EP2099295A1 - Prophylaxie et traitement de la fibrillation auriculaire avec des acides gras oméga-3 - Google Patents

Prophylaxie et traitement de la fibrillation auriculaire avec des acides gras oméga-3

Info

Publication number
EP2099295A1
EP2099295A1 EP07862162A EP07862162A EP2099295A1 EP 2099295 A1 EP2099295 A1 EP 2099295A1 EP 07862162 A EP07862162 A EP 07862162A EP 07862162 A EP07862162 A EP 07862162A EP 2099295 A1 EP2099295 A1 EP 2099295A1
Authority
EP
European Patent Office
Prior art keywords
amount
loading dose
fatty acids
omega
dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07862162A
Other languages
German (de)
English (en)
Other versions
EP2099295A4 (fr
Inventor
Robert A. Shalwitz
Roelof M.L. Rongen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Reliant Pharmaceuticals Inc
Original Assignee
Reliant Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Reliant Pharmaceuticals Inc filed Critical Reliant Pharmaceuticals Inc
Publication of EP2099295A1 publication Critical patent/EP2099295A1/fr
Publication of EP2099295A4 publication Critical patent/EP2099295A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates, generally, to methods of treatment 'and prophylaxis of atrial fibrillation in a subject, utilizing omega-3 fatty acids in a loading dose and thereafter in a maintenance dose.
  • Atrial fibrillation is one of the most common cardiac arrhythmias in humans, and it accounts for approximately one-third of hospitalizations for cardiac rhythm disturbance. It is estimated that two to three million people in America have this condition, and billions of dollars are spent on diagnosis and treatment. In addition, half a million new cases are diagnosed every year.
  • Atrial fibrillation is a rhythm disturbance of the atria characterized by rapid, uncoordinated contractions resulting from abnormal electrical discharges in the heart. This results in a reduced ability of the atria to pump blood into the ventricles and often a pooling of blood occurs in parts of the atria. The stagnation of blood can result in the formation of clots, which can then travel through the blood vessels and cause blockage.
  • Atrial fibrillation may increase the risk of stroke, ventricular arrhythmias, need for pacemaker therapy, and use of potentially harmful drugs.
  • Most people with atrial fibrillation have an underlying chronic cardiovascular condition, such as high blood pressure, coronary artery disease, i or diseases of the heart valves or the heart muscle.
  • atrial fibrillation can be caused by an acute reversible event such as the intake of certain drugs, physical or psychological stress, myocardial infarction, pericarditis, hyperthyroidism, or pulmonary embolism.
  • Atrial fibrillation is also commonly developed after surgery, such as heart, thoracic, abdominal, hip, and other surgeries and procedures. In fact, atrial fibrillation is the most common complication after coronary artery bypass graft (CABG) surgery. There is a 10 - 15% incidence in this setting, and it is also manifested more commonly in the elderly.
  • CABG coronary artery bypass graft
  • Treatment options for atrial fibrillation include pharmacological and non- pharmacological methods.
  • Pharmacological treatments include drugs which decrease the heart rate, such as digoxin, beta blockers, and calcium channel blockers.
  • Anticoagulants such as warfarin may also be used to decrease the risk of clot formation associated with atrial fibrillation.
  • Electrical cardioversion and chemical cardioversion with drugs such as sotalol, amiodarone, propafenone, fleicanide, disopyramide, and dofetilide are often performed to restore and maintain a normal sinus rhythm.
  • omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA is sold under the trademark LOVAZATM.
  • LOVAZATM a form of omega-3 fatty acid is described, for example, in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, each ⁇ incorporated herein by reference.
  • the use of a loading dose is often used when the time to reach steady state concentrations is appreciable, or when therapeutic levels must be achieved rapidly.
  • the loading dose is used to "load” or "fill up” the volume of distribution with the drug.
  • the volume of distribution is the proportionality factor that relates the total amount of drug in the body to the concentration in the plasma. It describes the drug's ability to distribute over the body from the blood to the tissues. The time required for the drug to accumulate in the body is referred to as the drug's half-life.
  • the half-life of a drug is the time it takes for the plasma concentration of a drug to reach half of its original concentration at time zero, and it often helps to determine whether there is a need to provide a loading dose.
  • One study by Katan et al. found that the mean half-life of EPA and DHA into plasma cholesteryl esters as fatty acids was 4.8 days and 10.3 days, respectively. The same study found that the mean half-life of EPA and DHA in erythrocytes as fatty acids was 28.1 days and 38.5 days, respectively.
  • Katan et al. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study.
  • omega-3 fatty acids are not classical and that free EPA, DHA, and/or ethyl esters thereof are not present in the blood in amounts anywhere near the relative amount ingested. Omega-3 fatty acids tend to be metabolized extensively in first pass in the liver for presentation and/or utilization in a broad range of biologically useful forms. As the kinetics of EPA and DHA are not classical (for example, the kinetics are dependent on the form of EPA and DHA and the location, such as erythrocyte membrane, serum cholesteruyl esters, adipose tissue), Katan et al. does not disclose establishing therapeutic levels of omega-3 fatty acids at an early point in therapy.
  • omega-3 fatty acids have anti- coagulatory effects which may have negative interactions with other active agents (for example, warfarin) or may potentially increase bleeding risk during or after surgery or other procedures. See, for example, Buckley et al., Ann
  • EPA and/or DHA is causing anti-arrhythmic activity post-surgery.
  • DHA and EPA may have a beneficial effect in both the prophylaxis and treatment of atrial fibrillation. Consequently, there is a need in the art for a therapeutic regimen that includes the administration of DHA and EPA before a procedure which is known to be associated with the risk of atrial fibrillation, or at the beginning of more long-term treatment of atrial fibrillation.
  • a therapeutic regimen that includes the administration of DHA and EPA before a procedure which is known to be associated with the risk of atrial fibrillation, or at the beginning of more long-term treatment of atrial fibrillation.
  • Embodiments of the present invention address the above-mentioned need for a therapeutic regimen for the treatment and prophylaxis of atrial fibrillation, which achieves therapeutic levels of omega-3 fatty acids at an early point in therapy.
  • One embodiment of the present invention is a method of treating or preventing atrial fibrillation in a subject, the method comprising administering to the subject an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days, and thereafter in a maintenance dose amount, wherein the loading dose amount is about twice the maintenance dose amount or more.
  • Another embodiment of the present invention is a method of preventing atrial fibrillation in a subject after an interventional procedure, the method comprising administering an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days before or immediately after the interventional procedure, and thereafter in a maintenance dose amount after the interventional procedure, wherein the loading dose amount is about twice the maintenance dose amount or more.
