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
- 108010073385 Fibrin Proteins 0.000 title claims abstract description 18
- 102000009123 Fibrin Human genes 0.000 title claims abstract description 18
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229950003499 fibrin Drugs 0.000 title claims abstract description 18
- 229940122388 Thrombin inhibitor Drugs 0.000 title claims abstract description 17
- 239000003868 thrombin inhibitor Substances 0.000 title claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 230000005764 inhibitory process Effects 0.000 title claims abstract description 6
- 108090000190 Thrombin Proteins 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 11
- 229960004072 thrombin Drugs 0.000 claims abstract description 11
- 102000007625 Hirudins Human genes 0.000 claims abstract description 10
- 108010007267 Hirudins Proteins 0.000 claims abstract description 10
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 claims abstract description 10
- 229940006607 hirudin Drugs 0.000 claims abstract description 10
- 230000000694 effects Effects 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 4
- 230000037396 body weight Effects 0.000 claims description 10
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 claims description 8
- 230000000699 topical effect Effects 0.000 claims description 5
- 102000010752 Plasminogen Inactivators Human genes 0.000 claims description 4
- 108010077971 Plasminogen Inactivators Proteins 0.000 claims description 4
- 239000002806 plasmin inhibitor Substances 0.000 claims description 4
- 239000002797 plasminogen activator inhibitor Substances 0.000 claims description 4
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 150000001413 amino acids Chemical group 0.000 claims description 2
- 229940122791 Plasmin inhibitor Drugs 0.000 claims 2
- 230000008021 deposition Effects 0.000 abstract description 8
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 description 8
- 108010049003 Fibrinogen Proteins 0.000 description 4
- 102000008946 Fibrinogen Human genes 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229940012952 fibrinogen Drugs 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 3
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000003480 fibrinolytic effect Effects 0.000 description 3
- 238000011477 surgical intervention Methods 0.000 description 3
- 229960000187 tissue plasminogen activator Drugs 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229940012957 plasmin Drugs 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 241000284156 Clerodendrum quadriloculare Species 0.000 description 1
- 108010058861 Fibrin Fibrinogen Degradation Products Proteins 0.000 description 1
- 241000223783 Glaucoma Species 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000237902 Hirudo medicinalis Species 0.000 description 1
- 208000031354 Hyphema Diseases 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 102000004179 Plasminogen Activator Inhibitor 2 Human genes 0.000 description 1
- 108090000614 Plasminogen Activator Inhibitor 2 Proteins 0.000 description 1
- 206010036346 Posterior capsule opacification Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000208 fibrin degradation product Substances 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000000608 laser ablation Methods 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000007395 thrombosis prophylaxis Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
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)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (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)
- Ophthalmology & Optometry (AREA)
- Hematology (AREA)
- Diabetes (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).
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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) | NO934653L (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 |
AR027686A1 (en) * | 2000-03-20 | 2003-04-09 | Knoll Ag | USE OF INHIBITING SUBSTANCES OF COAGULATION IN THE EXTRACORPORE TREATMENT OF BLOOD |
CA2431588A1 (en) | 2000-12-18 | 2002-06-27 | Merck & Co., Inc. | Benzylamine derivatives and their use as thrombin inhibitors |
US6528503B2 (en) | 2000-12-18 | 2003-03-04 | Merck & Co., Inc. | Thrombin inhibitors |
US7144899B2 (en) | 2001-02-09 | 2006-12-05 | 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 NO NO934653A patent/NO934653L/en not_active Application Discontinuation
- 1993-12-16 JP JP5316198A patent/JPH06228006A/en active Pending
- 1993-12-16 NO NO934653D patent/NO934653D0/en unknown
- 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 |
---|---|
NO934653D0 (en) | 1993-12-16 |
DE4242655A1 (en) | 1994-06-23 |
KR940013532A (en) | 1994-07-15 |
NO934653L (en) | 1994-06-20 |
JPH06228006A (en) | 1994-08-16 |
EP0603112A1 (en) | 1994-06-22 |
AU5243693A (en) | 1994-06-30 |
AU675090B2 (en) | 1997-01-23 |
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