WO1995009625A1 - Use of amiodarone for the treatment of heart failure - Google Patents

Use of amiodarone for the treatment of heart failure Download PDF

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Publication number
WO1995009625A1
WO1995009625A1 PCT/EP1994/003267 EP9403267W WO9509625A1 WO 1995009625 A1 WO1995009625 A1 WO 1995009625A1 EP 9403267 W EP9403267 W EP 9403267W WO 9509625 A1 WO9509625 A1 WO 9509625A1
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Prior art keywords
amiodarone
agent
use according
day
heart failure
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PCT/EP1994/003267
Other languages
French (fr)
Inventor
Hugo Grancelli
Sergio Perrone
Daniel Nul
Hernán DOVAL
Guillermo Bortman
Rodolfo Curiel
Angel Omar Scapin
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Handforth Investments Ltd.
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Priority to AU78540/94A priority Critical patent/AU7854094A/en
Publication of WO1995009625A1 publication Critical patent/WO1995009625A1/en

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    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • the present invention refers to a new therapeutic use (second medical indication) of the pharmaceutical active principle amiodarone, namely; the treatment of heart failure.
  • This indication is new and goes against the general trend which considers that
  • amiodarone is contraindicated for the treatment of patients suffering from heart failure.
  • heart failure is a particular frequent cause for human mortality.
  • this disease is clearly different from other heart diseases such as arrhythmia, angina
  • Amiodarone hydrochloride (hereinafter called simply amiodarone) was described in US 3.248.401 patent as a powerful antiangina and antiarrhythmic agent.
  • French patent FR 2.626.176 mentions amiodarone in combination with other agents in the treatment of coronary disease.
  • the main therapeutic use of amiodarone has been as an antiarrhythmic agent (of type III, according to Williams classification).
  • amiodarone is
  • a cardiotonic agent (group D18.130, ⁇ .g. acotyldigitoxin, digitoxin, digoxin...) or an ACE-inhibitor (group D18.40.220, e.g.: captopril, enalapril, lisinopril) is used, either alone or in combination with a diuretic.
  • the choice is usually a combination of a diuretic plus a cardiotonic (or an ACE-inhibitor) plus a vasodilating agent (group D18.915.920.180, e.g.: isosorbide mono nitrats, isosorbide dinitrate,
  • amiodarone is included as ingrediont.
  • amiodarone is used only as antiarrhythmic or antiangina agent.
  • amiodarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating patients suffering from heart failure.
  • the preferred salt of amiodarone is the hydrochloride, and the administration of the medicament is oral or
  • the medicament of this invention is useful as a method of treatment of a patient suffering from heart failure.
  • This method comprises the administration of a
  • a diuretic agent optionally in sequential or simultaneous association with a currently recommended dose of one or several of the following drugs: a diuretic agent, a cardiotonic agent, an ACE-inhibitor and a vasodilating agent;
  • amiodarone and the optional drugs being formulated with pharmaceutically acceptable excipients or carriers, suitable for their oral or parenteral administration.
  • the preferred dose of amiodarone is selected between 50 and 1000 mg/day; the diuretic agent is selected from
  • the cardiotonic agent is selected from acetyldigitoxin, digitoxin and digoxin, being administered at doses selected between 0.1 and 5 mg/day
  • the ACE-inhibitor is selected from enalapril, captopril and lisinopril, being administered at doses selected between 1 and 200 mg/day
  • the vasodilating agent is selected from isosorbide mononitrate, isosorbide dinitrate and nitroglycerin, being administered at doses selected between 2 and 200 mg/day.
  • FCCI Functional Capacity Class.
  • FCCI FCC number I, i.e. the class in which symptoms are caused by heavy effort.
  • FCCII Class in which symptoms are caused by moderate effort.
  • FCCIII Class in which symptoms are caused by usual effort.
  • FCCIV Class in which symptoms are caused while at rest.
  • Figures 1-3 are usual and self-explanatory graphical representations of the results of: functional capacity, functional capacity over mortality, and survival rate, respectively,
  • Patients of the amiodarone group received doses of 600 mg/day of amiodarone for the first 14 days, and 300 mg/day for the following days. Some of the patients were suffering from ventricular tachycardia, a severe Hind of arrhythmia (the results from patients not suffering from ventricular tachycardia are also
  • Example 2 Activity of amiodarone against heart failure in patients without ventriculag tachycardia

