CA2276564A1 - Modified c1 esterase inhibitor for blocking the infectiousness of hiv - Google Patents
Modified c1 esterase inhibitor for blocking the infectiousness of hiv Download PDFInfo
- Publication number
- CA2276564A1 CA2276564A1 CA002276564A CA2276564A CA2276564A1 CA 2276564 A1 CA2276564 A1 CA 2276564A1 CA 002276564 A CA002276564 A CA 002276564A CA 2276564 A CA2276564 A CA 2276564A CA 2276564 A1 CA2276564 A1 CA 2276564A1
- Authority
- CA
- Canada
- Prior art keywords
- hiv
- inhibitor
- esterase inhibitor
- modified
- infectiousness
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
- C07K14/8121—Serpins
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- AIDS & HIV (AREA)
- Immunology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
A modified C1 esterase inhibitor is described which on the one hand binds to the surface of HIV, but on the other hand not to human cell membranes.
This modified C1 esterase inhibitor can be used in vivo and in vitro for blocking the infectiousness of HIV.
This modified C1 esterase inhibitor can be used in vivo and in vitro for blocking the infectiousness of HIV.
Description
Modified C1 esterase inhibitor for blocking the infectiousness of HIV
The invention relates to a modified C1 esterase inhibitor which can be employed for blocking the infectiousness of human immunodeficiency virus (HIV) in vivo or in vitro.
It is known that the removal of HIV from biological fluids, but especially from blood, blood plasma or blood serum, is an important prerequisite for their risk-free use for all sorts of medical purposes. Numerous processes have therefore also already been proposed using which removal of HIV
from biological fluids should be achieved. Thus a process has been proposed in International Patent Application WO 97/07674 using which HIV can be removed from biological fluids or inactivated by treating them with certain ethylenimine oligomers. It is important in this case that other constituents of the blood, in particular the cellular constituents, especially the erythrocytes, are not damaged by a treatment of this type and the removal of HIV can be carried out in a simple manner and short time in order that sufficiently large amounts of purified blood can be obtained in an economically justifiable process.
It has also already been proposed to remove HIV from biological fluids adsorptively by means of filtration through a material impregnated with the C1 inhibitor.
The C1 inhibitor, also called C1 esterase inhibitor, is a protein present in the blood and is the main inhibitor of the classical pathway of the complement system and of the contact system. The C1 inhibitor can inhibit the activated form of factor XII and of kallikrein (Schapira M. et al., 1985, Complement 2: 111; Davis A.E., 1988, Ann Rev Immunol 6: 595; Sim R.B.
' CA 02276564 1999-06-29 et al., 1979, FEBS Lett 97: 111; De Agostini A. et al., 1984, J Clin Invest 73: 1542; Pixley R.A. et al., 1985, J Biol Chem 260: 1723; Schapira M, et al., 1982, J Clin Invest 69: 462; Van der Graaf F. et al., 1983, J Clin Invest 71: 149; Harpel P.C. et al., 1975, J clin Invest 55: 593). The C1 inhibitor thus regulates the activities of two plasma cascades, namely the complement system and the contact system, by which biologically active peptides are produced. The C1 inhibitor is therefore also an important regulator of the inflammatory system. The C1 inhibitor moreover inhibits the activated factor XI (Meijers J.C.M. et al., 1988, Biochemistry 27: 959;
Wuillemin W.A. et al., 1995, Blood 85: 1517). It follows from this that the C1 inhibitor can be considered as a coagulation inhibitor. The tissue plasminogen activator and plasmin are also inhibited to a certain extent by the C1 inhibitor, although that is not its main function (Harpel P.C. et al., 1975, J Clin Invest 55: 149; Booth N.A. et al., 1987, Blood 69: 1600).
The C1 inhibitor is obtained to a considerable extent from plasma by purification and utilized for clinical applications, in particular in the treatment of hereditary angioedema, a disorder which is caused by a genetically related tack of the C1 inhibitor. Moreover, it has already been described that by administration of the C1 inhibitor in systemic inflammations [International Patent Application WO 92/22320 (Genentech Inc.)], in severe burns, pancreatitis, bone marrow transplants, cytokine therapy and during use in a extracorporeal blood circulations [DE-A-4 227 762 (Behringwerke AG)] good therapeutic results were achieved.
