EP1565177A1 - Use of pharmaceutical compositions containing ethyl esters of omega-3 polyunsaturated acids to prevent atrial fibrillation - Google Patents
Use of pharmaceutical compositions containing ethyl esters of omega-3 polyunsaturated acids to prevent atrial fibrillationInfo
- Publication number
- EP1565177A1 EP1565177A1 EP03767610A EP03767610A EP1565177A1 EP 1565177 A1 EP1565177 A1 EP 1565177A1 EP 03767610 A EP03767610 A EP 03767610A EP 03767610 A EP03767610 A EP 03767610A EP 1565177 A1 EP1565177 A1 EP 1565177A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- atrial fibrillation
- epa
- ethyl esters
- drug
- dha ethyl
- 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.)
- Ceased
Links
Classifications
-
- 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
- A61K31/232—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 having three or more double bonds, e.g. etretinate
-
- 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
- A61K9/4866—Organic macromolecular compounds
-
- 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 to the use of ethyl esters of polyunsaturated acids of the ⁇ -3 series obtained from fish oil, and in particular ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in high concentrations, alone or mixed, for the preparation of medicaments for the prevention of atrial fibrillation.
- EPA eicosapentaenoic acid
- DHA docosahexaenoic acid
- Atrial fibrillation the most common alteration of the heart rhythm, is responsible for significant morbidity and mortality among the population as a whole. Its prevalence increases progressively with age, reaching percentages of over 9% in men aged between 65 and 80 years old. Atrial fibrillation (AF) is a particularly important risk factor for stroke, which is largely responsible for the fact that mortality associated with this alteration in the heart rhythm has doubled.
- the etiological factors responsible for sustained atrial fibrillation include histological alterations of the atrium such as dilation and fibrosis, which are among the normal age-associated cardiac modifications.
- post-operative atrial fibrillation has an incidence of between 20 and 70% after open-heart surgery such as artery bypasses and valve operations, which involve a significant increase in morbidity and hospital costs.
- Various antiarrhythmic drugs have been studied and used to treat atrial fibrillation, especially to prevent recurrences in patients with a history of paroxystic atrial fibrillation or persistent post-cardioversion atrial fibrillation, and to prevent post-operative atrial fibrillation.
- the ideal drug namely one which is wholly manageable and therefore suitable in all circumstances, and able to prevent arrhythmia entirely, is not yet available.
- the recommendation to select the treatment carefully on the basis of each patient's specific characteristics and history is commonly followed for safety reasons.
- the risk associated with the use of class I antiarrhythmic drugs due to their potential proarrhythmic effect, which makes their use inadvisable in the prevention of post-operative arrhythmia, as well as the organ toxicity induced by class III drugs such as amiodarone and the contraindications of beta-blockers are well known.
- Polyunsaturated fatty acids of the ⁇ -3 series, especially EPA and DHA, purified and concentrated as ethyl esters, are known for their potential usefulness in the treatment of some cardiovascular diseases and modulation of the corresponding risk factors.
- EP 0.409.903-B1 patent IT 1.235.978 and others describe their efficacy in the treatment of hyperlipaemia, hypercholesterolaemia and hypertension.
- Atrial fibrillation was induced in the dog by pacing with a suitable battery-operated pacemaker designed to provide rapid atrial pulses at a frequency starting from 500 bpm, for at least 20 beats, until atrial fibrillation took place.
- a complete atrioventricular block was previously effected by means of suitable ablation.
- compositions of ethyl esters of ⁇ -3 polyunsaturated acids to which the invention relates mainly represented by EPA and/or DHA ethyl esters at a high concentration, are easily obtainable according to methods well known to those skilled in the art, such as those described in WO 89/11521, US 5130061, IT 1.235.879, US 4.377.526, US 4.554.107 and others, which are incorporated herein as regards the production methods.
- the EPA and/or DHA ethyl ester content generally exceeds 25%; in particular it ranges between approx. 50% and approx. 100%, and preferably between 80% and 90% (approx. 85%).
- the percentage of EPA ethyl ester is preferably 40 to 60%, and the percentage of DHA ethyl ester is preferably in the 25-50% range; in any event the ratio between the EPA and DHA ethyl esters should be between 0.9 and 1.5.
- said oily compositions comprising high concentrations of EPA and/or DHA ethyl esters are used to make a drug useful in reducing the risk of mortality in patients suffering from heart failure.
- the drug is preferably administered orally, in particular using a pharmaceutical formulation of soft gelatin capsules.
