WO2004047835A1

WO2004047835A1 - Use of pharmaceutical compositions containing ethyl esters of omega-3 polyunsaturated acids to prevent atrial fibrillation

Info

Publication number: WO2004047835A1
Application number: PCT/EP2003/013125
Authority: WO
Inventors: Jadranka Rogan
Original assignee: VICTORIX ASSETS Ltd
Current assignee: VICTORIX ASSETS Ltd
Priority date: 2002-11-26
Filing date: 2003-11-21
Publication date: 2004-06-10
Anticipated expiration: 2005-05-26
Also published as: ITMI20022511A1; AU2003292080A1; EP1565177A1

Abstract

The use of ethyl esters of polyunsaturated acids of the ω-3 series obtained from fish oil, 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.

Description

USE OF PHARMACEUTICAL COMPOSITIONS CONTAINING ETHYL ESTERS OF OMEGA-3 POLYUNSATURATED ACIDS TO PREVENT ATRIAL FIBRILLATION

The present invention relates to the use of ethyl esters of polyunsaturated acids of the ω-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.

BASIS OF THE INVENTION

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.

In addition, 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.

However, 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. In particular, 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 ω-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.

By way of example, EP 0.409.903-B1, patent IT 1.235.978 and others describe their efficacy in the treatment of hyperlipaemia, hypercholesterolaemia and hypertension. A clinical trial conducted with formulations containing a high concentration of EPA and DHA ethyl esters on patients who had suffered prior myocardial infarctions demonstrated their efficacy in reducing mortality and especially sudden death (Lancet, 354, 4476, 1999).

These results were partly attributable to an effect of stabilisation of the cell membrane of the ventricular cardiomyocytes, which prevents the onset of malignant arrhythmia in the presence of ischaemic myocytes as in post- infarction patients, or in experimental models which reproduce their conditions. The literature about these polyunsaturated fatty acids, and in particular EPA and DHA ethyl esters, has not yet described or suggested their use to prevent atrial fibrillation.

In clinical use for the indications referred to above, these drugs, which are reversible derivatives of natural substances, have not manifested any noteworthy side effects or adverse interactions with other drugs commonly used in the cardiovascular field.

SUMMARY OF THE INVENTION

It has now been found that EPA and DHA ethyl esters can be used to prevent atrial fibrillation. The usefulness of this treatment, as clearly demonstrated by the pharmacological data, is independent of the etiopathogenesis of these types of arrhythmia, and therefore also extends to the prevention of post-operative atrial fibrillation.

DESCRIPTION OF THE INVENTION For ethical reasons, the treatment method has been tested on animal models described in the literature and adapted for the use in question.

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. In order to prevent ventricular interference, a complete atrioventricular block was previously effected by means of suitable ablation.

To reproduce the electrophysiological alterations responsible for the recurrences stimulated by the preceding fibrillations and their duration, rapid atrial pacing of a suitable duration was performed to induce electrical "remodelling", which can be evaluated in terms of shortening of the atrial effective refractory period.

Only episodes of atrial fibrillation lasting over 5 minutes were taken into consideration for the tests. The atrial stimulation was repeated after the animals had been divided into groups and treated for 4-8 weeks with one 0.5/1 g capsule a day of EPA and DHA ethyl esters or with placebo capsules.

A considerable reduction in induced atrial fibrillation and its duration was observed in the groups treated with EPA and DHA ethyl esters.

In another trial, a similar procedure was used in dogs: sterile pericarditis was surgically induced to evaluate the effect of the same drugs in preventing post-operative atrial fibrillation.

The preventive effect of EPA and DHA ethyl esters was also confirmed in this model. The compositions of ethyl esters of ω-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%). In the range of these EPA and DHA concentrations in a mixture, 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.

In accordance with the invention, 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. For this clinical use, in accordance with the experimental findings, 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.

Other 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.

Other pharmaceutical forms 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

Efficacy of EPA and DHA ethyl esters in preventing the inducement of atrial fibrillation in dogs.

The effect of EPA and DHA ethyl esters in preventing the inducement of atrial fibrillation was studied in a canine model developed by Shi-Huang

Lee et al. (Circulation, 101: 200-206, 2000).