Abstract

New therapeutic use (second medical indication) of the antiarrhythmic agent amiodarone, namely: treatment of heart failure. The functional capacity of patients (even without arrhythmia) improves after the administration of 300-600 mg/day in sequential or simultaneous association with a currently recommended dose of one or several of the following drugs: a diuretic agent, a cardiotonic agent, an ACE-inhibitor and a vasodilating agent. The second medical indication provided by the present invention is new and goes against the general trend which considers that amiodarone is contraindicated for the treatment of patients suffering from heart failure.

Description

Use of amiodarone for the treatment of heart failure
The present invention refers to a new therapeutic use (second medical indication) of the pharmaceutical active principle amiodarone, namely; the treatment of heart failure. This indication is new and goes against the general trend which considers that
amiodarone is contraindicated for the treatment of patients suffering from heart failure.
STATE OF THE ART
As reported in the medical literature, heart failure is a particular frequent cause for human mortality. Among specialists, this disease is clearly different from other heart diseases such as arrhythmia, angina
pectoris or myocardial infarction. Thus, for instance, in the hierarchical classification of heart diseases of the National Library of Medicine (or Index Medicus classification), the following three groups of diseases -among others- are found at the same hierarchical level: arrhythmia (including tachycardia), coronary disease (including angina pectoris and myocardial infarction) and heart: failure (including the congestive variant). It is important to realise that the present inventions rofers only to the treatment of the latter, namely: heart failure
Amiodarone hydrochloride (hereinafter called simply amiodarone) was described in US 3.248.401 patent as a powerful antiangina and antiarrhythmic agent. French patent FR 2.626.176 mentions amiodarone in combination with other agents in the treatment of coronary disease. In practice, the main therapeutic use of amiodarone has been as an antiarrhythmic agent (of type III, according to Williams classification). Thus amiodarone is
included in the D28.30.30 group of Excerpta-Medica Chemicals & Drugs Classification (EMTREE thesaurus).
The choice, of thα pharmaceutical trβatmont for treating heart failure is not satisfactorily solved, and there is still important discrepancies among practitioners. For the first step of the treatment a diuretic (group D8.225, e.g. : furoεemide, hydrochlorothiazide,
metolazone, amilσride, spironolactone...) is normally used. For the second step a cardiotonic agent (group D18.130, υ.g. acotyldigitoxin, digitoxin, digoxin...) or an ACE-inhibitor (group D18.40.220, e.g.: captopril, enalapril, lisinopril) is used, either alone or in combination with a diuretic. For the third step of the treatment the choice is usually a combination of a diuretic plus a cardiotonic (or an ACE-inhibitor) plus a vasodilating agent (group D18.915.920.180, e.g.: isosorbide mono nitrats, isosorbide dinitrate,
nitroglycerin....). However, the use of amiodarone in the treatment of heart failure has never been
indicated: in fact, it is explicitly contraindicated in a great majority of heart failure cases, as illustrated in the medical literature (cf. for example: Mason, "Amiodarone", New Eng. J. Med. 1987, vol. 316, pp. 455-66; De Paola et al., "Development of congestive heart failure and alterations in left ventricular function in patients with sustained ventricular tachyarrhythmiaβ treated with Amiodarone", Am. J, Cardiol, 1987, vol.
60, pp. 276-80). As a consequence, there is no
pharmaceutical speciality in the market intended for the treatment of heart failure in which amiodarone is included as ingrediont. Virtually, amiodarone is used only as antiarrhythmic or antiangina agent.
DESCRIPTION OF THE INVENTION
Despite the general trend in the medical literature and the therapeutic practice pointing towards the
contraindication of amiodarone in the treatment of patients suffering from heart failure, we have found that, surprisingly, a treatment with amiodarone causes a dramatic reduction of the mortality rate and a marked improvement of the cardiac function in said patients. Our prospective, multicenter, randomised clinical test, with more than 500 patients and more than 2 years of follow up, clearly proves this new and unexpected therapeutic activity of amiodarone.
Thus, it is an object of the present invention the use of amiodarone, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating patients suffering from heart failure. The preferred salt of amiodarone is the hydrochloride, and the administration of the medicament is oral or