The complete genomic and the cDNA which codes for the C1 inhibitor has already been cloned (Bock S.C. et al., 1986, Biochemistry 25: 4292; Carter P.E. et al., 1988, Eur J Biochem 173: 163). Various variants of the recombinant C1 inhibitor with amino acid mutations in the P1 and the P3 and/or P5 positions of the reactive center and variants which were isolated from patients with a hereditary angioedema have already been prepared recombinantly (Eldering E. et al., 1988, J Biol Chem 263: 11776; Eldering E. et al., 1993, J Biol Chem 267: 7013; Eldering E. et al., 1993, J Clin Invest 91: 1035; US-Patent 5,622,930; Davis A.E. et al., 1992, Nature Genetics 1: 354; Eldering E. et al., 1995, J Biol Chem 270: 2579; Verpy et al., 1995, J Clin Invest 95: 350).
The C1 inhibitor belongs to the large family of serine proteinase inhibitors which are also called serpines (Travis J. et al., 1983, Ann Rev Biochem 52:
655; Carrel R.W. et al., 1985, Trends Bioch Sci 10: 20). On SDS
polyacrylamide gels, the C1 inhibitor exhibits a molecular weight of approximately 105 KD. Its plasma concentration is approximately 270 mg/l (Schapira M et al., 1.985, Complement 2: 111; Nuijens JH et al., 1989, J
Clin Invest 84: 443). The C1 inhibitor is a protein whose plasma level can increase up to two-fold in uncomplicated infections and other inflammations (Kalter ES et al., 1985, J Infect Dis 151: 1019). The increased formation of the C1 inhibitor in inflammations probably serves to protect the body against the harmful effects of the intravascular activation of the complement system and of the contact system during the acute reactions.
The serpines react as inhibitors by formation of bimolecular complexes with the proteinase to be inhibited. In these complexes, the active center of the proteinase is bound by the active center of the serpine and thus inactive (Travis J. et al., 1983, Ann Rev Biochem 52: 655). The serpines react specifically with certain proteinases, this specificity being determined by the amino acid sequence of the reactive center.
The present invention starts from the observation that the infectiousness of HIV can be blocked by the administration of a C1 inhibitor.
As is known, the first step in an HIV infection consists in helper T
lymphocytes (TH cells) of the immune system, which carry CD4 receptors on their surface, entering into an interaction with the surface proteins of HIV. Antibodies against CD4 block the HIV infection of TH cells in vitro.
Even with an excess of free CD4 protein, the infection rate decreases in vitro. Both treatments admittedly block the infection, but do not destroy the virus. Similarly, the direct interaction between the surface proteins of HIV
and the CD4 receptors of the TH cells can be suppressed according to the invention by binding of HIV to the C1 inhibitor.
The human C1 inhibitor, however, not only has a great affinity for the coat proteins of HIV, but also a great affinity for the surface proteins of lymphocytes. By means of the C1 inhibitor, a bridge-like connection can be produced between the HIV and the TH cell in the manner of a spacer.
However, the infectiousness of HIV surprisingly still cannot be decreased by this. This can be achieved, however, if a modified C1 esterase inhibitor is employed which on the one hand has a high binding affinity for the coat proteins of HIV, but on the other hand does not bind to human cell membranes.
Modified C1 esterase inhibitors are available from different sources. Thus the C1 esterase inhibitors obtained from the blood of cattle or other mammals show no affinity for human cell membranes, in particular not for the CD4 receptors of the human TH cells. Their affinity for the surface proteins of HIV (gp120 and gp41), however, can be compared with that of the human C1 esterase inhibitor. An animal C1 esterase inhibitor is therefore able to bind to the surface proteins of HIV, but prevents any contact of HIV with the human CD4 receptors, since the C1 inhibitor does not adhere to the surfaces of the TH cells.
There is, however, also the possibility of preparing modified variants of the human C1 inhibitor by a genetic engineering route. The exact amino acid sequence of the human C1 inhibitor and the DNA sequence which codes for this human C1 inhibitor have been described by Bock et al., ' CA 02276564 1999-06-29 Biochemistry 25: 4292-4301, 1986 and by Davis et al., PNAS 83: 3161-3165, 1986. Biologically active variants of the C1 esterase inhibitor are known from the International Patent Application WO 91/06650. These variants can be prepared by recombinant expression processes, the DNA
coding for the C1 esterase inhibitor having specific deletions, insertions or substitutions of nucleotides.
Fundamentally, all non-human C1 esterase inhibitors which do not bind to lymphocytes can be employed for blocking the infectiousness of HIV.
