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WO1998018468A1 - Compositions synergiques comprenant de la rapamycine et du calcitriol - Google Patents

Compositions synergiques comprenant de la rapamycine et du calcitriol Download PDF

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Publication number
WO1998018468A1
WO1998018468A1 PCT/US1997/019378 US9719378W WO9818468A1 WO 1998018468 A1 WO1998018468 A1 WO 1998018468A1 US 9719378 W US9719378 W US 9719378W WO 9818468 A1 WO9818468 A1 WO 9818468A1
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WO
WIPO (PCT)
Prior art keywords
rapamycin
combination
mammal
dihydroxycholecalciferol
transdermally
Prior art date
Application number
PCT/US1997/019378
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English (en)
Inventor
Roger Bouillon
Dumitru Branisteanu
Chantal Mathieu
Original Assignee
American Home Products Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU49195/97A priority Critical patent/AU4919597A/en
Priority to CA002270373A priority patent/CA2270373A1/fr
Priority to EP97911933A priority patent/EP0954310A1/fr
Priority to JP10520650A priority patent/JP2001503061A/ja
Publication of WO1998018468A1 publication Critical patent/WO1998018468A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

  • graft rejection is a complex process involving the immune system. This process is briefly outlined below. Rejection appears to be initiated by blood borne antigen presenting cells (dendritic cells and monocytes expressing class II MHC molecules) of the allograft which migrate from the allograft. Antigen recognition and production of IL-1 by the antigen presenting cells causes the activation of CD4 + T-cells thereby initiating an immune response leading to the ultimate graft rejection. Activated CD4+ T-cells produce IL-2 which is a growth factor essential to the activation of both CD8 + T-cells and B-cells.
  • blood borne antigen presenting cells dendritic cells and monocytes expressing class II MHC molecules
  • T-cells cytotoxic CD8+ T-cells and CD4+ T-cells
  • cytotoxic CD8+ T-cells and CD4+ T-cells migrate from the host lymphoid tissue and infiltrate the graft tissue.
  • Infiltration involves initial adherence of the T-lymphocytes to vascular endothelium, transmigration through the vascular wall, migration within the graft, selective retention of activated cells within the graft, and local proliferation of cells.
  • Antigen presenting graft cells are destroyed direcdy by cytotoxic CD8 + T-cells.
  • CD4+ T-cells produce other lymphokines such as interferon- ⁇ (LFN- ⁇ ), IL-4, and IL-5 which also contribute to graft destruction.
  • LFN- ⁇ interferon- ⁇
  • IL-4 interferon- ⁇
  • IL-5 IL-5
  • LFN- ⁇ induces increased expression of HLA-A, -B, and -DR on graft tissue making it more vulnerable to effector mechanisms.
  • IFN- ⁇ also activates macrophages to initiate a delayed hypersensitivity reaction causing nonspecific damage to the graft.
  • IL-4 and LL-5 are implicated in inducing antibody production by plasma cells leading to antibody mediated damage of the graft. [Hutchinson, I., Transplantation 3: 722 (1991); Garovoy, M.R., Basic and Clinical Immunology, ed. Stites, 7th ed., 747 (1991)].
  • cyclosporin A is the most powerful and most frequentiy used, but has the unsatisfactory side-effect of nephrotoxicity in man, which can lead to structural renal damage.
  • rapamycin a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus [U.S. Patent 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Martel, R., Can. J. Physiol. Pharm. 55: 48 (1977)], inhibit murine T-cell activation [Staruch, M., FASEB 3: 3411 (1989)], prolong survival time of organ grafts in histoincompatible rodents [Morris, R., Med. Sci. Res. 17: 877 (1989)], and inhibit transplantation rejection in mammals [U.S. Patent 5,100,999].
  • Rapamycin has also been shown to be useful in treating pulmonary inflammation [U.S. Patent 5,080,899], systemic lupus erythematosis [U.S. Patent 5,078,899], immunoinflammatory skin disorders, such as psoriasis [U.S. Patent 5,286,730], immunoinflammatory bowel disorders [U.S. Patent 5,286,731], ocular inflammation [U.S. Patent 5,387,589], hyperproliferative vascular disorders, such as restenosis [U.S. Patents 5,512,781 and 5,288,711], carcinomas [U.S. Patent 5,206,018 and 4,885,171], and cardiac inflammatory disease [U.S.
  • Patent 5,496,832 ; and in preventing the onset of insulin dependent diabetes mellitus [U.S. Patent 5,321,009]. Additionally, rapamycin has been shown to be useful in treating adult T-cell leukemia/lymphoma [European Patent Application 525,960 Al].
  • vitamin D 1,25-dihydroxycholecalciferol
  • l,25(OH) 2 D 3 1,25-dihydroxycholecalciferol
  • l,25(OH)2D3 has a strong impact on the immune system, probably exerted via specific receptors present in both monocytes and activated T lymphocytes [Rigby, W.F.C., Immunol. Today 9: 54 (1988)].
  • l,25(OH)2U3 seems to impair immune cell interaction at the macrophage as well as at the T helper level [Rigby, W.F.C., Blood 76: 189 (1990)], and modulates the paracrine function of the two cell types [Manolagas, S.C, Semin. Nephrol. 14: 129 (1994)].
