WO2010020959A1

WO2010020959A1 - Resveratrol-containing composition for treating heart failure

Info

Publication number: WO2010020959A1
Application number: PCT/IB2009/053676
Authority: WO
Inventors: Lionel Henry Opie
Original assignee: University Of Cape Town
Priority date: 2008-08-21
Filing date: 2009-08-20
Publication date: 2010-02-25
Also published as: ZA201101773B

Abstract

This invention relates to a compound selected from resveratrol and pharmaceutically acceptable salts, esters, and conjugates thereof for use in a method of treating impaired contraction of the heart, manifest as heart failure, in the presence of ischaemic heart disease in a human subject. The invention further relates to a method of treating impaired contraction of the heart in the presence of ischaemic heart disease in a human subject with the use of resveratrol and pharmaceutically acceptable salts, esters, and conjugates thereof. In particular, the invention relates to a combination of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof, and perhexiline or pharmaceutically acceptable salt thereof for use in the treatment of impaired contraction of the heart, manifest as heart failure, in the presence of ischaemic heart disease in a human subject.

Description

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Resveratrol-containing composition for treating heart failure

BACKGROUND OF THE INVENTION

This invention relates to a therapeutic treatment and more particularly to the treatment of heart failure in human subjects.

Red wine polyphenol extracts have experimental cardioprotective properties¹, and may counter one of the mechanisms underlying atherosclerosis, namely thrombin- induced matrix invasion of vascular smooth muscle cells². An extract of cabernet sauvignon suppressed endothelin-1 synthesis and release in bovine aortic endothelial cells³. Another polyphenol extract protected against angiotensin-ll induced hypertension in rats by blunting endothelial dysfunction and promoting formation of nitric oxide⁴. Yet another polyphenol extract increased eNOS promoter and protective nitric oxide release in human umbilical endothelial cells⁵. Of the possible polyphenol components tested, resveratrol is a stilbene derivative found in grape skins, and hence found much more in red than white wine. Resveratrol was an active component of a red wine polyphenol extract that transcriptionally inhibited the expression of endothelial vascular cell adhesion molecule, VCAM-1⁶. Resveratrol and the procyanidins (the latter are flavan-3-ols and hence part of the flavonoid family) are the polyphenols currently attracting the most attention.

Resveratrol has been shown in animal studies to have beneficial effects such as anticancer, anti-viral, neuroprotective, anti-aging, anti-inflammatory and life-prolonging effects, as well as experimental properties that might limit the development of cardiovascular disease such as decreased insulin resistance⁷ and vascular protection. Several recent studies show experimental protection by resveratrol against another form of cardiac damage, namely that caused by ischemia which is a lack of blood flow⁸, against doxorubicin-induced cardiomyopathy⁹ and resveratrol inhibiting cardiac hypertrophy¹⁰.

Resveratrol is available as a nutritional supplement.

Resveratrol has the systematic name 5-((E)-2-(4-hydroxyphenyl)-ethenyl)benzene- 1 ,3-diol. Another name for resveratrol is 3,4'5-stilbenetriol. Resveratrol is generally used in the trans-form.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a method of treating impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease in a human subject, the method including a step of administering a therapeutically effective amount of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof to the subject.

Further according to the invention, there is provided the use of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof in the manufacture of a medicament for the treatment of impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease.

Still further according to the invention, there is provided a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof for use in the treatment of impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease.

The invention provides, according to yet another aspect, a method of treating impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease in a human subject, the method including a step of administering a therapeutically effective amount of a combination of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof and perhexiline or pharmaceutically acceptable salt thereof to the subject. In yet another form of the invention, there is provided the use of a combination of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof and perhexiline or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease.

In yet another form of the invention, there is provided a combination of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof and perhexiline or pharmaceutically acceptable salt thereof for use in the treatment of impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease.

In another form of the invention there is provided a pharmaceutical composition comprising a combination of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof and perhexiline or pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in more detail, by way of example only, with reference to the accompany Figures in which:

Figure 1 illustrates the proposed effect of resveratrol in countering heart failure by acting as an agonist to sirtuin;

Figure 2 illustrates graphically the results of the action of resveratrol on heart failure in isolated rat hearts; and

Figure 3 illustrates graphically the effects of the combination of resveratrol and perhexiline on heart failure in the isolated rat heart. - -

DESCRIPTION OF EMBODIMENTS

Heart failure is a chronic condition in which the heart, usually enlarged, typically fails to pump adequately as a result of impaired contractions which if severe enough leads to body fluid accumulation in the lungs, causing shortness of breath and, in the legs, causing swelling. The diagnosis is usually made by a combination of clinical assessment and imaging by echocardiography. Heart failure, in its advanced forms (stages 3 and 4), still has an extremely poor prognosis despite optimal current therapy. Many of the sufferers die within five years, despite current maximal therapy. The backbone of such therapy lies in drugs that counteract the abnormally stimulated hormonal-nervous system patterns in heart failure, namely beta-blockers, the angiotensin-converting enzyme inhibitors (ACE inhibitors), and aldosterone inhibitors. Diuretic drugs are given to lessen fluid retention.