These are either animal C1 esterase inhibitors isolated from natural material or animal C1 esterase inhibitors prepared recombinantly.
Moreover, a recombinantly modified, human C1 esterase inhibitor whose binding ability to the CD4 receptors of the T-helper cells is abolished can block the infectiousness of HIV. For this, modifications of the amino acid sequence of the C1 inhibitor causing the binding to the CD4 receptor are necessary, which can be carried out by recombinant methods known per se and are described in particular in the International Patent Application WO 92/22320.
The abovementioned non-human C1 esterase inhibitors and recombinantly modified, human C1 esterase inhibitors are expediently administered parenterally and in an amount sufficient for the therapeutic action. In general, they are administered to the patient in a physiological saline solution, a Ringer's solution or another excipient suitable for injection purposes.
The invention relates to a modified C1 esterase inhibitor which can be employed for blocking the infectiousness of human immunodeficiency virus (HIV) in vivo or in vitro.
It is known that the removal of HIV from biological fluids, but especially from blood, blood plasma or blood serum, is an important prerequisite for their risk-free use for all sorts of medical purposes. Numerous processes have therefore also already been proposed using which removal of HIV
from biological fluids should be achieved. Thus a process has been proposed in International Patent Application WO 97/07674 using which HIV can be removed from biological fluids or inactivated by treating them with certain ethylenimine oligomers. It is important in this case that other constituents of the blood, in particular the cellular constituents, especially the erythrocytes, are not damaged by a treatment of this type and the removal of HIV can be carried out in a simple manner and short time in order that sufficiently large amounts of purified blood can be obtained in an economically justifiable process.
It has also already been proposed to remove HIV from biological fluids adsorptively by means of filtration through a material impregnated with the C1 inhibitor.
The C1 inhibitor, also called C1 esterase inhibitor, is a protein present in the blood and is the main inhibitor of the classical pathway of the complement system and of the contact system. The C1 inhibitor can inhibit the activated form of factor XII and of kallikrein (Schapira M. et al., 1985, Complement 2: 111; Davis A.E., 1988, Ann Rev Immunol 6: 595; Sim R.B.
' CA 02276564 1999-06-29 et al., 1979, FEBS Lett 97: 111; De Agostini A. et al., 1984, J Clin Invest 73: 1542; Pixley R.A. et al., 1985, J Biol Chem 260: 1723; Schapira M, et al., 1982, J Clin Invest 69: 462; Van der Graaf F. et al., 1983, J Clin Invest 71: 149; Harpel P.C. et al., 1975, J clin Invest 55: 593). The C1 inhibitor thus regulates the activities of two plasma cascades, namely the complement system and the contact system, by which biologically active peptides are produced. The C1 inhibitor is therefore also an important regulator of the inflammatory system. The C1 inhibitor moreover inhibits the activated factor XI (Meijers J.C.M. et al., 1988, Biochemistry 27: 959;
Wuillemin W.A. et al., 1995, Blood 85: 1517). It follows from this that the C1 inhibitor can be considered as a coagulation inhibitor. The tissue plasminogen activator and plasmin are also inhibited to a certain extent by the C1 inhibitor, although that is not its main function (Harpel P.C. et al., 1975, J Clin Invest 55: 149; Booth N.A. et al., 1987, Blood 69: 1600).
The C1 inhibitor is obtained to a considerable extent from plasma by purification and utilized for clinical applications, in particular in the treatment of hereditary angioedema, a disorder which is caused by a genetically related tack of the C1 inhibitor. Moreover, it has already been described that by administration of the C1 inhibitor in systemic inflammations [International Patent Application WO 92/22320 (Genentech Inc.)], in severe burns, pancreatitis, bone marrow transplants, cytokine therapy and during use in a extracorporeal blood circulations [DE-A-4 227 762 (Behringwerke AG)] good therapeutic results were achieved.
The complete genomic and the cDNA which codes for the C1 inhibitor has already been cloned (Bock S.C. et al., 1986, Biochemistry 25: 4292; Carter P.E. et al., 1988, Eur J Biochem 173: 163). Various variants of the recombinant C1 inhibitor with amino acid mutations in the P1 and the P3 and/or P5 positions of the reactive center and variants which were isolated from patients with a hereditary angioedema have already been prepared recombinantly (Eldering E. et al., 1988, J Biol Chem 263: 11776; Eldering E. et al., 1993, J Biol Chem 267: 7013; Eldering E. et al., 1993, J Clin Invest 91: 1035; US-Patent 5,622,930; Davis A.E. et al., 1992, Nature Genetics 1: 354; Eldering E. et al., 1995, J Biol Chem 270: 2579; Verpy et al., 1995, J Clin Invest 95: 350).