  • This invention provides a combination of rapamycin and 1,25- dihydroxycholecalciferol (l,25(OH)2D3) which is useful for inducing immunosuppression, and in the treatment of transplantation rejection, graft vs. host disease, autoimmune diseases, diseases of inflammation, adult T-cell leukemia/lymphoma, neoplasms, fungal infections, and hyperproliferative vascular disorders.
  • the combination of rapamycin and l,25(OH) 2 D 3 can be administered to a mammal orally, parenterally, intranasally, intrabronchially, transdermally, topically, intravaginally, or rectally.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising rapamycin and l,25(OH)2D3, and a pharmaceutical carrier.
  • the ability the combination of rapamycin and l,25(OH)2D3 to act as an immunosuppressive agent was established in an in vitro and in vivo standard pharmacological test procedure.
  • the in vitro procedure evaluated the ability of the rapamycin and l,25(OH)2D3 combination to inhibit PHA-stimulated PMBC proliferation.
  • the in vivo test procedure measured the ability of the rapamycin and l,25(OH)2D3 combination to inhibit the development of experimental allergic encephalomyelitis, which is a test procedure emulating multiple sclerosis, an autoimmune disease.
  • the procedures used and the results obtained are briefly described below.
  • the PHA-stimulated PMBC proliferation standard pharmaceutical test procedure was used to evaluate the immunosuppressive activity of the combination of the rapamycin and l,25(OH)2D3 combination. Briefly, human PBMC were isolated from freshly collected heparinized venous blood of healthy volunteers by Ficoll-Hypaque density gradient centrifugation.
  • Radioactivity was measured with a ⁇ - scintillation counter, and the percent proliferation was calculated.
  • the results obtained in this standard pharmacological test procedure are provided in the table below, which shows the dosages necessary to produce specified percent inhibition of PHA-stimulated PMBC proliferation.
  • mice The experimental allergic encephalomyelitis (EAE) standard pharmacological test procedure was used to further evaluate the immunosuppressive activity of the combination of rapamycin and l,25(OH)2U3. This test procedure also evaluated the combination's activity against autoimmune disorders. Briefly, mouse spinal cord, isolated from NMRI mice, was lyophilized and stored as powder at +4°C. The mice were injected in their hind foot pads with 50 ⁇ l of an emulsion consisting in an equal volume mixture of mouse spinal cord in PBS (55 mg/ml) and mycobacterium tuberculosis strain H37-Ra in complete Freund's adjuvant (CFA, 4 mg/ml). The induction day was considered day 0. On days 0 and +2, pertussis toxin, 200 ng in a volume of 50 ⁇ l PBS, was given intravenously on the induction day and repeated two days later.
  • EAE experimental allergic encephalomyelitis
  • the last two groups were treated with combinations between l,25(OH)2U3 at 2 pg/kg every 2 days and the same total dose of rapamycin, but given either in daily administrations of 0.3 mg/kg (group MLX-1, 25 mice), or 0.6 mg/kg given every two days (group MLX-2, 23 mice).
  • rapamycin administered in the last group was alternated with that of l,25(OH)2D3, starting with rapamycin on day -3.
  • Three to seven urine samples were collected from each mouse which measured urinary calcium and collagen cross-links content (deoxypyridinoline, DPD). All mice were sacrificed on day 20, or earlier if severely paralyzed. Blood was collected by heart puncture, under ether anesthesia. Serum was stored at -20"C, for further measurement of calcium and osteocalcin. Duodenum, 1 cm below the pylorus, was isolated, rinsed and stored at -20°C, until assayed for calbindin D-9K content. Brain and spinal cord were removed and fixed in Bouin solution for histology.
  • mice were assessed for clinical signs of paralysis, starting on day 9. EAE signs were scored daily, on a scale from 0 to 4. Scores were evaluated blindly, by two independent observers. To be considered positive for clinical EAE, a mouse must have been scored 0.5 or higher for 2 consecutive days. For the mice found dead after previously presenting signs of disease, or for moribunds sacrificed before day 20, a score of 4 was considered from the day of their death until the end of the follow up.
  • the disease free survivorship representing the number of disease free mice of one group on the day of sacrifice, and the following parameters of disease severity were used: the cumulative score, defined as the sum of the daily mean scores of one group between days 11 and 20 of the follow up; the integrated disease score, calculated by making the mean of all individual daily scores of the last 10 days for one group, and the mean maximal disease score, which is the mean of the maximal disease scores reached by all the mice of one group.
  • the results of this standard pharmacological test procedure showed that treatment with both l,25(OH)2U3 and rapamycin alone significantly decreased disease severity (p ⁇ 0.0001 by ANOVA test). All but one of the control mice showed signs of paralysis.
