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WO1997021436A1 - Nouvelle utilisation du losartan - Google Patents

Nouvelle utilisation du losartan Download PDF

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Publication number
WO1997021436A1
WO1997021436A1 PCT/US1996/019781 US9619781W WO9721436A1 WO 1997021436 A1 WO1997021436 A1 WO 1997021436A1 US 9619781 W US9619781 W US 9619781W WO 9721436 A1 WO9721436 A1 WO 9721436A1
Authority
WO
WIPO (PCT)
Prior art keywords
losartan
heart
treatment
ischemia
vol
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.)
Ceased
Application number
PCT/US1996/019781
Other languages
English (en)
Inventor
Sheila M. Cohen
Jeffrey G. Werrmann
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.)
Merck and Co Inc
Original Assignee
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 GBGB9603376.6A external-priority patent/GB9603376D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU14164/97A priority Critical patent/AU704841C/en
Priority to EP96944328A priority patent/EP0868179A4/fr
Priority to JP9522199A priority patent/JP2000501736A/ja
Publication of WO1997021436A1 publication Critical patent/WO1997021436A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • a method of acute treatment for enhancing functional recovery of the heart post-ischemia comprising the administration of a therapeutically effective amount of losartan, its active metabolite, EXP3174, or a pharmaceutically acceptable salt therefrom, to a patient or a patient's isolated heart in need of such treatment.
  • the instant invention relates to a method of acute treatment for enhancing functional recovery of the heart post-ischemia comprising the administration of a therapeutically effective amount of losartan, its active metabolite, EXP3174, or a pharmaceutically acceptable salt therefrom, to a patient or a patient's isolated heart in need of such treatment.
  • An embodiment of this aspect of the invention is a method as described above, wherein the ischemia occurs during cardiac by-pass surgery.
  • a second aspect of this invention is a method of acute treatment for enhancing functional recovery of a patient's new heart post transplantation comprising the administration directly to the isolated heart during the preservation period prior to transplantation a therapeutically effective amount of losartan, its active metabolite, EXP3174, or a pharmaceutically acceptable salt therefrom.
  • a third aspect of this invention is the method of acute treatment of a patient's partially ischemic heart prior to interventional procedures to assess or correct a coronary blockage for the purpose of enhancing subsequent functional recovery of the heart after the procedure comprising the administration to such patient of a therapeutically effective amount of losartan, its active metabolite, EXP3174, or a pharmaceutically acceptable salt therefrom.
  • a fourth aspect of the instant invention relates to a method of acute treatment for enhancing functional recovery after a myocardial infarction comprising the administration to a patient in need of such treatment of a therapeutically effective amount of losartan, its active metabolite, EXP3174, or a pharmaceutically acceptable salt therefrom.
  • Losartan potassium salt is currently being sold in the US under the registered trademark COZAAR® for the treatment of hypertension.
  • EXP3174 has been identified as an active metabolite of losartan potassium.
  • Heart donors were male Sprague-Dawley rats weighing 400-500 g and were obtained from Charles River Breeding
  • Losartan was administered in vivo (Group 1 ) as an aqueous solution by gavage, whereas placebo rats received an equivalent volume of water (Group 2).
  • the 4.5 ⁇ M dose of losartan used in the in vitro experiments (Group 3) was chosen to insure saturation of the ATl receptor sites while remaining well below the K of losartan for the AT2 receptor subtype in heart [See Chang, R.S.L., et al., "In Vitro Pharmacology of MK-996, a New Potent and Selective Angiotensin II (AT l ) Receptor Antagonist", Drug Dev. Res., 1994, Vol. 32, pp. 161 - 171 [.
  • the 31p NMR spectra were measured using a Bruker AM360 wide-bore spectrometer. Each spectrum consisted of 84 to 160 scans of 60° free-induction decays with a 12 kHz window; two second recovery was allowed between pulses. Thus, each spectrum measured average metabolite levels over a 3.0 to 5.6 minute period. 3 1 p NMR peak areas were determined with PCr and ATP quantitated as described previously [See Werrmann. J.G. et al., J. Cardiovasc. Pharmacol., 1994, Vol. 24, pp. 573-586J. The 3 1 P NMR provided a direct measurement of intracellular pH in our isolated heart preparations.
  • Hearts from rats treated orally with losartan demonstrated a sustained significant improvement in CF by 30 min of reperfusion that continued until the end of the reperfusion period (Fig. 2).