The C1 inhibitor belongs to the large family of serine proteinase inhibitors which are also called serpines (Travis J. et al., 1983, Ann Rev Biochem 52:
655; Carrel R.W. et al., 1985, Trends Bioch Sci 10: 20). On SDS
polyacrylamide gels, the C1 inhibitor exhibits a molecular weight of approximately 105 KD. Its plasma concentration is approximately 270 mg/l (Schapira M et al., 1.985, Complement 2: 111; Nuijens JH et al., 1989, J
Clin Invest 84: 443). The C1 inhibitor is a protein whose plasma level can increase up to two-fold in uncomplicated infections and other inflammations (Kalter ES et al., 1985, J Infect Dis 151: 1019). The increased formation of the C1 inhibitor in inflammations probably serves to protect the body against the harmful effects of the intravascular activation of the complement system and of the contact system during the acute reactions.
The serpines react as inhibitors by formation of bimolecular complexes with the proteinase to be inhibited. In these complexes, the active center of the proteinase is bound by the active center of the serpine and thus inactive (Travis J. et al., 1983, Ann Rev Biochem 52: 655). The serpines react specifically with certain proteinases, this specificity being determined by the amino acid sequence of the reactive center.
The present invention starts from the observation that the infectiousness of HIV can be blocked by the administration of a C1 inhibitor.
As is known, the first step in an HIV infection consists in helper T
lymphocytes (TH cells) of the immune system, which carry CD4 receptors on their surface, entering into an interaction with the surface proteins of HIV. Antibodies against CD4 block the HIV infection of TH cells in vitro.
Even with an excess of free CD4 protein, the infection rate decreases in vitro. Both treatments admittedly block the infection, but do not destroy the virus. Similarly, the direct interaction between the surface proteins of HIV
and the CD4 receptors of the TH cells can be suppressed according to the invention by binding of HIV to the C1 inhibitor.
The human C1 inhibitor, however, not only has a great affinity for the coat proteins of HIV, but also a great affinity for the surface proteins of lymphocytes. By means of the C1 inhibitor, a bridge-like connection can be produced between the HIV and the TH cell in the manner of a spacer.
However, the infectiousness of HIV surprisingly still cannot be decreased by this. This can be achieved, however, if a modified C1 esterase inhibitor is employed which on the one hand has a high binding affinity for the coat proteins of HIV, but on the other hand does not bind to human cell membranes.
Modified C1 esterase inhibitors are available from different sources. Thus the C1 esterase inhibitors obtained from the blood of cattle or other mammals show no affinity for human cell membranes, in particular not for the CD4 receptors of the human TH cells. Their affinity for the surface proteins of HIV (gp120 and gp41), however, can be compared with that of the human C1 esterase inhibitor. An animal C1 esterase inhibitor is therefore able to bind to the surface proteins of HIV, but prevents any contact of HIV with the human CD4 receptors, since the C1 inhibitor does not adhere to the surfaces of the TH cells.
There is, however, also the possibility of preparing modified variants of the human C1 inhibitor by a genetic engineering route. The exact amino acid sequence of the human C1 inhibitor and the DNA sequence which codes for this human C1 inhibitor have been described by Bock et al., ' CA 02276564 1999-06-29 Biochemistry 25: 4292-4301, 1986 and by Davis et al., PNAS 83: 3161-3165, 1986. Biologically active variants of the C1 esterase inhibitor are known from the International Patent Application WO 91/06650. These variants can be prepared by recombinant expression processes, the DNA
coding for the C1 esterase inhibitor having specific deletions, insertions or substitutions of nucleotides.
Fundamentally, all non-human C1 esterase inhibitors which do not bind to lymphocytes can be employed for blocking the infectiousness of HIV.
These are either animal C1 esterase inhibitors isolated from natural material or animal C1 esterase inhibitors prepared recombinantly.
Moreover, a recombinantly modified, human C1 esterase inhibitor whose binding ability to the CD4 receptors of the T-helper cells is abolished can block the infectiousness of HIV. For this, modifications of the amino acid sequence of the C1 inhibitor causing the binding to the CD4 receptor are necessary, which can be carried out by recombinant methods known per se and are described in particular in the International Patent Application WO 92/22320.