  • Another embodiment of the invention is a method of treating atrial fibrillation in a subject, the method comprising administering to the subject an effective amount of omega-3 fatty acids in a loading dose amount for a loading dose period of 1 to 30 days, and thereafter a maintenance dose amount, wherein the amount of the loading dose is about twice the maintenance dose amount or more.
  • the goal of such therapy is the reduction of atrial fibrillation time or occurrences in these subjects.
  • One such group of individuals with atrial fibrillation who would benefit from this therapy is patients with pacemakers for conditions such as atrioventricular node dysfunction and block, sinus node dysfunction, sinoatrial bradycardia disease, bradytachycardia syndrome, cardiac decompensation, chronic heart failure, chronic bifascicular and trifascicular block, hypertrophic obstructive cardiomyopathy, idiopathic dilated cardiomyopathy, long-QT syndrome, hypersensitive carotid sinus, and neurocardiogenic syncope.
  • the present invention relates to methods of treatment and prophylaxis of atrial fibrillation, utilizing omega-3 fatty acids in a loading dose and thereafter in a maintenance dose.
  • Atrial fibrillation refers to a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function, as discussed in the ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation (J Am Coll Cardiol. 2001. 38(4):1266i-1266lxx). Atrial fibrillation is characterized on an electrocardiogram (ECG) by the replacement of consistent P waves by rapid oscillations or fibrillatory waves that vary in size, shape, and timing, associated with an irregular, frequently rapid ventricular response when atrioventricular (AV) conduction is intact. Examples of different types of atrial fibrillation are acute, chronic, paroxysmal, intermittent, constant, persistent, and permanent.
  • the term “loading dose” refers to an initial dose given at the start of therapy.
  • the term “maintenance dose” refers to the dose given after the loading dose or doses. In the presently claimed invention, the loading dose can be about twice the maintenance dose or more.
  • the loading dose of omega-3 fatty acids can be 1.5 to 8 times the maintenance dose. In a preferred embodiment, the loading dose of omega-3 fatty acids can be 2 to 10 grams/day. [0026] In one embodiment of the invention, the maintenance dose can be 1 to 4 grams/day.
  • the "loading dose period” is the amount of time in which the loading dose is administered.
  • the “maintenance dose period” is the amount of time in which the maintenance dose is administered.
  • the loading dose period can be 1 to 30 days, followed by a maintenance dose period.
  • the loading dose period can be 1 to 14 days, most preferred 1 to 7 days, followed by the maintenance dose period.
  • the omega-3 fatty acids comprise LovazaTM omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, hereby incorporated by reference.
  • the omega-3 fatty acids are present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition.
  • the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA as compared to the total fatty acid content of the composition.
  • the EPA and DHA are in a weight ratio of EPA:DHA of from 99:1 to 1 :99, preferably from 1 :4 to 4:1 , more preferably from 1 :3 to 3:1 , and .
  • omega-3 fatty acids may also comprise pure EPA or pure DHA.
  • omega-3 fatty acids includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,811 , each hereby incorporated by reference), precursors or salts thereof and mixtures thereof.
  • omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ⁇ -linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters.
  • Preferred omega-3 fatty acid oils are long- chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof.
  • omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified fish oil concentrates.
  • Commercial examples of omega-3 fatty acids suitable for use in the invention include lncromega F2250, F2628, E2251 , F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare a.s., 1327 Lysaker, Norway).
  • omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80% by weight, or even at least 90% by weight.
  • the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight.
  • the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA.
  • the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids even if other forms are utilized in accordance with the present invention.
  • the omega-3 fatty acids can be present in an amount from about 300 mg to about 10 grams, more preferably about 500 mg to about 6 grams, and most preferably from about 750 mg to about 4 grams. This amount may be in one or more dosage forms, preferably one dosage form.
  • the omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same.
  • the most preferred form of omega-3 fatty acids is LOVAZATM omega-3 fatty acids (K85EE, Pronova Biocare A.S., Lysaker, Norway) and preferably comprises the following characteristics (per dosage form):
  • the active ingredients of the present invention may be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients").
  • Non-active ingredients serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.
  • Excipients include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils.
  • surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical art, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof.
  • the omega-3 fatty acids may be administered in a loading dose amount for a loading dose period prior to an interventional procedure.
  • interventional procedures include coronary arterial bypass graft (CABG) surgery, aortic valve replacement, mitral valve replacement, balloon angioplasty, thoracic surgery, abdominal surgery, hip surgery, and other surgeries and procedures.
  • the interventional procedure can be CABG surgery.
  • the omega-3 fatty acids may be administered with other pharmaceutical compounds. These pharmaceutical compounds may include cardiovascular drugs.
  • Examples include antiarrhythmics of Type IA (such as disopyramide, procainamide, and quinidine), Type 1 B (such as tocainide, lidocaine, and mexiletine), Type 1 C (such as flecainide, moricizine, propafenone, and indecainide), Type Il (beta blockers such as atenolol, propranolol, and esmolol), Type III (such as amiodarone, bretylium, dofetilide, ibutilide, and sotalol), and Type IV (calcium channel blockers such as verapamil and diltiazem).
  • Type IA such as disopyramide, procainamide, and quinidine
  • Type 1 B such as tocainide, lidocaine, and mexiletine
  • Type 1 C such as flecainide, moricizine, propafenone, and indecainide
  • Type Il beta blockers such
  • digoxin may be administered.
  • anticoagulants such as warfarin and heparin
  • antiplatelet agents such as aspirin, ticlopidine, and clopidogrel
  • digoxin may be administered.
  • anticoagulants such as warfarin and heparin
  • antiplatelet agents such as aspirin, ticlopidine, and clopidogrel
  • UU37J I nrougnout this application various patents and publications have been cited. The disclosures of these patents and publications in their entireties are hereby incorporated by reference into this application, in order to more fully describe the state of the art to which this invention pertains.
  • the invention is capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne, d'une manière générale, des procédés thérapeutiques et prophylactiques de la fibrillation auriculaire chez un sujet, en utilisant des acides gras oméga-3 dans une dose de charge, puis dans une dose d'entretien.
EP07862162A 2006-11-22 2007-11-21 Prophylaxie et traitement de la fibrillation auriculaire avec des acides gras oméga-3 Withdrawn EP2099295A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86049506P 2006-11-22 2006-11-22
PCT/US2007/024283 WO2008066745A1 (fr) 2006-11-22 2007-11-21 Prophylaxie et traitement de la fibrillation auriculaire avec des acides gras oméga-3

