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Home , Amrinone, Bucladesine, Delapril, Deslanoside, Enoximone, Lanatoside C

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 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 , arteriolar and venular vasodilators, e.g. hydralazine and isosorbide dinitrate, beta CROSS-REFERENCE TO RELATED blockers e.g. metoprolol and bisoprolol and 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 , methyldigoxin and gitoformat, in particular in a percentage ranging from 25% to about 45% by weight , , 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 , in particular . 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. ture of eicosapentaenoic acid ethyl ester (EPA) and docosa 0027. The term “another therapeutic agent’ means an hexaenoic acid ethyl ester (DHA), in combination with additional single agent or two or more additional agents, another therapeutic agent. preferably from 2 to 10, in particular from 2 to 6 according to 0042. The term “in combination” means that the essential physician's instructions, which may be administered in com fatty acid containing the mixture EPA+DHA and the other bination, namely either along or separately (Substantially therapeutic agent are administered in Such an amount and simultaneously or sequentially) with the essential fatty acid separated by Such administration times as to produce athera containing the mixture of EPA and DHA. peutic effect. 0028. Examples of therapeutic agents for such a prophy 0043. The use of an essential fatty acid according to the laxis or combined therapy according to the invention are invention is extremely useful in the prevention and treatment ACE-inhibitors, NEP-inhibitors, ACE/NEP-inhibitors, of cardiac insufficiency and heart failure both chronic and II converting enzyme inhibitors, diuretics, posi acute, in particular, in the elderly people, e.g. older than 60 tive inotropic drugs, phosphodiesterase inhibitors, arteriolar years, in subjects with other further cardiopathic forms and, and Venular vasodilators, beta-blockers and digitalis glyco in particular, in Subjects Surviving a myocardial infarction, sides, or a mixture thereof. thanks to the fact that this is a well tolerated drug. 0029 NEP means degradation peptidase of atrial natri 0044) The amount of essential fatty acid to be adminis uretic peptide (ANP). tered to a patient, either as a single therapeutic agent or in 0030 Examples of ACE-inhibitors are: , enala combination with another therapeutic agent, depends on its pril, , , , benazapril, , EPA/DHA content. In particular, the amount of essential fatty , , and delapril, in particular acid having a EPA/DHA content of about 85%, to be admin cilaZapril, captopril and . istered to a patient, may vary from about 0.7 g to about 1.5 g. 0031 Examples of ACE/NEP-inhibitors are: , daily. More specifically, the amount of essential fatty acid, Sampatrilat and L-phenylalanine.N-(2S)-2-(mercaptom with a EPA/DHA content of about 85% and an EPA/DHA ethyl)-1-oxo-3-phenylpropyl4-(2-thiazolyl) (compound ratio of about 0.9/1.5 is of about 1 g daily. Z13752A, a product of Zambon Company). 0045. This amount of product may be administered in the 0032 Examples of angiotensin II receptors antagonists form of several daily divided doses or preferably as a single (angiotensin II converting inhibitors) are: , Val dose, in order to reach the desired blood level. Of course, the Sartan and . clinician may vary the amount of product (or mixture with 0033 Examples of diuretics are: hydrochlorothiazide, another therapeutic agent) to be administered, basing on the trichloromethiazide, chlorothiazide, chlortalidone, triam patient's conditions, age and weight. terene, clofenamide, , torasemide, ethacrynic 0046. The amount of additional therapeutic agent, when acid, etoZoline, spironolactone and amiloride, if the case in administered in combination with the essential fatty acid, is association with sparing drugs, which are well Substantially the amount usually employed by the clinician in known in the art, in particular furosemide and hydrochlo therapy. At any rate, the clinician may vary the amount of this rothiazide. additional drug (or mixture of additional drugs) basing on the 0034 Examples of agents are and patient's clinical picture. . 0047. The combined use of an essential fatty acid accord 0035 Examples of phosphodiesterase inhibitors are: ing to the invention and of another therapeutic agent produces , , and , in particu a synergic or Superadditive effect, namely an improvement of lar amrinone and enoXimone. the patient's clinical picture Surely greater than the one 0036) Examples of arteriolar and venular vasodilators are: observed with the administration of the essential fatty acid or hydralazine and isosorbide dinitrate. of the “other therapeutic agent” alone. Moreover, the greater 0037 Examples of beta-blockers are: visoprolol, practo therapeutic effect in the combined treatment is not accompa tol, metoprolol, bucindol, carvedilol, atenolol, bisoprolol. nied by an increased toxicity. celiprolol and nevibolol, in particular visoprolol, carvedilol 0048. Therefore, the present invention provides the clini and metoprolol. cian with a new method of therapeutic treatment effective for 0038 Examples of digitalis glycoside agents are: acetyl preventing and treating cardiac insufficiency and heart failure digitoxin, acetyldigoxin, digitoxin, digoxin, . or at least improving the conditions of a patient Suffering from US 2009/0005327 A1 Jan. 1, 2009