24 Mongrel dogs of both genders, weighing around 25 kg, were divided into two equal groups, one of which was treated with 0.5 g capsules of EPA and DHA ethyl esters a day as from 3 weeks before the start of the trial; the other was kept as an untreated control group.

After suitable intravenous anaesthesia, 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.

After a week rest, rapid atrial pacing was performed for a week, the AERP being measured before and after pacing. Four hours after the end of rapid atrial pacing, atrial fibrillation was induced by means of premature atrial stimulation.

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%). These results demonstrate that EPA and DHA ethyl esters significantly prevent atrial fibrillation and reduce the electrophysiological alterations responsible for recurrences.

Example 2

Efficacy of EPA and DHA ethyl esters in preventing atrial fibrillation in dogs after heart surgery.

The effect of EPA and DHA ethyl esters in preventing post-operative atrial fibrillation was studied in a canine model of sterile pericarditis developed by P. Page et al. (J.Am.Coll.Cardiol. 8: 872-879, 1986).

24 Mongrel dogs of both genders were divided into two equal groups, one of which was treated with 1 g capsules of EPA and DHA ethyl esters a day as from 2 weeks before the start of the trial; the other group was kept as untreated controls.

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.

This result demonstrates that EPA and DHA ethyl esters significantly reduce atrial fibrillation after open-heart surgery. Example 3 Composition of soft gelatin capsules containing 1 g of a mixture of

EPA and DHA ethyl esters with a titre of approx. 85%. EPA ethyl ester 525 mg

DHA ethyl ester 315 mg d-alpha tocopherol 4 IU gelatin 246 mg glycerol 118 mg red iron oxide 2.27 mg yellow iron oxide 1.27 mg

Example 4 Composition of soft gelatin capsules containing 1 g of a mixture of

EPA and DHA ethyl esters with a titre of approx. 85%.

Ethyl esters of polyunsaturated fatty acids 1000 mg with an EPA ethyl ester and DHA ethyl ester content of 850 mg d-l- tocopherol 0.3 mg gelatin succinate 233 mg glycerol 67 mg sodium p-oxybenzoate 1.09 mg sodium propyl p-oxybenzoate 0.54 mg Example 5

Composition of soft gelatin capsules containing 0.5 g of EPA and DHA ethyl esters with a titre of approx. 85%.

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 -α 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

Composition of soft gelatin capsules containing 0.5 g of ethyl esters of polyunsaturated fatty acids DHA ethyl ester > 400 mg d-l-α 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

Claims

1. The use of EPA and DHA ethyl esters for the preparation of a medicament useful for the prevention of atrial fibrillation, whose EPA and DHA ethyl ester content exceeds 25%.

2. The use as claimed in claim 1, wherein the drug is useful to prevent atrial fibrillation in patients with a history of paroxystic atrial fibrillation.

3. The use as claimed in claim 1, wherein the drug is useful to prevent recurrence in patients cardioverted after persistent atrial fibrillation.

4. The use as claimed in claim 1, wherein the drug is useful to prevent post-operative atrial fibrillation.

5. The use as claimed in claims 1 and 4, wherein the drug is useful to prevent atrial fibrillation after open-heart surgery.

6. The use as claimed in claims 1-5, wherein the EPA and DHA ethyl ester content is between 50 and 100%.

7. The use as claimed in claims 1-5, wherein the EPA and DHA ethyl ester content is between 80 and 90%.

8. The use as claimed in claims 1-7, wherein the drug is used for oral administration.

9. The use as claimed in claims 1-8, wherein the drug is used in soft gelatin capsules.

10. The use as claimed in claims 8 and 9, wherein the drug is used at the dose of 0.5 - 2 g a day.

11. The use as claimed in claims 8-10, wherein the drug is used at the dose of 1 g a day.

12. The use as claimed in claims 1-11, wherein the EPA ethyl ester content is between 40 and 60% and the DHA ethyl ester content is between 25 and 50%.

13. The use as claimed in claims 1-11, wherein the ratio between the EPA and DHA ethyl ester contents is between 0.9 and 1.5.

14. The use as claimed in claims 1-11, wherein EPA or DHA ethyl ester is mainly used.