formation ara a frequen-t occurrence. This ~avors inter alia the development of glaucomas ~interference with the outflow of ~luid). The ,~. . ..
; ' i--' described inhibitors are also used after lens implanta-tions because the resulting fibrin deposits ~caused inter alia by the artificial surfaces) may cause iridocyclitis, inflammation of the iris and of the ciliary body. Also not uncommon ~re retinal arterial or venous thromhoses (for example during the course of diabetes mellitus, autoimmune diseases or after operations), which can be prevented by the inhibitors. These inhibitors can be used in combination with volume replacers such as, for example, hyaluronic acid, for example in surgical inter-ventions. Suitable for the prophylaxis or therapy of infl~mmatory or infectious irritations or diseases of the eye are, correspondingly, combinations with steroidal or non-steroidal antiinflammatory drugs or antibiotics.
It is additionally possible to use together with the thrombin inhibitor inhibitors of plasmin as well as plasminogen activator inhibitors (examples: PAI-1 and PAI-2), especially inhibitors of urokinase (proteins and low molecular weight substances).
,.
A pharmaceutical which contains these thrombin inhibitors and, where appropriate, others of the indicated active substances can be administered intravenously, orally, intraocularly or topically (eye drops) before, during or after operations. It can contain a thrombin inhibitor in an amount of 0.01 to 20 mg/kg of body weight ~oral or i.v. administration), preferably 0.05 to 5 mg/kg of body weight, and of G.01 to 100 ~g/kg o~ body weight ~intra-ocular, topical), pre~erably 0.1 to 10 ~g/kg of body weight.
The active sobstances as for example inhibitors of plasmin and/or plasminogen activator inhibitors which can be administered in addition to the thrombin inhibitors can be used in an amount of 0.001 to 50 mg/kg (oral/i.v.), preferably 0.01 to 10 mg/kg~ and of 0.001 to 100 ~g/kg, preferably 0.01 to 10 ~g/kg (in-traocular, topical).
; . -~.:
.". ~ .
:"'~ '`' .. .
:~
..:..
i :
.,.,:
Claims (7)
1. The use of substances which are able to inhibit the activity of soluble and fibrin- and cell-bound thrombin in a process for the preparation of a pharmaceutical for the inhibition of ocular fibrin formation and disposition.
2. The use as claimed in claim 1, wherein the thrombin inhibitor is hirudin, one of its derivatives or a peptide derived therefrom, which contain sequences from the amino-acid sequence of hirudin, or is an analog or generally a functional equivalent of hirudin.
3. The use as claimed in claim 1, wherein the thrombin inhibitor is a low molecular weight thrombin inhibitor.
4. The use as claimed in claim 1, wherein the thrombin inhibitor is used in a concentration of 0.01 to 20 mg/kg of body weight (oral or i.v. administra-tion), or of 0.01 to 100 µg/kg of body weight (intraocular, topical).
5. The use as claimed in claim 1, wherein the thrombin inhibitor is used in a concentration of 0.05 to 5 mg/kg of body weight (oral or i.v. administration) and of 0.1 to 10 µg/kg of body weight intraocular, topical).
6. The use as claimed in claim 1, wherein a pharma-ceutical or a pack unit which additionally contains a plasmin inhibitor or a plasminogen activator inhibitor is prepared.
