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(12) Patent Application Publication (10) Pub. No.: US 2004/0077723 A1 Granata Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0077723 A1 Granata Et Al US 2004OO77723A1. (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0077723 A1 Granata et al. (43) Pub. Date: Apr. 22, 2004 (54) ESSENTIALN-3 FATTY ACIDS IN CARDIAC (30) Foreign Application Priority Data INSUFFICIENCY AND HEART FAILURE THERAPY Jan. 25, 2001 (IT)............................... MI2OO1 AOOO129 (76) Inventors: Francesco Granata, Milan (IT): Publication Classification Franco Pamparana, Milan (IT); 7 Eduardo Stragliotto, Milan (IT) (51) Int. Cl." .................................................. A61K 31/202 (52) U.S. Cl. .............................................................. 514/560 Correspondence Address: ARENT FOX KINTNER PLOTKIN & KAHN 1050 CONNECTICUT AVENUE, N.W. (57) ABSTRACT SUTE 400 WASHINGTON, DC 20036 (US) The present invention concerns a method of therapeutic prevention and treatment of a heart disease chosen from (21) Appl. No.: 10/451,623 cardiac insufficiency and heart failure including the admin istration of an essential fatty acid containing a mixture of (22)22) PCT Fed: Jan. 16,9 2002 eicosapentaenoicp acid ethvily ester (EPA) and docosa hexaenoic acid ethyl ester (DHA), either alone or in com (86) PCT No.: PCT/EP02/00507 bination with another therapeutic agent. US 2004/0077723 A1 Apr. 22, 2004 ESSENTIAL, N-3 FATTY ACIDS IN CARDIAC and inhibitors of phosphodiesterase, arteriolar and Venular INSUFFICIENCY AND HEART FAILURE vasodilators, e.g. hydralazine and isosorbide dinitrate, beta THERAPY blockers e.g. metoprolol and bisoprolol and digitalis deriva 0001. The present invention belongs to the field of phar tives, e.g. digotoxin. maceutical chemistry and cardiovascular medicine and pro 0011 Heart failure is at present one of the most important vides a method of prevention and management of cardiac causes of morbidity and mortality in the industrialized insufficiency and heart failure: two heart diseases in which countries, as clearly demonstrated by the present case-Series: the Second one is the result of the progressive evolution of in USA 4.7 million perSons have a congestive heart failure, the first one. with an incidence equal to 400,000 new cases a year. 0002 Cardiac insufficiency is a condition in which the 0012. The prevalence of chronic cardiac insufficiency heart pump function is inadequate to meet the bodily meta rises from 8 cases of heart failure out of 1,000 subjects of bolic requirements. Depending on the different Severity of age ranging from 50 to 59 years, to 66 cases out of 1,000 the pump deficit, cardiac insufficiency may be Symptom-free subjects between 80 and 89 years. or clinically manifest. 0013) If we consider that about 35% of patients with heart 0.003 Cardiac insufficiency could have various causes, failure are hospitalised at least once a year and that 80% of C.9. men and 65% of women die within 6 years, the social-health 0004 disorders of myocardial function, which is the entity of the problem emerges in its full dramatic evidence. most frequent cause, due to a reduced contractility, 0014) Moreover, the incidence of heart failure seems to but also to a loSS of contractile tissue; increase paradoxically with the reduction of death rate for myocardial infarction and for other cardiovascular diseases. 0005 a volume load, due to disorders requiring the The ageing of the population seems to be a contributing Ventricle to expel more blood than the normal per factor to amplify the relevance of the phenomenon. minute; 0015 Therefore, there is the need of a safe and conve 0006 a pressure load, due to disorders increasing nient method of prevention and therapeutic treatment of the resistance to the outflow from the ventricles. cardiac insufficiency and heart failure, in particular in eld 0007 Heart failure is the result of the progressive evo erly patients, in order to restore (or to control) the usual lution of cardiac insufficiency. Moreover, a broad Spectrum pump function of the heart. of diseases could cause an impaired filling or emptying of 0016. The present invention provides a method for the heart chambers, Such as: the diseaseS resulting from a prevention and therapeutic treatment of cardiac insufficiency monogenic (familial hypertrophic cardiomyopathy, mito and heart failure in a patient in need of this treatment chondral cardiomyopathies) or multigenic defect which are comprising the administration to Such patient of a therapeu bound to environmental factorS Such as cigarette Smoking, tically effective amount of an essential fatty acid containing diet, physical exercise, Secondary heart diseases. All these a mixture of (20:5ci) 3) eicosapentaenoic acid ethyl ester diseases take the “common end path' towards heart failure, (EPA) and of (20:6() 3) docosahexaenoic