The abovementioned non-human C1 esterase inhibitors and recombinantly modified, human C1 esterase inhibitors are expediently administered parenterally and in an amount sufficient for the therapeutic action. In general, they are administered to the patient in a physiological saline solution, a Ringer's solution or another excipient suitable for injection purposes.
Claims (6)
1. A modified C1 esterase inhibitor, which on the one hand binds to the surface proteins of HIV, but on the other hand not to human cell membranes.
2. The C1 esterase inhibitor as claimed in claim 1, which is of animal origin.
3. The C1 esterase inhibitor as claimed in claim 1, which is of recombinant origin.
4. A process for blocking the infectiousness of HIV, which comprises contacting it with a modified C1 esterase inhibitor which on the one hand binds to HIV, but on the other hand not to human cell membranes.
5. A pharmaceutical preparation, which comprises a C1 esterase inhibitor as claimed in claims 1 to 3 in a therapeutically efficacious amount.
6. The use of a C1 esterase inhibitor of claims 1 to 3, which is employed for blocking the infectiousness of HIV in vivo or in vitro.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19829014.4 | 1998-06-30 | ||
| DE19829014A DE19829014A1 (en) | 1998-06-30 | 1998-06-30 | Modified C1 esterase inhibitor to block the infectivity of HIV |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2276564A1 true CA2276564A1 (en) | 1999-12-30 |
Family
ID=7872412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002276564A Abandoned CA2276564A1 (en) | 1998-06-30 | 1999-06-29 | Modified c1 esterase inhibitor for blocking the infectiousness of hiv |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0969017A1 (en) |
| JP (1) | JP2000044599A (en) |
| KR (1) | KR20000006553A (en) |
| AU (1) | AU766767B2 (en) |
| CA (1) | CA2276564A1 (en) |
| DE (1) | DE19829014A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7220557B2 (en) | 1997-04-24 | 2007-05-22 | Human Genome Sciences, Inc. | METH1 polynucleotides |
| EP1658094A1 (en) * | 2003-08-19 | 2006-05-24 | ZLB Behring GmbH | C1-inh as a drug for treating viruses pathogenic to humans |
| WO2013005425A1 (en) | 2011-07-07 | 2013-01-10 | イハラケミカル工業株式会社 | Nitrobenzene compound manufacturing method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2601034B1 (en) * | 1986-07-03 | 1989-11-17 | Pasteur Institut | INHIBITOR OF THE ACTIVITY OF C1-ESTERASE PLASMATIC (C1-INHIBITOR) AND OF OTHER PROTEOLYTIC ENZYMES OF THE SERINE PROTEASE GROUP, PROCESS FOR PREPARING SAME, NUCLEIC ACIDS ENCODING THE SAME, DETECTION METHODS FOR DEFECTIVE CONDITIONS SAID INHIBITOR USING ANTIBODIES OR NUCLEOTIDE PROBES AND MEDICINES CONTAINING SAID SYNTHESIS INHIBITOR |
| WO1991006650A1 (en) * | 1989-10-27 | 1991-05-16 | Cetus Corporation | C1 inhibitor muteins and uses thereof |
| WO1992022320A1 (en) * | 1991-06-14 | 1992-12-23 | Genentech, Inc. | C1 inhibitor variants and treating inflammatory response with c1 inhibitor |
| DK0716611T3 (en) * | 1993-09-01 | 2002-05-21 | Sanquin Bloedvoorziening | Method of reducing myocardial lesion during acute myocardial infarction |
-
1998
- 1998-06-30 DE DE19829014A patent/DE19829014A1/en not_active Ceased
-
1999
- 1999-06-18 EP EP99111763A patent/EP0969017A1/en not_active Withdrawn
- 1999-06-29 AU AU36865/99A patent/AU766767B2/en not_active Ceased
- 1999-06-29 KR KR1019990025166A patent/KR20000006553A/en not_active Application Discontinuation
- 1999-06-29 CA CA002276564A patent/CA2276564A1/en not_active Abandoned
- 1999-06-29 JP JP11182805A patent/JP2000044599A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU3686599A (en) | 2000-01-13 |
| EP0969017A1 (en) | 2000-01-05 |
| KR20000006553A (en) | 2000-01-25 |
| JP2000044599A (en) | 2000-02-15 |
| DE19829014A1 (en) | 2000-01-05 |
| AU766767B2 (en) | 2003-10-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |