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WO2006005620A1 - Utilisation de manzamines dans la transplantation et les maladies auto-immunes - Google Patents

Utilisation de manzamines dans la transplantation et les maladies auto-immunes Download PDF

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Publication number
WO2006005620A1
WO2006005620A1 PCT/EP2005/007678 EP2005007678W WO2006005620A1 WO 2006005620 A1 WO2006005620 A1 WO 2006005620A1 EP 2005007678 W EP2005007678 W EP 2005007678W WO 2006005620 A1 WO2006005620 A1 WO 2006005620A1
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WO
WIPO (PCT)
Prior art keywords
manzamine
manzamines
recipient
organ
cell
Prior art date
Application number
PCT/EP2005/007678
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English (en)
Inventor
Peter C. Hiestand
Frank Petersen
Silvio Roggo
Mark T. Hamann
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
The University Of Mississippi
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Filing date
Publication date
Application filed by Novartis Ag, Novartis Pharma Gmbh, The University Of Mississippi filed Critical Novartis Ag
Publication of WO2006005620A1 publication Critical patent/WO2006005620A1/fr

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Classifications

    • 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
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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

Definitions

  • the present invention relates to a new use of a group of sponge-derived alkaloids known as or closely related to the "manzamines" as well as rationally prepared and natural derivatives and analogs thereof, particularly as an immunosuppressive agent, e.g. for the prevention, treatment or inhibition of acute or chronic graft rejection or autoimmune diseases.
  • Manzamines are defined as a class of alkaloids isolated from the Phylum Porifera and containing a sophisticated array of aromatic and aliphatic rings.
  • manzamines are complex, polycyclic, marine-derived alkaloids first reported by Higa and coworkers in 1986 and isolated from the Okinawan sponge genus Haliclona. See, Sakai, R; Higa, T.; Jefford, C.W.; Bernardinelli, G. "Manzamine A; An Antitumor Alkaloid From a Sponge," J. Am. Chem, Soc. 1986, 108, 6404-6405. These compounds possess a fused and bridged tetra- or pentacydic ring system that is attached to a ⁇ -carboline moiety.
  • the manzamine alkaloids can be isolated from a diversity of unrelated species .
  • the manzamines can be produced by a microorganism from the actinomycete class based on WO2004013297, Microbial Production of Manzamines, Russell, T. Hill, Mark T. Hamann, Olivier Peraud and Noer Kasanah, The Center of Marine Biotechnology, University of Maryland Biotechnology Institute, The University of Mississippi, and the National Center for the Development of Natural Products.
  • WO2004013297 Microbial Production of Manzamines, Russell, T. Hill, Mark T. Hamann, Olivier Peraud and Noer Kasanah
  • manzamine comprises, unless specified differently, a manzamine or a manzamine derivative or analog or an optical isomer or racemate or tautomer thereof or a pharmaceutically acceptable salt thereof or a mixture of any of these.
  • a manzamine may also be defined as the product obtained by a process comprising the use of marine sponge extracts, preferably as described in detail above.
  • Preferred manzamines are manzamines which may be represented by the following general formulae (I) to (VIII)
  • the subject invention relates to the use of manzamines of the formula (I):
  • R 1 to R 23 are, independently, hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 acyloxy, or C 1 -C 6 alkyl, C 1 -C 6 alkyl, di-CrC 6 alkyl amino.
  • Each of the rings in the compound can range from 3 to 18-membered of carbon, nitrogen, oxygen and/or sulfur.
  • the invention pertains to the use of manzamines of the formula (II): -A-
  • R 1 to R 22 are, independently, hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 acyloxy, or C 1 -C 6 alkyl, C 1 -C 6 alkyl, di-CrC 6 alkyl amino.
  • Each of the rings in the compound can range from 3 to 18-membered of carbon, nitrogen, oxygen and/or sulfur.
  • the invention pertains to the use of manzamines of the formula (III):
  • R-i to R 22 are, independently, hydrogen, halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 acyloxy, or C 1 -C 6 alkyl, C 1 -C 6 alkyl, di-C-i-C 6 alkyl amino.
  • Each of the rings in the compound can range from 3 to 18-membered of carbon, nitrogen, oxygen and/or sulfur.
  • at least one of R 1 to R 23 in formula (I) 1 (II) or (III) is C 1 -C 6 alkylcarbonylamino or substituted C 1 -C 6 alkyl, more particularly, sulfonyl or aminosulfonyl C 1 -C 6 alkyl.
