Treatment Methods and Therapeutics

Abstract

The present invention features pharmaceutical compositions and methods of using the pharmaceutical compositions for treating left ventricular diastolic dysfunction. In particular, the pharmaceutical compositions include an apolipoprotein complex comprising a lipid fraction and a protein fraction. Other pharmaceutical compositions for use in the methods of the invention are CETP inhibitor drugs including dalcetrapib, evacetrapib, and anacetrapib.

Derwent Title : Composition, useful for treating left ventricular diastolic dysfunction, comprising an apolipoprotein complex having a lipid fraction and a protein fraction
Status : Applications are currently pending in the U.S. (13/812,376), Canada (CA 2,806,606) and Europe (EP2598158). 
Priority Date: July 28, 2010
Inventors: Dr Jean-Claude Tardif; David Busseuil; Éric Rhéaume

Background

Current standard of care for left ventricular diastolic dysfunction (LVDD) is limited to elimination of fluid overload with diuretics and to the identification and treatment of contributing factors such as left ventricular hypertrophy and myocardial ischemia. The most common cause of left ventricular hypertrophy is arterial hypertension, and attention is therefore given to treatment and control of blood pressure in patients with diastolic dysfunction.
The presence of myocardial ischemia is also investigated and treated in the relevant patients with anti-ischemic drugs or revascularization. In a small number of patients, medical and/or mechanical treatment of hypertrophic cardiomyopathy can also lead to an improvement of diastolic dysfunction. Finally, beta-blockers and non-dihydropyridine calcium channel blocker have been used for the treatment of diastolic dysfunction because
they reduce heart rate (see below).The diagnosis of left ventricular diastolic dysfunction is applied to a broad range of patients with variable pathophysiology ranging from primary myocardial disease to progressive renal failure. The pathophysiologic mechanisms responsible for the development of diastolic dysfunction and diastolic
heart failure remain poorly understood, in part because of the heterogeneous nature of the disorder. Known etiologies for left ventricular diastolic dysfunction include but are not limited to arterial hypertension with or without left ventricular hypertrophy, hypertrophic cardiomyopathy, myocardial ischemia, aging, diabetes mellitus, restrictive cardiomyopathy, amyloidosis, and constrictive pericarditis. Of note, coronary artery disease (coronary atherosclerosis) has been shown to be present in less than half of patients (47%) with diastolic heart failure (also called heart failure with preserved left ventricular ejection fraction) and relief of myocardial ischemia with revascularization has been shown to improve diastolic dysfunction in selected patients.Limitations and problems with the standard of care include the paucity of well-conducted randomized clinical trials in the field of left ventricular diastolic dysfunction, as well as the absence of well-powered trials demonstrating benefits of therapies. Also, beta-blockers and calcium-channel blockers are sometimes used in patients with diastolic dysfunction to slow heart rate in the hope that giving more time to diastolic filling will have favourable effects,
but there are no robust data from randomized trials supporting their use. Indeed, to date there has been no specific pharmacologic treatment that has been approved by the FDA or endorsed in the guidelines of major societies for improving outcomes in patients with diastolic dysfunction. Considering this new and more effective approaches for treating diastolic dysfunction are needed.

Related Publications

Tardif J, Rouleau J. Diastolic dysfunction.[Pubmed]. The Canadian Journal of Cardiology. 1996;12(4):389–98. 8 Busseuil D, Shi Y, Mecteau M, et al. Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits. British Journal of Pharmacology. 2008;154(4):765–73. [Pubmed]

Trapeaux J, Busseuil D, Shi Y, et al. Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice.. British Journal of Pharmacology. 2013;169(7):1587–1599. [Pubmed]

Nicholls S, Tuzcu E, Brennan D, Tardif J-C, Nissen S. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation. 2008;118(24):2506–14. [Pubmed]

Barter P, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. The New England Journal of Medicine. 2007;357(21):2109–22. [Pubmed] 

Abstract

A method of treating a diastolic dysfunction in a mammal comprising administering a therapeutically effective amount of a reverse lipid transport agonist to said mammal. The most preferred agonist is an Apolipoprotein-A1 (APO-A1) mimetic peptide/phospholipid complex.

Derwent Title : Use of a reverse lipid transport agonist useful for preventing or treating a diastolic dysfunction in a subject
Status : Applications pending in U.S. (US 13/185,737), Canada (CA 2,788,223), Europe (EP2389189).
Priority Date : January 23, 2009.
Inventeurs : Jean-Claude Tardif; David Busseuil; Éric Rhéaume

Background

Current standard of care for left ventricular diastolic dysfunction (LVDD) is limited to elimination of fluid overload with diuretics and to the identification and treatment of contributing factors such as left ventricular hypertrophy and myocardial ischemia. The most common cause of left ventricular hypertrophy is arterial hypertension, and attention is therefore given to treatment and control of blood pressure in patients with diastolic dysfunction. The presence of myocardial ischemia is also investigated and treated in the relevant patients with anti-ischemic drugs or revascularization. In a small number of patients, medical and/or mechanical treatment of hypertrophic cardiomyopathy can also lead to an improvement of diastolic dysfunction. Finally, beta-blockers and
non-dihydropyridine calcium channel blocker have been used for the treatment of diastolic dysfunction because they reduce heart rate (see below).The diagnosis of left ventricular diastolic dysfunction is applied to a broad range of patients with variable pathophysiology ranging from primary myocardial disease to progressive renal failure. The pathophysiologic mechanisms responsible for the development of diastolic dysfunction and diastolic heart failure remain poorly understood, in part because of the heterogeneous nature of the disorder. Known etiologies for left ventricular diastolic dysfunction include butare not limited to arterial hypertension with or without left ventricular hypertrophy, hypertrophic cardiomyopathy, myocardial ischemia, aging, diabetes
mellitus, restrictive cardiomyopathy, amyloidosis, and constrictive pericarditis. Of note, coronary artery disease (coronary atherosclerosis) has been shown to be present in less than half of patients (47%) with diastolic heart failure (also called heart failure with preserved left ventricular ejection fraction) and relief
of myocardial ischemia with revascularization has been shown to improve diastolic dysfunction in selected patients.Limitations and problems with the standard of care include the paucity of well-conducted randomized clinical trials in the field of left ventricular diastolic dysfunction, as well as the absence of well-powered trials demonstrating benefits of therapies. Also, beta-blockers and calcium-channel blockers are
sometimes used in patients with diastolic dysfunction to slow heart rate in the hope that giving more time to diastolic filling will have favourable effects, but there are no robust data from randomized trials supporting their use. Indeed, to date there has been no specific pharmacologic treatment that has been
approved by the FDA or endorsed in the guidelines of major societies for improving outcomes in patients with diastolic dysfunction. Considering this newand more effective approaches for treating diastolic dysfunction are needed.