  • mice In the group treated with l,25(OH) 2 D 3 at 2 ⁇ g/kg every 2 days, 8 of 23 mice were disease free at the end of the follow up (30 %, group D2), whereas 5 ⁇ g/kg every 2 days prevented the appearance of disease in 65 % of the treated mice (13 out of 25 mice, group D5) and postponed the disease onset in the mice who did develop the disease (p ⁇ 0.01). Rapamycin at 1 mg/kg/day (group RP1) conferred near to total protection (only 2 out of 28 animals developed mild disease), whereas lower doses were only partially protective.
  • rapamycin at 0.3 mg/kg/day prevented disease evolution in 45 % of the animals (group RP0.3), while the same drug quantity given every two days (0.6 mg/kg every 2 days, group RP0.06') was somehow less protective (31 % disease free animals at the end of the observation period).
  • mice with mild or no central nervous system inflammation were four, five and three out of eight for groups D2, RP0.3 and RPO.6' respectively.
  • groups D2, RP0.3 and RPO.6' were inflammation - free, only one showing mild mononuclear infiltration.
  • Mean histological score was significantly lower than that of group D2 in both combination groups.
  • the combination of rapamycin and l,25(OH) 2 U3 is useful in treating or preventing diseases or disorders involving the immune system.
  • diseases or disorders involving the immune system include, but are not limited to, in the treatment or inhibition of transplantation rejection such as kidney, heart, liver, lung, bone marrow, pancreas (islet cells), cornea, small bowel, and skin allografts, and heart valve xenografts; treatment or inhibition of autoimmune diseases and diseases of inflammation such as systemic lupus erythematosis, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, scleroderma, Wegener's granulomatosis, chronic active hepatitis, biliary cirrhosis, sarcioidosis, nephrotic syndrome, multiple sclerosis, Steven- John
  • rapamycin and l,25(OH>2D3 may be used in combination with other agents useful in treating or preventing diseases or disorders involving the immune system, such as azathioprine, corticosteroids, such as prednisone and methylprednisolone, cyclophosphamide, cyclosporin A, FK-506, OKT-3, and ATG to further reduce dosage requirements needed to achieve the desired effect.
  • azathioprine corticosteroids, such as prednisone and methylprednisolone
  • cyclophosphamide cyclosporin A
  • FK-506, OKT-3 OKT-3
  • ATG cyclosporin A
  • the combination of rapamycin and l,25(OH)2U3 can be formulated neat or with a pharmaceutical carrier to a mammal in need thereof.
  • the pharmaceutical carrier may be solid or liquid.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compound can also be administered orally either in liquid or solid composition form.
  • the combination of rapamycin and l,25(OH)2D3 may be administered rectally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the combination of rapamycin and l,25(OH)2D 3 may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermiable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the combination of rapamycin and l,25(OH) 2 D3 may be administered topically as a solution, cream, or lotion by formulation with pharmaceutically acceptable vehicles containing 0.1 - 5 percent, preferably 2%, of active compound.
  • the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily intravenous dosages of the combination of rapamycin and l,25(OH) 2 D 3 would be 0.001 - 25 mgkg rapamycin and 0.001 - 50 ⁇ g l,25(OH) 2 D 3 . Projected daily oral dosages of the combination of rapamycin and l,25(OH)2U3 would be 0.01 - 50 mg/kg rapamycin and 0.01 - 100 ⁇ g l,25(OH) 2 D 3 .
  • Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, intranasal, intrabronchial, transdermal, or rectal administration will be determined by the administering physician based on experience with the individual subject treated.
  • the combination of rapamycin and l,25(OH) 2 D3 is most desirably administered at a concentration that will generally afford effective results without causing any harmful or deleterious side effects.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Transplantation (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Cette invention a trait à une combinaison de rapamycine et de 1,25-dihydroxy-cholecalciférol (1,25(OH)2D3) efficace s'agissant de provoquer une immuno-dépression ainsi que pour traiter un rejet de transplantation, transplant c. maladie-hôte, des maladies auto-immunes, des maladies inflammatoires, une leucémie et/ou un lymphome T chez l'adulte, des néoplasmes, des mycoses ainsi que des troubles vasculaires hyperprolifératifs.
PCT/US1997/019378 1996-10-31 1997-10-28 Compositions synergiques comprenant de la rapamycine et du calcitriol WO1998018468A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU49195/97A AU4919597A (en) 1996-10-31 1997-10-28 Synergistic composition comprising rapamycin and calcitriol
CA002270373A CA2270373A1 (fr) 1996-10-31 1997-10-28 Compositions synergiques comprenant de la rapamycine et du calcitriol
EP97911933A EP0954310A1 (fr) 1996-10-31 1997-10-28 Compositions synergiques comprenant de la rapamycine et du calcitriol
JP10520650A JP2001503061A (ja) 1996-10-31 1997-10-28 ラパマイシンおよびカルシトリオールを含んでなる相乗組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US74200096A 1996-10-31 1996-10-31
US08/742,000 1996-10-31

