ZA200404656B - A method for determining the biological activity of defibrotide. - Google Patents
A method for determining the biological activity of defibrotide. Download PDFInfo
- Publication number
- ZA200404656B ZA200404656B ZA200404656A ZA200404656A ZA200404656B ZA 200404656 B ZA200404656 B ZA 200404656B ZA 200404656 A ZA200404656 A ZA 200404656A ZA 200404656 A ZA200404656 A ZA 200404656A ZA 200404656 B ZA200404656 B ZA 200404656B
- Authority
- ZA
- South Africa
- Prior art keywords
- plasmin
- defibrotide
- substrate
- concentration
- determining
- Prior art date
Links
- JNWFIPVDEINBAI-UHFFFAOYSA-N [5-hydroxy-4-[4-(1-methylindol-5-yl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-propan-2-ylphenyl] dihydrogen phosphate Chemical compound C1=C(OP(O)(O)=O)C(C(C)C)=CC(C=2N(C(=O)NN=2)C=2C=C3C=CN(C)C3=CC=2)=C1O JNWFIPVDEINBAI-UHFFFAOYSA-N 0.000 title claims description 81
- 229960004120 defibrotide Drugs 0.000 title claims description 81
- 238000000034 method Methods 0.000 title claims description 57
- 230000004071 biological effect Effects 0.000 title claims description 19
- 229940012957 plasmin Drugs 0.000 claims description 60
- 239000000758 substrate Substances 0.000 claims description 30
- 238000012360 testing method Methods 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000006911 enzymatic reaction Methods 0.000 claims description 5
- JBIJLHTVPXGSAM-UHFFFAOYSA-N 2-naphthylamine Chemical compound C1=CC=CC2=CC(N)=CC=C21 JBIJLHTVPXGSAM-UHFFFAOYSA-N 0.000 claims description 4
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 claims description 4
- GQAAGJRJCUHPEZ-GLKKMWKASA-N (2s)-6-amino-2-[[2-[[(2r)-2-amino-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-n-(4-nitrophenyl)hexanamide Chemical compound CC(C)[C@@H](N)C(=O)NC(C(C)CC)C(=O)N[C@@H](CCCCN)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 GQAAGJRJCUHPEZ-GLKKMWKASA-N 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000002798 spectrophotometry method Methods 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims 1
- 108010088842 Fibrinolysin Proteins 0.000 description 40
- 239000000523 sample Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- 238000002835 absorbance Methods 0.000 description 12
- 238000005259 measurement Methods 0.000 description 9
- 239000000872 buffer Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000002255 enzymatic effect Effects 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000023597 hemostasis Effects 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102100040423 Transcobalamin-2 Human genes 0.000 description 2
- 101710124862 Transcobalamin-2 Proteins 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003593 chromogenic compound Substances 0.000 description 2
- 238000004590 computer program Methods 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- -1 for example Chemical class 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- ORXWLYZHKCZVIC-RJGXRXQPSA-N (2s)-6-amino-n-[(2s)-2-[[(2r)-2-amino-3-methylbutanoyl]amino]-3-phenylpropanoyl]-2-(4-nitroanilino)hexanamide Chemical compound C([C@H](NC(=O)[C@H](N)C(C)C)C(=O)NC(=O)[C@H](CCCCN)NC=1C=CC(=CC=1)[N+]([O-])=O)C1=CC=CC=C1 ORXWLYZHKCZVIC-RJGXRXQPSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- XMTQQYYKAHVGBJ-UHFFFAOYSA-N 3-(3,4-DICHLOROPHENYL)-1,1-DIMETHYLUREA Chemical compound CN(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XMTQQYYKAHVGBJ-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 108010087249 S 2403 Proteins 0.000 description 1
- 102000005686 Serum Globulins Human genes 0.000 description 1
