WO1991017767A1 - Procede de traitement de l'inhibition de la dipeptidyle aminopeptidase de type iv - Google Patents
Procede de traitement de l'inhibition de la dipeptidyle aminopeptidase de type iv Download PDFInfo
- Publication number
- WO1991017767A1 WO1991017767A1 PCT/US1991/003571 US9103571W WO9117767A1 WO 1991017767 A1 WO1991017767 A1 WO 1991017767A1 US 9103571 W US9103571 W US 9103571W WO 9117767 A1 WO9117767 A1 WO 9117767A1
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- tat
- protein
- binding
- inhibition
- sample
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- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4813—Exopeptidases (3.4.11. to 3.4.19)
Definitions
- This invention relates to treating diseases associated with inhibition of physiologically significant enzymes.
- DP-IV Dipeptidyl aminopeptidase
- EC number 3.4.14.5 serine protease
- CD-4+ and some CD-8+ T-cells and in low amounts in the central nervous system. It is thought to be involved in T-cell activation and immune regulation.
- HIV the virus believed to be the causative agent of Acquired Immune Deficiency Syndrome (AIDS)
- AIDS Acquired Immune Deficiency Syndrome
- the present invention features a method of treating, in a human patient, a disease state associated with inhibition of DP-IV by a protein by interfering with the inhibition caused by the protein.
- the disease state involves immunosuppression, e.g., such as that associated with HIV infection.
- the method involves interfering with the HIV protein Tat, a protein encoded by HIV which inhibits antigen-induced, but not mitogen-induced, lymphocyte proliferation in cell culture systems.
- Tat causes DP-IV inhibition and thus immunosuppression.
- the method of the invention preferably involves interfering with that binding, e.g., by competitive inhibition using a substance capable of binding to Tat to inhibit DP-IV-Tat binding; a preferred substance includes DP-IV or a Tat-binding fragment or analog thereof.
- Tat-DP-IV interaction also permits the exploitation of that interaction in the treatment of a different class of diseases, in which immunosuppression is desired, e.g. , autoimmune diseases such as rheumatoid arthritis and SLE, as well as malignancies such as T-cell leukemias.
- That method of effecting immunosuppression in a human patient in need of immunosuppression includes administering to the patient an immunosuppressive amount of Tat protein or a DP-IV-binding fragment or analog thereof.
- the invention also provides an assay for measuring the amount of Tat protein, and thus HIV activity, in a sample, e.g., a blood sample from an AIDS patient being monitored, that includes the steps of adding a pre-determined amount of DP-IV to the sample and measuring the level of DP-IV activity as an inverse measure of the amount of Tat protein in the sample.
- a sample e.g., a blood sample from an AIDS patient being monitored
- the level of DP-IV activity is measured colorimetrically.
- the invention provides an effective treatment for patients suffering from immunosuppressive diseases such as AIDS in which DP-IV activity is inhibited.
- the course of the therapy can be monitored readily by measuring the amount of Tat protein in a serum sample taken from the patient to which DP-IV has been added; the extent to which DP-IV activity is inhibited is a measure of the amount of Tat protein in the sample.
- the invention also provides an effective means of inducing immunosuppression in patients suffering from certain diseases by administering Tat protein.
- Fig. 1 is the nucleotide sequence and deduced amino acid sequence of DP-IV.
- Fig. 2 is the amino acid sequence of Tat protein. The Tat-DP-IV Interaction
- Tat protein found in patients infected with AIDS inhibits the activity of DP-IV.
- T-cells die they are not replenished at a sufficiently high rate, causing the patient to become immuno-compromised.
- HIV may act to cause T-cell depletion at least in part indirectly, by production of the Tat protein, which binds to and inhibits DP-IV, and prevents DP-IV from fulfilling its normal function in the T-cell proliferation process.
- DP-IV a Tat-binding fragment or analog thereof
- Administration is preferably by intravenous injection, so that DP-IV is placed directly into the bloodstream.
- Other forms of administration e.g., oral, topical, intramuscular, intraperitoneal, parenteral, nasal, or suppository
- Known techniques may be used to improve the efficacy and decrease the side effects of IV-administered DP-IV.
- DP-IV can be modified by attachment to the enzyme of numerous polyethylene glycol (PEG) molecules.
- PEG modification of the enzyme could increase half-life and in addition prevent administered enzyme from triggering an unwanted immune response.
- PEG treatment has been employed successfully with the enzyme adencsine deaminase (produced by Enzon, Inc., New Jersey).
- Tat could also be removed by administration of antibody (monoclonal or polyclonal) to Tat. Specificity can be enhanced by producing the antibody using, as an immunogen, a region of Tat which binds specifically to DP-IV.