- the preparation process of said capsules, which are particularly suitable to carry oily active ingredients, is well known to those skilled in the art.
- the unit dose of the capsules is usually 0.5-1 g, and preferably 1 g, while the daily dose is between 0.5 and 2 g, depending on the severity of the disorder and the doctor's opinion, and preferably around 1 g/day.
- oral formulations may also be suitable, such as hard capsules, tablets and granulates in which the oily composition can be adsorbed on a solid medium, or drops, syrups, etc., as known in pharmaceutical technology.
- compositions include parenteral formulations such as sterile emulsions and the like.
- the medicament in accordance with this invention may also include other active ingredients with synergic or complementary activity, diluents, thickeners, surfactants, dyes, flavouring agents, stabilisers and antioxidants, in accordance with the usual practice.
- Vitamin E (tocopherol) and p-oxybenzoates are particularly preferred as antioxidants.
- Typical pharmacological results of the therapeutic activity claimed are reported in Examples 1 and 2, and some compositions of soft gelatin capsule formulations are reported in Examples 3-6.
- Example 1 Example 1
- the electrodes required to record the atrial electrogram were inserted through the femoral vein and the pacing wires required to measure the atrial effective refractory period (AERP) were sutured to the two atria; a complete atrioventricular block was then effected by means of radiofrequency ablation to prevent ventricular involvement.
- Unipolar epicardial leads were then sutured to the right ventricle and atrium and connected to a pacemaker regulated at 80 bpm and a pulse generator programmed to pace the atrium at 780 bpm, respectively.
- Rapid atrial pacing shortened the AERP by approx. 30 milliseconds in the controls; this shortening was reduced by approx. 60% in the animals treated with EPA and DHA ethyl esters.
- Atrial fibrillation was induced in 8 out of 12 animals in the control group (67%) and 3 out of 12 animals in the treated group (25%).
- the dogs underwent thoracotomy under anaesthesia; after pericardiotomy the heart was cradled in the pericardium and three pairs of partly coated stainless steel wire electrodes were sutured to the atria, and one to the right ventricle.
- a complete atrioventricular block was effected by means of radiofrequency ablation to prevent ventricular interference, and the ventricular rate was maintained with pacing at 80-100 bpm.
- An attempt was made to induce atrial fibrillation with rapid atrial pacing for at least 20 beats at a frequency of 500-800 bpm until fibrillation was obtained; the fibrillation was only taken into consideration for the analysis if it lasted for at least 5 minutes.
- Atrial fibrillation was induced in 9 dogs out of 12 (75%) in the control group, and 3 dogs out of 12 (25%) in the treated group.
- Example 3 Composition of soft gelatin capsules containing 1 g of a mixture of
- Example 4 Composition of soft gelatin capsules containing 1 g of a mixture of
- Ethyl esters of polyunsaturated fatty acids 500 mg with an EPA ethyl ester and DHA ethyl ester content, ratio 0.9-1.5, of 425 mg d- 1 - ⁇ tocopherol 0.15 mg gelatin succinate 139 mg glycerol 40 mg sodium ethyl p-oxybenzoate 0.66 mg sodium propyl p-hydroxybenzoate 0.32 mg
- Example 6 Ethyl esters of polyunsaturated fatty acids 500 mg with an EPA ethyl ester and DHA ethyl ester content, ratio 0.9-1.5, of 425 mg d- 1 - ⁇ tocopherol 0.15 mg gelatin succinate 139 mg glycerol 40 mg sodium ethyl p-oxybenzoate 0.66 mg sodium propyl p-hydroxybenzoate 0.32 mg
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI20022511 | 2002-11-26 | ||
IT002511A ITMI20022511A1 (en) | 2002-11-26 | 2002-11-26 | USE OF PHARMACEUTICAL COMPOSITIONS CONTAINING ETHYL ESTERS OF OMEGA-3 POLYUNSATURATED ACIDS IN THE ORDER OF ATRIAL FIBRILLATION. |