  • the subject invention relates to the use of manzamines of the formula (IV):
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are, independently, hydrogen, halogen, hydroxy, CrC 6 -alkoxy, C 1 - C 6 -acyloxy, or mono-C r C 6 -alkyl- or di-C r C 6 -alkyl-amino;
  • R 1 is hydrogen, C r C 6 -alkyl, or C r C 6 -acyl group;
  • R 2 is hydrogen, hydroxy, C r C 6 -alkoxy, or C r C 6 -acyloxy.
  • manzamine A having the following structure:
  • the subject invention relates to the use of manzamines of the formula (V):
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are the same or different and are hydrogen, halogen, hydroxyl, C r C 6 -alkoxy, CrCe-acyloxy, thiol, C r C 6 -alkylthiol, nitro, amino, C r C 6 -alkylsulfonyl, aminosulfonyl, hydroxy sulfonyl (-SO 3 H), CrC 6 -acylamino, C r C 6 -alkyl, or mono-C r C ⁇ -alkyl- or di-C r C 6 -alkyl-amino and R 1 and R 2 are the same or different and are hydrogen, C 1 -C 6 -alkyl, or C r C 6 -acyl.
  • manzamine B having the following structure:
  • the subject invention relates to the use of manzamines of the formula (Vl):
  • X 1 , X 2 , X 3 , and X 4 are the same or different and are hydrogen, halogen, hydroxyl, C 1 -C 6 - alkoxy, C r C 6 -acyloxy, thiol, C r C 6 -alkylthiol, nitro, amino, C r C 6 -aIkylsulfonyl, aminosulfonyl, hydroxy sulfonyl (-SO 3 H), CrC 6 -acylamino, CrC 6 -alkyl, ormono-CrCe-alkyl- or diC r C 6 -alkyl-amino; and R 1 is hydrogen, CrC 6 -alkyl, or CrC 6 -acyl.
  • Each of the rings in the compound can range from 3 to 18- membered consisting of carbon, nitrogen, oxygen and/or sulfur.
  • manzamine C having the following structure:
  • the subject invention relates to the use of manzamines of the formula (VII):
  • manzamine D having the following structure:
  • the subject invention relates to the use of manzamines of the formula (VIII):
  • R is hydrogen, halogen, hydroxy, or d-C ⁇ -acyloxy
  • X is a double bonded oxygen, or is the same or different and is any two of hydrogen, hydroxy, C r C 6 -alkyl, CrC 5 -alkoxy, or C 1 -C 6 - acyloxy.
  • manzamine E and F having the following structures:
  • the double bonds in the general formulae (I)-(VIII) are partially or fully reduced.
  • the manzamine is in the form of a pharmaceutically acceptable salt which includes salts with a mineral acid (e.g., HCI, HBr, H 2 SO 4 , H 3 PO 4 , HNO 3 , etc.) or with an organic acid, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts.
  • a mineral acid e.g., HCI, HBr, H 2 SO 4 , H 3 PO 4 , HNO 3 , etc.
  • an organic acid such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts.
  • the manzamine compounds of the invention also encompass hydrate and solvate forms. Methods for obtaining these compounds are described in, for example, U.
  • Skilled chemists having the benefit of the present disclosure of the structure of these manzamines can readily use procedures to prepare the subject compounds from sponge/microbial extracts or through synthetic or biocatalytic transformations.
  • suitable filtration, chromatographic, crystallization and other purification techniques well known in the art may be used. These techniques may include, for example, reversed phase (RPLC) 1 column, vacuum flash, medium pressure (MPLC) and high performance liquid chromatography (HPLC) with a suitable column such as silica gel, Sephadex LH-20, ammonia-treated silica gel, bonded phase RP-18, RP-8 and amino columns.
  • RPLC reversed phase
  • MPLC medium pressure
  • HPLC high performance liquid chromatography
  • Such columns are eluted with suitable solvents such as hexanes, ethyl acetate, acetone, methylene chloride, methanol, isopropanol, acetonitrile, water, trifiuoroacetic acid (TFA) and various combinations thereof.
  • suitable solvents such as hexanes, ethyl acetate, acetone, methylene chloride, methanol, isopropanol, acetonitrile, water, trifiuoroacetic acid (TFA) and various combinations thereof.
  • graft refers to organs and/or tissues and/or cells which can be obtained from first a mammal (or donor) and transplanted into a second mammal (or recipient), preferably a human.