7. The use as claimed in claim 1, wherein a pharmaceutical or a pack unit which additionally contains 0.001 to 50 mg/kg body weight (oral/i.v.) or 0.001 to 100 µg/kg body weight (intraocular, topical) of a plasmin inhibitor or a plas-minogen activator inhibitor is prepared.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4242655A DE4242655A1 (en) | 1992-12-17 | 1992-12-17 | Use of thrombin inhibitors to inhibit ocular fibrin formation |
| DEP4242655.3 | 1992-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2111644A1 true CA2111644A1 (en) | 1994-06-18 |
Family
ID=6475561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002111644A Abandoned CA2111644A1 (en) | 1992-12-17 | 1993-12-16 | Use of thrombin inhibitors for the inhibition of ocular fibrin formation |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0603112A1 (en) |
| JP (1) | JPH06228006A (en) |
| KR (1) | KR940013532A (en) |
| AU (1) | AU675090B2 (en) |
| CA (1) | CA2111644A1 (en) |
| DE (1) | DE4242655A1 (en) |
| NO (2) | NO934653D0 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5510369A (en) * | 1994-07-22 | 1996-04-23 | Merck & Co., Inc. | Pyrrolidine thrombin inhibitors |
| US5629324A (en) * | 1995-04-10 | 1997-05-13 | Merck & Co., Inc. | Thrombin inhibitors |
| US5798377A (en) * | 1996-10-21 | 1998-08-25 | Merck & Co., Inc. | Thrombin inhibitors |
| EP1265639A1 (en) * | 2000-03-20 | 2002-12-18 | Knoll GmbH | The use of anticoagulant agents in the extracorporeal treatment of blood |
| US6528503B2 (en) | 2000-12-18 | 2003-03-04 | Merck & Co., Inc. | Thrombin inhibitors |
| WO2002050056A1 (en) | 2000-12-18 | 2002-06-27 | Merck & Co., Inc. | Benzylamine derivatives and their use as thrombin inhibitors |
| WO2002064559A2 (en) | 2001-02-09 | 2002-08-22 | Merck & Co., Inc. | Thrombin inhibitors |
| US7084134B2 (en) | 2002-05-02 | 2006-08-01 | Merk & Co., Inc. | Thrombin inhibitors |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8203887D0 (en) * | 1982-06-23 | 1982-06-23 | Kabivitrum Ab | NEW TROMBIN INHIBITIVE ASSOCIATIONS |
| DE3445532A1 (en) * | 1984-12-13 | 1986-06-19 | Plantorgan Werk Heinrich G.E. Christensen, KG, 2903 Bad Zwischenahn | HIRUDIN-PA, DESULFATOHIRUDINE-PA, METHOD FOR PRODUCTION AND PHARMACEUTICAL AGENTS THAT CONTAIN THESE ACTIVE SUBSTANCES |
| GB8504025D0 (en) * | 1985-02-16 | 1985-03-20 | Biopharm Ltd | Hyaluronidase |
| PT84170B (en) * | 1986-01-24 | 1989-03-30 | Sanofi Sa | N-ALPHA-ARIL-SULFONYLAMINOACYL D-AMIDINEFENYL-ALANINAMID D NON-SUBSTITUTED DERIVATIVES PROCESS FOR THE PREPARATION OF N ALPHA-SUBSTITUTED DERIVATIVES |
| NL8902454A (en) * | 1989-10-03 | 1991-05-01 | Stichting Centraal Lab | MUTANTS OF THE HUMANE PLASMINOGENIC ACTIVATOR INHIBITOR 1 (PAI-1), THEIR PREPARATION AND USE, AND RECOMBINANT POLYNUCLEOTIDES INCLUDING GENETIC INFORMATION CODING FOR THESE MUTANTS. |
| TW201303B (en) * | 1990-07-05 | 1993-03-01 | Hoffmann La Roche | |
| DE4111394A1 (en) * | 1991-04-09 | 1992-10-15 | Behringwerke Ag | AMIDINOPHENYLALANINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE USE THEREOF AND MEANS THEREOF |
-
1992
- 1992-12-17 DE DE4242655A patent/DE4242655A1/en not_active Withdrawn
-
1993
- 1993-12-04 EP EP93710021A patent/EP0603112A1/en not_active Withdrawn
- 1993-12-15 AU AU52436/93A patent/AU675090B2/en not_active Ceased
- 1993-12-16 JP JP5316198A patent/JPH06228006A/en active Pending
- 1993-12-16 NO NO934653D patent/NO934653D0/en unknown
- 1993-12-16 NO NO934653A patent/NO934653L/en not_active Application Discontinuation
- 1993-12-16 CA CA002111644A patent/CA2111644A1/en not_active Abandoned
- 1993-12-16 KR KR1019930027965A patent/KR940013532A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0603112A1 (en) | 1994-06-22 |
| JPH06228006A (en) | 1994-08-16 |
| NO934653D0 (en) | 1993-12-16 |
| NO934653L (en) | 1994-06-20 |
| DE4242655A1 (en) | 1994-06-23 |
| AU675090B2 (en) | 1997-01-23 |
| KR940013532A (en) | 1994-07-15 |
| AU5243693A (en) | 1994-06-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |