EP0835106A1 - Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii - Google Patents

Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii

Info

Publication number
EP0835106A1
EP0835106A1 EP96921794A EP96921794A EP0835106A1 EP 0835106 A1 EP0835106 A1 EP 0835106A1 EP 96921794 A EP96921794 A EP 96921794A EP 96921794 A EP96921794 A EP 96921794A EP 0835106 A1 EP0835106 A1 EP 0835106A1
Authority
EP
European Patent Office
Prior art keywords
recited
ace inhibitor
receptor antagonist
lisinopril
phn
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.)
Withdrawn
Application number
EP96921794A
Other languages
German (de)
English (en)
Other versions
EP0835106A4 (fr
Inventor
Giuseppe Remuzzi
Ronald S. Eydelloth
Roger A. Owen
Shahnaz Shahinfar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratories Merck Sharp and Dohme Chibret SAS
Merck and Co Inc
Original Assignee
Laboratories Merck Sharp and Dohme Chibret SAS
Merck and Co Inc
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
Priority claimed from GBGB9602854.3A external-priority patent/GB9602854D0/en
Application filed by Laboratories Merck Sharp and Dohme Chibret SAS, Merck and Co Inc filed Critical Laboratories Merck Sharp and Dohme Chibret SAS
Publication of EP0835106A1 publication Critical patent/EP0835106A1/fr
Publication of EP0835106A4 publication Critical patent/EP0835106A4/fr
Withdrawn legal-status Critical Current

