US20040077723A1 - Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy - Google Patents

Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy Download PDF

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Publication number
US20040077723A1
US20040077723A1 US10/451,623 US45162303A US2004077723A1 US 20040077723 A1 US20040077723 A1 US 20040077723A1 US 45162303 A US45162303 A US 45162303A US 2004077723 A1 US2004077723 A1 US 2004077723A1
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use according
epa
dha
heart failure
ethyl ester
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Abandoned
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US10/451,623
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Inventor
Francesco Granata
Franco Pamparana
Eduardo Stragliotto
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Pfizer Italia SRL
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Pharmacia Italia SpA
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Assigned to PHARMACIA ITALIA S.P.A. reassignment PHARMACIA ITALIA S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GRANATA, FRANCESCO, PAMPARANA, FRANCO, STRAGLIOTTO, EDUARDO
Publication of US20040077723A1 publication Critical patent/US20040077723A1/en
Priority to US11/333,387 priority Critical patent/US7439267B2/en
Priority to US12/207,068 priority patent/US20090005327A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry and cardiovascular medicine and provides a method of prevention and management of cardiac insufficiency and heart failure: two heart diseases in which the second one is the result of the progressive evolution of the first one.
  • Cardiac insufficiency is a condition in which the heart pump function is inadequate to meet the bodily metabolic requirements. Depending on the different severity of the pump deficit, cardiac insufficiency may be symptom-free or clinically manifest.
  • Cardiac insufficiency could have various causes, e.g.:
  • Heart failure is the result of the progressive evolution of cardiac insufficiency. Moreover, a broad spectrum of diseases could cause an impaired filling or emptying of heart chambers, such as: the diseases resulting from a monogenic (familial hypertrophic cardiomyopathy, mitochondral cardiomyopathies) or multigenic defect which are bound to environmental factors such as cigarette smoking, diet, physical exercise, secondary heart diseases. All these diseases take the “common end path” towards heart failure, which sees at first an impairment of the molecular mechanisms and then an impairment of the ventricular function and heart failure. Therefore, heart failure is a syndrome with a various etiology resulting from an anatomo-functional anomaly of the heart with inability in keeping a stroke adequate to the metabolic requirements of the tissues or maintaining the stroke volume by a high filling pressure.
  • Heart failure is characterized by clinical signs and symptoms secondary to the inadequate response to the body metabolic requirements. This condition could occur acutely or have a chronic course.
  • the present drug therapy of cardiac “pump function” includes the use of drugs acting by various modes of action on different points of the etiopathogenesis of the diseases.
  • ACE-inhibitors Angiotensin Converting Enzymes inhibitors
  • diuretics non-digitalis positive inotropic drugs such as adrenergics and inhibitors of phosphodiesterase
  • non-digitalis positive inotropic drugs such as adrenergics and inhibitors of phosphodiesterase
  • arteriolar and venular vasodilators e.g. hydralazine and isosorbide dinitrate
  • beta-blockers e.g. metoprolol and bisoprolol and digitalis derivatives, e.g. digotoxin.
  • Heart failure is at present one of the most important causes of morbidity and mortality in the industrialized countries, as clearly demonstrated by the present case-series: in USA 4.7 million persons have a congestive heart failure, with an incidence equal to 400,000 new cases a year.
  • the present invention provides a method for the prevention and therapeutic treatment of cardiac insufficiency and heart failure in a patient in need of this treatment comprising the administration to such patient of a therapeutically effective amount of an essential fatty acid containing a mixture of (20:5 ⁇ 3) eicosapentaenoic acid ethyl ester (EPA) and of (20:6 ⁇ 3) docosahexaenoic acid ethyl ester (DHA), either alone or in combination with another therapeutic agent.
