US20020132764A1 - Combinations of immunosupressive agents for the treatment or prevention of graft rejections - Google Patents
Combinations of immunosupressive agents for the treatment or prevention of graft rejections Download PDFInfo
- Publication number
- US20020132764A1 US20020132764A1 US10/035,663 US3566301A US2002132764A1 US 20020132764 A1 US20020132764 A1 US 20020132764A1 US 3566301 A US3566301 A US 3566301A US 2002132764 A1 US2002132764 A1 US 2002132764A1
- Authority
- US
- United States
- Prior art keywords
- human
- rejection
- treatment
- pharmaceutical composition
- mediated
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- 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.
- 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.
- 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.
- 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.
- the invention provides in another aspect a pharmaceutical composition useful in the prevention or treatment of xenograft rejection comprising combinations of immuno-suppressant 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.
- 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.
- 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.
- 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.
- 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.
- 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-propanediol, or mycophenolic acid (MPA) or pharmaceutically acceptable salts thereof, or cyclophosphamide.
- 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-propanediol, or mycophenolic acid (MPA) or pharmaceutically acceptable salts thereof, or cyclophosphamide.
- 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.
- 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.
- 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.
- MPA mycophenolic acid
- 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)-rapamycin.
- compositions according to the invention act synergistically, i.e. the immuno-suppressive 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.
- 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.
- IL-2 transcription inhibitor 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- the invention provides the use of pharmaceutical compositions comprising combinations of MPA sodium salt and one or more immunosuppressant compounds selected from the group consisting of (a) an IL-2 transcription inhibitor, especially cyclo-sporine, and (b) rapamycin and/or derivatives thereof, especially 40-O-(2-hydroxyethyl)-rapamycin, in the treatment of a condition as hereinabove described.
- immunosuppressant compounds selected from the group consisting of (a) an IL-2 transcription inhibitor, especially cyclo-sporine, and (b) rapamycin and/or derivatives thereof, especially 40-O-(2-hydroxyethyl)-rapamycin, in the treatment of a condition as hereinabove described.
- kit-of-parts comprising any of the pharmaceutical compositions hereinabove described, especially a pharmaceutical compo-sition comprising MPA sodium salt and one or more immunosuppressant compounds selected from the group consisting of (a) an IL-2 transcription inhibitor, especially cyclo-sporine, and (b) rapamycin and/or derivatives thereof, especially 40-O-(2-hydroxyethyl)-rapamycin, together with instructions for use in the treatment or prevention of a condition as hereinabove described.
- a pharmaceutical compo-sition comprising MPA sodium salt and one or more immunosuppressant compounds selected from the group consisting of (a) an IL-2 transcription inhibitor, especially cyclo-sporine, and (b) rapamycin and/or derivatives thereof, especially 40-O-(2-hydroxyethyl)-rapamycin, together with instructions for use in the treatment or prevention of a condition as hereinabove described.
- the dosages of the compounds will vary depending on the individual to be treated, the route of administration and the nature and severity of the condition to be treated.
- an initial dose of about 2 to 3 times the maintenance dose may suitably be administered about 4 to 12 hours before transplantation, followed by a daily dosage of 2 to 3 times the maintenance dosage for one to two weeks, before gradually tapering down the dose at a rate of about 5% per week to reach the maintenance dose.
- each compound may be determined having regard to the particular therapeutic blood levels required for each compound.
- pharmaceutical compositions may be formed that are tolerated and which display synergistic action in immune suppression.
- a pharmaceutical composition comprising (a) an IL-2 transcription inhibitor, in particular cyclosporine, that may be delivered to a patient at a dosage such that the 16 hour blood trough level is e.g. up to 1500 ng per ml, e.g. 50 to 1500, e.g. 50 to 1000 ng per ml, e.g. up to 500 ng per ml, , e.g. 50 to 500 ng per ml, more particularly 100 to 500 ng per ml, e.g.