The invention provides a method of treating one particular form of heart failure in a human, namely impaired contraction of the heart leading to heart failure in the presence of ischaemic heart disease. If part of the heart is diseased as a result of ischaemic heart disease and therefore receiving too little blood, that part of the heart will not contract properly. The heart becomes weaker than it should be and the amount of blood ejected at every beat (the ejection fraction) will fall. The treatment involves administering to the subject a therapeutically effective amount of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof.

The resveratrol will be in a purified form, e.g. isolated from a natural source, or produced synthetically. The resveratrol may be used as such or in the form of a suitable, salt, ester or conjugate, e.g. as a glucoside or sulphate.

The resveratrol may be in the trans-form, cis-form or a mixture of these two forms. The trans-form is preferred.

The resveratrol may be administered in a suitable pharmaceutical form such as tablet or capsule. The pharmaceutical form is preferably a slow release form.

Figure 1 illustrates the proposed effect of resveratrol in countering heart failure by acting as an agonist to sirtuin, considered as a longevity factor. Hypothetically, heart failure induces overactivity of poly(ADP-ribose) polymerase (PARP), a multifunctional - -

DNA-bound nuclear enzyme, that inhibits NAD-dependent paths thereby decreasing the activity of sirtuin. The proposal is that resveratrol, by increasing the activity of sirtuin, deacetylates and inhibits the pro-apoptotic (increased programmed cell death) effector p53 (a transcription factor). The result is that resveratrol protects cells from failing hearts against PARP-mediated cell death.

Results of a further study on isolated rat hearts in which heart failure was produced by a model of ischaemic heart disease, achieved by reduction of the normal coronary perfusion pressure, is illustrated in Figure 2. The pressure within the left ventricle was then measured and found to be 91 +/- 3.0 mmHg in the non-failing hearts, 16 +/- 2.5 mmHg in the failing hearts and 26.7 +/- 2.8 mmHg in the failing hearts treated with resveratrol. Figure 2 shows the traces of the pressure developed inside the left ventricle of the failing rat heart before and after addition of resveratrol to the fluid perfusing the heart.

To explain these improvements and with a view to proving the mechanism of action, the paths that convey the molecular signals from an external stimulus inwardly to within the heart muscle cells were examined in order to lead to their beneficial or adverse remodelling growth patterns. In preliminary experiments, rat hearts were subjected to analyses by Western blotting to show that resveratrol increased the amount of total STAT-3 (Signal Transducer and Activator of Transcription-3) and also increased the amount of active STAT-3 (phosphoSTAT-3). The significance is that STAT-3 is the signal that acts on the cell nucleus to promote beneficial protective patterns of growth in the heart muscle and to prevent apoptosis (programmed cell death). The definitive experiments were recently done using a genetically modified knock-out mouse model in which the cardiac activity of STAT-3 had been abolished.¹¹ In that model, the protective effects of resveratrol were lost showing that STAT-3 was an essential part of the protective signalling path evoked by resveratrol.

Thus, these experiments have led to the view that resveratrol increases the contractile activity of the failing heart, i.e. a heart with impaired contraction caused by decreased coronary perfusion (ie blood flow), or ischaemia, as found in coronary heart disease, while, at the same time, promoting the activity of intracellular repair paths that benefit the protective remodelling processes occurring in the heart muscle in heart failure.

The resveratrol, salt, ester or conjugate thereof may be used as one of the agents in adjunctive or combination therapy of heart failure. The other agent will typically be a drug which acts on the abnormally stimulated hormonal-nervous system patterns in heart failure such as a beta-blocker or an ACE (angiotensin converting enzyme) inhibitor or an aldosterone blocker or a drug acting to improve the energy status of the heart, i.e. a metabolic modulator, such as trimetazidine or perhexiline or ranolazine, or any combination of these or other standard drugs used in the therapy of heart failure, including a statin.