  • an essential fatty acid containing a mixture of (20:5 ⁇ 3) eicosapentaenoic acid ethyl ester (EPA) and of (20:6 ⁇ 3) docosahexaenoic acid ethyl ester (DHA), either alone or in combination with another therapeutic agent.
  • EPA eicosapentaenoic acid ethyl ester
  • DHA docosahexaenoic acid ethyl ester
  • WO 89/11521 describes in particular an industrial process for the extraction of mixtures having a high content in poly-unsaturated acids, also including EPA and DHA and their ethyl esters, from animal and/or vegetable oils. Mixtures of fatty acids, in particular EPA/DHA, obtained according to WO 89/11521, are indicated as particularly useful in the treatment of cardiovascular pathologies.
  • object of the present invention is the use of an essential fatty acid containing a mixture of eicosapentaenoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA) in the preparation of a medicament for the prevention and treatment of a heart disease chosen from cardiac insufficiency and heart failure, both chronic and acute.
  • EPA eicosapentaenoic acid ethyl ester
  • DHA docosahexaenoic acid ethyl ester
  • An essential fatty acid is preferably a fatty acid having a high content in EPA and DHA, for example with a content in EPA and DHA higher than 25% by weight, preferably from about 30% to about 100% by weight, in particular about 85%.
  • EPA is present in the EPA/DHA mixture preferably in a percentage ranging from 25% to about 45% by weight and DHA is present preferably in a percentage ranging from 55% to about 75% by weight.
  • the most preferred ratio between EPA and DHA is about 0.6-1.1/1.3-1.8; in particular about 0.9/1.5.
  • An essential fatty acid according to the present invention can be obtained by known methods, e.g. as described in U.S. Pat. No. 5,656,667 and WO 89/11521.
  • Object of the present invention is also the use of an essential fatty acid containing a mixture of eicosapentaenoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA) in the preparation of a medicament for the prevention and treatment of a heart disease chosen from cardiac insufficiency and heart failure, both chronic and acute, where the medicament is for combined therapy with another therapeutic agent.
  • EPA eicosapentaenoic acid ethyl ester
  • DHA docosahexaenoic acid ethyl ester
  • another therapeutic agent means an additional single agent or two or more additional agents, preferably from 2 to 10, in particular from 2 to 6 according to physician's instructions, which may be administered in combination, namely either along or separately (substantially simultaneously or sequentially) with the essential fatty acid containing the mixture of EPA and DHA.
  • Examples of therapeutic agents for such a prophylaxis or combined therapy according to the invention are ACE-inhibitors, NEP-inhibitors, ACE/NEP-inhibitors, angiotensin II converting enzyme inhibitors, diuretics, positive inotropic drugs, phosphodiesterase inhibitors, arteriolar and venular vasodilators, beta-blockers and digitalis glycosides, or a mixture thereof.
  • NEP means degradation peptidase of atrial natriuretic peptide (ANP).
  • Examples of ACE-inhibitors are: captopril, enalapril, lisinopril, fosinopril, cilazapril, benazapril, perindopril, quinapril, ramipril, trandolapril and delapril, in particular cilazapril, captopril and enalapril.
  • ACE/NEP-inhibitors are: omapatrilat, sampatrilat and L-phenylalanine,N-[(2S)-2-(mercaptomethyl)-1-oxo-3-phenylpropyl]4-(2-thiazolyl) (compound Z13752A, a product of Zambon Company).
  • angiotensin II receptors antagonists examples include candesartan, valsartan and losartan.
  • diuretics are: hydrochlorothiazide, trichlormethiazide, chlorothiazide, chlortalidone, triamterene, clofenamide, furosemide, torasemide, ethacrynic acid, etozoline, spironolactone and amiloride, if the case in association with potassium sparing drugs, which are well known in the art, in particular furosemide and hydrochlorothiazide.
  • Examples of dopaminergic agents are dopamine and ibopamine.
  • Examples of phosphodiesterase inhibitors are: amrinone, milrinone, enoximone and bucladesine, in particular amrinone and enoximone.
  • Examples of arteriolar and venular vasodilators are: hydralazine and isosorbide dinitrate.
  • beta-blockers are: visoprolol, practotol, metoprolol, bucindol, carvedilol, atenolol, bisoprolol, celiprolol and nevibolol, in particular visoprolol, carvedilol and metoprolol.
  • Examples of digitalis glycoside agents are: acetyl digitoxin, acetyldigoxin, digitoxin, digoxin, lanatoside C, deslanoside, methyldigoxin and gitoformat, in particular digitoxin, digoxin, acetyldigoxin and metidigoxin.
  • Examples of positive inotropic agents are: pimobendan and vesnarinone, in particular pimobendan.
  • a further object of the invention is a method for preventing and treating a heart disease chosen from cardiac insufficiency and heart failure, both chronic and acute, comprising administering to a patient in need thereof a therapeutically effective amount of an unsaturated essential acid containing a mixture of eicosapentaenoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA).
  • EPA eicosapentaenoic acid ethyl ester
  • DHA docosahexaenoic acid ethyl ester
  • a further object of the invention is a method to prevent and treat a heart disease chosen from cardiac insufficiency and heart failure, both chronic and acute, comprising administering to a patient in need thereof a therapeutically effective amount of an essential fatty acid containing a mixture of eicosapentaenoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl ester (DHA), in combination with another therapeutic agent.
  • EPA eicosapentaenoic acid ethyl ester
  • DHA docosahexaenoic acid ethyl ester
  • combination means that the essential fatty acid containing the mixture EPA+DHA and the other therapeutic agent are administered in such an amount and separated by such administration times as to produce a therapeutic effect.
  • an essential fatty acid according to the invention is extremely useful in the prevention and treatment of cardiac insufficiency and heart failure both chronic and acute, in particular, in the elderly people, e.g. older than 60 years, in subjects with other further cardiopathic forms and, in particular, in subjects surviving a myocardial infarction, thanks to the fact that this is a well tolerated drug.
  • the amount of essential fatty acid to be administered to a patient depends on its EPA/DHA content.
  • the amount of essential fatty acid having a EPA/DHA content of about 85%, to be administered to a patient may vary from about 0.7 g to about 1.5 g daily. More specifically, the amount of essential fatty acid, with a EPA/DHA content of about 85% and an EPA/DHA ratio of about 0.9/1.5 is of about 1 g daily.
  • This amount of product may be administered in the form of several daily divided doses or preferably as a single dose, in order to reach the desired blood level.
  • the clinician may vary the amount of product (or mixture with another therapeutic agent) to be administered, basing on the patient's conditions, age and weight.
  • the amount of additional therapeutic agent, when administered in combination with the essential fatty acid, is substantially the amount usually employed by the clinician in therapy. At any rate, the clinician may vary the amount of this additional drug (or mixture of additional drugs) basing on the patient's clinical picture.
  • the present invention provides the clinician with a new method of therapeutic treatment effective for preventing and treating cardiac insufficiency and heart failure or at least improving the conditions of a patient suffering from such heart diseases or improving his/her quality of life. Indeed, on the basis of clinical markers, which are to-day useful to understand the various stages of cardiac insufficiency and progressive evolution towards an overt heart failure, the clinician can make use of the present invention and prevent or at least delay its evolution.
  • compositions according to the present invention can be prepared by methods well known in the art.
  • a preferred route of administration is the oral one, but the physician may use to adopt other routes of administration e.g. the parenteral one.
  • the therapeutic agent for the combined therapy can be formulated as well known in the art.
  • the essential fatty acid can be formulated, for example, in the form of gelatin capsules as stated below.
  • capsules are prepared with the following composition and containing 1 g of active ingredient (85% EPA-DHA) in each capsule.
  • active ingredient 85% EPA-DHA
  • Formulation 1 EPA ethyl ester 525 mg/capsule; DHA ethyl ester 315 mg/capsule; d-alpha-tocopherol 4 IU/capsule; gelatin 246 mg/capsule; glycerol 118 mg/capsule; red iron oxide 2.27 mg/capsule; yellow iron oxide 1.27 mg/capsule.
  • Formulation 2 EPA ethyl ester 525 mg/capsule
  • d-alpha-tocopherol 4 IU/capsule gelatin 246 mg/capsule
  • glycerol 118 mg/capsule red iron oxide 2.27 mg/capsule
  • yellow iron oxide 1.27 mg/capsule.
  • unsaturated acids eicosapentaeonic EPA, docosahexaenoic DHA