- the 16 hour blood trough level is e.g. 0.1 to 20, e.g. 0.1 to 10, e.g. 1 to 10, preferably 3 to 6 ⁇ g per ml of the active substance, or is e.g. 1 to 90, e.g. 5 to 50, e.g. 10 to 35 ng per ml, more particularly 10 to 20 ng per ml.
- a pharmaceutically acceptable salt of MPA for example the sodium salt of MPA
- the 16 hour blood trough level is e.g. 0.1 to 20, e.g. 0.1 to 10, e.g. 1 to 10, preferably 3 to 6 ⁇ g per ml of MPA.
- IL-2 transcription inhibitors, e.g. cyclosporine may be delivered to a patient at a dosage such that the 16 hour blood trough level of, e.g. cyclosporine is e.g. up to 1500 ng per ml, e.g. 50 to 1500, e.g. 50 to 1000 ng per ml, e.g.
- Rapamycin and/or derivatives thereof, e.g. 40-O-(2-hydroxyethyl)-rapamycin may be delivered to a patient at a dosage such that the 16 hour blood trough level of, e.g. 40-O-(2-hydroxyethyl)-rapamycin is e.g. 1 to 90, e.g. 5 to 50, e.g. 10 to 35 ng per ml, more particularly 10 to 20 ng per ml.
- the blood concentrations hereinabove described may be determined according to any convenient method known in the art.
- blood may be collected in EDTA-coated containers, and detection of blood levels may be carried out by, e.g. radioimmunoassay or by ELISA.
- Detection of MPA is suitably carried out after protein precipitation using acetonitrile using an HPLC method with UV detection at 305 nm. From the data collected in this way, the blood trough levels may be calculated by methods known in the art.
- the weight ratio of component compounds of the pharmaceutical compositions may vary having regard to the desired blood trough levels stated hereinabove.
- compositions may comprise combinations of (a) an IL-2 transcription inhibitor and (b) an immunosuppressant compound or compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts in a weight ratio of e.g. about 1:50 to 1000:1, e.g. about 1:50 to 500:1, e.g. about 1:50 to 200:1, more particularly 1:2 to 50:1, e.g. 10:1.
- a weight ratio e.g. about 1:50 to 1000:1, e.g. about 1:50 to 500:1, e.g. about 1:50 to 200:1, more particularly 1:2 to 50:1, e.g. 10:1.
- the combined weight of said immunosuppressant compounds is reflected in the aforementioned weight ratio.
- a pharmaceutical composition comprises MPA sodium salt and cyclosporine in a weight ratio of e.g. about 1:0.03 to about 1:2, e.g. about 1:0.03 to about 1:0.5.
- a pharmaceutical composition comprises MPA sodium salt and 40-O-(2-hydroxyethyl)-rapamycin in a weight ratio of about 1:0.0005 to 0.015, to 1:0.001 to 0.0075, in particular, 1:0.0025.
- MPA sodium salt may be applied at a dosage of e.g. 10 to 200, e.g. 10 to 100 mg/kg/day, preferably 20 to 60 mg/kg/day, in particular 40 to 60 mg/kg/day; whereas cyclosporine may be applied at a dosage of e.g. 10 to 100, e.g. 10 to 50 mg/kg/day, preferably 10 to 15 mg/kg/day, in particular 3 to 6 mg/kg/day. Most preferably MPA sodium salt may be applied at a dosage of 20 mg/kg/day and cyclosporine may be applied at a dosage of 10 mg/kg/day.
- MPA may be applied at dosages referred to in the preceding paragraph, whereas 40-O-(2- hydroxyethyl)-rapamycin may be applied at a dosage of from 0.05 to 1.5 mg/kg/day, e.g. 0.1 to 0.75 mg/kg/day, e.g. 0.25 to 0.5 mg/kg/day.
- MPA sodium salt may be applied at a dosage of 20 mg/kg/day and 40-O-(2-hydroxyethyl)-rapamycin may be applied at a dosage of 1.5 mg/kg/day.