  • the term "graft” encompasses, for example, skin, eye or portions of the eye (e.g., cornea, retina, lens), muscle, bone marrow or cellular components of the bone marrow (e.g., stem cells, progenitor cells), heart, lung, liver, kidney, pancreas (e.g., islet cells, p-cells), parathyroid, bowel (e.g., colon, small intestine, duodenum), neuronal tissue, bone and vasculature (e.g., artery, vein).
  • a graft can be obtained from a suitable mammal (e.g., human or pig), or under certain circumstances a graft can be produced in vitro by cuituring cells, for example embryonal, skin or blood cells and bone marrow cells.
  • a graft is preferably obtained from a human.
  • Organ transplants of kidney, heart, liver and lung are now regularly performed as treatment for endstage organ disease. Allograft as well as xenograft transplants have been performed. However, because of problems with long-term chronic rejection, organ transplantation is not yet a permanent solution to irreversible organ disease. There is also a need for improved agents for treatment of acute rejection.
  • Chronic rejection which manifests itself as progressive and irreversible graft dysfunction is the leading cause of organ transplant loss.
  • the clinical problem of chronic rejection is clear from transplantation survival times; about half of kidney allografts are lost by around 10 years after transplantation, and a similar value is observed in patients with a heart allograft.
  • Chronic rejection is considered as a multifactorial process in which not only the immune reaction towards the graft but also the response of the blood vessel wall in the grafted organ to injury ("response- to-injury" reaction) plays a role.
  • the variant of chronic rejection with the worst prognosis is an arteriosclerosis-like alteration, also called transplant vasculopathy, graft vessel disease, graft atherosclerosis, transplant coronary disease, etc.
  • This vascular lesion is characterized by migration and proliferation of smooth muscle cells under influence of growth factors that are amongst others synthesized by endothelium.
  • a contribution of blood-borne stem cells as precursors of neo-intimal tissue has recently been demonstrated. It appears to progress also through repetitive endothelial injury induced amongst others by host antibody or antigen-antibody complexes, through intimal proliferation and thickening, smooth muscle cell hypertrophy repair, and finally to gradual luminal obliteration.
  • non-immunological factors like hypertension, hyperlipidemia, hypercholesterolemia etc. play a role.
  • Chronic rejection appears to be inexorable and uncontrollable because there is no known effective treatment or prevention modality. Thus, there continues to exist a need for a treatment effective in preventing, controlling or reversing manifestations of chronic graft vessel diseases.
  • the manzamines are useful in the treatment and/or prevention of diseases or disorders mediated by T lymphocytes and/or B lymphocytes, e.g. acute or chronic rejection of organ, tissue or cell allografts, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, autoimmune diseases e.g.
  • rheumatoid arthritis osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroidis, myasthenia gravis, diabetes type I and the disorders associated therewith, skin diseases such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Sjoegren's syndrome, keratoconjunctivitis, uveitis or myocarditis and multiple sclerosis (similar neuroinfammatory conditions).
  • skin diseases such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Sjoegren's syndrome, keratoconjunctivitis, uveitis or myocarditis and multiple
  • a method for preventing, treating or inhibiting acute graft rejection in a recipient of cell, tissue or organ allotransplant comprising the step of administering to said recipient a therapeutically effective amount of a manzamine;
  • a method of preventing, treating or inhibiting graft vessel diseases e.g. transplant vasculopathy, arteriosclerosis or atherosclerosis, in a recipient of tissue or organ allotransplant, comprising the step of administering to said recipient a therapeutically effective amount of a manzamine;
  • a method for preventing, treating or inhibiting an autoimmune disease in a subject in need thereof comprising the step of administering to said subject a therapeutically effective amount of a manzamine;
  • a manzamine for preventing, treating or inhibiting (a) acute or chronic graft rejection in a recipient of cell, tissue or organ allotransplant, (b) vein graft stenosis, restenosis and/or vascular occlusion following vascular injury or (c) an autoimmune disease;
  • a manzamine for the preparation of a medicament for preventing, treating or inhibiting (a) acute or chronic graft rejection in a recipient of cell, tissue or organ allotransplant, (b) vein graft stenosis, restenosis and/or vascular occlusion following vascular injury or (c) an autoimmune disease.
  • a pharmaceutical composition for use in any method as defined under 1.1 to 1.5 above comprising a manzamine, together with one or more pharmaceutically acceptable diluents or carriers thereof.
  • Figure 1 shows the effect of Manzamine A in the inhibition of knee swelling in the antigen- induced arthritis in mice as described in the Examples.
