Method and compound for the treatment of valvular disease

Abstract

The present invention provides methods for preventing or treating a valvular stenosis or a valvular calcification in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide / phospholipid complex, wherein the peptide of the complex is an Apolipoprotein A-1 mimetic peptide. In one embodiment the Apolipoprotein A-1 mimetic peptide has the sequence set forth in SEQ ID NO: 1. In another embodiment the phospholipid of the complex is egg sphingomyelin and 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine.

Description

[0001]This application is a division of U.S. application Ser. No. 12 / 227,872, filed on Dec. 1, 2008, which is the national stage of International Application No. PCT / CA2007 / 000895, filed on May 23, 2007, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 809,850 filed Jun. 1, 2006, the disclosure of each of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to the general field of medical methods and compounds and is particularly concerned with a method and compound for the treatment of valvular disease.BACKGROUND OF THE INVENTION[0003]The function of the heart is to supply the energy required for the circulation of blood in the cardiovascular system. Blood flow through all organs is passive and occurs only because arterial pressure is kept higher than venous pressure by the pumping action of the heart. The right heart pump provides the energy necessary to move blood through the pulmonary vesse...

AI Technical Summary

Benefits of technology

"The patent describes a method for preventing or treating valvular stenosis and calcification in a subject by administering a reverse lipid transport agonist. This method can slow down or stop the progression of valvular diseases and even cause regression of aortic valve stenosis. The method involves administering a therapeutically effective amount of a reverse lipid transport agonist to a subject in need. The reverse lipid transport agonist can be a peptide, a lipid, a peptide complexed with a lipid, an HDL mimetic peptide, a CETP modulator, an SRB1 modulator, an LXR / RXR agonist, an ApoA-1 mimetic peptide, or a combination of these. The method can also involve increasing reverse cholesterol transport in a subject. Overall, this patent provides a new and effective treatment for valvular diseases that is less invasive and can lead to better outcomes compared to existing treatments."

Problems solved by technology

For any of several reasons, it can happen that the aortic valve is somehow damaged and may become stenosed.

Indeed, mechanical sheer stress typically leads to calcific injury.

More than 50% of adults with aortic stenosis are found to have a bicuspid valve, but fibrosis and calcification may make it difficult to determine whether the valve is bicuspid or tricuspid.

The less compliant, thickened left ventricle becomes more dependent on the atrial contribution to diastolic filling, such that left ventricular performance can deteriorate when atrial contraction is lost, for example during atrial fibrillation or atrial-ventricular dissociation.

The abnormal relaxation and increased stiffness of the thickened left ventricle during diastole also result in diastolic dysfunction and elevations of left ventricular and left atrial diastolic pressures.

Thus, significant aortic stenosis creates conditions in which high myocardial oxygen demands are inadequately supported by reduced oxygen supply, which leads to subendocardial ischemia.

Further elevation of the left ventricular end diastolic pressure (secondary to diastolic dysfunction with or without systolic dysfunction) results in pulmonary venous hypertension.

The increased myocardial oxygen demands in aortic stenosis with the underperfused subendocardial myocardium can produce angina pectoris, arrhythmias, and even sudden death.

Hence, aortic stenosis is associated not only with high mortality but also with substantial morbidity.

These nodules decrease the flexibility of the leaflets, thereby limiting their mobility and capacity to fully open.

The operative mortality for this procedure, particularly in the elderly, is relatively large.

Mechanical heart valves are durable and, hence, more likely to result in long-lasting function but require careful chronic anticoagulation because of thrombo-embolic risk.

Chronic anticoagulation therapy, however, carries with it a risk of haemorrhage similar in incidence to that of the residual risk for thrombotic events.

Such valves, however, carry a significantly higher risk of calcification than mechanical valves.

Since treatment of a functionally compromised bio-prosthetic heart valve frequently requires replacement with a new valve (and hence a second open-heart surgery), limitations on the useful life expectancy of a bio-prosthetic heart valve are both a serious medical problem for the patient and a financial drain on the medical system.

Furthermore, all prosthetic heart valves are somewhat stenotic.

Prosthetic dysfunction secondary to thrombosis or calcification can lead to increased obstruction or the development of regurgitation.

Regurgitation can also result from a perivalvular leak, that is a leak in the area of the sewing ring of the valve.

Turbulence associated with valve dysfunction can cause haemolysis and anemia.

Even normally functioning prosthetic valves can cause haemolysis in some patients.

Furthermore, some patients have aortic dimensions that are not large enough to easily accommodate conventional replacement valves.

Hence, there is a significant number of patients for whom valve replacement is impossible, impractical, or undesirable.

Nevertheless, this technique still requires the patient to be healthy enough to survive and recuperate from thoracic surgery, and involves all the costs and risks attendant with such surgery.

Although this procedure eliminates many of the risks and disadvantages attendant with the preceding two techniques, re-stenosis is very common within one year, limiting the usefulness of the technique to temporarily mitigating symptoms for those patients who are poor surgical candidates or refuse surgery.

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