- cyclosporine may be applied at a dosage of e.g. 10 to 100, e.g. 10 to 50 mg/kg/day, preferably 10 to 15 mg/kg/day, in particular 3 to 6 mg/kg/day; whereas 40-O-(2-hydroxyethyl)-rapamycin may be applied at a dosage of 0.05 to 1.5 mg/kg/day, e.g. 0.1 to 0.75 mg/kg/day, e.g. 0.25 to 0.5 mg/kg/day.
- MPA sodium salt may be applied at a dosage of e.g. 10 to 200, e.g. 10 to 100 mg/kg/day, preferably 20 to 60 mg/kg/day, in particular 40 to 60 mg/kg/day; cyclosporine may be applied at a dosage of e.g. 10 to 100, e.g. 10 to 50 mg/kg/day, preferably 10 to 15 mg/kg/day, in particular 3 to 6 mg/kg/day.
- 40-O-(2-hydroxyethyl)-rapamycin may be applied at a dosage of from 0.05 to 1.5 mg/kg/day, e.g. 0.1 to 0.75 mg/kg/day, e.g.
- MPA sodium salt may be applied at a dosage of 20 mg/kg/day
- 40-O-(2-hydroxyethyl)-rapamycin may be applied at a dosage of 1.5 mg/kg/day
- Cyclosporine may be applied at a dosage of 10 mg/kg/day.
- the dosages referred to hereinabove may be administered to a patient in any convenient way, for example individual dosages referred to hereinabove may be administered daily in 2 divided doses. Any regimen may be used, provided that therapeutic amounts of the individual compounds are delivered to the patient.
- an indicated daily dosage for MPA sodium salt is in the range of 0.5 to 2.0 g/day, e.g. about 1.5 g/day
- cyclosporine is in the range of from about 25 mg to about 1000 mg per day, preferably 50 mg to 500 mg per day
- 40-O-(2-hydroxyethyl)-rapamycin is in the range from about 0.25 mg to about 15 mg per day.
- the application of the pharmaceutical composition may be preceded by the administration of a suitable induction therapy, chosen from any suitable induction therapy known in the art, for example a short course of cyclophosphamide, e.g. up to 40 mg/kg, e.g. 20 to 40 mg/kg i.v. per day for 4 days.
- a tapering course of steroids e.g. methylprednisolone at a concentration of 1 mg/kg at day one tapering to a baseline of 0.2 mg/kg/day may be administered.
- the compounds hereinabove described may be used in pharmaceutical compositions according to the invention in free or fixed combination, preferably in free combination.
- free is meant that each compound is formulated separately in a discrete dosage form.
- fixed is meant that the compounds are formulated together in one carrier.
- the pharmaceutical compositions may be both free and fixed whereby two or more compounds may be formulated in a single carrier whereas a further compound of the pharmaceutical composition may be formulated as a discrete dosage form.
- the individual dosage forms may be taken together or substantially at the same time (e.g. within fifteen minutes or less) so that, in the case of oral administration for example, said compounds are present simultaneously in the stomach.
- composition according to the invention may be formulated in any convenient dosage form, the component compounds being either in a single carrier or formulated as discrete dosage forms as in a free combination, for example oral dosage forms, e.g. solid oral dosage forms or solutions or dispersions, or in forms suitable for intravenous administration.
- oral dosage forms e.g. solid oral dosage forms or solutions or dispersions, or in forms suitable for intravenous administration.
- compositions for oral administration of, e.g. cyclosporine and/or 40-O-(2-hydroxyethyl)-rapamycin are suitably emulsions, microemulsions, preconcentrates of either, or solid dispersions, especially water-in-oil microemulsion preconcentrates or oil-in-water microemulsions.
- Cyclosporine may be formulated in any of the ways known in the art, in particular the known microemulsion preconcentrate formulations of cyclosporine are particularly suitable for use in the present invention.
- 40-O-(2-hydroxyethyl)-rapamycin may be formulated in any of the ways known in the art, for example as a microemulsion (see WO 96/13273), as a fat emulsion for use in intravenous administration (see WO 97/25977), as a suspension (see WO 96/13239) or as a solid oral dosage form, for example, as a co-precipitate with a suitable carrier medium (a so-called solid dispersion) as more fully described in WO 97/03654 all of which documents are incorporated herein by reference.
