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  Combinations of immunosupressive agents for the treatment or prevention of graft rejectionsUSPTO Application #: 20050277585Title: Combinations of immunosupressive agents for the treatment or prevention of graft rejections Abstract: A pharmaceutical composition useful in the treatment or prevention of transgenic xenograft rejection comprising immunosuppressant compounds selected from the group consisting of an IL-2 transcription inhibitor and immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts, and pharmaceutically acceptable diluents or carriers, and a method of preventing hyperacute rejection, reducing early graft damage, improving early xenograft function and promoting long term survival of said transgenic xenografts comprising the steps of i) contacting the body fluid removed from a human recipient with a xenoantigenic material which is bound to a biocompatible solid support, ii) reintroducing the treated body fluid into the recipient, and iii) treating the recipient with said pharmaceutical composition. (end of abstract)
Agent: Novartis Corporate Intellectual Property - East Hanover, NJ, US Inventors: Hendrik J. Schuurman, Emanuele Luigi Cozzi, Francoise Richard, Guy Taccard, David James Graham White, Peter John Friend, John Wallwork, Paolo Brenner USPTO Applicaton #: 20050277585 - Class: 514011000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, Monocyclic The Patent Description & Claims data below is from USPTO Patent Application 20050277585. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This is a continuation of International Application No. PCT/EP00/04250, filed May 10, 2000, the contents of which are incorporated herein by reference. [0002] This invention is concerned with certain novel pharmaceutical compositions comprising combinations of immunosuppressive agents, the use of such compositions for the treatment or prevention of xenograft rejection, and novel therapies for facilitating transplantation of xenogenic tissues or organs into humans and to promote long term survival of said tissues or organs. [0003] In order for xenotransplantation to present a clinically viable treatment for organ disease, it is necessary to effectively treat or prevent acute rejection and chronic rejection of donor organs. Effective treatments need to inhibit T-cells, and also B-cell-mediated or antibody-mediated rejection. [0004] However, a problem associated with combining compounds that suppress T-cells as well as compounds that act against B-cell-mediated rejection or antibody-mediated rejection is the potential and unpredictable pharmacokinetic interaction of the compounds which may influence the toxicity or the immunosuppression of the combination. [0005] Surprisingly, the applicant has found that pharmaceutical compositions comprising a certain combination of immunosuppressant compounds display good tolerability whilst at the same time display prolonged xenograft survival of donor organs, few rejection episodes and good graft function. [0006] The invention provides in one aspect a method of treatment or prevention of xenograft rejection which comprises administering of at least two immunosuppressant compounds indepentally selected from the group consisting of (a) IL-2 transcription inhibitors and (b) immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts. [0007] Pharmaceutical compositions useful in the treatment or prevention of xenograft rejection comprise at least two immunosuppressant compounds selected from the group consisting of (a) IL-2 transcription inhibitors and (b) immunosuppressant compounds that immuno-suppress for B-cell-mediated or antibody-mediated rejection of xenografts. [0008] Therefore, the invention provides in another aspect a pharmaceutical composition useful in the prevention or treatment of xenograft rejection comprising combinations of immunosuppressant compounds selected from the group consisting of (a) IL-2 transcription inhibitors and (b) immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts. [0009] In another aspect, the group of immunosuppressant compounds consists of (a) an IL-2 transcription inhibitor and (b) immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts. [0010] As used herein, including the claims, the combinations of immunosuppressant agents cover the administration of the agents for simultaneous, separate or sequential use. Thus e.g. they may be in a package or in a blister. [0011] The term "IL-2 transcription inhibitor" refers to immunosuppressive compounds whose immunosuppressive activity derives principally or in significant part from their direct or indirect inhibition of IL-2 gene transcription, e.g. corticosteroids, ascomycins and cyclosporines, FK506 and their various derivatives and