WO1996012500A1 - BEHANDLUNG VON HLA-DR-ASSOZIIERTER IMMUNDEFIZIENZ MIT INTERFERON-$g(g) - Google Patents
BEHANDLUNG VON HLA-DR-ASSOZIIERTER IMMUNDEFIZIENZ MIT INTERFERON-$g(g) Download PDFInfo
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- WO1996012500A1 WO1996012500A1 PCT/EP1995/004099 EP9504099W WO9612500A1 WO 1996012500 A1 WO1996012500 A1 WO 1996012500A1 EP 9504099 W EP9504099 W EP 9504099W WO 9612500 A1 WO9612500 A1 WO 9612500A1
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- hla
- interferon
- expression
- treatment
- patients
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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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/217—IFN-gamma
Definitions
- the invention relates to the treatment of immunodeficiency, which is associated with serious and long-lasting reduction in monocytic HLA-DR expression, with interferon- ⁇ (IFN- ⁇ ).
- IFN- ⁇ interferon- ⁇
- the major histocompatibility complex plays a central role in the ability of the immune system to distinguish between "self” and "not-self".
- the MHC refers to a cluster of genes that are responsible for the production of cell membrane surface molecules.
- the cell membrane molecules that are produced in response to the MHC genes are referred to as human leukocyte antigens (human leukocyte antigens, HLA).
- HLA human leukocyte antigens
- Three HLA classes were identified (see Fig. 1).
- HLA class I antigen referred to as HLA-A, -B, -C and HLA-E
- HLA class II antigen referred to as HLA-D (DR, DQ, DP, DZ, DX and DV ), and HLA Class III (Trowsdale J.
- HLA class I antigens are expressed on the surface of most cells in the human body
- HLA class II antigens are only expressed on the cell membranes of a limited number of cell types including monocytes / macrophages and B lymphocytes.
- Antigen-presenting cells such as macrophages process the microbial antigen and present it in association with HLA class II.
- T helper cells with a receptor binding site which is specific for this antigen bind to the exposed complex of the macrophages (Allen P.M., et al, Nature 327, 713-716, 1987). This activates the T helper cells.
- These activated T helper cells regulate all aspects of the immune response, including antibody production by B lymphocytes and the activity of the cytotoxic T cells. This activation is therefore a critical step in triggering the specific immune response.
- the density of HLA class II molecules on the cell surface of macrophages is one of the most important determinants in the recognition and response of T helper cells to processed antigen.
- Interferon- ⁇ plays a central role in the regulation and coordination of the immune response.
- Interferon- ⁇ is synthesized from activated T cells and NK cells (Vilcek J. et al., Lymphokines 11: 1-32, 1985). Alone or in combination with other cytokines, interferon- ⁇ regulates many aspects of the immune response.
- Interferon- ⁇ is a potent activator of macrophages, which play a central role in phagocytosis and antigen presentation.
- Interferon- ⁇ enhances HLA class I and HLA class Ü expression, thus intensifying recognition by T-lymphocytes and triggering the specific immune response.
- Interferon- ⁇ modulates antibody production by B lymphocytes, stimulates Ig production and inhibits IgE production.
- Interferon- ⁇ activates a wide range of target cells that can destroy antigen, including macrophages, granulocyte natural killer cells (NK cells) and cytotoxic T cells.
- interferon has a strong influence on HLA class Ü expression. This is remarkable because HLA class II expression by antigen-presenting cells is essential for the induction of the specific immune response and antibody formation (Janeway CA et al, Im munology Today 5: 99-105, 1984).
- the density of HLA class Ü expression on anti-gene presenting cells such as macrophage monocytes directly influences the extent of T cell activation.
- Interferon- ⁇ increases HLA class II expression.
- Antigen-presenting cells and can induce expression on cells that are normally HLA class II negative, such as endothelial, epithelial and endocrine cells.