  • hearts treated with losartan in vitro showed a significant improvement in coronary flow for only one brief interval near the end of the reperfusion period.
  • ATP levels fell to I - to 4- ⁇ moles/g dry weight in all treatment groups after 20 min of ischemia then recovered to 12- to 14- ⁇ moles/g dry weight in all treatment groups after 54 min of reperfusion.
  • Phosphocreatine levels were 23 ⁇ 1 to 27 ⁇ 1 ⁇ mol/g dry weight at baseline; drug treatment did not significantly affect the decrease in phosphocreatine levels observed during ischemia or the degree of recovery of phosphocreatine during reperfusion.
  • Compound A another structurally distinct All ATl receptor antagonist, and may thus be characteristic of this class of compounds [See Werrmann, J.G., et al, "Comparison of the Effects of ACE Inhibition with Those of All Receptor Antagonism on Functional and Metabolic Recovery in the Post-ischemic Working Rat Heart as Studied by 3 l P NMR", J. Cardiovasc. Pharmacol, 1994, Vol.
  • lisinopril treatment in vitro did not reduce myocardial injury [See Werrmann, J.G. et al, J. Cardiovasc. Pharmacol, 1994, Vol. 24, pp.
  • tissue All levels were not measured, one can speculate that lack of an acute effect of ACE inhibitor treatment in vitro in our isolated heart model may be due to incomplete washout of endogenous tissue All subsequent to ACE inhibition and prior to the ischemic insult. It is possible that AH ATl receptor antagonists will prove useful in the acute treatment of myocardial infarction because they act directly at the receptor level, thus providing a rapid mechanism for blocking the effects of AIL
  • Stimulation of Na+/H+ exchange in rabbit ventricular myocytes by angiotensin II has been reported recently [See Matsui, H., et al, "Angiotensin II Stimulates Sodium-hydrogen Exchange in Adult Rabbit Ventricular Myocytes", Cardiovasc. Res., 1995, Vol. 29, pp. 215-221 1. Stimulation of Na+/H+ exchange by angiotensin II was also demonstrated in OKP cells [See Cano, A., et al, "Angiotensin II Stimulation of Na-H Antiporter Activity is cAMP Independent in OKP Cells", Am. J. Physiol, 1994, Vol. 266 (Cell Physiol 35), pp. Cl 603- C1608], an opossum kidney cell line, where is was further shown by use of losartan that this effect was mediated by an ATl receptor coupled mechanism.
  • the preferred salts of this invention include, but are not limited to: potassium, sodium, calcium and ammonium salts of losartan and its active metabolite, EXP3174.
  • compositions comprising losartan, its active metabolite, EXP3174 or a pharmaceutically acceptable salt therefrom and a suitable pharmaceutical carrier.
  • compositions of this invention can be administered for this method of treatment by any means that effects contact of the active ingredient compound with the site of action.
  • administration can be parenteral, i.e., subcutaneous, intravenous, intramuscular or intra peritoneal. Alternatively, or concurrently in some cases administration 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.
  • the term patient is defined as a mammal, preferably 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 glycols 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.
  • Useful pharmaceutical dosage-forms for administration of losartan or EXP3174 for this invention can be illustrated as follows:
  • 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.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil 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.
  • 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.
  • 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 above dosage forms and routes of administration will depend upon the method of treatment. If the method of treatment is to enhance the functional recovery of the isolated heart during transplantation or while the heart is on by pass, then the route of administration will be via the direct addition to the preservation solution that is typically employed during a transplant procedure or addition to the heart while it is on by-pass. Additionally, the method of treatment may require the administration of losartan or EXP3174 to the patient by one of the traditional routes outlined above.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne l'utilisation du losartan, de son métabolite actif, EXP3174, et des sels pharmaceutiquement acceptables de ces composés, pour renforcer la récupération fonctionnelle du coeur après une attaque ischémique.
PCT/US1996/019781 1995-12-12 1996-12-09 Nouvelle utilisation du losartan Ceased WO1997021436A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU14164/97A AU704841C (en) 1995-12-12 1996-12-09 New use for losartan
EP96944328A EP0868179A4 (fr) 1995-12-12 1996-12-09 Nouvelle utilisation du losartan
JP9522199A JP2000501736A (ja) 1995-12-12 1996-12-09 ロサルタンの新用途