- a microemulsion see WO 96/13273
- a fat emulsion for use in intravenous administration see WO 97/25977
- a suspension see WO 96/13239
- solid oral dosage form for example, as a co-precipitate with a suitable carrier medium (a so-called solid dispersion) as more fully described in WO 97/03654 all of which documents are
- MPA sodium salt may be formulated in any of the ways described in WO 97/38689 which is incorporated herein by reference, in particular as a solid oral dosage form, e.g. an enteric-coated tablet.
- compositions according to the invention are useful as therapies in the treatment or prevention of xenograft rejection, including acute or chronic rejection of an organ from a discordant species, e.g. heart, lung, combined heart-lung, liver, kidney, islet cells, most especially when the rejection is mediated by B-cells or antibodies.
- a discordant species e.g. heart, lung, combined heart-lung, liver, kidney, islet cells, most especially when the rejection is mediated by B-cells or antibodies.
- compositions are useful in the treatments as set forth in the preceding paragraph, nevertheless a significant obstacle in the successful treatment of patients with the afore-mentioned pharmaceutical compositions is the prevention or amelioration of hyperacute rejection.
- Hyperacute rejection is the first immunological barrier to the transplantation of a donor organ from discordant species into humans. It occurs when the recipient's own immune system attacks and destroys the transplanted organ, usually within minutes or within a number of hours. Hyperacute rejection occurs in a xenograft because humans have pre-formed xenoreactive antibodies which bind to the animal tissue activating the human complement cascade and leading to graft damage. Accordingly, organ transplants from animal species, such as a pig, into humans may not be viable unless treatments are available that prevent hyperacute rejection.
- the invention provides in another aspect a method of treating a patient in need of such therapy comprising i) exposing the body fluid removed from a human recipient with a xenoantigenic material or anti human mono- or polyclonal antibodies or an other antibody adsorbent, which is bound to a biocompatible solid support, ii) reintroducing the treated body fluid into the recipient, and iii) treating the recipient with immunosuppressive drug therapy comprising a combination of immunosuppressant compounds selected from the group consisting of (a) IL-2 transcription inhibitor and (b) immunosuppressant compounds that immunosuppress for B-cell-mediated or antibody-mediated rejection of xenografts.
- 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.
- the step i) may be carried out using an Ig-Therasorb® column thereby selectively immunoadsorbing IgM, IgG and IgA.
- the step i) is usually carried out pre-operatively. However, alternatively or additionally it may be used perioperatively or post-operatively in parallel with the immunosuppressive drug therapy. Such post-operative use may be used if during treatment a build up of xenospecific antibodies is detected. Judicious use of the step i) and ii) pre-operatively, perioperatively and/or post-operatively in parallel with the immunosuppressive drug therapy may contribute significantly to the long term survival of donor organs. In addition to the improvement of the early graft function, effective treatments need to inhibit T-cells and also B-cell-mediated or antibody-mediated rejection. Accordingly, preferred immunosuppressive drug therapies for use in step iii) comprise any of the pharmaceutical compositions, dosages and other aspects as hereinabove described.
- Immunosuppression consists of induction therapy consisting of cyclophosphamide, Neoral® and a tapering course of steroids followed by maintenance therapy with a free combination of cyclosporine and MPA sodium salt as set forth in Table 1.
- Induction therapy consists of four non-consecutive daily intravenous injections of cyclo-phosphamide (40 mg/kg), Neoral® and methylprednisolone low dose treatment (1 mg/kg) day one and thereafter reducing the dose each day by 0.05 mg/kg, and subsequently to a baseline dose of 0.02 mg/kg/day as part of the maintenance therapy.
- Maintenance therapy subsequent to the induction therapy, consists of cyclosporine (Neoral®) and MPA sodium salt (MPA Na in Table 1) in the form of a powder in a 1% methylcellulose (Courtauld's Chemicals) solution.