- TNF tumor necrosis factor
- IL interleukin
- IL-6 interleukin-6
- TGF-ß transforming growth factor ß
- HLA-DR-associated immunodeficiency is characterized by a reduction in HLA-DR expression of monocytes to a value of less than 20% (by Baehr R. et al, Z. Klin. Med. 45: 1130-1137, 1990; Volk HD et al, Behring Inst. Mitt. 88: 208-215, 1991).
- HLA class II antigen expression of the B lymphocytes and the HLA class I antigen express sion normal.
- the selective loss of HLA-DR expression on the surface of monocytes lowers the ability of the monocytes / macrophages to present antigen (Volk HD et al, The Microbiologist 3: 20-26, 1992).
- mice Treatment of mice that are subsequently exposed to an experimental traumatic event, the in vitro treatment of human cells from patients with trauma and the prophylactic treatment of patients with serious injury immediately after hospitalization with interferon- ⁇ .
- interferon- ⁇ is an extremely efficient enhancer of monocytic HLA-DR expression.
- the critical condition of sepsis patients with HLA-DR depression is, however, characterized by a strong increase in TNF secretion.
- interferon- ⁇ is able to induce TNF. Therefore, in the public scientific discussion, the view prevailed that the treatment of sepsis patients with interferon- ⁇ could be harmful. Because interferon- ⁇ induces TNF production in monocytes, it has always been considered a dangerous agent for these patients and contraindicated.
- the object of the present invention was to provide agents for the treatment of diseases which are characterized by an immunodeficiency associated with a reduction in HLA-DR expression.
- diseases which are characterized by an immunodeficiency associated with a reduction in HLA-DR expression.
- diseases are in particular certain forms of septic diseases and serious infections.
- the task could be solved by providing interferon- ⁇ as a means.
- interferon- ⁇ resulted in a therapeutic benefit for the indicated indication.
- the invention thus relates to the use of interferon- ⁇ for the treatment of diseases which are characterized by a reduction in monocytic HLA-DR antigen expression, in particular if it is long-lasting and serious, and to pharmaceutical compositions for this indication, which contain interferon- ⁇ .
- the present invention relates to the use of in- terferon- ⁇ for the treatment of a subgroup of patients who have experienced a septic shock with or without organ failure and who are characterized by a serious and long-lasting decrease in monocytic HLA-DR expression.
- the therapy is particularly advantageous if the monocytic HLA-DR expression is ⁇ 30% and / or the duration of the lowered HLA-DR antigen expression is two or more days.
- the invention also includes IFN- ⁇ derivatives which can be prepared by a method known per se (e.g. EP-A 170 917, EP-A 219 781). Also included are IFN- ⁇ polypeptides that can be prepared by known synthetic methods on the protein and DNA level (e.g. EP-A 161 504; Tanaka S. et al, Nucl. Acids. Res. 11.1707-23 ( 1983)).
- the pharmaceutical or pharmaceutical formulations known and customary to the person skilled in the art are suitable for the respective application, but preferably those for parenteral application, in particular for intravenous, intramuscular, subcutaneous, intracutaneous, intra-articular, intrathecal, intraperitoneal infusion or injection, continuous infusions or intermittent infusions with the pumps available to the person skilled in the art or administration via microencapsulated preparations, e.g. B. based on liposomes z. B. are included according to EP-A 213 523.
- a ready-to-use solution for the use of interferon according to the invention for example as a bolus injection or as an injection or infusion
- the person skilled in the art has the aqueous infusion and injection solutions known to him for this purpose, optionally together with those known to him Auxiliary, carrier and / or stabilizing substances.
- a ready-to-use solution for the Use is to be made, for example, by adding highly purified interferon in "water for injections" or in physiological saline solution (pH 7 to 7.5) buffered with phosphate, optionally supplemented with tween and / or gelatin or an albumin, dissolved before application and sterile filled into suitable containers (e.g. syringes, ampoules, bags).
- the amount of interferon to be administered for the use according to the invention is based on the dosages known to the person skilled in the art, on the severity of the disease, on the response rate and on the further course of the disease and on the side effects. In general, it can therefore be assumed that the dosage must be based on individual criteria.