Of these, the metabolic modulators, in particular perhexiline, are of particular interest. Perhexiline is known to have a metabolic effect on the heart. That means it does not act, in the first instance, by altering the contraction of the heart, nor does it act by lessening the adverse fluid retention that gives rise to shortness of breath and leg swelling in heart failure, but it acts on the process of energy generation in the failing heart. The two major myocardial sources of energy are fatty acids in the form of free fatty acids (FFA) and glucose, both of which get converted by enzymatic breakdown to 2-carbon fragments and hence into the energy-generating cycle. In heart failure, there is breakdown of body fat, which puts up the blood FFA and allows an excess of FFA to enter the metabolic paths that generate energy in the heart muscle¹². Such an oversupply leads to excess stimulation of processes requiring oxygen in the heart muscle at the level of the mitochondria, a process called "oxygen wastage". Perhexiline specifically inhibits this excess passage of FFA into the heart muscle and thereby improves the uptake of glucose by the heart and hence better provides the energy needed by the heart¹³. In an important clinical trial, Professor Michael Frenneaux and colleagues from the University of Birmingham in England tested the effects of adding perhexiline 100 mg twice daily over 8 weeks to the existing optimal therapy against heart failure in 28 patients with 28 acting as controls who continued on their prior existing therapy. The results were positive as published in the major heart journal, Circulation¹⁴. Exercise capacity, quality of life and contraction of the heart ("ejection fraction") all improved, as did the patients' ability to exercise and the strength of their leg muscles.

Thus, it is evident that the metabolically active agent perhexiline acts on the failing heart on a different biological process from resveratrol (Figure 1). Because of these different mechanisms of action, it is reasonable to propose that the combination of resveratrol and perhexiline should give added benefit to heart failure patients with impaired contraction of the heart in the presence of ischaemic heart disease beyond that obtained by either agent alone. Therefore the combination of resveratrol and perhexiline was tested in the following experimental rat model of heart failure. In control well-perfused hearts the peak contractions as measured by a balloon in the normally pumping left ventricle reached 120 mmHg (Figure 3, left panel), similar to the normal blood pressure in humans. After severe reduction of the coronary flow to mimic the situation in heart failure caused by ischaemic artery disease, the contractions only reached 7.2 +/- 2.2 mmHg (Figure 3, top right). In hearts that were exposed to perhexiline, the contractions increased to 16.3 +/-1.1 mmHg (Figure 3, middle panel on right), and in those exposed to both perhexiline and resveratrol, the contractions reached 22.9 +/-1.8 mmHg (Figure 3, bottom panel on the right). These data support the contention that a combination of resveratrol and perhexiline, two metabolically active drugs acting by different mechanisms, would be effective in the therapy of heart failure.

The combination of agents (resveratrol and perhexiline) may be included in a single dosage form or administered in separate dosage forms.

The resveratrol salt, ester or conjugate thereof will generally be administered in a daily dose or doses of 100 mg, preferably greater in total than 500 mg, up to 5000 mg.

The resveratrol salt, ester or conjugate thereof and combination of agents will be administered in suitable pharmaceutically acceptable dosage forms. Suitable dosage forms include tablet, capsule, liquid and the like. The dosage form is preferably a slow release form.

When a combination is used, the perhexiline would be administered as described in reference 14, that is 100 mg twice daily with checks of blood levels to avoid hepatic toxicity that may develop especially with higher doses, but no toxicity was found in the heart failure study of Lee et al¹⁴. REFERENCES

1. de Gaetano G, De Curtis A, di Castelnuovo A, Donati MB, lacoviello L, Rotondo S. Antithrombotic effect of polyphenols in experimental models: a mechanism of reduced vascular risk by moderate wine consumption. Ann N Y Acad Sci. 2002;957: 174-188.

2. Oak MH, El Bedoui J, Anglard P, Schini-Kerth VB. Red wine polyphenols compounds strongly inhibit pro-matrix metalloproteinase-2 expression and its activation in response to thrombin via direct inhibition of membrane type 1- matrix metalloproteinase in vascular smooth muscle cells. Circulation. 2004;110:1861-1867.

3. Corder R, Douthwaite JA, Lees DM, Khan NQ, Viseu Dos Santos AC, Wood EG, Carrier MJ. Endothelin-1 synthesis reduced by red wine. Nature. 2001 ;414:863-864.

4. Sarr M, Chataigneau M, Martins S, Schott C, El Bedoui J, Oak MH, Muller B, Chataigneau T, Schini-Kerth VB. Red wine polyphenols prevent angiotensin ll-induced hypertension and endothelial dysfunction in rats: role of NADPH oxidase. Cardiovasc Res. 2006;71 :794-802.

5. Leikert JF, Rathel TR, Wohlfart P, Cheynier V, Vollmar AM, Dirsch VM. Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation. 2002;106:1614-1617.