  • Filled square Vehicle (saline) alone 5 ml/kg Empty square: Dexamethasone 1 mg/kg Filled triangle: Manzamine A 15 mg/kg Empty triangle: Manzamine A 30 mg/kg EXAMPLES
  • Manzamine A in treating diseases or disorders as hereinbefore specified, may be demonstrated in animal test methods as well as in Clinic, for example in accordance with the methods hereinafter described.
  • the two-way MLR is performed according to standard procedures (J. Immunol. Methods, 1973, 2, 279 and Meo T. et al., Immunological Methods, New York, Academic Press, 1979, 227-39). Briefly, spleen cells from CBA and BALB/c mice (1.6 x 10 5 cells from each strain per well in flat bottom tissue culture microtiter plates, 3.2 x 10 5 in total) are incubated in RPMI medium containing 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 50 ⁇ M 2-mercaptoethanol, non-essential amino- acids, sodium pyruvate (2 mM), sodium selenite (22 ng/ml), ethanolamine (20 ⁇ M), bovine insulin (5 ⁇ g/ml), human transferring (32 ⁇ g/ml), human albumin 0.1%, lecithine 0.0024%, L-gluta-mine (2 mM) and sodium bicarbonate (23.8 mM) and serially diluted compounds.
  • This assay measures in vivo alloreactivity of donor T-cells transferred into an allo-mismatched recipient chosen to be incapable of mounting a host-versus- graft response, i.e. an immunodeficient recipient.
  • the model is performed according to the published method ["Effect of immunosuppressants on T-cell subsets observed in vivo using carboxy-fluorescein diacetate succinimidyl ester labeling" Hu H, Dong Y, Feng P, Fechner J, Hamawy M and Knechtle SJ. Transplantation. 2003 75, 1075-7].
  • lymphocytes from wild type B6 mice are transferred to fully-allo-mismatched CB17 SCID/beige (BALB/C congenic) mice.
  • Donor alloreactivity is reflected by T cell expansion ( numbers of T cells retrieved from recipient spleens) and T cell proliferation.
  • donor spleen cells are stained with the fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) prior to transfer into recipients.
  • CFSE carboxyfluorescein diacetate succinimidyl ester
  • This dye binds covalently and non-specifically to cellular proteins.
  • daughter cells 'inherit' half of the stained protein, thereby displaying half of the parental cell's fluorescence intensity. This allows quantifying the number of cell divisions and cells per cycle by flow cytometry.
  • Four days after transfer of CFSE-stained B6 splenocytes CB17 SCID/beige recipients are sacrificed, and their spleens processed for FACS analysis.
  • Cyclosporine A is dissolved in 20%KZI vehicle 80% PBS. Manzamine A is dissolved in corn oil 1% ethanol. The results are as follows:
  • mice were sensitised intradermal ⁇ on the back at two sites to methylated bovine serum albumin (mBSA) homogenised 1 :1 with complete Freund's adjuvant on days -21 and -14 (0.1 ml containing 1 mg/ml mBSA).
  • mBSA methylated bovine serum albumin
  • the mice were anaesthetised using a 5% isoflurane/air mixture and maintained using isoflurane in a face mask for the intra-articular.
  • the right knee received 10 ⁇ l of 10mg/ml mBSA in 5% glucose solution (antigen injected knee), while the left knee received 10 ⁇ l of 5% glucose solution alone (vehicle injected knee).
  • the diameters of the left and right knees were then measured using calipsers immediately after the intra-articular injections and again on days 2, 4, 7, 9, 11 and 14.
  • Treatments were administered daily as follows by oral gavage; vehicle (saline) at 5ml/kg, Dexamethasone at 1 mg/kg and Manzamine A at 15 and 30 mg/kg.
  • Right knee swelling was calculated as a ratio of left knee swelling, and the R/L knee swelling ratio plotted against time to give Area Under the Curve (AUC) graphs for control and treatment groups.
  • AUC Area Under the Curve
  • the percentage inhibition of the individual treatment group AUCs were calculated vs the control group AUC (0% inhibition) using an Excel spreadsheet.
  • the mice were killed by CO 2 inhalation and the right and left knees removed for histology.
  • the knees were processed for decalcified histology using a Histodur plastic embedding method (Leica AG, Germany). Sections (5 ⁇ m) from both the control and arthritic knees were cut on a RM 2165 rotation microtome (Leica AG, Germany). After staining adjacent sections with toluidine blue (metachromatic stain for cartilage proteoglycans) and Haemotoxylin and Eosin (general morphology stain), the slides were number coded as left knee/right knee pairs from each animal. The slides were read in a blinded fashion. The left knee joint from each animal was examined for comparison, immediately prior to scoring the arthritic right knee joint from the same animal, to establish the anatomy of the non-arthritic knee in each case.