Links

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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • Angiotensin II (All) is a potent vasoconstrictor. Its generation in the renin-angiotensin cascade results from the enzymatic action of renin on a blood plasma, 2-globulin, angiotensinogen, to produce angiotensin I (AI). AI is then converted by angiotensin converting enzyme (ACE) to the octapeptide hormone, AIL All has been implicated as a causitive agent in hypertension. Therefore, ACE inhibitiors, which inhibit the production of All, and and All receptor antagonists, which inhibit the function of All, are useful in the treatment of hypertension. The efficacy of these compounds in the treatment of heart failure is also being studied.
  • Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating All (Pals et aL, Circulation Research. 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B. V., p. 246 (1984)).
  • saralasin due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AIL Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective.
  • AIL Being a peptide
  • ACE angiotensin converting enzyme
  • ACEI angiotensin converting enzyme
  • Losartan potassium represents the first antihypertensive in the class of All receptor antagonists which is disclosed in a U.S. Patent 5,138,069 issued on August 1 1, 1992, and which is assigned to E. I. du Pont de Nemours. Losartan has been demonstrated to be a potent orally active A II antagonist, selective for the ATl receptor subtype useful in the treatment of hypertension.
  • ACE inhibitors e.g. captopril, enalapril or lisinopril
  • ATI selective All receptor antagonists e.g.
  • losartan selectively inhibit the function of All at the receptor site, it is reasonable to suggest that an enhanced beneficial effect might be achieved through the coadministration of compounds from these therapeutic classes.
  • the coadministration of an ACE inihibitor with and All antagonist has been disclosed in patent applications filed by SmithKline Beecham (WO 92/10097) and Pfizer (WO 91/17771) and have shown the combination to be useful in the treatment of hypertension and cogestive heart failure. Additionally, a patent application filed by Merck and INSERM (EPO 629408) claims enhanced renal blood flow when treating with the combination.
  • a method of treating and/or preventing renal disease of a warm-blooded animal with a therapeutically effective dose amount of a pharmaceutical composition of an ACE inhibitor and an Angiotensin II receptor antagonist is disclosed. Included within the scope of the term renal disease are diabetic (insulin- and noninsulin-dependent) and non- diabetic nephropathy, including immunologically- and nonimmunologically-based nephropathies and/or glomerulopathies.
  • Also included within the scope of the invention is a method of protecting renal structure and/or renal function of a mammal with a therapeutically effective amount of a pharmaceutical composition of an ACE inhibitor and an Angiotensin II antagonist. Included within the scope of the term pharmaceutical composition are a fixed combination and a concomitant therapy of an ACE inhibitor and an All antagonist.
  • the present invention relates to a method of treating and/or preventing renal disease with the coadministration, either concomitant therapy or a fixed combination, of an ACE inhibitor and an All receptor antagonist.
  • Concomitant therapy would include the sequential administration of members from the two classes of compounds.
  • renal disease includes diabetic nephropathy and non-diabetic nephropathy, including immunologically- and nonimmunologically- based nephropathies and/or glomerulopathies.
  • non-diabetic nephropathy includes the condition referred to as human membranous glomerular nephritis.
  • the present invention further relates to a method for protection of renal structure and/or renal function with the coadministration, either concomitant therapy or a fixed combination therapy, of an ACE inhibitor and an All receptor antagonist.
  • the combination is also useful in preventing renal injury and protecting glomerular structure.
  • the angiotensin coverting enzyme inhibitors useful in this method of treatment include, but are not limited to: AB-47, alacepril, benazepril, BIBR-277, BIBS39, BMS-186716, BPI.137, captopril, ceranopril, cilazapril, delapril, DU-1777, enalapril, fosinopril, FPL- 66564, idrapril, imidapril, libenzapril, lisinopril, MDL- 100240, moexipril, moveltopril, perindopril, Prentyl, quinapril, ramapril, spirapril, Synecor, S-5590, temocapril, trandolapril, utibapril, zabicipril, and zofenopril.
  • An embodiment of the ACE inhibitors useful in this method of treatment are: captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, and zofenopril.
  • the angiotensin II antagonists useful in this method of treatment include, AT-1 selective angiotensin II receptor antagonists, as well as non-selective angiotensin II receptor antagonists.
  • angiotensin II antagonists within the scope of the invention include, but are not limited to: candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, BMS-184698, 3-(2'-(tetrazol-5-yl)- 1 , l '-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5- b]pyridine, BAY106734, BIBR363, CL329167, E4177, EMD73495, HN65021 , HR720, HOE720, LRB081 , SC52458, SL910102, UP2696, YM358, EMD66397, ME3221 , TAK536, BMS184698, CGP421 12A, CGP49870, CP148130, E4188, EMD66684, EX
  • angiotensin II antagonists useful in this method of treatment are: candesartan cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, valsartan, BMS- 184698 and 3-(2'-(tetrazol-5- yl)-l,l '-biphen-4-yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5- bjpyridine.
  • renal injury (See JASN 3:624, 1992) is representative of human i munologically-mediated glomerulonepropathy.of renal disease, which also noted enhanced renal protection with the coadministration of lisinopril and 3-(2'-(tetrazol-5-yl)-l ,r-biphen-4-yl)methyl-5,7- dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine.
  • Passive Heymann is representative of human i munologically-mediated glomerulonepropathy.of renal disease, which also noted enhanced renal protection with the coadministration of lisinopril and 3-(2'-(tetrazol-5-yl)-l ,r-biphen-4-yl)methyl-5,7- dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine.
  • an ACE inhibitor and an Angiotensin II (All) receptor antagonist has been demonstrated in rats to provide a method of treatment for the renally impaired.
  • the administration of compounds from these two classes can also be effect in treating renal disease, including diabetic nephropathy insulin- and noninsulin-dependent) and non-diabetic nephropathy including immunologically- and nonimmunologically-mediated nephropathies and/or glomerulopathathies.