- transition state analogs of DP-IV substrates bind tightly to and inhibit DP-IV; these analogs, described in Bachovchin et al. U.S. Serial No. 510,274, filed April 17, 1990, hereby incorporated by reference, contain the DP-IV-binding unit Ala-boro Pro. Antibodies to these transition state analogs can be expected to bind specifically to Tat.
- the amount of DP-IV administered is selected to cause the total circulating DP-IV level to be higher than the Tat protein level. In this way, a portion of the DP-IV is available to bind to the Tat protein, thereby causing it to be eliminated from the body, and the remaining portion is available to replenish depleted DP-IV levels in the body. Once normal DP-IV levels are restored, the body can begin replenishing depleted T-cells. Once normal immune function has been restored, the immune system may be able to more effectively combat HIV.
- the proper DP-IV dosage is selected by first measuring the level of Tat protein in the patient. This is preferably done by titration, i.e., by adding a pre-determined amount of DP-IV to a serum sample taken from the patient and then measuring the extent to which the Tat protein inhibits DP-IV activity, using standard protocols. Once the Tat protein level is known, an excess of DP-IV (e.g. , 2-3 times the molar Tat level) is administered to the patient, in a conventional pharmaceutically acceptable carrier, e.g., saline. Typical dosages are 1 - 500 mg/kg/day. AIDS patients may require periodic, e.g., daily, administration of DP-IV for life, much as a diabetic requires regular insulin injections for life.
- DP-IV can be administered in conjunction with other therapies, e.g., anti-viral agents such as AZT.
- DP-IV administeration could also be carried in conjunction with administeration of one or more products of DP-IV enzymatic action, e.g., cleaved cytokines, to replenish those products depleted by DP-IV deficiency.
- Cytokines e.g., IL-1 B and IL-2, which might be acted upon by DP-IV could be administered as well.
- Both DP-IV and Tat protein have been cloned and expressed, and can be made in quantity using conventional recombinant cell growth techniques.
- DP-IV is described in Hong et al., Proc. Natl. Acad. Sci.
- DP-IV nucleotide and amino acid sequence of DP-IV is shown in Fig. 1.
- the Tat protein is described in Frankel et. al., Proc. Natl. Acad. Sci. USA 86:7397-7401, and the amino acid sequence of Tat protein is shown in Fig. 2.
- Appropriate DP-IV or Tat-binding fragments or analogs of each protein can be determined using standard screening techniques.
- a second approach to therapeutically interfering with binding between Tat protein and DP-IV is to prepare a chromatography column containing DP-IV (or a Tat-binding fragment or analog thereof) . Blood from the patient is then passed through the column as in kidney dialysis. The DP-IV in the column binds Tat protein in the blood, thereby removing it from the blood. The cleansed blood is then returned to the patient.
- Other embodiments are within the following claims.
- the above-described procedures can be modified to treat patients suffering from diseases characterized by an excess of white blood cells such as leukemia by substituting Tat protein for DP-IV in the therapeutic method.
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- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
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- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Peptides Or Proteins (AREA)
Abstract
Procéde de traitement, chez un patient humain, d'un état pathologique associé à l'inhibition de la DP-IV par une protéine, consistant à interférer avec l'inhibition causée par ladite protéine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52613390A | 1990-05-21 | 1990-05-21 | |
US526,133 | 1990-05-21 |
Publications (1)
Publication Number | Publication Date |
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WO1991017767A1 true WO1991017767A1 (fr) | 1991-11-28 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1991/003571 WO1991017767A1 (fr) | 1990-05-21 | 1991-05-21 | Procede de traitement de l'inhibition de la dipeptidyle aminopeptidase de type iv |
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Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998050066A1 (fr) * | 1997-05-07 | 1998-11-12 | Trustees Of Tufts College | Potentialisation de la reponse immunitaire par production de composes se fixant a une dipeptidase cytoplasmique |