- 108010045362 Serum Globulins Proteins 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012886 linear function Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940036310 program Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 108010056926 valyl-phenylalanyl-lysine-4-nitroanilide Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
- C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/968—Plasmin, i.e. fibrinolysin
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Neurosurgery (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01830770A EP1325962A1 (en) | 2001-12-17 | 2001-12-17 | A method for determining the biological activity of defibrotide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200404656B true ZA200404656B (en) | 2005-06-13 |
Family
ID=8184814
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200404656A ZA200404656B (en) | 2001-12-17 | 2004-06-11 | A method for determining the biological activity of defibrotide. |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US7338777B2 (zh) |
| EP (2) | EP1325962A1 (zh) |
| JP (1) | JP4348192B2 (zh) |
| KR (1) | KR100912424B1 (zh) |
| CN (1) | CN100408690C (zh) |
| AR (1) | AR037870A1 (zh) |
| AT (1) | ATE480637T1 (zh) |
| AU (1) | AU2002360945B2 (zh) |
| CA (1) | CA2468877C (zh) |
| DE (1) | DE60237639D1 (zh) |
| DK (1) | DK1456404T3 (zh) |
| ES (1) | ES2349509T3 (zh) |
| HK (1) | HK1077332A1 (zh) |
| HR (1) | HRP20040548A2 (zh) |
| HU (1) | HUP0402231A3 (zh) |
| IL (2) | IL162511A0 (zh) |
| IS (1) | IS7312A (zh) |
| MX (1) | MXPA04005958A (zh) |
| NO (1) | NO20042972L (zh) |
| NZ (1) | NZ533594A (zh) |
| PL (1) | PL373243A1 (zh) |
| PT (1) | PT1456404E (zh) |
| RS (1) | RS63104A (zh) |
| RU (1) | RU2323979C2 (zh) |
| UA (1) | UA80104C2 (zh) |
| WO (1) | WO2003052130A2 (zh) |
| ZA (1) | ZA200404656B (zh) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1325962A1 (en) | 2001-12-17 | 2003-07-09 | Gentium S.p.A. | A method for determining the biological activity of defibrotide |
| EP1872787A1 (en) * | 2006-06-27 | 2008-01-02 | Gentium S.p.A. | Use of defibrotide for the inhibition of heparanase |
| EP1982722A1 (en) * | 2007-04-16 | 2008-10-22 | Gentium S.p.A. | Use of oligotide for the treatment of renal diseases |
| EP2103689A1 (en) * | 2008-03-19 | 2009-09-23 | Gentium S.p.A. | Synthetic phosphodiester oligonucleotides and therapeutical uses thereof |
| AU2010363814B2 (en) | 2010-11-12 | 2016-05-19 | Gentium S.R.L. | Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD). |
| KR20150044877A (ko) * | 2012-06-22 | 2015-04-27 | 젠티엄 에스피에이 | 디파이브로타이드의 생물학적 활성 측정을 위한 유우글로불린에 기초한 방법 |
| US9655761B2 (en) | 2012-11-12 | 2017-05-23 | Djo, Llc | Orthopedic back brace |
| TWI615473B (zh) * | 2013-11-26 | 2018-02-21 | 金提恩責任有限公司 | 用於測定去纖維蛋白多核苷酸的生物活性之基於優球蛋白的方法 |
| EP3026122A1 (en) * | 2014-11-27 | 2016-06-01 | Gentium S.p.A. | Cellular-based method for determining the potency of defibrotide |
| RU2766143C2 (ru) * | 2017-07-26 | 2022-02-08 | Джентиум С.Р.Л. | Жидкая композиция дефибротида для лечения и профилактики веноокклюзионной болезни |
| CN111132663A (zh) | 2017-08-03 | 2020-05-08 | 爵士制药爱尔兰有限公司 | 包含高浓度核酸的制剂 |
| MX2020010689A (es) | 2018-04-12 | 2021-01-20 | Jazz Pharmaceuticals Inc | Defibrotida para la prevencion y tratamiento del sindrome de liberacion de citocinas y la neurotoxicidad asociada con la inmunodeplecion. |
| US20220023533A1 (en) | 2018-12-07 | 2022-01-27 | Jazz Phrmaceticals Ireland Limited | Subcutaneous delivery of high concentration formulations |
| EP4110287A1 (en) | 2020-02-28 | 2023-01-04 | Jazz Pharmaceuticals Ireland Limited | Delivery of low viscosity formulations |