PCT/EP2003/013125 WO2004047835A1 (en) | 2002-11-26 | 2003-11-21 | Use of pharmaceutical compositions containing ethyl esters of omega-3 polyunsaturated acids to prevent atrial fibrillation |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1565177A1 true EP1565177A1 (en) | 2005-08-24 |
Family
ID=32375543
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03767610A Ceased EP1565177A1 (en) | 2002-11-26 | 2003-11-21 | Use of pharmaceutical compositions containing ethyl esters of omega-3 polyunsaturated acids to prevent atrial fibrillation |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1565177A1 (en) |
AU (1) | AU2003292080A1 (en) |
IT (1) | ITMI20022511A1 (en) |
WO (1) | WO2004047835A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8324276B2 (en) | 2005-01-24 | 2012-12-04 | Pronova Biopharma Norge As | Fatty acid composition for treatment of alzheimer's disease and cognitive dysfunction |
FR2902659A1 (en) | 2006-06-23 | 2007-12-28 | Pierre Fabre Medicament Sa | DHA ESTER AND ITS USE IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASES |
WO2008066745A1 (en) * | 2006-11-22 | 2008-06-05 | Reliant Pharmaceuticals, Inc. | Prophlyaxis and treatment of atrial fibrillation with omega-3 fatty acids |
SG174314A1 (en) | 2009-03-09 | 2011-10-28 | Pronova Biopharma Norge As | Compositions comprising a fatty acid oil mixture and a surfactant, and methods and uses thereof |
CA2759176C (en) * | 2009-04-29 | 2016-03-15 | Amarin Corporation Plc | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
WO2010127103A1 (en) * | 2009-04-29 | 2010-11-04 | Amarin Pharma, Inc. | Stable pharmaceutical composition and methods of using same |
WO2011041710A2 (en) * | 2009-10-01 | 2011-04-07 | Martek Biosciences Corporation | Docosahexaenoic acid gel caps |
FR2963790B1 (en) | 2010-08-11 | 2012-09-28 | Pf Medicament | PANTHENYL DOCOSAHEXAENEOATE AND USE THEREOF IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASES |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1308613B1 (en) * | 1999-02-17 | 2002-01-09 | Pharmacia & Upjohn Spa | ESSENTIAL FATTY ACIDS IN THE PREVENTION OF CARDIOVASCULAR EVENTS. |
ATE305810T1 (en) * | 2000-05-22 | 2005-10-15 | Pro Aparts Investimentos E Con | PHARMACEUTICAL COMPOSITION CONTAINING FATTY ACID WHICH IS AT LEAST 80 Wt. CONTAINS EPA AND DHA |
ITMI20010129A1 (en) * | 2001-01-25 | 2002-07-25 | Pharmacia & Upjohn Spa | ESSENTIAL FATTY ACIDS IN THE THERAPY OF HEART INSUFFICIENCY AND HEART FAILURE |
ITMI20020269A1 (en) * | 2002-02-12 | 2003-08-12 | Victorix Assets Ltd | USE OF OMEGA-3 POLYUNSATURATED ACID ETHYL STERES IN PATIENTS WITH HEART INSUFFICIENCY |
-
2002
- 2002-11-26 IT IT002511A patent/ITMI20022511A1/en unknown
-
2003
- 2003-11-21 WO PCT/EP2003/013125 patent/WO2004047835A1/en not_active Application Discontinuation
- 2003-11-21 EP EP03767610A patent/EP1565177A1/en not_active Ceased
- 2003-11-21 AU AU2003292080A patent/AU2003292080A1/en not_active Abandoned
Non-Patent Citations (5)
Title |
---|
BARTOSOVA L. ET AL, BIOMED. PAP. MED. FAC. UNIV. PALACKY OLOMOUC CZECH REPUB., vol. 149, 2005, pages 339 - 343 * |
GUTIERREZ B. ET AL: "Inhibition of aconitine-induced mortality in the conscious rat: a screening test for antiarrhythmic drugs", METH. FIND EXP. CLIN PHARMACOL., vol. 9, no. 5, 1987, pages 307 - 310 * |
HE SHU ET AL: "Increased susceptibility of ventricular arrhytmias to aconitine in anaesthetized rats is attrubuted to the inhibition of baroreflex", CLIN. EXP. PHARMACOL. PHYSIOL., vol. 31, 2004, pages 249 - 253 * |
LU H.R. ET AL: "R56865, a Na+/Ca+-overload inhibitor , protects against aconitine-induced cardiac arrhytmias in vivo", J. CARDIOVASC. PHARMACOL., vol. 22, 1993, pages 120 - 125 * |
See also references of WO2004047835A1 * |
Also Published As
Publication number | Publication date |
---|---|
ITMI20022511A1 (en) | 2004-05-27 |
AU2003292080A1 (en) | 2004-06-18 |
WO2004047835A1 (en) | 2004-06-10 |
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