- Donor male Chinese hamsters are obtained from Tongji Medical University.
- Recipient male SD rats are obtained from Tongji Medical University.
- Maintenance therapy consists of MPA sodium in the form of a powder in a 1% methylcellulose (Courtauld's Chemicals) solution, cyclosporine (Neoral®), and/or 40-O-(2-hydroxyethyl)-rapamycin in the form of a solid dispersion at 9.09% by weight, together with HPMC (81.82% by weight) and lactose (9.09% by weight).
- MPA sodium in the form of a powder in a 1% methylcellulose (Courtauld's Chemicals) solution, cyclosporine (Neoral®), and/or 40-O-(2-hydroxyethyl)-rapamycin in the form of a solid dispersion at 9.09% by weight, together with HPMC (81.82% by weight) and lactose (9.09% by weight).
- All compounds are freshly prepared before administration and dissolved in distilled water. The compounds are administered daily per oral by gavage ( ⁇ 2 ml/kg body weight).
- Cyclosporin A (Sandimmun®) given via intramuscular injection at a concentration of 100 mg/ml; and Optoral® given by oral gavage at 100 mg/mi.
- Cyclophosphamide (CyP) Endoxan® for injection at 200 mg/ml
- Methylprednisolon (MPS) Urbason® in a 40 mg vial.
- Prednisolon (PDN) Prednesol® as a 5 mg tablet.
- CyP is given i.v. on the day before surgery at 40 mg/kg, on the day of surgery at 20 mg/kg and on the second post-operative day at 20-30 mg/kg.
- An additional dose may be given up to 20 mg/kg on day 4.
- the last dose may be modified according to WBC and platelet count. Thereafter, CyP is administered only for rejection treatment.
- Mycophenolic acid sodium is given orally twice a day to ensure trough levels of 3-6 ⁇ g/ml.
- MPS is given at the time of surgery at a dose of 1 mg/kg i.v. On the following two days the same dose will be applied orally and thereafter the dose is reduced to 0.05 mg/kg/day until a baseline of 0.2 mg/kg is reached.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/178,573 US20050277585A1 (en) | 1999-05-10 | 2005-07-11 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US11/599,814 US20070060511A1 (en) | 1999-05-10 | 2006-11-15 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US12/109,210 US20080199478A1 (en) | 1999-05-10 | 2008-04-24 | Combinations of Immunosupressive Agents for the Treatment or Prevention of Graft Rejections |
US13/025,347 US8435520B2 (en) | 1999-05-10 | 2011-02-11 | Combinations of immunosuppressive agents for the treatment or prevention of graft rejections |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9910835.9A GB9910835D0 (en) | 1999-05-10 | 1999-05-10 | Organic compounds |
GB9910835.9 | 1999-05-10 | ||
GB9925443.5 | 1999-10-27 | ||
GBGB9925443.5A GB9925443D0 (en) | 1999-10-27 | 1999-10-27 | Organic compounds |
PCT/EP2000/004250 WO2000067773A2 (fr) | 1999-05-10 | 2000-05-10 | Composes organiques |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/004250 Continuation WO2000067773A2 (fr) | 1999-05-10 | 2000-05-10 | Composes organiques |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/178,573 Continuation US20050277585A1 (en) | 1999-05-10 | 2005-07-11 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
Publications (1)
Publication Number | Publication Date |
---|---|
US20020132764A1 true US20020132764A1 (en) | 2002-09-19 |
Family
ID=26315533
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/035,663 Abandoned US20020132764A1 (en) | 1999-05-10 | 2001-11-07 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US11/178,573 Abandoned US20050277585A1 (en) | 1999-05-10 | 2005-07-11 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US11/599,814 Abandoned US20070060511A1 (en) | 1999-05-10 | 2006-11-15 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US12/109,210 Abandoned US20080199478A1 (en) | 1999-05-10 | 2008-04-24 | Combinations of Immunosupressive Agents for the Treatment or Prevention of Graft Rejections |