acid ethyl ester which SeeSat first an impairment of the molecular mecha (DHA), either alone or in combination with another thera nisms and then an impairment of the Ventricular function peutic agent. and heart failure. Therefore, heart failure is a syndrome with a various etiology resulting from an anatomo-functional 0017. It is well known in the art that some essential fatty anomaly of the heart with inability in keeping a Stroke acids, in particular () 3 PUFA, contained for example in the adequate to the metabolic requirements of the tissueS or fish oil, have a therapeutic effect in the prevention and maintaining the Stroke Volume by a high filling pressure. therapy of cardiovascular disorders, e.g. in the prevention and treatment of atherothrombotic events and hyperlipi 0008 Heart failure is characterized by clinical signs and demia. Symptoms Secondary to the inadequate response to the body metabolic requirements. This condition could occur acutely 0018 WO 89/11521 describes in particular an industrial or have a chronic course. process for the extraction of mixtures having a high content in poly-unsaturated acids, also including EPA and DHA and 0009. The pathophysiological interpretations of heart their ethyl esters, from animal and/or vegetable oils. Mix failure have had a remarkable evolution in time. This tures of fatty acids, in particular EPA/DHA, obtained Syndrome was considered as a pump deficiency associated according to WO 89/11521, are indicated as particularly with a renal dysfunction in years 50-60, a pump dysfunc useful in the treatment of cardiovascular pathologies. tion associated with an increase in peripheral resistance in years 70-80 and is considered at present as a failure of the 0019. Therefore, object of the present invention is the use pump function associated with the neuro-hormonal activa of an essential fatty acid containing a mixture of eicosap tion with resulting hemodynamic impairments which take to entaenoic acid ethyl ester (EPA) and docosahexaenoic acid a dysfunction of many organs and apparatuses. ethyl ester (DHA) in the preparation of a medicament for the 0.010 The present drug therapy of cardiac “pump func prevention and treatment of a heart disease chosen from tion' includes the use of drugs acting by various modes of cardiac insufficiency and heart failure, both chronic and action on different points of the etiopathogenesis of the acute. diseases. We mention as an example: ACE-inhibitors 0020 For convenience of description, eicosapentaenoic (Angiotensin Converting Enzymes inhibitors), diuretics, acid ethyl ester and docosahexaenoic acid ethyl ester are non-digitalis positive inotropic drugs. Such as adrenergics mentioned here below respectively as “EPA' and “DHA’. US 2004/0077723 A1 Apr. 22, 2004 0021. An essential fatty acid, according to the invention, 0033 Examples of dopaminergic agents are dopamine is preferably a fatty acid having a high content in EPA and and ibopamine. DHA, for example with a content in EPA and DHA higher 0034) Examples of phosphodiesterase inhibitors are: than 25% by weight, preferably from about 30% to about amrinone, milrinone, enoXimone and bucladesine, in par 100% by weight, in particular about 85%. ticular amrinone and enoXimone. 0022 EPA is present in the EPA/DHA mixture preferably in a percentage ranging from 25% to about 45% by weight 0035 Examples of arteriolar and venular vasodilators and DHA is present preferably in a percentage ranging from are: hydralazine and isosorbide dinitrate. 55% to about 75% by weight. 0036) Examples of beta-blockers are: visoprolol, practo tol, metoprolol, bucindol, carvedilol, atenolol, bisoprolol, 0023. At any rate, the most preferred ratio between EPA celiprolol and nevibolol, in particular visoprolol, carvedilol and DHA is about 0.6-1.1/1.3-1.8; in particular about 0.9/ and metoprolol. 1.5. 0037 Examples of digitalis glycoside agents are: acetyl 0024. An essential fatty acid according to the present digitoxin, acetyldigoxin, digitoxin, digoxin, lanatoside C, invention can be obtained by known methods, e.g. as deslanoSide, methyldigoxin and gitoformat, in particular described in U.S. Pat. No. 5,656,667 and WO 89/11521. digitoxin, digoxin, acetyldigoxin and metidigoxin. 0.025 Object of the present invention is also the use of an 0038 Examples of positive inotropic agents are: essential fatty acid containing a mixture of eicosapentaenoic pimobendan and Vesnarinone, in particular pimobendan. acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester 0039. A further object of the invention is a method for (DHA) in the preparation of a medicament for the preven preventing and treating a heart disease chosen from cardiac tion and treatment of a heart disease chosen from cardiac insufficiency and heart failure, both chronic and acute, insufficiency and heart failure,
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