Publications (2)

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EP2099295A1 true EP2099295A1 (fr) 2009-09-16
EP2099295A4 EP2099295A4 (fr) 2010-02-24

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EP (1) EP2099295A4 (fr)
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ITMI20012384A1 (it) 2001-11-12 2003-05-12 Quatex Nv Uso di acidi grassi poliinsaturi per la prevenzione primaria di eventi cardiovascolari maggiori
EP3552602B1 (fr) 2009-03-18 2025-03-05 Incarda Therapeutics, Inc. Unité de doses, aérosols, kits et procédés pour le traitement de maladies cardiaques par administration pulmonaire
CA2826663A1 (fr) * 2011-02-07 2012-08-16 Mochida Pharmaceutical Co., Ltd. Agent therapeutique pour l'insuffisance cardiaque congestive diastolique
CN109069495A (zh) 2016-02-01 2018-12-21 英凯达治疗公司 电子监测联合吸入药理学疗法管理包括心房颤动在内的心律失常
AU2018266199A1 (en) 2017-05-10 2019-11-07 Incarda Therapeutics, Inc. Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration
US10744087B2 (en) 2018-03-22 2020-08-18 Incarda Therapeutics, Inc. Method to slow ventricular rate
AU2020323594B2 (en) 2019-08-01 2022-02-03 Incarda Therapeutics, Inc. Antiarrhythmic formulation
US11007185B2 (en) 2019-08-01 2021-05-18 Incarda Therapeutics, Inc. Antiarrhythmic formulation
RU2722052C1 (ru) * 2019-12-30 2020-05-26 Федеральное государственное бюджетное образовательное учреждение высшего образования "Самарский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ определения риска развития фибрилляции предсердий у пациентов с ишемической болезнью сердца, принимающих омега-3 полиненасыщенные жирные кислоты, при проведении коронарного шунтирования

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See also references of WO2008066745A1

Also Published As

Publication number Publication date
JP2010510313A (ja) 2010-04-02
WO2008066745A1 (fr) 2008-06-05
EP2099295A4 (fr) 2010-02-24
WO2008066745A9 (fr) 2008-08-28

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