US13/025,347 Expired - Fee Related US8435520B2 (en) | 1999-05-10 | 2011-02-11 | Combinations of immunosuppressive agents for the treatment or prevention of graft rejections |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/178,573 Abandoned US20050277585A1 (en) | 1999-05-10 | 2005-07-11 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US11/599,814 Abandoned US20070060511A1 (en) | 1999-05-10 | 2006-11-15 | Combinations of immunosupressive agents for the treatment or prevention of graft rejections |
US12/109,210 Abandoned US20080199478A1 (en) | 1999-05-10 | 2008-04-24 | Combinations of Immunosupressive Agents for the Treatment or Prevention of Graft Rejections |
US13/025,347 Expired - Fee Related US8435520B2 (en) | 1999-05-10 | 2011-02-11 | Combinations of immunosuppressive agents for the treatment or prevention of graft rejections |
Country Status (7)
Country | Link |
---|---|
US (5) | US20020132764A1 (fr) |
EP (2) | EP1181034B1 (fr) |
JP (1) | JP2002544167A (fr) |
AT (1) | ATE474590T1 (fr) |
AU (1) | AU4565000A (fr) |
DE (1) | DE60044717D1 (fr) |
WO (1) | WO2000067773A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060189683A1 (en) * | 2003-04-01 | 2006-08-24 | Markus Ahlheim | Parenteral formulation of mycophenolic acid, a salt or prodrug thereof |
US20070036857A1 (en) * | 2003-10-03 | 2007-02-15 | Dieter Becker | Pharmaceutical multiparticulate composition comprising mycophenolic acid or mycophenolate sodium and combination with rapamycin |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1208847E (pt) * | 1996-07-30 | 2007-07-24 | Novartis Ag | Composições farmacêuticas para o tratamento da rejeição de transplantes, doenças autoimunes ou inflamatórias compreendendo ciclosporina a e 40-0-(2-hidroxietil)-rapamicina |
AU3095601A (en) | 2000-01-14 | 2001-07-24 | Univ Pennsylvania | O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders |
GB0124953D0 (en) * | 2001-10-17 | 2001-12-05 | Novartis Ag | Organic Compounds |
CA2924681C (fr) | 2013-09-24 | 2019-12-31 | Giner, Inc. | Systeme pour le traitement gazeux d'un implant cellulaire |
US11033666B2 (en) | 2016-11-15 | 2021-06-15 | Giner Life Sciences, Inc. | Percutaneous gas diffusion device suitable for use with a subcutaneous implant |
US11642501B2 (en) | 2017-05-04 | 2023-05-09 | Giner, Inc. | Robust, implantable gas delivery device and methods, systems and devices including same |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5593677A (en) * | 1987-12-02 | 1997-01-14 | Becton Dickinson And Company | Method for prevention of graft versus host disease |
US5631282A (en) * | 1995-06-07 | 1997-05-20 | Merck & Co., Inc. | Triterpenes |
US5651968A (en) * | 1991-08-23 | 1997-07-29 | Alberta Research Council | Methods and compositions for attenuating antibody-mediated xenograft rejection in human recipients |
US5665728A (en) * | 1992-01-09 | 1997-09-09 | American Home Products Corporation | Method of treating hyperproliferative vascular disease |
US5688824A (en) * | 1994-07-05 | 1997-11-18 | Williams; James | Use of leflunomide to prevent or control xenograft rejection |