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US875795P 1995-12-12 1995-12-12
US60/008,757 1995-12-12
GB9603376.6 1996-02-16
GBGB9603376.6A GB9603376D0 (en) 1996-02-16 1996-02-16 New use for Iosartan

Publications (1)

Publication Number Publication Date
WO1997021436A1 true WO1997021436A1 (fr) 1997-06-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/019781 Ceased WO1997021436A1 (fr) 1995-12-12 1996-12-09 Nouvelle utilisation du losartan

Country Status (4)

Country Link
EP (1) EP0868179A4 (fr)
JP (1) JP2000501736A (fr)
CA (1) CA2238975A1 (fr)
WO (1) WO1997021436A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999016437A1 (fr) * 1997-09-30 1999-04-08 Merck Sharp Dohme (Italia) S.P.A. Utilisation d'un antagoniste du recepteur de l'angiotensine ii pour la preparation de medicaments servant a accroitre le taux de survie des patients ayant subi une transplantation renale
GB2337701A (en) * 1998-05-26 1999-12-01 United Medical And Dental Schools Of Guys St Thomas Hospitals Treatment of ischemia with an angiotensin II antagonist
EP0855392A3 (fr) * 1997-01-22 2000-01-05 Hoechst Aktiengesellschaft Hétérocycles à cinq chaínons contenant des substituants biphénylylsulphoniques, leur procédé de préparation, leur utilisation comme médicament ou agent diagnostique ainsi que médicament les contenant
WO1999020260A3 (fr) * 1997-10-17 2000-03-09 Eurogene Limited Utilisation d'inhibiteurs du systeme renine-angiotensine
WO2003035039A1 (fr) * 2001-10-25 2003-05-01 Depomed, Inc. Traitement utilisant une dose posologique de losartan a retention gastrique
WO2006087395A1 (fr) * 2005-02-21 2006-08-24 Flamel Technologies Forme pharmaceutique orale multimicroparticulaire a liberation modifiee d'antagonistes des recepteurs de l'angiotensine ii
WO2006087394A1 (fr) * 2005-02-21 2006-08-24 Flamel Technologies Forme pharmaceutique orale de losartan
FR2884145A1 (fr) * 2005-04-06 2006-10-13 Flamel Technologies Sa Forme pharmaceutique orale de losartan
US7560446B2 (en) 1999-01-26 2009-07-14 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
US7825132B2 (en) 2002-08-23 2010-11-02 Novartis Vaccines And Diagnostics, Inc. Inhibition of FGFR3 and treatment of multiple myeloma
US7838527B2 (en) 2002-11-13 2010-11-23 Novartis Vaccines And Diagnostics, Inc. Methods of treating cancer and related methods
US7875624B2 (en) 2004-02-20 2011-01-25 Novartis Vaccines And Diagnostics, Inc. Modulating and measuring cellular adhesion
US20120095067A1 (en) * 2009-06-25 2012-04-19 Jin Yang Pharm. Co., Ltd. Pharmaceutical composition containing carboxylosartan and a production method therefor
US8299081B2 (en) 2005-05-13 2012-10-30 Novartis Ag Methods for treating drug resistant cancer
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030225254A1 (en) 1989-08-07 2003-12-04 Rathjen Deborah Ann Tumour necrosis factor binding ligands