parenteral.
The medicament of this invention is useful as a method of treatment of a patient suffering from heart failure. This method comprises the administration of a
therapeutically effective dose of amiodarone,
optionally in sequential or simultaneous association with a currently recommended dose of one or several of the following drugs: a diuretic agent, a cardiotonic agent, an ACE-inhibitor and a vasodilating agent;
amiodarone and the optional drugs being formulated with pharmaceutically acceptable excipients or carriers, suitable for their oral or parenteral administration. In particular embodiments of the present invention the preferred dose of amiodarone is selected between 50 and 1000 mg/day; the diuretic agent is selected from
furosemide, hydrochiorothiazids, metolazone, arailoride, spironolaσtone, being administered at doses selected between 1 and 200 mg/day; the cardiotonic agent is selected from acetyldigitoxin, digitoxin and digoxin, being administered at doses selected between 0.1 and 5 mg/day; the ACE-inhibitor is selected from enalapril, captopril and lisinopril, being administered at doses selected between 1 and 200 mg/day; the vasodilating agent is selected from isosorbide mononitrate, isosorbide dinitrate and nitroglycerin, being administered at doses selected between 2 and 200 mg/day.
As illustrated by the accompanying examples, tables and figures, treatment of patients suffering from heart failure with amiodorone doses of 600 mg/day for 14 days, and doses of 300 mg/day for the following days, causes a marked improvement in patients' functional capacity index, as well as a reduction of their
mortality rate. Many patients in functional capacity classes 117 and IV were able to improve to classes I and II.
As illustrated in Example 2 and Figure 3, the activity of amiodarone against heart failure is clear even among patients without severe arrhythmia. This suggests that when amiodarone is used according to the present
invention, it is acting by a different mechanism than when used as an antiarrhythmic or antiangina agent.
This represents an important novelty in heart therapy.
In tables and figures the following acronyms are used: FCC = Functional Capacity Class. FCCI = FCC number I, i.e. the class in which symptoms are caused by heavy effort.
FCCII = Class in which symptoms are caused by moderate effort.
FCCIII = Class in which symptoms are caused by usual effort.
FCCIV = Class in which symptoms are caused while at rest.
Figures 1-3 are usual and self-explanatory graphical representations of the results of: functional capacity, functional capacity over mortality, and survival rate, respectively,
EXAMPLES
Example 1. Activity of amiodarone against heart failure in general patients
A prospective, multicenter, randomised clinical study has been conducted on 516 patients suffering from heart failure, during a follow up period of 180 days. The results of functional capacity are summarised in Table 1, and Figures 1-2. Patients were divided in two groups: amiodarone and control.
Patients of the amiodarone group received doses of 600 mg/day of amiodarone for the first 14 days, and 300 mg/day for the following days. Some of the patients were suffering from ventricular tachycardia, a severe Hind of arrhythmia (the results from patients not suffering from ventricular tachycardia are also
analysed in example 2). Patients of the control group did nor received amiodarone. All the patients, both from the amiodarone and the control group, ware being treated simultaneously by some of the standard
treatments against heart failure mentioned above. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Table ] : Functional capacity analysis (num. patients) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - control group
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
FCCT FCCII FCCIII FCCIV Mortal. Desert. Total - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - day 0 - 53 123 80 - - 256 day 180 19 53 61 34 53 36 220 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Amiodarone group
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
FCCI FCCII FCCIII FCCIV Mortal. Desert. Total - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - day 0 - 56 123 78 - - 260 day 180 34 70 54 30 42 30 230 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Mortal. = Mortality; Dasert. = Test desertion
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Example 2. Activity of amiodarone against heart failure in patients without ventriculag tachycardia
From the patient population of example 1, the 333 patients suffering from ventricular tachycardia were selected and followed up for 700 days. The analysis of the results of survival rate, done by the usual log-rank test, is shown in Figure 3 .