US5962415A (en) * | 1996-09-20 | 1999-10-05 | Bristol-Myers Squibb Co. | Compositions comprising a peptide inhibitor of nuclear protein translocation and an immunosuppressant and methods of use thereof |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5135934A (en) | 1990-07-06 | 1992-08-04 | Du Pont Merck Pharmaceutical Company | 3-phenyl-5,6-dihydrobenz(c) acridine-7-carboxylic acids and related compounds as immunosuppressive agents |
GB9221220D0 (en) | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
US5843452A (en) * | 1992-11-09 | 1998-12-01 | Pharmagenesis, Inc. | Immunotherapy composition and method |
EP0804734B1 (fr) | 1994-05-13 | 2005-05-04 | Miltenyi Biotec GmbH | Colonne sterile et apyrogene couplee a une proteine en vue de la fixation et de l'extraction de substances donnees du sang |
IL115742A (en) | 1994-10-26 | 2000-06-01 | Novartis Ag | Pharmaceutical compositions comprising a difficultly soluble active agent a hydrophilic phase a lipophilic phase and a surfactant |
US5697109A (en) | 1994-10-28 | 1997-12-16 | Barton Medical Corporation | Patient transport system |
BE1009856A5 (fr) | 1995-07-14 | 1997-10-07 | Sandoz Sa | Composition pharmaceutique sous la forme d'une dispersion solide comprenant un macrolide et un vehicule. |
GB9601120D0 (en) | 1996-01-19 | 1996-03-20 | Sandoz Ltd | Organic compounds |
GB9606452D0 (en) * | 1996-03-27 | 1996-06-05 | Sandoz Ltd | Organic compounds |
ID18663A (id) | 1996-04-12 | 1998-04-30 | Novartis Ag | Komposisi farmasi berlapis enterik |
PT1208847E (pt) * | 1996-07-30 | 2007-07-24 | Novartis Ag | Composições farmacêuticas para o tratamento da rejeição de transplantes, doenças autoimunes ou inflamatórias compreendendo ciclosporina a e 40-0-(2-hidroxietil)-rapamicina |
GB9619706D0 (en) | 1996-09-20 | 1996-11-06 | Pharmacia Spa | Synergistic immunosuppressant composition containing a 2,2'-bi-1H-pyrrole comp und |
WO1998047915A1 (fr) | 1997-04-18 | 1998-10-29 | Novartis Ag | Neoglycoproteines |
WO1999003336A1 (fr) | 1997-07-14 | 1999-01-28 | Nippon Meat Packers, Inc. | Mammiferes transgeniques |
-
2000
- 2000-05-10 AT AT00927193T patent/ATE474590T1/de active
- 2000-05-10 DE DE60044717T patent/DE60044717D1/de not_active Expired - Lifetime
- 2000-05-10 WO PCT/EP2000/004250 patent/WO2000067773A2/fr active Application Filing
- 2000-05-10 AU AU45650/00A patent/AU4565000A/en not_active Abandoned
- 2000-05-10 EP EP00927193A patent/EP1181034B1/fr not_active Expired - Lifetime
- 2000-05-10 JP JP2000616798A patent/JP2002544167A/ja active Pending
- 2000-05-10 EP EP08158054A patent/EP1980263A1/fr not_active Withdrawn
-
2001
- 2001-11-07 US US10/035,663 patent/US20020132764A1/en not_active Abandoned
-
2005
- 2005-07-11 US US11/178,573 patent/US20050277585A1/en not_active Abandoned
-
2006
- 2006-11-15 US US11/599,814 patent/US20070060511A1/en not_active Abandoned
-
2008
- 2008-04-24 US US12/109,210 patent/US20080199478A1/en not_active Abandoned
-
2011
- 2011-02-11 US US13/025,347 patent/US8435520B2/en not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5593677A (en) * | 1987-12-02 | 1997-01-14 | Becton Dickinson And Company | Method for prevention of graft versus host disease |
US5651968A (en) * | 1991-08-23 | 1997-07-29 | Alberta Research Council | Methods and compositions for attenuating antibody-mediated xenograft rejection in human recipients |
US5665728A (en) * | 1992-01-09 | 1997-09-09 | American Home Products Corporation | Method of treating hyperproliferative vascular disease |
US5688824A (en) * | 1994-07-05 | 1997-11-18 | Williams; James | Use of leflunomide to prevent or control xenograft rejection |
US5631282A (en) * | 1995-06-07 | 1997-05-20 | Merck & Co., Inc. | Triterpenes |