US5965532A (en) * | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
EP1084705A2 (fr) * | 1996-04-25 | 2001-03-21 | Probiodrug Gesellschaft für Arzneimittelforschung mbH | Méthode pour diminuer le taux de glucose sanguin des mammifères |
US6300314B1 (en) | 1998-05-04 | 2001-10-09 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US6355614B1 (en) | 1998-06-05 | 2002-03-12 | Point Therapeutics | Cyclic boroproline compounds |
US6503882B2 (en) | 1997-05-07 | 2003-01-07 | Trustees Of Tufts College | Treatment of HIV |
US6548481B1 (en) | 1998-05-28 | 2003-04-15 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV |
US6703238B2 (en) | 1997-09-29 | 2004-03-09 | Point Therapeutics, Inc. | Methods for expanding antigen-specific T cells |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US6844316B2 (en) | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
US6946480B2 (en) | 2002-02-28 | 2005-09-20 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
US6949515B2 (en) | 1999-08-24 | 2005-09-27 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US7053055B2 (en) | 1998-06-24 | 2006-05-30 | Prosidion Ltd. | Compounds of unstable DP IV-inhibitors |
US7084120B2 (en) | 1998-06-24 | 2006-08-01 | Probiodrug Ag | Prodrugs of DP IV-inhibitors |
US7109347B2 (en) | 2001-06-27 | 2006-09-19 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7132104B1 (en) | 2000-10-27 | 2006-11-07 | Probiodrug Ag | Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
US7371871B2 (en) | 2003-05-05 | 2008-05-13 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US7381537B2 (en) | 2003-05-05 | 2008-06-03 | Probiodrug Ag | Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease |
US7462599B2 (en) | 2003-10-15 | 2008-12-09 | Probiodrug Ag | Use of effectors of glutaminyl and glutamate cyclases |
US7608577B2 (en) | 2001-10-12 | 2009-10-27 | Osi Pharmaceuticals, Inc. | Peptidyl ketones as inhibitors of DPIV |
US20130089564A1 (en) * | 2001-06-06 | 2013-04-11 | Diamedica Inc. | Therapeutic Uses of Glandular Kallikrein |
US9364521B2 (en) | 2012-06-04 | 2016-06-14 | Diamedica Inc. | Human tissue kallikrein 1 glycosylation isoforms |
US9616015B2 (en) | 2012-05-25 | 2017-04-11 | Diamedica Inc. | Formulations of human tissue kallikrein-1 for parenteral delivery and related methods |
US11857608B2 (en) | 2017-03-09 | 2024-01-02 | Diamedica Inc. | Dosage forms of tissue kallikrein 1 |
-
1991
- 1991-05-21 WO PCT/US1991/003571 patent/WO1991017767A1/fr unknown
Non-Patent Citations (6)
Title |
---|
BIOL. CHEM. HOPPE-SEYLER, Volume 371(8), issued August 1990, E. SCHOEN et al., "Dipeptidyl Peptidase IV in the Immune Systems", pages 699-705. * |
CHEMICAL ABSTRACTS, Volume 112, No. 1, issued 29 January 1990, T. AOYAGI et al., "Suppression of the Activities of T-Lymphocyte-Related Enzymes in Spleen by Administration of an Immunosuppressant, 15-Deoxy-Spergualin", see page 27, 1, abstract no. 30376a; & BIOCHEM. INT. (1989), 19(4), 821-826. * |
EXPERIMENTAL CELL RESEARCH, Volume 178, issued September 1988, C. HANSKI et al., "Direct Evidence for the Binding of Rat Liver DPP IV to Collagen in Vitro", pages 64-72. * |
JOURNAL OF LEUKOCYTE BIOLOGY, Volume 48(4), issued October 1990, R.W. BARTON et al., "Binding of the T Cell Activation Monoclonal Antibody Ta 1 to Dipeptidyl Peptidase IV", pages 291-296. * |
PROC. NAT'L ACAD. SCI., USA, Volume 88, issued 15 February 1991, G.R FLENTKE et al., "Inhibition of Dipeptidyl Aminopeptidase IV (DP-IV) by Xaa-boro-Pro Dipeptides and Use of These Inhibitors to Examine the Role of DP-IV in T-Cell Function", pages 1556-1559. * |
SCAND. J. IMMUNOL., Volume 31(4), issued April 1990, A.J. ULMER et al., "CD26 Antigen is a Surface Dipeptidyl Peptidase IV (DPPIV) as Characterized by Monoclonal Antibodies Clone TII-19-4-7 and 4EL1C7", pages 429-435. * |
Cited By (43)
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US7230074B2 (en) | 1991-10-22 | 2007-06-12 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
US6825169B1 (en) | 1991-10-22 | 2004-11-30 | Trustees Of Tufts College | Inhibitors of dipeptidyl-aminopeptidase type IV |
EP1084705A3 (fr) * | 1996-04-25 | 2002-05-15 | Probiodrug Gesellschaft für Arzneimittelforschung mbH | Méthode pour diminuer le taux de glucose sanguin des mammifères |