6. Carluccio MA, Siculella L, Ancora MA, Massaro M, Scoditti E, Storelli C, Visioli F, Distante A, De Caterina R. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler Thromb Vase Biol. 2003:23:622-629.

7. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu W, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high- calorie diet.

Nature. 2006;444:337-342

8. Dawn B. Resveratrol: ready for prime time? J MoI Cell Cardiol. 2007; 42:484- 486.

9. Tatlidede E, Sehirli O, Velioglu-Ogϋnc A, Cetinel S, Yegen BC, Yarat A, Sϋieymanoglu S, Sener G. Resveratrol treatment protects against doxorubicin-induced cardiotoxicity by alleviating oxidative damage. Free Radic Res. 2009;43: 195-205

10. Chan AY, Dolinsky VW, Soltys CL, Viollet B, Baksh S, Light PE, Dyck JRB. Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt. J Biol Chem. 2008;283:24194-201

11. Smith RM, Suleman N, Lacerda L, Opie LH, Akira S, Chien KR, Sack MN. Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning.. Cardiovascular Research. 2004; 63;611-616,

12. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure.

Circulation. 2007; 116:434-48.

13. Opie LH, Knuuti J. The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol 2009: in press

14. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Lynne Williams L, Ashrafian H, Horowitz J, Fraser AG, Clarke K, and Frenneaux M. M. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment Circulation, 2005; 112: 3280 - 3288.

Claims

1. A method of treating impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease in a human subject including the step of administering a therapeutically effective amount of a compound selected from resveratrol and pharmaceutically acceptable salts, esters, and conjugates thereof to the subject.

2. A method according to claim 1 , wherein the compound is resveratrol.

3. A method according to claim 2, wherein the compound is in a purified form isolated from a natural source.

4. A method according to claim 2, wherein the compound is produced synthetically.

5. A method according to any one of the preceding claims, wherein the compound is administered in a daily dose in the range of 100 mg to 5000 mg.

6. A method according to claim 5, wherein the daily dose exceeds 500 mg.

7. A method according to any one of the preceding claims, wherein the compound is administered in the form of a slow-release formulation.

8. A method according to any one of the preceding claims, wherein the compound is administered to the human subject in combination with perhexiline or a pharmaceutically acceptable salt thereof.

9. A compound selected from resveratrol and pharmaceutically acceptable salts, esters, and conjugates thereof for use in a method of treating impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease in a human subject, the method including the step of administering a therapeutically effective amount of the compound to the subject.

10. A compound according to claim 9, wherein the compound is resveratrol.

11. A compound according to claim 10, wherein the compound is in a purified form isolated from a natural source.

12. A compound according to claim 10, wherein the compound is produced synthetically.

13. A compound according to any one of claims 9 to 12, wherein the compound is administered in a daily dose in the range of 100 mg to 5000 mg.

14. A compound according to claim 13, wherein the daily dose exceeds 500 mg.

15. A compound according to any one of claims 9 to 14, wherein the compound is administered in the form of a slow-release formulation.

16. A compound according to any one of claims 9 to 15, wherein the compound is administered to the human subject in combination with perhexiline or a pharmaceutically acceptable salt thereof.

17. Use of a compound selected from resveratrol and pharmaceutically acceptable salts, esters, and conjugates thereof in the manufacture of a medicament for use in a method of treating impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease in a human subject, the method including the step of administering a therapeutically effective amount of the compound to the subject.

18. Use according to claim 17, wherein the compound is resveratrol.

19. Use according to claim 18, wherein the compound is in a purified form isolated from a natural source.

20. Use according to claim 18, wherein the compound is produced synthetically.

21. Use according to any one of claims 17 to 20, wherein the compound is administered in a daily dose in the range of 100 mg to 5000 mg.

22. Use according to claim 21 , wherein the daily dose exceeds 500 mg.

23. Use according to any one of claims 17 to 22, wherein the compound is administered in the form of a slow-release formulation.

24. Use according to any one of claims 17 to 23, wherein the compound is administered to the human subject in combination with perhexiline or a pharmaceutically acceptable salt thereof.

25. A combination of a compound selected from resveratrol and pharmaceutically acceptable salts, esters and conjugates thereof, and perhexiline or pharmaceutically acceptable salt thereof for use in the treatment of impaired contractions of the heart leading to heart failure in the presence of ischaemic heart disease in a human subject.

26. A pharmaceutical composition comprising a compound selected from resveratrol, and pharmaceutically acceptable salts, esters and conjugates thereof and perhexiline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.