Claims

1. Use of amiodarone, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating patients suffering from heart failure.
2. Use according to claim l where the pharmaceutically acceptable salt of amiodarone is the hydrochloride, and the administration of the medicament is oral or
parenteral.
3. Use according to any of the claims l or 2 where the medicament is administered in sequential or
simultaneous association with a currently recommended dose of one or several of the following drugs: a diuretic agent, a cardiotonic agent, an ACE-inhibitor and a vasodilating agent. 1. Use according to any of the claims 2 or 3 where the dose of amiodarone hydrochloride is selected between 50 and 1000 mg/day.
5. Use according to claim 4 where the dose of
amiodarone hydrochloride is about 600 mg/day at a first phase of the treatment, and about 300 mg/day at a second phase of the treatment.
6. Use according to any of the claims 3-5 where the diuretic agent is selected from furosemide,
hydrochiorothiazide, metolazone, amiloride,
spironolactone.
7. Use according to any of the claims 3-6 where the dose or the diuretic agent is selected between 1 and 200 mg/day.
8. Use according to any of the claims 3-5 where the cardiotonic agent is selected from acetyldigitoxin, digitoxin and digoxin.
9. Use according to any of the claims 3-5 or 8 where the dose of the cardiotonic agent is selected between 0.1 and 5 mg/day.
10. Use according to any of the claims 3-5 where the
ACE-inhibitor is selected from enalapril, captopril and lisinopril.
11. Use according to any of the claims 3-5 or 10 where the dose of the ACE-inhibitor is selected between 1 and 200 mg/day.
12. Use according to any of the claims 3-5 where the vasodilating agent is selected from isosorbide mononitrate, isosorbide dinitrate and nitroglycerin.
13. Use according to any of the claims 3-5 or 12 where the dose of the vasodilating agent is solected between 2 and 200 mg/day.
PCT/EP1994/003267 1993-10-04 1994-09-30 Use of amiodarone for the treatment of heart failure WO1995009625A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996024358A1 (en) * 1995-02-10 1996-08-15 G.D. Searle & Co. Use of low dose amount of spironolactone for treatment of cardiovascular disease
WO1996024373A2 (en) * 1995-02-10 1996-08-15 G.D. Searle & Co. Combination of angiotensin converting enzyme inhibitor and side-effect-reduced amount of aldosterone antagonist
FR2735365A1 (en) * 1995-06-14 1996-12-20 Sanofi Sa USE OF AN ANGIOTENSIN II ANTAGONIST AND A BENZOFURANE DERIVATIVE FOR THE PREPARATION OF A MEDICAMENT USEFUL IN THE TREATMENT OF CARDIOVASCULAR CONDITIONS
FR2760364A1 (en) * 1997-03-10 1998-09-11 Sanofi Sa USE OF ANTIARRHYTHMIC COMPOUNDS FOR REDUCING MORTALITY AFTER MYOCARDIAL INFARCTION
US5985915A (en) * 1996-03-18 1999-11-16 Sanofi Use of antiarrhythmic compounds in the prevention of post-infarction mortality
US6048874A (en) * 1999-01-26 2000-04-11 Medeva Pharmaceuticals Manufacturing, Inc. Parenteral metolazone formulations
CN102423305A (en) * 2011-12-23 2012-04-25 中国药科大学 Isosorbide mononitrate micro-porous osmotic pump tablet and preparation method thereof