- a possible dosage is 25-200 ⁇ g, which can be given several times a day or at daily intervals, the duration and dose of interferon- ⁇ being dependent on the level of HLA-DR expression reached. As a rule, it can be assumed that values of approximately 50% and more indicate that the interferon- ⁇ therapy has ended
- the interferon- ⁇ therapy can advantageously be combined with other forms of therapy, particularly preferably with antibiotic or antifungal therapy.
- antibiotics that can be used in such combinations, are ampicillin, fosfomycin, cefazolin, chloramphenicol, Netilmiein, colistin, cefotaxime, cefamandole, cefoperazone, polymyxin B, cefotiam, cefmenoxime, ceftizoxime, ceftriaxone, ceftazidime, aztreonam, imipenem, cilastatin, Gentamicin, ofloxacin, cefotetan, cytarabine, ciprofloxacin, teicoplanin, gentamicin and amoxicillin.
- antifungals examples include amphotericin B, natamycin, clotrimazole, bifonazole, 4-hexylresorcinol, griseofulvin, tolnaftate, miconazole nitrate and nystatin.
- amphotericin B natamycin
- clotrimazole bifonazole
- 4-hexylresorcinol 4-hexylresorcinol
- griseofulvin tolnaftate
- miconazole nitrate miconazole nitrate
- nystatin examples of antifungals that can be used in such combinations.
- the different classes of active substances can be administered simultaneously or sequentially via the appropriate route in each case.
- Fig. 1 Arrangement of the human MHC loci on chromosome 6.
- Arrows indicate the direction of transcription. The number and order of class I loci i w unknown.
- Example 1 Treatment of a sepsis patient
- Sepsis was defined by tachypnea (breathing> 20 breaths / min.
- the patient is mechanically ventilated,> 10 1 / min., FiO 2 > 0.4 in the presence of PEEP ⁇ 5cm H j O]), tachycardia (heart rate> 110 beats / min.), Hyperthermia or hypothermia (core or rectal temperature> 38.5 ° C or ⁇ 35.6 ° C).
- Peripheral blood mononuclear cells from a sepsis patient were examined for HLA-DR expression by cytofluorometric analysis.
- the method according to Docke et al Docke, WD, P. Reinke, R. v. Baehr, H.-D. Volk. Monitoring of monocytic HLA-DR antigen expression during transplantation and sepsis.
- Schmitz, G, G Rothe ed.
- Vancomycin 750 mg, iV, active ingredient vancomycin-HCl
- Fortum (6 g, iV, active ingredient ceftazidime x 5 H 2 O)
- Certomycin 400 mg, iV, active ingredient netilmicinsulfate
- Targocid 800 mg, IV, active ingredient Teicoplanin
- Tobramycin 120 mg, IV
- Diflucan 200 mg, iv, active ingredient fluconazole
- amphomoronal (8 ml, per os, active ingredient amphotericin B
- Interferon- ⁇ administration (100 ⁇ g / 0.5ml, subcutaneously) started on the 2nd day of a decreased HLA-DR expression ⁇ 30%. Interferon- ⁇ therapy was terminated when the HLA-DR expression reached a value of over 50%.
- Septic syndrome was defined as clinical evidence suggesting an infection, plus signs of a systemic response to the infection, tachypnea (breathing> 20 breaths [when patients were mechanically ventilated,> 10 1 / min, FiO 2 > 0.4 in the present from PEEP ⁇ 5 cw H j O]), tachycardia (heart rate> 110 beats / min), hyper- or hypothermia (core or rectal temperature> 38.5 ° C or ⁇ 35.6 ° C), plus evidence of altered organ perfusion (at least one of the following parameters): PaO 2 / FiO 2 not higher than 280 (in the absence of other pulmonary or cardiovascular diseases), lactate levels above the upper limit of the normal value ( ⁇ 1.5 mmol / L) or kidney failure (urine release ⁇ 5 m is kg ' 1 IT 1 or> 12 ml kg- 1 h "1 , or serum BUN>
- Interferon gamma-lb (I ukin®, Boehringer Ingelheim, Germany) was obtained as a sterile solution for injection. Each tube contained 100 ⁇ g / 0.5 ml IFN- ⁇ . 5
- Treatment was continued until HLA-DR expression remained above 50% for 3 days.