  • diabetic nephropathy it is understood that the disease state is the result of either non-insulin dependent diabetes mellitus or insulin dependent diabetes mellitus.
  • compositions include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences. 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydro- scopicity and solubility.
  • the preferred salts of this invention include, but are not limited to: potassium, sodium, calcium and ammonium salts of the ACE inhibitor and/or All receptor antagonist.
  • compositions of this invention can be administered for the treatment and or prevention of renal disease according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm ⁇ blooded animal.
  • administration can be parenteral, i.e., subcutaneous, intravenous, intramuscular or intra peritoneal.
  • admmistration can be by the oral route.
  • the pharmaceutical compositions of this invention can be administered by any conventional means available for use in conjunction with pharmaceuticals.
  • the pharmaceutical compositions can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • a warm-blooded animal is a member of the animal kingdom which includes but is not limited to mammals and birds.
  • the preferred mammal of this invention is human.
  • the dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
  • a daily dosage of active ingredient compound will be from about 1 -500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results.
  • the active ingredients can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours.
  • Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene gyclols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. A. Osol, a standard reference text in this field.
  • CAPSULES A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with a pharmacologically appropriate amount in milligrams of the powdered active ingredients, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • SOFT GELATIN CAPSULES A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive olil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing a pharmacologically appropriate amount in milligrams of the active ingredient. The capsules are washed and dried.
  • a digestible oil such as soybean oil, cottonseed oil or olive olil
  • the dosage unit is a pharmacologically appropriate amount in milligrams of the active ingredients, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 1 1 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase palatability or delay abso ⁇ tion.
  • a parenteral composition suitable for administration by injection is prepared by stirring a pharmacologically appropriate amount by weight of the active ingredients in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
  • An aqueous suspension is prepared for oral administration so that each 5 milliliters contain a pharmacologically appropriate amount in milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
  • the same dosage forms can generally be used when the ACE inhibitor compounds and All antagonist compounds of this invention are administered in a concomitant fashion.
  • the above dosage forms and route of administration for a fixed combination ACE inhibitor and All antagonist should be selected depending on the compatibility of the combined drugs. Suitable dosages, dosage forms • and administration routes are illustrated in Tables A and B.
  • Table A Examples of ACE inhibitors that can be combined with the below A II receptor antagonist is useful for the treatment and/or prevention of renal disease
  • Drug Dose (mg/day) Formulation Route of Admin. lisinopril 5, 10, 20, 40 Tablet Oral enalapril 10-40 Tablet Oral
  • Table B Examples of All receptor antagonists that can be combined with the above ACE inhibitors for the treatment and/or prevention of renal disease
  • Diabetes was induced with intravenous streptozotocin (60 mg/kg) in male Sprague-Dawley rats on study day 1.
  • a daily dose of subcutaneously administered insulin was adjusted on a weekly basis to maintain serum glucose levels between 200 and 400 mg/dl.
  • Losartan was administered alone and in combination with lisinopril in the drinking water from study day 5; final dosage levels were 30 and 30/3.5 mg/kg/day, respectively.
  • the effects on renal function and structure were evaluated after one year of treatment. Various parameters were ' assessed.
  • losartan/lisinopril treatment sixteen-hour urinary protein excretion [total protein (TUP), high molecular weight protein (HMW)], histomorphological quantitative assessment of glomerular area (GA) and glomerular basement membrane thickness (GBMT).
  • TUP total protein
  • HMW high molecular weight protein
  • GA histomorphological quantitative assessment of glomerular area
  • GBMT glomerular basement membrane thickness
  • SBP stolic blood pressure
  • GFAR whole- kidney function
  • RPF clearance of p- aminohippuric acid
  • PHN rats developed significant (p ⁇ 0.01) proteinuria as early as 7 days after induction of the disease. Proteinuria progressively increased with time, averaging 702.06+77.02 mg/day at the end of the study. In normal control rats protein excretion rose only to 79.46+15.43 mg/day after 12 months. 3-(2'-(tetrazol-5-yl)-l,l'-biphen-4-yl)methyl-5,7- dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine and lisinopril were both effective in limiting the development of proteinuria of PHN rats.
  • Proteinuria values of rats treated with 3-(2'-(tetrazol-5-yl)-l ,l '-biphen-4-yl)methyl-5,7-dimethyl- 2-ethyl-3H-imidazo[4,5-b]pyridine + lisinopril were even significantly lower than those of PHN + 3-(2'-(tetrazol-5-yl)-l ,l'-biphen-4- yl)methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine or PHN + lisinopriltreated groups during the entire study period and significantly lower than those of control rats starting from month 6.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé de traitement et/ou de prévention de néphropathies consistant à administrer conjointement un inhibiteur de l'enzyme de conversion de l'angiotensine (ACE) et un antagoniste de récepteur de l'angiotensine II (A II). La présente invention concerne également un procédé de protection de la structure rénale et/ou de la fonction rénale consistant à administrer conjointement un inhibiteur de ACE et un antagoniste de récepteur de A II. Ladite combinaison est également utile pour prévenir la lésion rénale et protéger la structure glomérulaire.
EP96921794A 1995-06-30 1996-06-26 Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii Withdrawn EP0835106A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US77095P 1995-06-30 1995-06-30
US770P 1995-06-30
GBGB9602854.3A GB9602854D0 (en) 1996-02-13 1996-02-13 Method of treating renal disease using an ace inhibitor and an II antagonist
GB9602854 1996-02-13
PCT/US1996/010942 WO1997002032A1 (fr) 1995-06-30 1996-06-26 Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii

Publications (2)

Publication Number Publication Date
EP0835106A1 true EP0835106A1 (fr) 1998-04-15
EP0835106A4 EP0835106A4 (fr) 1998-09-30

Family

ID=26308665

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96921794A Withdrawn EP0835106A4 (fr) 1995-06-30 1996-06-26 Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii

Country Status (5)

Country Link
EP (1) EP0835106A4 (fr)
JP (1) JPH11508894A (fr)
AU (1) AU716519B2 (fr)
CA (1) CA2224451A1 (fr)
WO (1) WO1997002032A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6107323A (en) * 1996-04-05 2000-08-22 Takeda Chemical Industries, Ltd. Pharmaceutical composition
WO2001060362A1 (fr) * 2000-02-18 2001-08-23 Takeda Chemical Industries, Ltd. INHIBITEURS DE TNF-$g(a)
CZ20023381A3 (cs) * 2000-04-12 2003-02-12 Novartis Ag Kombinované farmaceutické prostředky obsahující antagonistu AT1-receptoru nebo/a inhibitor HMG-CoA reduktázy nebo/a ACE inhibitor
PL366419A1 (en) * 2000-08-22 2005-01-24 Boehringer Ingelheim Pharma Bmbh & Co.Kg Pharmaceutical combination of angiotensin ii antagonists and angiotensin i converting enzyme inhibitors
GB0020691D0 (en) * 2000-08-22 2000-10-11 Boehringer Ingelheim Pharma Pharmaceutical combination
ATE401876T1 (de) 2001-08-31 2008-08-15 Australian Biomedical Company Herstellung und verwendung von gibberellinen bei diabetes
US7413751B2 (en) 2001-10-25 2008-08-19 Depomed, Inc. Methods of treatment using a gastric retained losartan dosage
WO2003047573A1 (fr) * 2001-12-03 2003-06-12 Takeda Chemical Industries, Ltd. Agents pour améliorer l'état de résistance à l'insuline
JP4484427B2 (ja) * 2001-12-03 2010-06-16 武田薬品工業株式会社 インスリン抵抗性改善剤
DE10229180A1 (de) * 2002-06-28 2004-01-29 Aventis Pharma Deutschland Gmbh Verwendung von Vasopeptidase-Inhibitoren bei der Behandlung von metabolischen Erkrankungen, Nephropathie und mit AGE assoziierten Erkrankungen
EP1627638B1 (fr) * 2003-05-09 2017-07-12 Toray Industries, Inc. Béraprost et un inhibiteur du système rénine-angiotensine utilisés dans le traitement de maladies rénales
TR201004754A1 (tr) * 2010-06-11 2012-01-23 Sanovel �La� San. Ve T�C. A.�. Yeni Farmasötik Kombinasyonlar
CN107011229B (zh) * 2012-01-06 2019-11-05 诺华股份有限公司 杂环化合物和它们的使用方法
CN107157999A (zh) * 2017-05-27 2017-09-15 青岛海蓝医药有限公司 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用