  • toluidine blue metalchromatic stain for cartilage proteoglycans
  • Haemotoxylin and Eosin general morphology stain
  • Dosages required in practicing the method of the present invention using a manzamine will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.01 to about 200 mg/kg body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 g p.o., conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • the manzamines may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form.
  • Pharmaceutical compositions comprising a manzamine in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier.
  • manzamines to be used in the present invention can be formulated according to known methods for preparing pharmaceutically useful compositions. Formulations are described in detail in a number of sources that are well known and readily available to those skilled in the art. For example, Remington's Phat ⁇ iaceutical Scien ⁇ by E.W. Martin describes formulations that can be used in connection with the subject invention. In general, the compositions of the subject invention will be formulated such that an effective amount of the bioactive compound(s) is combined with a suitable carrier in order to facilitate effective administration of the composition.
  • the manzamine may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or other anti-inflammatory agents e.g. for the treatment or prevention of allograft acute or chronic rejection or autoimmune disorders or malignant proliferative diseases.
  • a manzamine may be used in combination with a calcineurin inhibitor, e.g. cyclosporine A, cyclosporine G, FK-506, ABT-281 , ASM 981; an mTOR inhibitor, e.g.
  • rapamycin 40-O-(2-hydroxy)ethyl-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus-7 or bioimus-9; a corticosteroid; cyclophosphamide; azathioprine; methotrexate; a S1P receptor agonist, e.g.
  • a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LE ⁇ A29Y, or other adhesion molecule inhibitors, e.g. mAbs or low molecular weight inhibitors including LFA-1 antagonists, Selectin antagonists and VLA-4 antagonists.
  • dosages of the co ⁇ administered drug will of course vary depending on the type of co-drug employed, on the condition to be treated, and so forth.
  • the present invention provides in a yet further:
  • a pharmaceutical combination for use in any method as defined under 1.1 to 1.5 above comprising a) a first agent which is a manzamine, e.g. Manzamine A, and b) a co-agent, e.g. a second drug agent as defined above, in particular a drug used in immunomodulating regimens or an anti- inflammatory agent.
  • a first agent which is a manzamine, e.g. Manzamine A
  • a co-agent e.g. a second drug agent as defined above, in particular a drug used in immunomodulating regimens or an anti- inflammatory agent.
  • a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a manzamine, e.g. manzamine A, and at least one second drug substance, e.g. as indicated above.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur l'utilisation d'une manzamine permettant d'empêcher, de traiter ou d'inhiber (a) le rejet d'un greffon aigu ou chronique chez un receveur de cellules, de tissus ou d'allogreffe, (b) la sténose de greffon veineux, la resténose et/ou l'occlusion vasculaire suite à un accident vasculaire ou (c) une maladie auto-immune.
PCT/EP2005/007678 2004-07-15 2005-07-14 Utilisation de manzamines dans la transplantation et les maladies auto-immunes WO2006005620A1 (fr)

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US60/588,078 2004-07-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105055409A (zh) * 2015-08-22 2015-11-18 南京华宽信息咨询中心 一种治疗缺血性脑损伤药物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000056304A2 (fr) * 1999-03-24 2000-09-28 Harbor Branch Oceanographic Institution, Inc. Utilisation de manzamines en tant qu'anti-inflammatoires
WO2002017917A1 (fr) * 2000-08-29 2002-03-07 The University Of Mississippi Procedes de traitement d'infections resistant aux medicaments par administration de compositions pharmaceutiques comprenant des alcaloides de manzamine
WO2005084157A2 (fr) * 2003-06-26 2005-09-15 University Of Mississippi Methodes de traitement des maladies par administration d'un analogue ou d'un derive de manzamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000056304A2 (fr) * 1999-03-24 2000-09-28 Harbor Branch Oceanographic Institution, Inc. Utilisation de manzamines en tant qu'anti-inflammatoires
WO2002017917A1 (fr) * 2000-08-29 2002-03-07 The University Of Mississippi Procedes de traitement d'infections resistant aux medicaments par administration de compositions pharmaceutiques comprenant des alcaloides de manzamine
WO2005084157A2 (fr) * 2003-06-26 2005-09-15 University Of Mississippi Methodes de traitement des maladies par administration d'un analogue ou d'un derive de manzamine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105055409A (zh) * 2015-08-22 2015-11-18 南京华宽信息咨询中心 一种治疗缺血性脑损伤药物及其应用

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