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(12) Patent Application Publication (10) Pub. No.: US 2009/0005327 A1 GRANATA Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0005327 A1 GRANATA Et Al US 20090005327A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0005327 A1 GRANATA et al. (43) Pub. Date: Jan. 1, 2009 (54) ESSENTIAL, N-3 FATTY ACDS IN CARDAC continuation of application No. 10/451,623, filed on IN SUFFICIENCY AND HEART FAILURE Nov. 21, 2003, now abandoned, filed as application THERAPY No. PCT/EP02/00507 on Jan. 16, 2002. (75) Inventors: Francesco GRANATA, Milan (IT): (30) Foreign Application Priority Data Franco Pamparana, Milan (IT): Eduardo Stragliotto, Milan (IT) Jan. 25, 2001 (IT) .......................... MI2OO1 AOOO129 Correspondence Address: Publication Classification ARENT FOX LLP (51) Int. Cl. 1050 CONNECTICUT AVENUE, N.W., SUITE A6II 3L/202 (2006.01) 400 A63L/704 (2006.01) WASHINGTON, DC 20036 (US) A6IP 9/10 (2006.01) (73) Assignee: PFIZER ITALIA S.R.L., Latina (52) U.S. Cl. ........................................... 514/34: 514/560 (IT) (57) ABSTRACT (21) Appl. No.: 12/207,068 The present invention concerns a method of therapeutic pre vention and treatment of a heart disease chosen from cardiac (22) Filed: Sep. 9, 2008 insufficiency and heart failure including the administration of an essential fatty acid containing a mixture of eicosapen Related U.S. Application Data taenoic acid ethyl ester (EPA) and docosahexaenoic acid (63) Continuation of application No. 1 1/333.387, filed on ethyl ester (DHA), either alone or in combination with Jan. 17, 2006, now Pat. No. 7,439,267, which is a another therapeutic agent. US 2009/0005327 A1 Jan. 1, 2009 ESSENTIALN-3 FATTY ACDS IN CARDAC tensin Converting Enzymes inhibitors), diuretics, non-digi IN SUFFICIENCY AND HEART FAILURE talis positive inotropic drugs such as adrenergics and THERAPY inhibitors of phosphodiesterase, arteriolar and venular vasodilators, e.g. hydralazine and isosorbide dinitrate, beta CROSS-REFERENCE TO RELATED blockers e.g. metoprolol and bisoprolol and digitalis deriva APPLICATIONS tives, e.g. digotoxin. 0001. This application is a continuation of U.S. patent 0012 Heart failure is at present one of the most important application Ser. No. 10/451,623, which is a National Stage of causes of morbidity and mortality in the industrialized coun International Application No. PCT/EP02/00507, filed Jan. tries, as clearly demonstrated by the present case-series: in 16, 2002. The disclosures of the above applications are incor USA 4.7 million persons have a congestive heart failure, with porated herein by reference. an incidence equal to 400,000 new cases a year. 0002 The present invention belongs to the field of phar 0013 The prevalence of chronic cardiac insufficiency maceutical chemistry and cardiovascular medicine and pro rises from 8 cases of heart failure out of 1,000 subjects of age vides a method of prevention and management of cardiac ranging from 50 to 59 years, to 66 cases out of 1,000 subjects insufficiency and heart failure: two heart diseases in which the between 80 and 89 years. second one is the result of the progressive evolution of the first 0014 If we consider that about 35% of patients with heart OC. failure are hospitalised at least once a year and that 80% of 0003 Cardiac insufficiency is a condition in which the men and 65% of women die within 6 years, the social-health heart pump function is inadequate to meet the bodily meta entity of the problem emerges in its full dramatic evidence. bolic requirements. Depending on the different severity of the 0015 Moreover, the incidence of heart failure seems to pump deficit, cardiac insufficiency may be symptom-free or increase paradoxically with the reduction of death rate for clinically manifest. myocardial infarction and for other cardiovascular diseases. 0004 Cardiac insufficiency could have various causes, The ageing of the population seems to be a contributing factor C.2. to amplify the relevance of the phenomenon. 0005 disorders of myocardial function, which is the most 0016. Therefore, there is the need of a safe and convenient frequent cause, due to a reduced contractility, but also to a loss method of prevention and therapeutic treatment of cardiac of contractile tissue; insufficiency and heart failure, in particular in elderly 0006 a volume load, due to disorders requiring the ven patients, in order to restore (or to control) the usual pump tricle to expel more blood than the normal per minute; function of the heart. 