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WO1991017771A1 (fr) * 1990-05-11 1991-11-28 Pfizer Inc. Compositions et procedes therapeutiques synergiques
WO1992010097A1 (fr) * 1990-12-14 1992-06-25 Smithkline Beecham Corporation Compositions de blocage de recepteur de l'angiotensine ii
EP0527534A1 (fr) * 1991-08-13 1993-02-17 Merck & Co. Inc. Dérivés de la quinoline et de l'azaquinoline comme antagonistes de l'angiotensine II
EP0537937A2 (fr) * 1991-10-07 1993-04-21 Merck & Co. Inc. Pyrazino (2,3-D)pyrimidinones substituées comme angiotensin II antagonistes
EP0629408A1 (fr) * 1993-06-16 1994-12-21 LABORATOIRES MERCK, SHARP & DOHME-CHIBRET Combination d'inhibiteurs ACE et d'antagonistes AII
US5376666A (en) * 1992-11-30 1994-12-27 The Du Pont Merck Pharmaceutical Company Angiotension-II receptor blocking, azacycloalkyl or azacycloalkenyl
WO1996031234A1 (fr) * 1995-04-07 1996-10-10 Novartis Ag Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane
WO1997037688A2 (fr) * 1996-04-05 1997-10-16 Takeda Chemical Industries, Ltd. Combinaison pharmaceutique comprenant un compose contenant de l'angiotensine ii et presentant une activite antagoniste

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WO1991017771A1 (fr) * 1990-05-11 1991-11-28 Pfizer Inc. Compositions et procedes therapeutiques synergiques
WO1992010097A1 (fr) * 1990-12-14 1992-06-25 Smithkline Beecham Corporation Compositions de blocage de recepteur de l'angiotensine ii
EP0527534A1 (fr) * 1991-08-13 1993-02-17 Merck & Co. Inc. Dérivés de la quinoline et de l'azaquinoline comme antagonistes de l'angiotensine II
EP0537937A2 (fr) * 1991-10-07 1993-04-21 Merck & Co. Inc. Pyrazino (2,3-D)pyrimidinones substituées comme angiotensin II antagonistes
US5376666A (en) * 1992-11-30 1994-12-27 The Du Pont Merck Pharmaceutical Company Angiotension-II receptor blocking, azacycloalkyl or azacycloalkenyl
EP0629408A1 (fr) * 1993-06-16 1994-12-21 LABORATOIRES MERCK, SHARP & DOHME-CHIBRET Combination d'inhibiteurs ACE et d'antagonistes AII
WO1996031234A1 (fr) * 1995-04-07 1996-10-10 Novartis Ag Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane
WO1997037688A2 (fr) * 1996-04-05 1997-10-16 Takeda Chemical Industries, Ltd. Combinaison pharmaceutique comprenant un compose contenant de l'angiotensine ii et presentant une activite antagoniste

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Title
BURDMANN ET AL: "Prevention of Experimental Cyclosporin-Induced Interstitial Fibrosis by Losartan and Enalapril" AMERICAN JOURNAL OF PHYSIOLOGY, vol. 269, no. 4, October 1995, pages f491-f499, XP002072709 *
POLLOCK ET AL: "Angiotensin II Receptor Blockade Improves Renal Function in Rats with Reduced Renal Mass" JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 367, no. 2, 1993, pages 657-663, XP002072710 *
See also references of WO9702032A1 *

Also Published As

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AU6291696A (en) 1997-02-05
EP0835106A4 (fr) 1998-09-30
CA2224451A1 (fr) 1997-01-23
JPH11508894A (ja) 1999-08-03
AU716519B2 (en) 2000-02-24
WO1997002032A1 (fr) 1997-01-23

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