US20050256141A1 - Remedies for glomerular diseases - Google Patents

Remedies for glomerular diseases Download PDF

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Publication number
US20050256141A1
US20050256141A1 US10/504,851 US50485104A US2005256141A1 US 20050256141 A1 US20050256141 A1 US 20050256141A1 US 50485104 A US50485104 A US 50485104A US 2005256141 A1 US2005256141 A1 US 2005256141A1
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agent
hmg
glomerular disease
preventive
coa reductase
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US10/504,851
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Takashi Nakagawa
Sayaka Toyoizumi
Masako Isuge
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Kowa Co Ltd
Nissan Chemical Corp
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Kowa Co Ltd
Nissan Chemical Corp
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Assigned to KOWA CO., LTD., NISSAN CHEMICAL INDUSTRIES, LTD. reassignment KOWA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ISUGE, MASAKO, NAKAGAWA, TAKASHI, TOYOIZUMI, SAYAKA
Publication of US20050256141A1 publication Critical patent/US20050256141A1/en
Priority to US11/434,061 priority Critical patent/US7776354B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a preventive or therapeutic agent for a glomerular disease.
  • a glomerular disease (primary glomerular nephritis) brought about by causing lesion in a glomerulus of a kidney is clinically classified into any of seven diseases consisting of acute nephritis after infected with hemolytic streptococcus, crescentic glomerulonephritis (rapidly progressive nephritis), IgA nephropathy, membranous nephropathy, membranous proliferative nephropathy, focal glomerulonephritis and minimal change nephrotic syndrome.
  • the diseases other than the acute nephritis after infected with hemolytic streptococcus, the crescentic glomerulonephritis and the minimal change nephrotic syndrome are generally called chronic glomerular nephritis, and the cause and the time of onset thereof are relatively indistinct in many cases. Further, the lesion processes thereof is mostly progressive and results in renal failure in many cases.
  • the anti-thrombocytic agent has a function to inhibit discharge of various mediators such as thromboxane A2, histamine, a leukocyte migrating factor, cytokine and a proliferative factor from a blood platelet, and therefore it is considered that use of the present agent makes it possible to inhibit progressive augmentation of a glomerular disease caused by proliferation of a mesangium cell and a failure in a barrier mechanism in a glomerular snare wall which are brought about by various mediators (Cameron J S et al.: Coagulation and thromboembolic complications in the nephrotic syndrome. Adv Nephrol 13:75, 1984).
  • the degree of hyperlipidemia statistically correlates with the degree of proteinuria deterioration or aggravation in renal function, and a hyperlipidemia therapeutic agent such as an HMG-CoA reductase inhibitor is used as well for therapy of a kidney disease for the purpose of removing an augmentative factor of a kidney disease of hyperlipidemia.
  • kidney disease-improving effect brought about when using an anti-thrombocytic agent and a hyperlipidemia therapeutic agent is limited, and still remains unsatisfactory.
  • An object of the present invention is to provide a drug exhibiting an excellent effect in prevention or therapy of a glomerular disease.
  • the present invention provides a preventive or therapeutic agent for a glomerular disease which comprises an anti-thrombocytic agent and an HMG-CoA reductase inhibitor as active ingredients.
  • the present invention provides a medicinal composition for prevention or therapy of a glomerular disease, which comprises an anti-thrombocytic agent, an HMG-CoA reductase inhibitor and a pharmaceutically acceptable carrier.
  • the present invention provides use of an anti-thrombocytic agent and an HMG-CoA reductase inhibitor for producing a preventive or therapeutic agent for a glomerular disease.
  • the present invention provides a treating method for a glomerular disease, which comprises administering an anti-thrombocytic agent and an HMG-CoA reductase inhibitor.
  • FIG. 1 is a drawing showing a total amount of protein excretion in urine observed when administering pitavastatin calcium alone. Each value in the drawing shows an average value ⁇ standard error.
  • FIG. 2 is a drawing showing a total amount of protein excretion in urine observed when administering dilazep hydrochloride alone. Each value in the drawing shows an average value ⁇ standard error.
  • FIG. 3 is a drawing showing a total amount of protein excretion in urine observed when administering pitavastatin calcium and dilazep hydrochloride in combination. Each value in the drawing shows an average value ⁇ standard error.
  • the anti-thrombocytic agent of the present invention means a drug which inhibits adhesion and coagulation of a blood platelet and includes, for example, ticlopidine, cilostazol, ozagrel, beraprost, sarpogrelate, dipyridamole, argatroban, aspirin, dilazep, ethyl icosapentate, limaprost alfadex, alprostadil, alprostadil alfadex, trimetazidine, trapidil and clopidogrel (Japanese Patent Application Laid-Open No. 955/1979), CS-747 (Japanese Patent No.