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5538991A (en) * 1994-09-14 1996-07-23 Merck & Co., Inc. Endothelin antagonists bearing 5-membered heterocyclic amides
US5565485A (en) * 1993-03-19 1996-10-15 Merck & Co., Inc. Biphenyl compounds useful or endothelin antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565485A (en) * 1993-03-19 1996-10-15 Merck & Co., Inc. Biphenyl compounds useful or endothelin antagonists
US5538991A (en) * 1994-09-14 1996-07-23 Merck & Co., Inc. Endothelin antagonists bearing 5-membered heterocyclic amides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0868179A4 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6486189B2 (en) 1997-01-22 2002-11-26 Hoechst Aktiengesellschaft Five-membered heterocycles having biphenylsulfonyl substitution, process for their preparation, their use as a medicament or diagnostic, and medicament comprising them
EP0855392A3 (fr) * 1997-01-22 2000-01-05 Hoechst Aktiengesellschaft Hétérocycles à cinq chaínons contenant des substituants biphénylylsulphoniques, leur procédé de préparation, leur utilisation comme médicament ou agent diagnostique ainsi que médicament les contenant
US6335451B1 (en) 1997-01-22 2002-01-01 Hoechst Aktiengesellschaft Five-membered heterocycles having biphenylsulfonyl substitution, with sulfonylcyanamide side chain, compositions containing them, and methods of using them
WO1999016437A1 (fr) * 1997-09-30 1999-04-08 Merck Sharp Dohme (Italia) S.P.A. Utilisation d'un antagoniste du recepteur de l'angiotensine ii pour la preparation de medicaments servant a accroitre le taux de survie des patients ayant subi une transplantation renale
US6576652B2 (en) 1997-09-30 2003-06-10 Merck Sharp & Dohme (Italia) S.P.A. Use of an angiotensin II receptor antagonist for the preparation of drugs to increase the survival rate of renal transplant patients
CN1123342C (zh) * 1997-10-17 2003-10-08 欧洲基因有限公司 肾素－血管紧张素系统的抑制剂的用途
WO1999020260A3 (fr) * 1997-10-17 2000-03-09 Eurogene Limited Utilisation d'inhibiteurs du systeme renine-angiotensine
US7998953B2 (en) 1997-10-17 2011-08-16 Ark Therapeutics Group, p.l.c. Use of inhibitors of the renin-angiotensin system
AP1300A (en) * 1997-10-17 2004-09-08 Eurogene Ltd The use of inhibitors of the renin-angiotensin system for the treatment of hypoxia or impaired metabolic function.
EP1498124A3 (fr) * 1997-10-17 2005-08-17 Ark Therapeutics Limited Utilisation d'inhibiteurs du système rénine-angiotensine
US7071183B2 (en) 1997-10-17 2006-07-04 Ark Therapeutics Limited Use of inhibitors of the renin-angiotensin system
EP1559424A3 (fr) * 1997-10-17 2009-11-11 Ark Therapeutics Limited Utilisation d'inhibiteurs du système rénine-angiotensine
US8003679B2 (en) 1997-10-17 2011-08-23 ArkTherapeutics Group, plc Use of inhibitors of the renin-angiotensin system
GB2337701A (en) * 1998-05-26 1999-12-01 United Medical And Dental Schools Of Guys St Thomas Hospitals Treatment of ischemia with an angiotensin II antagonist
US7560446B2 (en) 1999-01-26 2009-07-14 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
US7413751B2 (en) 2001-10-25 2008-08-19 Depomed, Inc. Methods of treatment using a gastric retained losartan dosage
WO2003035039A1 (fr) * 2001-10-25 2003-05-01 Depomed, Inc. Traitement utilisant une dose posologique de losartan a retention gastrique
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US10004693B2 (en) 2002-04-09 2018-06-26 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US7825132B2 (en) 2002-08-23 2010-11-02 Novartis Vaccines And Diagnostics, Inc. Inhibition of FGFR3 and treatment of multiple myeloma
US7838527B2 (en) 2002-11-13 2010-11-23 Novartis Vaccines And Diagnostics, Inc. Methods of treating cancer and related methods
US7875624B2 (en) 2004-02-20 2011-01-25 Novartis Vaccines And Diagnostics, Inc. Modulating and measuring cellular adhesion
WO2006087394A1 (fr) * 2005-02-21 2006-08-24 Flamel Technologies Forme pharmaceutique orale de losartan
WO2006087395A1 (fr) * 2005-02-21 2006-08-24 Flamel Technologies Forme pharmaceutique orale multimicroparticulaire a liberation modifiee d'antagonistes des recepteurs de l'angiotensine ii
FR2884145A1 (fr) * 2005-04-06 2006-10-13 Flamel Technologies Sa Forme pharmaceutique orale de losartan
US8299081B2 (en) 2005-05-13 2012-10-30 Novartis Ag Methods for treating drug resistant cancer
US20120095067A1 (en) * 2009-06-25 2012-04-19 Jin Yang Pharm. Co., Ltd. Pharmaceutical composition containing carboxylosartan and a production method therefor

Also Published As

Publication number Publication date
JP2000501736A (ja) 2000-02-15
CA2238975A1 (fr) 1997-06-19
AU704841B2 (en) 1999-05-06
AU1416497A (en) 1997-07-03
EP0868179A1 (fr) 1998-10-07
EP0868179A4 (fr) 2002-01-30

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