- the intended treatment period was 28 days and the observation period was 28 days.
- Each patient received a subcutaneous injection of 100 ⁇ g / 0.5 ml IFN- ⁇ into the upper arm, thigh or abdomen every day at the same time before noon, but not in the posterior region. The patients were continuously monitored for tolerance.
- the primary endpoint of this study was the increase in HLA-DR + expression on monocytes, which was measured in the blood. Secondary endpoints were sepsis-related mortality, laboratory and clinical evaluation, and cytokine plasma levels (TNF- ⁇ , IL-6). All evaluations were carried out by the same doctor for each patient. All undesirable side effects were carefully documented and handled in accordance with the protocol.
- TNF- ⁇ and IL-6 were determined using a commercially available quantitative "sandwich" enzyme immunoassay (R&D Systems, Minneapolis, MN, USA). The assay uses a monoclonal antibody which is specific for TNF- ⁇ or IL-6, which is layered on a microtiter plate, and an enzyme-linked polyclonal antibody which is specific for the Cytokine is added after washing.
- the sensitivity of the assay is 0.7 pg / ml (IL-6) or 2.0 pg / ml (TNF- ⁇ ).
- Body temperature, heart rate, respiratory rate and blood pressure were monitored during the intensive treatment.
- Blood gases SaO 2 , paO 2 , paCO 2
- pH and FiO 2 were recorded daily.
- HLA-DR + monocytes IFN- ⁇ therapy led to a recovery of the decreased s HLA-DR expression on monocytes (Fig. 3). Eight out of ten patients showed an increase in HLA-DR monocytic expression within one day of treatment, while the other two responded within two to three days. On day 1 of treatment, HLA-DR + monocytes increased from a pre-treatment level of 27 ⁇ 6 to 62 ⁇ 8% (p ⁇ 0.01) and remained elevated in 8 patients during the 28-day observation period. w The administration of IFN- ⁇ was continued until the proportion of HLA-DR + monocytes remained stable for at least 3 days> 50%. Two patients received IFN- ⁇ a second time after HLA-DR + monocytes decreased again to ⁇ 30% to restore the decreased HLA-DR antigen expression on monocytes.
- IFN- ⁇ Treatment with IFN- ⁇ was accompanied by the restoration of the monocytic function. The latter was reflected by a significant increase in TNF- ⁇ - (p ⁇ 0.05) and IL-6- (p ⁇ 0.05) plasma levels in all 10 patients during treatment (Figs. 4 and 5). 0
- IFN- ⁇ was well tolerated by the patients and no adverse effects as demonstrated by clinical or laboratory findings were observed. Deteriorations in the condition of the patients or their laboratory values, as described, corresponded to the course of the underlying diseases. IFN- ⁇ treatment induced a decrease in body temperature (p ⁇ 0.05). No significant changes in systolic or diastolic pressures or leukocyte counts were observed during the 28-day observation phase.