Such heart diseases or improving his/her quality of life. 22. A method according to claim 19, wherein the content of Indeed, on the basis of clinical markers, which are to-day EPA+DHA in the essential fatty acid is about 85% by weight. useful to understand the various stages of cardiac insuffi 23. A method according to claim 19, wherein the essential ciency and progressive evolution towards an overt heart fail fatty acid is orally administered at a dose of from about 0.7g ure, the clinician can make use of the present invention and to about 1.5 g daily. prevent or at least delay its evolution. 0049. The pharmaceutical preparations according to the 24. A method according to claim 19 wherein the heart present invention can be prepared by methods well known in disease is cardiac insufficiency. the art. A preferred route of administration is the oral one, but 25. A method according to claim 19, wherein the heart the physician may use to adopt other routes of administration disease is heart failure. e.g. the parenteral one. 26. A method according to claim 25, wherein the heart 0050. The therapeutic agent for the combined therapy, failure is chronic. according to the present invention, can be formulated as well 27. A method according to claim 25, wherein the heart known in the art. failure is acute. 0051. The essential fatty acid can be formulated, for 28. A method according to claim 19, wherein the therapeu example, in the form of gelatin capsules as stated below. tic agent for the combined therapy is selected from the group 0052 Gelatin Capsules consisting of ACE-inhibitors, NEP-inhibitors, ACE/NEP-in 0053 According to the methods known from pharmaceu hibitors, angiotensin 11 converting enzyme inhibitors, diuret tical technique, capsules are prepared with the following ics, positive inotropic drugs, phosphodiesterase inhibitors, composition and containing 1 g of active ingredient (85% arteriolar and Venular vasodilators, beta blockers, digitalis EPA-DHA) in each capsule. glycosides, and combinations thereof. 29. The method according to claim 19, wherein the another therapeutic agent is selected from the group consisting of Formulation 1. captopril, enalapril, lisinopril, fosinopril, cilaZapril, benaza pril, perindopril, quinapril, ramipril, trandolapril, delapril, EPA ethyl ester 525 mg capsule: DHAethyl ester 315 mg capsule: omapatrilat, Sampatrilat, Z13752A, candesartan, , d-alpha-tocopherol 4 IU capsule: losartan, hydrochlorothiazide, trichloromethiazide, chlo gelatin 246 mg capsule: rothiazide, chlortalidone, triamterene, clofenamide, furo glycerol 118 mg/capsule: semide, torasemide, ethacrynic acid, etozoline, spironolac red iron oxide 2.27 mg capsule: yellow iron oxide 1.27 mg capsule tone, amiloride, dopamine, ibopamine, amrinone, milrinone, Formulation 2. enoXimone, bucladesine, hydralazine, isosorbide dinitrate, visoprolol, practotol, metoprolol, bucindol, carvedilol. Ethyl esters of poly-unsaturated fatty acids 1000 mg: atenolol, bisoprolol, celiprolol, nevibolol, acetyl digitoxin, with content in ethyl esters of c)-3 poly- 850 mg: unsaturated acids (eicosapentaeonic EPA, acetyldigoxin, digitoxin, digoxin, lanatoside C, deslanoside, docosahexaenoic DHA) methyldigoxin, metidigoxin, gitoformat, pimobendan, d.1-alpha-tocopherol 0.3 mg: Vesnarinone, and combinations thereof. gelatin Succinate 233 mg glycerol 67 mg: 30. A method according to claim 29, wherein the therapeu sodium p-hydroxybenzoate 1.09 mg: tic agent for the combined therapy is selected from the group propylsodium p-hydroxybenzoate 0.54 mg. consisting of cilaZapril, captopril, enalapril, candesartan, Val Sartan, losartan, furosemide, hydrochlorothiazide, dopamine, 1-18. (canceled) ibopamine, amrinone, enoXimone, hydralazine, isosorbide 19. A method to preventor treat a heart disease chosen from dinitrate, visopropol, carvedilol, metoprolol, digitoxin, cardiac insufficiency and heart failure, comprising adminis digoxin, acetyldigoxin, metidigoxin, pimobendan, omapatri tering to a patient in need thereof a therapeutically effective lat, Sampatrilat, the compound Z13752A, and combinations amount of an essential fatty acid comprising eicosapen thereof. taenoic acid ethyl ester (EPA) and docosahexaenoic acid 31. A method according to claim 19, wherein the treated ethyl ester (DHA), in combination with another therapeutic patient is a person older than 60 years. agent. 32. A method according to claim 19, wherein the treated 20. A method according to claim 19, wherein the content of patient is a person Suffering from other further cardiopathic EPA+DHA in the essential fatty acid is higher than 25% by disorders. weight. 33. A method according to claim 19, wherein the treated 21. A method according to claim 19, wherein the content of patient is a person who survived a myocardial infarction. EPA+DHA in the essential fatty acid is from about 30% to about 100% by weight. c c c c c