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  • Heart & Thoracic Surgery (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US10/451,623 2001-01-25 2002-01-16 Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy Abandoned US20040077723A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/333,387 US7439267B2 (en) 2001-01-25 2006-01-17 Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy
US12/207,068 US20090005327A1 (en) 2001-01-25 2008-09-09 Essential n-3 fatty acids in cardiac in sufficiency and heart failure therapy

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT2001MI000129A ITMI20010129A1 (it) 2001-01-25 2001-01-25 Acidi grassi essenziali nella terapia di insufficienza cardiaca e scompenso cardiaco
ITMI2001A000129 2001-01-25
PCT/EP2002/000507 WO2002058793A1 (en) 2001-01-25 2002-01-16 Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy

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US11/333,387 Expired - Fee Related US7439267B2 (en) 2001-01-25 2006-01-17 Essential n-3 fatty acids in cardiac insufficiency and heart failure therapy
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US12/207,068 Abandoned US20090005327A1 (en) 2001-01-25 2008-09-09 Essential n-3 fatty acids in cardiac in sufficiency and heart failure therapy

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EP (2) EP2258447A3 (ru)
JP (1) JP2004517148A (ru)
AU (1) AU2002225026B2 (ru)
BG (1) BG108071A (ru)
CA (1) CA2433762A1 (ru)
CZ (1) CZ20031947A3 (ru)
EA (1) EA200300830A1 (ru)
EE (1) EE05320B1 (ru)
HR (1) HRP20030561A2 (ru)
HU (1) HUP0303019A2 (ru)
IS (1) IS6862A (ru)
IT (1) ITMI20010129A1 (ru)
MX (1) MX282405B (ru)
NO (1) NO20033304L (ru)
NZ (1) NZ526609A (ru)
PL (1) PL363269A1 (ru)
SK (1) SK8332003A3 (ru)
UA (1) UA78693C2 (ru)
WO (1) WO2002058793A1 (ru)
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US9585859B2 (en) 2013-10-10 2017-03-07 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
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US9624492B2 (en) 2013-02-13 2017-04-18 Amarin Pharmaceuticals Ireland Limited Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof
US9662307B2 (en) 2013-02-19 2017-05-30 The Regents Of The University Of Colorado Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof
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US10172818B2 (en) 2014-06-16 2019-01-08 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids
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US10493058B2 (en) 2009-09-23 2019-12-03 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
US10537544B2 (en) 2011-11-07 2020-01-21 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
US10561631B2 (en) 2014-06-11 2020-02-18 Amarin Pharmaceuticals Ireland Limited Methods of reducing RLP-C
US10668042B2 (en) 2018-09-24 2020-06-02 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of cardiovascular events in a subject
US10888539B2 (en) 2013-09-04 2021-01-12 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing prostate cancer
US10966968B2 (en) 2013-06-06 2021-04-06 Amarin Pharmaceuticals Ireland Limited Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof
US10966951B2 (en) 2017-05-19 2021-04-06 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides in a subject having reduced kidney function
US11058661B2 (en) 2018-03-02 2021-07-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L
US11141399B2 (en) 2012-12-31 2021-10-12 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
US11179362B2 (en) 2012-11-06 2021-11-23 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
US11291643B2 (en) 2011-11-07 2022-04-05 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
US11547710B2 (en) 2013-03-15 2023-01-10 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin
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NO20033304D0 (no) 2003-07-22
YU59303A (sh) 2006-08-17
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AU2002225026B2 (en) 2007-09-13
CA2433762A1 (en) 2002-08-01
EP1365841A1 (en) 2003-12-03
CZ20031947A3 (cs) 2003-12-17
ITMI20010129A1 (it) 2002-07-25
EA200300830A1 (ru) 2003-12-25
EE05320B1 (et) 2010-08-16
HUP0303019A2 (hu) 2003-12-29
EP2258447A3 (en) 2012-07-25
EE200300297A (et) 2003-10-15
HRP20030561A2 (en) 2005-06-30
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US20090005327A1 (en) 2009-01-01
UA78693C2 (en) 2007-04-25
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SK8332003A3 (en) 2003-11-04
US7439267B2 (en) 2008-10-21
JP2004517148A (ja) 2004-06-10
NZ526609A (en) 2005-10-28
NO20033304L (no) 2003-07-22
US20060205814A1 (en) 2006-09-14
EP2258447A2 (en) 2010-12-08
BG108071A (bg) 2005-04-30

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