Publications (1)

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WO1998018468A1 true WO1998018468A1 (fr) 1998-05-07

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PCT/US1997/019378 WO1998018468A1 (fr) 1996-10-31 1997-10-28 Compositions synergiques comprenant de la rapamycine et du calcitriol

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EP (1) EP0954310A1 (fr)
JP (1) JP2001503061A (fr)
AU (1) AU4919597A (fr)
CA (1) CA2270373A1 (fr)
WO (1) WO1998018468A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5876709A (en) * 1997-05-26 1999-03-02 New Vision Co., Ltd. Ophthalmic composition containing active Vitamin D
US6162801A (en) * 1995-11-20 2000-12-19 Kita; Kiyoshi External ophthalmic preparation containing vitamin D
WO2001072292A3 (fr) * 2000-03-27 2002-05-16 Wisconsin Alumni Res Found Composes de vitamine d utilises pour stabiliser des transplantations renales
WO2002094247A3 (fr) * 2001-05-22 2003-05-01 Bioxell Spa Utilisation d'analogue de la vitamine d3 pour le traitement de diabetes auto-immuns
WO2003045523A2 (fr) 2001-11-26 2003-06-05 Swaminathan Jayaraman Enrobage therapeutique pour implant intravasculaire
WO2004087170A1 (fr) * 2003-04-04 2004-10-14 Novartis Ag Combinaison d'un immunomodulateur de lymphocyte t macrolide et d'un calciferol destinee au traitement de maladies de la peau ou d'une maladie intestinale inflammatoire
WO2005011651A3 (fr) * 2003-07-30 2005-08-11 Abbott Lab Utilisation de vitamines d ou d'analogue de la vitamine d pour traiter les maladies cardio-vasculaires
WO2012076429A1 (fr) * 2010-12-06 2012-06-14 Dsm Ip Assets B.V. Traitement d'états associés à une éotaxine augmentée, par la 25-hydroxyvitamine d3
WO2012103575A1 (fr) * 2011-02-02 2012-08-09 Ent Technologies Pty Ltd Compositions et procédés pour le traitement de voies nasales
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (2)