  • AT101S Japanese Patent Application Laid-Open No. 3135/1996)
  • SR-46349 Japanese Patent No. 2562503
  • the salts thereof preferred are those having an adenosine-enhancing function or a phospholipase-inhibiting function such as dilazep, dipyridamole, trimetazidine, trapidil and the salts thereof, with dilazep and the salts thereof (hydrochloride and the like) being particularly preferred.
  • the HMG-CoA reductase inhibitor of the present invention includes all of so-called statin-type compounds which have a cholesterol synthesis inhibiting activity and which are known to be a hyperlipidemia therapeutic agent. It includes preferably compounds having a 3,5-dihydroxyheptanoic acid or 3,5-dihydroxy-6-heptenoic acid. Specifically, preferred are compounds described in Japanese Patent Application Laid-Open No. 2240/1982, Japanese Patent Application Laid-Open No. 163374/1982, Japanese Patent Application Laid-Open No. 122375/1981, Japanese Patent Application Laid-Open (through PCT) No. 500015/1985, Japanese Patent Application Laid-Open No. 216974/1989, Japanese Patent Application Laid-Open No.
  • lactone bodies lactone ring-opened bodies or the salts thereof are included therein. Further, included therein are the hydrates of these compounds and the salts thereof and the solvates thereof with solvents which are acceptable as medicines. When asymmetric carbon atoms are present in these compounds and when they have unsaturated bonds and the stereoisomers thereof are present, all isomers thereof are included therein.
  • the suited HMG-CoA reductase inhibitor includes, for example, pravastatin ((+)-(3R, 5R)-3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-6-hydroxy-2-methyl-8-[(S)-2-methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoic acid, Japanese Patent Application Laid-Open No.
  • lovastatin (+)-(1S, 3R, 7S, 8S, 8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(2R, 4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl)-1-napthyl (S)-2-methylbutyrate, Japanese Patent Application Laid-Open No.
  • simvastatin (+)-(1S, 3R, 7S, 8S, 8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(2R, 4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-napthyl 2,2-dimethylbutyrate, Japanese Patent Application Laid-Open No.
  • fluvastatin ( ⁇ )-(3R*, 5S*, 6E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, Japanese Patent Application Laid-Open (through PCT) No.
  • cerivastatin (+)-(3R, 5S, 6E)-7-[4-(4-fluorophenyl)-2,6-di-(1-methylethyl)-5-methoxymethylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid, Japanese Patent Application Laid-Open No. 216974/1989), atorvastatin ((3R, 5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid, Japanese Patent Application Laid-Open No.
  • atorvastatin, rosuvastatin, pitavastatin and the salts thereof are more preferred, and pitavastatin and the salts thereof (a sodium salt, a calcium salt and the like) are more preferred.
  • anti-thrombocytic agent and the HMG-CoA reductase inhibitor each described above can be produced by publicly known methods in addition to the methods described in the published patent applications described above.
  • the drug of the present invention is used by combining the anti-thrombocytic agent with the HMG-CoA reductase inhibitor each described above. As shown in examples described later, the drug has a function to notably inhibit the total protein excretion amount in urine in a progressive anti-Thy-1 nephritic rat which is a glomerular disease model as compared with a case where the anti-thrombocytic agent and the HMG-CoA reductase inhibitor are each administered solely.
  • the drug of the present invention is effective for prevention or therapy of a glomerular disease of animals, particularly prevention or therapy of a glomerular disease of mammals including human beings.
  • glomerular disease include chronic glomerular nephritis such as IgA nephropathy, focal, glomerulonephritis, membranous nephropathy and membranous proliferative nephropathy.
  • a use form of the anti-thrombocytic agent and the HMG-CoA reductase inhibitor in the preventive or therapeutic agent of the present invention for a glomerular disease shall not specifically be restricted, and both drugs may be administered at the same time or may be separately administered leaving an interval.
  • the anti-thrombocytic agent and the HMG-CoA reductase inhibitor may be mixed with a diluent, a filler and the like which can pharmaceutically be allowed to prepare a single preparation or the drugs may separately be turned into preparations to prepare a set (kit). When both drugs are turned into separate preparations, the dosage forms may be different from each other.
  • the preventive or therapeutic agent of the present invention for a glomerular disease can have various dosage forms according to uses thereof. Examples include a powder, a granule, a particle, a dry syrup, a tablet, a capsule and an injection form.