| WO2022234101A1 (en) | 2021-05-06 | 2022-11-10 | Jazz Pharmaceuticals Ireland Limited | Defibrotide for the treatment and prevention of acute respiratory distress syndrome |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2154279A1 (de) * | 1970-11-03 | 1972-05-25 | Crinos Industria Farmaco | Medikamente für das fibrinolytische System |
| DE2812943C3 (de) * | 1978-03-23 | 1981-05-14 | Boehringer Mannheim Gmbh, 6800 Mannheim | Verfahren und Reagens zur Bestimmung der biologischen Aktivität von Heparin im Plasma |
| IT1170215B (it) * | 1983-09-12 | 1987-06-03 | Crinos Industria Farmaco | Composizione farmaceutica per il trattamento di stati di insufficienza renale acuta |
| IT1206341B (it) * | 1984-02-16 | 1989-04-14 | Crinos Industria Farmaco | Composizione farmaceutica per il trattamento dell'ischemia acuta del miocardio. |
| US5231006A (en) * | 1986-10-16 | 1993-07-27 | Behringwerke Aktiengesellschaft | Method for the determination of plasminogen |
| US5321006A (en) * | 1992-12-09 | 1994-06-14 | International Flavors & Fragrances Inc. | Flavor and fragrance compositions produced using process for quantitatively and qualitatively substantially continuously analyzing the aroma emitted from a living fruit |
| CN1187201A (zh) * | 1995-05-05 | 1998-07-08 | 生物药物研究与发展有限公司 | 血纤维蛋白交联和/或转谷氨酰胺酶的抑制剂 |
| GB9719161D0 (en) * | 1997-09-09 | 1997-11-12 | Glaxo Group Ltd | New therapeutic method |
| EP1325962A1 (en) | 2001-12-17 | 2003-07-09 | Gentium S.p.A. | A method for determining the biological activity of defibrotide |
-
2001
- 2001-12-17 EP EP01830770A patent/EP1325962A1/en not_active Withdrawn
-
2002
- 2002-11-27 RU RU2004121962/13A patent/RU2323979C2/ru not_active IP Right Cessation
- 2002-11-27 AT AT02795074T patent/ATE480637T1/de active
- 2002-11-27 WO PCT/EP2002/013371 patent/WO2003052130A2/en active Application Filing
- 2002-11-27 AU AU2002360945A patent/AU2002360945B2/en not_active Expired
- 2002-11-27 ES ES02795074T patent/ES2349509T3/es not_active Expired - Lifetime
- 2002-11-27 UA UA20040705856A patent/UA80104C2/uk unknown
- 2002-11-27 EP EP02795074A patent/EP1456404B1/en not_active Expired - Lifetime
- 2002-11-27 NZ NZ533594A patent/NZ533594A/xx unknown
- 2002-11-27 PT PT02795074T patent/PT1456404E/pt unknown
- 2002-11-27 JP JP2003552997A patent/JP4348192B2/ja not_active Expired - Lifetime
- 2002-11-27 PL PL02373243A patent/PL373243A1/xx not_active Application Discontinuation
- 2002-11-27 RS YU63104A patent/RS63104A/sr unknown
- 2002-11-27 CA CA2468877A patent/CA2468877C/en not_active Expired - Lifetime
- 2002-11-27 HU HU0402231A patent/HUP0402231A3/hu unknown
- 2002-11-27 DE DE60237639T patent/DE60237639D1/de not_active Expired - Lifetime
- 2002-11-27 KR KR1020047009476A patent/KR100912424B1/ko active IP Right Grant
- 2002-11-27 MX MXPA04005958A patent/MXPA04005958A/es unknown
- 2002-11-27 IL IL16251102A patent/IL162511A0/xx unknown
- 2002-11-27 DK DK02795074.0T patent/DK1456404T3/da active
- 2002-11-27 CN CNB028269799A patent/CN100408690C/zh not_active Expired - Lifetime
- 2002-12-17 AR ARP020104901A patent/AR037870A1/es not_active Application Discontinuation
-
2004
- 2004-06-11 ZA ZA200404656A patent/ZA200404656B/en unknown
- 2004-06-14 IS IS7312A patent/IS7312A/is unknown
- 2004-06-14 IL IL162511A patent/IL162511A/en active IP Right Grant
- 2004-06-16 HR HR20040548A patent/HRP20040548A2/hr not_active Application Discontinuation
- 2004-06-17 US US10/868,798 patent/US7338777B2/en not_active Expired - Lifetime
- 2004-07-14 NO NO20042972A patent/NO20042972L/no not_active Application Discontinuation
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2005
- 2005-10-20 HK HK05109348.5A patent/HK1077332A1/xx not_active IP Right Cessation
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