US5962415A (en) * | 1996-09-20 | 1999-10-05 | Bristol-Myers Squibb Co. | Compositions comprising a peptide inhibitor of nuclear protein translocation and an immunosuppressant and methods of use thereof |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060189683A1 (en) * | 2003-04-01 | 2006-08-24 | Markus Ahlheim | Parenteral formulation of mycophenolic acid, a salt or prodrug thereof |
US20070036857A1 (en) * | 2003-10-03 | 2007-02-15 | Dieter Becker | Pharmaceutical multiparticulate composition comprising mycophenolic acid or mycophenolate sodium and combination with rapamycin |
Also Published As
Publication number | Publication date |
---|---|
ATE474590T1 (de) | 2010-08-15 |
AU4565000A (en) | 2000-11-21 |
US20080199478A1 (en) | 2008-08-21 |
US20050277585A1 (en) | 2005-12-15 |
US8435520B2 (en) | 2013-05-07 |
EP1980263A1 (fr) | 2008-10-15 |
US20110142953A1 (en) | 2011-06-16 |
EP1181034A2 (fr) | 2002-02-27 |
WO2000067773A2 (fr) | 2000-11-16 |
JP2002544167A (ja) | 2002-12-24 |
DE60044717D1 (de) | 2010-09-02 |
EP1181034B1 (fr) | 2010-07-21 |
US20070060511A1 (en) | 2007-03-15 |
WO2000067773A3 (fr) | 2001-06-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8435520B2 (en) | Combinations of immunosuppressive agents for the treatment or prevention of graft rejections | |
EP1988882B1 (fr) | Prolongation de la survie d'un allogreffon par inhibition d'activite complementaire | |
AU2005244012C1 (en) | Prolongation of survival of an allograft by inhibiting complement activity | |
US7776829B2 (en) | Use of 15-deoxyspergualin for the treatment of hyperreactive inflammatory diseases and autoimmune diseases | |
ES2348077T3 (es) | Combinaciones de agentes inmunosupresores para el tratamiento o la prevención del rechazo de injertos. | |
US20240197816A1 (en) | Composition and method for prolong survival of transplant and recipient | |
Fasola et al. | DACLIZUMAB (DZB) INDUCTION IN ADULT HEPATITIS C (HCV) LIVER TRANSPLANT RECIPIENTS (OLT): A SINGLE CENTER EXPERIENCE WITH DIFFERENT ANTIBODY DOSES.: 176 | |
McCauley | Steroid-Free Lymphocyte Depletion Protocols | |
Lorf et al. | PRIMARY SIROLIMUS BASED IMMUNOSUPPRESSION ALLOWS DELAYED USE OF CNI IN LIVER TRANSPLANTATION.: 173 | |
Kirimlioglu et al. | LIVER PATHOLOLOGY AND CELL PROLIFERATION AFTER CALCINEURIN INHIBITORS AND ANTIPROLIFERATIVE DRUGS FOLLOWING PARTIAL HEPATECTOMY IN RAT.: 174 | |
Abdelaziz et al. | TACROLIMUS (FK 506) TOXICITY IN THE EARLY POSTOPERATIVE PERIOD FOLLOWING LIVING DONOR LIVER TRANSPLANTATION (LDLT) AMONG EGYPTIAN ADULTS: LIMITED EXPERIANCE.: 175 | |
Rodrigo | Share this story: RELATED ARTICLES | |
Ekberg | Malononitrilamides 715 and 279 Prolong Rat Cardiac Allograft Survival, Reverse Ongoing Rejection, Inhibit Allospecific Antibody Production and Interact Positively with Cyclosporin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: COZZI, EMANUELE LUIGI, ITALY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: RICHARD, FRANCOISE, FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: WHITE, DAVID JAMES GRAHAM, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: SCHUURMAN, HENDRIK J, MASSACHUSETTS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: FRIEND, PETER JOHN, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: WALLWORK, JOHN, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: TACCARD, GUY, FRANCE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 Owner name: BRENNER, PAOLO, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021471/0452 Effective date: 20080610 |
|
AS | Assignment |
Owner name: BRENNER, PAOLO, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS AG;REEL/FRAME:021514/0255 Effective date: 20080910 |