analogues. [0012] Cyclosporine, (also known as cyclosporin A or cyclosporin) is an immunosuppressive cyclic undecapeptide. Its structure is disclosed, e.g. in the Merck Index, 11th edition; Merck & Co. Inc., Rahway, N.J., USA (1989) under listing 2759. Formulations of cyclosporine are commercially available under the trademark SANDIMMUN or SANDIMMUNE and a microemulsion preconcentrate formulation of cyclosporine is sold under the trademark NEORAL or OPTORAL. [0013] Immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts include rapamycin and/or derivatives thereof including 40-O-(2-hydroxyethyl)-rapamycin, or myriocin analogues such as 2-amino-2-[2-(4-octylphenyl)-ethyl]-1,3-propan- ediol, or mycophenolic acid (MPA) or pharmaceutically acceptable salts thereof, or cyclophosphamide. [0014] A preferred rapamycin derivative is 40-O-(2-hydroxyethyl)-rapamycin- . 40-O-(2-hydroxyethyl)-rapamycin is a rapamycin derivative the structure of which is disclosed in WO 94/09010, example 8, and is a semi-synthetic derivative of rapamycin. The structure of rapamycin is given in Kesseler, H., et al.; 1993; Helv. Chim. Acta; 76; 117, and numerous immunosuppressive derivatives and analogues of rapamycin are known. [0015] MPA sodium salt is known and is disclosed in published patent application No. WO 97/38689. Even more preferred is a MPA sodium salt in form of a formulation as described in U.S. Pat. No. 6,025,391 which is incorporated herein by reference. [0016] More preferred pharmaceutical compositions according to the invention comprise combinations of a pharmaceutically acceptable salt of mycophenolic acid (MPA), for example the sodium salt of MPA, rapamycin and/or derivatives thereof including 40-O-(2-hydroxy-ethyl)-rapamycin, and IL-2 transcription inhibitors. [0017] Most preferred pharmaceutical compositions according to the invention comprise double combinations of MPA sodium salt and cyclosporine or 40-O-(2-hydroxyethyl)-rapamycin, the double combination of cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin, or a triple combination of MPA sodium salt, cyclosporine and 40-O-(2-hydroxyethyl)-ra- pamycin. [0018] Pharmaceutical compositions according to the invention act synergistically, i.e. the immunosuppressive effect of the combination of compounds is greater than additive. This has the advantage that relatively low doses of each compound may be used in the pharmaceutical compositions. Synergy may be calculated according to a method described in Berenbaum, Clin. Exp. Immunol. (1977) 28:1. [0019] The indications for which the pharmaceutical compositions are useful are conditions associated with, or causal to, transplant rejection, for example treatment (including amelioration, reduction, elimination or cure of etiology or symptoms) or prevention (including substantial or complete restriction, prophylaxis or avoidance) of xenograft rejection, including acute and chronic rejection of an organ when the organ donor is of a different species from the recipient, most especially rejection mediated by B-cells or antibody-mediated rejection. [0020] Preferably, in one group of embodiments there is no IL-2 transcription inhibitor present. In another group of embodiments, one IL-2 transcription inhibitor is present, and yet in another group of embodiments, two or more IL-2 transcription inhibitors are present. [0021] More particularly the method comprises the administration of a pharmaceutical composition comprising a combination of a pharmaceutically acceptable salt of MPA, for example the sodium salt of MPA, rapamycin and/or derivatives thereof including 40-O-(2-hydroxyethyl)-rapamycin, and IL-2 transcription inhibitors. [0022] Preferably the method comprises the administration of a pharmaceutical composition comprising a combination of MPA sodium salt and one or more immunosuppressant compounds selected from the group consisting of (a) an IL-2 transcription inhibitor, especially cyclosporine, and (b) rapamycin and/or derivatives thereof, especially 40-O-(2-hydroxyethyl)-rapamycin. [0023] In a further aspect of the invention there is provided the use of a pharmaceutical composition comprising compounds selected from the group consisting of (a) an IL-2 transcription inhibitor and (b) immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts, in the treatment of a condition as hereinabove described. [0024] More particularly the invention provides the use of a pharmaceutical composition comprising a combination of a pharmaceutically acceptable salt of MPA, for example the sodium salt of MPA, rapamycin and/or derivatives thereof including 40-O-(2-hydroxyethyl)-rapamycin, and IL-2 transcription inhibitors, in the treatment of a condition as hereinabove described. Continue reading... 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