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Abstract
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU50959/96A AU5095996A (en) | 1994-10-22 | 1995-10-19 | Interferon-gamma treatment of HLA-DR-associated immunodeficiency |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4437868.8 | 1994-10-22 | ||
DE4437868A DE4437868A1 (de) | 1994-10-22 | 1994-10-22 | Behandlung von HLA-DR-assoziierter Immundefizienz mit Interferon-gamma |
Publications (1)
Publication Number | Publication Date |
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WO1996012500A1 true WO1996012500A1 (de) | 1996-05-02 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP1995/004099 WO1996012500A1 (de) | 1994-10-22 | 1995-10-19 | BEHANDLUNG VON HLA-DR-ASSOZIIERTER IMMUNDEFIZIENZ MIT INTERFERON-$g(g) |
Country Status (5)
Country | Link |
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AU (1) | AU5095996A (de) |
CA (1) | CA2203255A1 (de) |
DE (1) | DE4437868A1 (de) |
WO (1) | WO1996012500A1 (de) |
ZA (1) | ZA958950B (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003074057A1 (de) * | 2002-03-05 | 2003-09-12 | Universitätsklinikum Charite Der Humboldt-Universität Zu Berlin Technologietransferstelle | Antiinfektiva und/oder immunnodulatoren zur präventiven therapie nach akutem schlaganfall |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102005053679A1 (de) * | 2005-06-24 | 2006-12-28 | Bayer Healthcare Ag | Therapeutischer Einsatz von Moxifloxacin zur Rekonstruktion von Funktionsstörungen des Immunsystems |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0356900A2 (de) * | 1988-08-29 | 1990-03-07 | BOEHRINGER INGELHEIM INTERNATIONAL GmbH | Verwendung von IFN-gamma enthaltenden Arzneimitteln zur Vorbeugung und Behandlung von durch primäre Immundefekte verursachte Krankheiten |
US5198212A (en) * | 1988-10-31 | 1993-03-30 | University Of Lousville Research Foundation Incorporated | Method and compositions for treatment of trauma-associated sepsis with gamma interferon |
-
1994
- 1994-10-22 DE DE4437868A patent/DE4437868A1/de not_active Withdrawn
-
1995
- 1995-10-19 WO PCT/EP1995/004099 patent/WO1996012500A1/de active Application Filing
- 1995-10-19 CA CA002203255A patent/CA2203255A1/en not_active Abandoned
- 1995-10-19 AU AU50959/96A patent/AU5095996A/en not_active Abandoned
- 1995-10-23 ZA ZA958950A patent/ZA958950B/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0356900A2 (de) * | 1988-08-29 | 1990-03-07 | BOEHRINGER INGELHEIM INTERNATIONAL GmbH | Verwendung von IFN-gamma enthaltenden Arzneimitteln zur Vorbeugung und Behandlung von durch primäre Immundefekte verursachte Krankheiten |
US5198212A (en) * | 1988-10-31 | 1993-03-30 | University Of Lousville Research Foundation Incorporated | Method and compositions for treatment of trauma-associated sepsis with gamma interferon |
Non-Patent Citations (4)
Title |
---|
GIBBONS R.A. ET AL: "Reduction in HLA-DR, HLA-DQ and HLA-DP expression by Leu-M3+ cells from the peripheral blood of patients with thermal injury", CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 75, OXFORD, pages 371 - 375 * |
HERSHMAN M.J. ET AL: "Interferon-gamma treatment increases HLA-DR expression on monocytes in severely injured patients", CLINICAL EXPERIMENTAL IMMUNOLOGY, vol. 77, OXFORD, pages 67 - 70 * |
HERSHMAN M.J. ET AL: "Modulation of Infection by gamma interferon treatment following trauma", INFECTION AND IMMUNITY, vol. 56, no. 9, WASHINGTON US, pages 2412 - 2416 * |
VOLK H.-D. ET AL: "Alterations in function and phenotype of monocytes from patients with septic disease- Predictive value and new therapeutic strategies", BEHRING INSTITUTE MITTEILUNGEN, vol. 88, MARBURG, pages 208 - 215 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003074057A1 (de) * | 2002-03-05 | 2003-09-12 | Universitätsklinikum Charite Der Humboldt-Universität Zu Berlin Technologietransferstelle | Antiinfektiva und/oder immunnodulatoren zur präventiven therapie nach akutem schlaganfall |
JP2005525361A (ja) * | 2002-03-05 | 2005-08-25 | ヒャリテ−ウニヴェルズィテーツメディジン ベルリン | 急性発作後の予防的治療用の作用物質 |
US8673934B2 (en) | 2002-03-05 | 2014-03-18 | Hans-Dieter Volk | Anti-infective agents and/or immunomodulators used for preventive therapy following an acute cerebrovascular accident |
Also Published As
Publication number | Publication date |
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ZA958950B (en) | 1996-04-22 |
DE4437868A1 (de) | 1996-04-25 |
AU5095996A (en) | 1996-05-15 |
CA2203255A1 (en) | 1996-05-02 |
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