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Publication number Priority date Publication date Assignee Title
EP0525960A1 (fr) * 1991-06-18 1993-02-03 American Home Products Corporation Utilisation de rapamycine pour le traitement de la lymphome/leucéme des cellules T adultes
US5286730A (en) * 1991-09-17 1994-02-15 American Home Products Corporation Method of treating immunoinflammatory disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0525960A1 (fr) * 1991-06-18 1993-02-03 American Home Products Corporation Utilisation de rapamycine pour le traitement de la lymphome/leucéme des cellules T adultes
US5286730A (en) * 1991-09-17 1994-02-15 American Home Products Corporation Method of treating immunoinflammatory disease

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Title
BRANISTEANU, DUMITRU D. ET AL: "Synergism between sirolimus and 1,25- dihydroxyvitamin D3 in vitro and in vivo", J. NEUROIMMUNOL. (1997), 79(2), 138-147 CODEN: JNRIDW;ISSN: 0165-5728, XP002053686 *
GARDNER C.R.: "THE PHARMACOLOGY OF IMMUNOSUPPRESSANT DRUGS IN SKIN TRANSPLANT REJECTION IN MICE AND OTHER RODENTS", GENERAL PHARMACOLOGY, vol. 26, no. 2, 1995, UK, pages 245 - 271, XP002053689 *
JOFFE, IAN ET AL: "Lack of change of cancellous bone volume with short-term use of the new immunosuppressant rapamycin in rats", CALCIF. TISSUE INT. (1993), 53(1), 45-52 CODEN: CTINDZ;ISSN: 0171-967X, XP002053688 *
LEMIRE J M: "IMMUNOMODULATORY ROLE OF 1,25-DIHYDROXYVITAMIN D3", JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 49, no. 1, May 1992 (1992-05-01), pages 26 - 31, XP000653445 *
RIGBY W.F.C.: "THE IMMUNOBIOLOGY OF VITAMIN D", IMMUNOL. TODAY, vol. 9, no. 54, 1988, HOLLAND, pages 54 - 58, XP002053690 *
SHANE ET AL: "IMMUNOSUPPRESIVE THERAPY AND THE SKELETON", TRENDS ENDOCRINOL. METAB., vol. 5, no. 4, 1994, USA, pages 169 - 175, XP002053687 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6162801A (en) * 1995-11-20 2000-12-19 Kita; Kiyoshi External ophthalmic preparation containing vitamin D
US5876709A (en) * 1997-05-26 1999-03-02 New Vision Co., Ltd. Ophthalmic composition containing active Vitamin D
WO2001072292A3 (fr) * 2000-03-27 2002-05-16 Wisconsin Alumni Res Found Composes de vitamine d utilises pour stabiliser des transplantations renales
WO2002094247A3 (fr) * 2001-05-22 2003-05-01 Bioxell Spa Utilisation d'analogue de la vitamine d3 pour le traitement de diabetes auto-immuns
WO2003045523A2 (fr) 2001-11-26 2003-06-05 Swaminathan Jayaraman Enrobage therapeutique pour implant intravasculaire
US6641611B2 (en) 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
WO2004087170A1 (fr) * 2003-04-04 2004-10-14 Novartis Ag Combinaison d'un immunomodulateur de lymphocyte t macrolide et d'un calciferol destinee au traitement de maladies de la peau ou d'une maladie intestinale inflammatoire
JP2006522058A (ja) * 2003-04-04 2006-09-28 ノバルティス アクチエンゲゼルシャフト 皮膚疾患または炎症性腸疾患の処置のための、マクロライド系ｔ細胞免疫調節剤およびカルシフェロールの組み合わせ
AU2004226820B2 (en) * 2003-04-04 2008-02-21 Novartis Ag Combination of a macrolide T-cell immunomodulator and a calciferol for the treatment of skin diseases or of inflammatory bowel disease
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CN106924268A (zh) * 2010-12-06 2017-07-07 帝斯曼知识产权资产管理有限公司 用25‑羟基‑维生素d3治疗与嗜酸性粒细胞趋化因子增高有关的病症
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KR101895764B1 (ko) 2010-12-06 2018-09-07 디에스엠 아이피 어셋츠 비.브이. 25-하이드록시비타민 d3을 사용한, 증가된 에오탁신과 관련된 질환의 치료
US10357501B2 (en) 2010-12-06 2019-07-23 Dsm Ip Assets B.V. Treating conditions associated with increased eotaxin with 25-hydroxyvitamin D3
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CA2270373A1 (fr) 1998-05-07
AU4919597A (en) 1998-05-22
EP0954310A1 (fr) 1999-11-10

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