0007 a pressure load, due to disorders increasing the resis 0017. The present invention provides a method for the tance to the outflow from the ventricles. prevention and therapeutic treatment of cardiac insufficiency 0008 Heart failure is the result of the progressive evolu tion of cardiac insufficiency. Moreover, a broad spectrum of and heart failure in a patient in need of this treatment com diseases could cause an impaired filling or emptying of heart prising the administration to such patient of a therapeutically chambers, such as: the diseases resulting from a monogenic effective amount of an essential fatty acid containing a mix (familial hypertrophic cardiomyopathy, mitochondral cardi ture of (20:5 () 3) eicosapentaenoic acid ethyl ester (EPA) and omyopathies) or multigenic defect which are bound to envi of (20:6 (O3) docosahexaenoic acid ethyl ester (DHA), either ronmental factors such as cigarette Smoking, diet, physical alone or in combination with another therapeutic agent. exercise, secondary heart diseases. All these diseases take the 0018. It is well known in the art that some essential fatty “common end path' towards heart failure, which sees at first acids, in particular () 3 PUFA, contained for example in the an impairment of the molecular mechanisms and then an fish oil, have atherapeutic effect in the prevention and therapy impairment of the ventricular function and heart failure. of cardiovascular disorders, e.g. in the prevention and treat Therefore, heart failure is a syndrome with a various etiology ment of atherothrombotic events and hyperlipidemia. resulting from an anatomo-functional anomaly of the heart (0019 WO 89/11521 describes in particular an industrial with inability in keeping a stroke adequate to the metabolic process for the extraction of mixtures having a high content in requirements of the tissues or maintaining the stroke Volume poly-unsaturated acids, also including EPA and DHA and by a high filling pressure. their ethyl esters, from animal and/or vegetable oils. Mixtures 0009 Heart failure is characterized by clinical signs and offatty acids, in particular EPA/DHA, obtained according to symptoms secondary to the inadequate response to the body WO 89/11521, are indicated as particularly useful in the metabolic requirements. This condition could occur acutely treatment of cardiovascular pathologies. or have a chronic course. 0020. Therefore, object of the present invention is the use 0010. The pathophysiological interpretations of heart fail of an essential fatty acid containing a mixture of eicosapen ure have had a remarkable evolution in time. This syndrome taenoic acid ethyl ester (EPA) and docosahexaenoic acid was considered as a pump deficiency associated with a renal ethyl ester (DHA) in the preparation of a medicament for the dysfunction in years 50-60, a pump dysfunction associated prevention and treatment of a heart disease chosen from car with an increase in peripheral resistance in years 70-80 and diac insufficiency and heart failure, both chronic and acute. is considered at present as a failure of the pump function 0021 For convenience of description, eicosapentaenoic associated with the neuro-hormonal activation with resulting acid ethyl ester and docosahexaenoic acid ethyl ester are hemodynamic impairments which take to a dysfunction of mentioned here below respectively as “EPA' and “DHA’. many organs and apparatuses. 0022. An essential fatty acid, according to the invention, is 0011. The present drug therapy of cardiac “pump func preferably a fatty acid having a high content in EPA and DHA. tion' includes the use of drugs acting by various modes of for example with a content in EPA and DHA higher than 25% action on different points of the etiopathogenesis of the dis by weight, preferably from about 30% to about 100% by eases. We mention as an example: ACE-inhibitors (Angio weight, in particular about 85%. US 2009/0005327 A1 Jan. 1, 2009 0023) EPA is present in the EPA/DHA mixture preferably deslanoside, methyldigoxin and gitoformat, in particular in a percentage ranging from 25% to about 45% by weight digitoxin, digoxin, acetyldigoxin and metidigoxin. and DHA is present preferably in a percentage ranging from 0039 Examples of positive inotropic agents are: pimoben 55% to about 75% by weight. dan and Vesnarinone, in particular pimobendan. 0024. At any rate, the most preferred ratio between EPA 0040. A further object of the invention is a method for and DHA is about 0.6-1.1/1.3-1.8; in particular about 0.9/1.5. preventing and treating a heart disease chosen from cardiac 0025. An essential fatty acid according to the present insufficiency and heart failure, both chronic and acute, com invention can be obtained by known methods, e.g. as prising administering to a patient in need thereof a therapeu described in U.S. Pat. No. 5,656,667 and WO 89/11521. tically effective amount of an unsaturated essential acid con 0026. Object of the present invention is also the use of an taining a mixture of eicosapentaenoic acid ethyl ester (EPA) essential fatty acid containing a mixture of eicosapentaenoic and docosahexaenoic acid ethyl ester (DHA). acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester 0041. A further object of the invention is a method to (DHA) in the preparation of a medicament for the prevention prevent and treat a heart disease chosen from cardiac insuffi and treatment of a heart disease chosen from cardiac insuffi ciency and heart failure, both chronic and acute, comprising ciency and heart failure, both chronic and acute, where the administering to a patient in need thereof a therapeutically medicament is for combined therapy with another therapeutic effective amount of an essential fatty acid containing a mix agent.
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