  • preparations can be produced according to a conventional method by suitably mixing, diluting or dissolving with medicinal additives such as an excipient, a disintegrating agent, a binder, a glossing agent, a diluent, a buffer solution, an isotonizing agent, an antiseptic agent, a wetting agent, an emulsifier, a dispersant, a stabilizing agent and a dissolution aid which are pharmaceutically allowable according to the formulation forms thereof.
  • medicinal additives such as an excipient, a disintegrating agent, a binder, a glossing agent, a diluent, a buffer solution, an isotonizing agent, an antiseptic agent, a wetting agent, an emulsifier, a dispersant, a stabilizing agent and a dissolution aid which are pharmaceutically allowable according to the formulation forms thereof.
  • the powder preparation can be prepared by adding, if necessary, a suitable excipient, glossing agent and the like to the active ingredients (the anti-thrombocytic agent and/or the HMG-CoA reductase inhibitor) and admixing them well
  • the tablet can be prepared by adding, if necessary, a suitable excipient, disintegrating agent, binder, glossing agent and the like and making a tablet.
  • the tablet can be provided with a coating to prepare a film-coated tablet and a sugar-coated tablet.
  • the injection preparation can have the forms of a liquid formulation (an aseptic solution or a non-aqueous solution), an emulsion and a suspension, and a non-aqueous carrier, a diluent, a solvent or a vehicle used therefor includes, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil and organic acid esters such as ethyl oleate which can be injected.
  • a liquid formulation an aseptic solution or a non-aqueous solution
  • a diluent emulsion and a suspension
  • a non-aqueous carrier emulsion and a suspension
  • a non-aqueous carrier emulsion and a suspension
  • a non-aqueous carrier emulsion and a suspension
  • a non-aqueous carrier emulsion and a suspension
  • a non-aqueous carrier emulsion and a suspension
  • a non-aqueous carrier emulsion and a suspension
  • a content of the anti-thrombocytic agent and the HMG-CoA reductase inhibitor in the preventive or therapeutic agent of the present invention for a glomerular disease may suitably be selected according to the formulations, and it is about 1 to 50 mass %, preferably about 10 to 50 mass % in the case of the anti-thrombocytic agent and about 0.1 to 10 mass %, preferably about 0.5 to 5 mass % in the case of the HMG-CoA reductase inhibitor.
  • the anti-thrombocytic agent and the HMG-CoA reductase inhibitor which have separately been formulated as described above can be administered at the same time or at intervals difference, and in the latter case, an administering frequency of the respective components may be different.
  • a dosage of the preventive or therapeutic agent of the present invention for a glomerular disease is suitably selected according to the kind and the symptom of the glomerular disease, and are 1 to 1000 mg, preferably 10 to 500 mg a day in the case of the anti-thrombocytic agent and 0.1 to 100 mg, preferably 1 to 50 mg a day in the case of the HMG-CoA reductase inhibitor. This dosage can be divided into once to several times a day.
  • Wistar female rats (5 weeks of age, purchased from Japan SLC Co., Ltd.) were quarantined and acclimatized for 4 days and then used for the test.
  • a right kidney of the rat was removed through a flank incision under anesthesia with pentobarbital.
  • an anti-Thy-1 antibody (monoclonal antibody 1-22-3; purchased from Panafarm Laboratories Co., Ltd.) was intravenously administered (500 g/rat) into the tail vein to thereby bring about progressive renal damage, and the following tests 1 to 3 were immediately investigated.
  • Test 2 dilazep hydrochloride (10 mg/kg) dissolved in a physiological saline was continuously intraperitoneally administered for 10 weeks.
  • the total amount of protein excretion in frine after administering pitavastatin calcium (10 mg/kg) for 10 weeks was almost the same as that of the compound-non-administered group in the control, and an effect of pitavastatin calcium was not observed ( FIG. 1 ). Further, the total amount of protein excretion in urine after administering dilazep hydrochloride (10 mg/kg) for 10 weeks also was almost the same as that of the compound-non-administered group in the control, and an effect of dilazep hydrochloride was not observed ( FIG. 2 ).
  • a tablet having the following composition per tablet was produced by the following method. TABLE 1 Pitavastatin calcium 2 mg Dilazep hydrochloride 100 mg Lactose 70 mg Low-substituted hydroxypropyl cellulose 20 mg Hydroxypropyl cellulose 6 mg Magnesium stearate 2 mg Total 200 mg
  • the preventive or therapeutic agent of the present invention for a glomerular disease is useful for prevention and therapy of various glomerular diseases including chronic glomerular nephritis such as IgA nephropathy, focal glomerulonephritis, membranous nephropathy and membranous proliferative nephropathy.
  • chronic glomerular nephritis such as IgA nephropathy, focal glomerulonephritis, membranous nephropathy and membranous proliferative nephropathy.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
US10/504,851 2002-03-28 2003-03-28 Remedies for glomerular diseases Abandoned US20050256141A1 (en)