EP1084705A2 (fr) * | 1996-04-25 | 2001-03-21 | Probiodrug Gesellschaft für Arzneimittelforschung mbH | Méthode pour diminuer le taux de glucose sanguin des mammifères |
EP2289513A3 (fr) * | 1996-04-25 | 2013-07-10 | Royalty Pharma Collection Trust | Méthode pour diminuer le taux de glucose sanguin des mammifères |
US5965532A (en) * | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
US6875737B1 (en) | 1996-06-28 | 2005-04-05 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
US6692753B2 (en) | 1997-05-07 | 2004-02-17 | Trustees Of Tufts College | Potentiation of the immune response |
US6503882B2 (en) | 1997-05-07 | 2003-01-07 | Trustees Of Tufts College | Treatment of HIV |
WO1998050066A1 (fr) * | 1997-05-07 | 1998-11-12 | Trustees Of Tufts College | Potentialisation de la reponse immunitaire par production de composes se fixant a une dipeptidase cytoplasmique |
US6040145A (en) * | 1997-05-07 | 2000-03-21 | Tufts University | Potentiation of the immune response |
AU724257B2 (en) * | 1997-05-07 | 2000-09-14 | Trustees Of Tufts College | Potentiation of the immune response through delivery of compounds binding a cytoplasmic dipeptidase |
US6703238B2 (en) | 1997-09-29 | 2004-03-09 | Point Therapeutics, Inc. | Methods for expanding antigen-specific T cells |
US6300314B1 (en) | 1998-05-04 | 2001-10-09 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US6770628B2 (en) | 1998-05-04 | 2004-08-03 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US7067489B2 (en) | 1998-05-04 | 2006-06-27 | Point Therapeutics, Inc. | Hematopoietic stimulation |
US6548481B1 (en) | 1998-05-28 | 2003-04-15 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV |
US6355614B1 (en) | 1998-06-05 | 2002-03-12 | Point Therapeutics | Cyclic boroproline compounds |
US7053055B2 (en) | 1998-06-24 | 2006-05-30 | Prosidion Ltd. | Compounds of unstable DP IV-inhibitors |
US7166579B2 (en) | 1998-06-24 | 2007-01-23 | Prosidion Limited | Prodrugs of DP IV-inhibitors |
US7084120B2 (en) | 1998-06-24 | 2006-08-01 | Probiodrug Ag | Prodrugs of DP IV-inhibitors |
US6949514B2 (en) | 1999-05-25 | 2005-09-27 | Point Therapeutics, Inc. | Anti-tumor agents |
US6890904B1 (en) | 1999-05-25 | 2005-05-10 | Point Therapeutics, Inc. | Anti-tumor agents |
US6949515B2 (en) | 1999-08-24 | 2005-09-27 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US7335645B2 (en) | 1999-08-24 | 2008-02-26 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV for topical use |
US7435420B2 (en) | 2000-10-27 | 2008-10-14 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors for the treatment of anxiety |
US7132104B1 (en) | 2000-10-27 | 2006-11-07 | Probiodrug Ag | Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders |
US6890905B2 (en) | 2001-04-02 | 2005-05-10 | Prosidion Limited | Methods for improving islet signaling in diabetes mellitus and for its prevention |
US20130089564A1 (en) * | 2001-06-06 | 2013-04-11 | Diamedica Inc. | Therapeutic Uses of Glandular Kallikrein |
US7368421B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
US7368576B2 (en) | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7109347B2 (en) | 2001-06-27 | 2006-09-19 | Probiodrug Ag | Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents |
US7144856B2 (en) | 2001-09-06 | 2006-12-05 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US6844316B2 (en) | 2001-09-06 | 2005-01-18 | Probiodrug Ag | Inhibitors of dipeptidyl peptidase I |
US7608577B2 (en) | 2001-10-12 | 2009-10-27 | Osi Pharmaceuticals, Inc. | Peptidyl ketones as inhibitors of DPIV |
US6946480B2 (en) | 2002-02-28 | 2005-09-20 | Hans-Ulrich Demuth | Glutaminyl based DPIV inhibitors |
US7371871B2 (en) | 2003-05-05 | 2008-05-13 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
US7381537B2 (en) | 2003-05-05 | 2008-06-03 | Probiodrug Ag | Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease |
US7462599B2 (en) | 2003-10-15 | 2008-12-09 | Probiodrug Ag | Use of effectors of glutaminyl and glutamate cyclases |
US9616015B2 (en) | 2012-05-25 | 2017-04-11 | Diamedica Inc. | Formulations of human tissue kallikrein-1 for parenteral delivery and related methods |
US9364521B2 (en) | 2012-06-04 | 2016-06-14 | Diamedica Inc. | Human tissue kallikrein 1 glycosylation isoforms |
US9839678B2 (en) | 2012-06-04 | 2017-12-12 | Diamedica Inc. | Human tissue kallikrein 1 glycosylation isoforms |
US11857608B2 (en) | 2017-03-09 | 2024-01-02 | Diamedica Inc. | Dosage forms of tissue kallikrein 1 |
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