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WO1990009171A1 (en) * 1989-02-20 1990-08-23 Soorianarain Baligadoo Cardio-protective drug preparations comprising amiodarone, a nitrate derivate, in particular isosorbide dinitrate and optionally a beta-blocker

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FR2626176A1 (en) * 1988-01-25 1989-07-28 Baligadoo Soorianarain Cardioprotective medicinal preparations comprising amiodarone, a nitro derivative and optionally a beta-blocker
US4931464A (en) * 1989-02-15 1990-06-05 E. R. Squibb & Sons, Inc. Method of reducing pre- and post-ischemic myocardial arrhythmias and fibrillation
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DOVAL, H.C. ET AL: "RANDOMISED TRIAL OF LOW DOSE AMIODARONE IN SEVERE CONGESTIVE HEART FAILURE", THE LANCET, vol. 344, no. 8921, 20 August 1994 (1994-08-20), pages 493 - 498 *
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996024373A2 (en) * 1995-02-10 1996-08-15 G.D. Searle & Co. Combination of angiotensin converting enzyme inhibitor and side-effect-reduced amount of aldosterone antagonist
WO1996024373A3 (en) * 1995-02-10 1996-09-26 Searle & Co Combination of angiotensin converting enzyme inhibitor and side-effect-reduced amount of aldosterone antagonist
WO1996024358A1 (en) * 1995-02-10 1996-08-15 G.D. Searle & Co. Use of low dose amount of spironolactone for treatment of cardiovascular disease
EP1136078A3 (en) * 1995-02-10 2002-07-24 G.D. Searle & Co. Combination of angiotensin converting enzyme inhibitor and side- effect-reduced amount of aldosterone antagonist
EP1136078A2 (en) * 1995-02-10 2001-09-26 G.D. Searle & Co. Combination of angiotensin converting enzyme inhibitor and side- effect-reduced amount of aldosterone antagonist
US6218414B1 (en) 1995-06-14 2001-04-17 Sanofi Use of an angiotensin II antagonist and a benzofuran derivative in the treatment of cardiovascular complaints
FR2735365A1 (en) * 1995-06-14 1996-12-20 Sanofi Sa USE OF AN ANGIOTENSIN II ANTAGONIST AND A BENZOFURANE DERIVATIVE FOR THE PREPARATION OF A MEDICAMENT USEFUL IN THE TREATMENT OF CARDIOVASCULAR CONDITIONS
EP0752249A2 (en) * 1995-06-14 1997-01-08 Sanofi Use of an angiotensin II antagonist and a benzofurane derivative having antiarithmic activity for the manufacture of a medicament for the treatment of cardiovascular disorders
EP0752249A3 (en) * 1995-06-14 1997-01-15 Sanofi Use of an angiotensin II antagonist and a benzofurane derivative having antiarithmic activity for the manufacture of a medicament for the treatment of cardiovascular disorders
US5985915A (en) * 1996-03-18 1999-11-16 Sanofi Use of antiarrhythmic compounds in the prevention of post-infarction mortality
FR2760364A1 (en) * 1997-03-10 1998-09-11 Sanofi Sa USE OF ANTIARRHYTHMIC COMPOUNDS FOR REDUCING MORTALITY AFTER MYOCARDIAL INFARCTION
WO1998040067A1 (en) * 1997-03-10 1998-09-17 Sanofi Use of benzofuran derivatives for reducing death rate after myocardial infarction
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CN102423305A (en) * 2011-12-23 2012-04-25 中国药科大学 Isosorbide mononitrate micro-porous osmotic pump tablet and preparation method thereof

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