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JP2002-092238 2002-03-28
PCT/JP2003/003995 WO2003082338A1 (fr) 2002-03-28 2003-03-28 Remedes contre les maladies glomerulaires

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060276486A1 (en) * 2003-04-17 2006-12-07 Kowa Co., Ktd. Lklf/klf2 gene expression promoter
US20100311843A1 (en) * 2009-06-04 2010-12-09 Avexxin As Compositions and methods for the treatment of glomerulonephritis
US9682930B2 (en) 2010-09-02 2017-06-20 Avexxin As Rheumatoid arthritis treatment
US10953004B2 (en) 2016-03-14 2021-03-23 Avexxin As Combination therapy for proliferative diseases
US11351127B2 (en) 2016-09-21 2022-06-07 Avexxin As Pharmaceutical composition

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MY131170A (en) 2002-03-28 2007-07-31 Nissan Chemical Ind Ltd Therapeutic agent for glomerular disease
SG141430A1 (en) 2003-05-30 2008-04-28 Ranbaxy Lab Ltd Substituted pyrrole derivatives and their use as hmg-co inhibitors
US8022086B2 (en) * 2004-10-29 2011-09-20 Kowa Co., Ltd. Therapeutic agent for glomerular disease
US7598233B2 (en) * 2005-03-28 2009-10-06 Kowa Co., Ltd. Method for treating thrombosis
BRPI0618379A2 (pt) * 2005-11-08 2011-08-30 Ranbaxy Lab Ltd processo para preparação do hemi-sal de cálcio do ácido (3r,5r) -7-[2-(4-fluorofenil)-5-isopropil-3-fenil-4-[(4-hidroxime tilfenilamino) carbonil]-pirrol-1-il] -3, 5-diidroxi heptanóico
US7811549B2 (en) 2006-07-05 2010-10-12 Adenobio N.V. Methods, compositions, unit dosage forms, and kits for pharmacologic stress testing with reduced side effects
WO2009092516A2 (en) * 2008-01-22 2009-07-30 Adenobio N.V. Methods, compositions, unit dosage forms, and kits for pharmacologic stress testing with reduced side effects

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EP1488808A4 (en) 2007-05-23
HK1082668A1 (en) 2006-06-16
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TWI290833B (en) 2007-12-11
US7776354B2 (en) 2010-08-17
CN1642574A (zh) 2005-07-20
EP1488808B1 (en) 2012-03-21
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ATE550039T1 (de) 2012-04-15
CA2478017A1 (en) 2003-10-09
EP1488808A1 (en) 2004-12-22
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JPWO2003082338A1 (ja) 2005-07-28
MY131170A (en) 2007-07-31

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