Related Publications

Tardif J, Rouleau J. Diastolic dysfunction. The Canadian Journal of Cardiology. 1996;12(4):389–98. [Pubmed] 

Busseuil D, Shi Y, Mecteau M, et al. Regression of aortic valve stenosis by ApoA-I mimetic peptide infusions in rabbits. British Journal of Pharmacology. 2008;154(4):765–73. [Pubmed]

Trapeaux J, Busseuil D, Shi Y, et al. Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve
remodelling in mice. British Journal of Pharmacology. 2013;169(7):1587–1599. [Pubmed] 

Abstract

Over-expression of angiopoietin like-2 (ANGPTL2) by endothelia cells (EC) accelerates atherosclerotic lesion formation by inducing a pro-inflammatory response by EC and leukocyte adhesion to the vascular endothelium. ANGPTL2 stimulates the expression of ICAM-1 and P-Selectin by EC. Blocking EC expression of ICAM-1 and P-selectin prevents leukocyte adhesion to the EC slowing the progression of atherogenesis. The invention
encompasses: methods of using an ANGPTL2 modulator to prevent or reduce atherogenesis; methods for monitoring vascular health, detecting active atherogenesis; and diagnosing atherosclerosis; treatment selection methods and drug screening methods.

Status: Technology currently under development, provisional U.S. application filed April 2013.
Priority Date : April 10, 2013
Inventors: Éric Thorin, Nada Farhat, Cécile Martal

Background

Early diagnosis, monitoring and inhibiting atherogenesis to treat atherosclerosis is a critical need in the treatment of cardiovascular disease. Currently treatment strategies focus on reducing the risk factors such as high cholesterol, high glucose, hypertension and obesity. The molecular factors that promote
or contribute to atherogenesis which leads to atherosclerosis and associated catastrophic event are not well understood. Current therapies, such as statin therapy, for treating and preventing atherosclerosis, although widely used, are often ineffective including at the earliest stages of the disease and are
associated with adverse side effects in particular statin-induced myopathy.The angiopoietin-like (ANGPTL) family proteins consists of eight members: ANGPTL1, ANGPTL2, ANGPTL3, ANGPTL4, ANGPTL5, ANGPTL6, ANGPTL7 and ANGPTL8. Of these, ANGPTL3, ANGPTL4 and ANGPTL6 are known to have a role in the regulation of lipid and energy metabolism and may contribute to the regulation of the cardiovascular functions influencing the progression of cardiovascular disease, including atherosclerosis. ANGPTL proteins are also
known to participate in angiogenesis promoting the survival and migration of endothelial cells. ANGPTL2, a circulating glycoprotein abundantly expressed in the heart, adipose tissue, lung, kidney and skeletal muscle, acts as a growth factor stimulating the expansion and the survival of hematopoietic stem cells.
ANGPTL2expression is stimulated by hypoxia and it is known to induce angiogenesis and endothelial cell (EC) migration. ANGPTL2 may play a role in inflammation in various pathologies, a positive correlation between the circulating levels of ANGPTL2 and the concentration of the biomarker C-reactive protein (CRP) has been observed. Over-expression of ANGPTL2 is pro-inflammatory in keratinocytes, adipose tissue and EC. ANGPTL2 is currently consideredan orphan ligand; the receptors that mediate its activities are largely unknown. However, studies of its interactions have lead to the suggestion that ANGPTL2 signally may involve activation of Mitogen Activated Protein Kinase (MAPK) phosporylation cascades and trans-activation of the Epidermal
Growth Factor Receptor (EGFR). More recently, it was demonstrated that immune inhibitory receptors such as human leukocyte immunoglobulin-like receptor B2 bind to various ANGPTL proteins including ANGPTL2.
Both circulating and aortic levels of ANGPTL2 increase progressively with healthy aging. A rise in ANGPTL2 blood levels, compared to healthy subjects, has also been observed in both diabetic and obese subjects. Furthermore, increased plasma levels of ANGPTL2 correlate with inflammation, adiposity and
insulin resistance. Plasma levels of ANGPTL2 were found to be higher in Japanese patients with coronary artery disease (CAD) compared to healthy subjects and correlated with the severity of CAD. Studies investigating the physiological and pathophysiological role of ANGPTL2 are limited and none have demonstrated that ANGPTL2 is pro-atherogenic or participates in the pathology associated with atherosclerosis. Despite strong evidence that ANGPTL2 is positively associated with chronic inflammatory diseases, its role in atherogenesis is unknown.

Related Publications

Farhat N, Thorin-Trescases N, Mamarbachi M, et al. Angiopoietin-like 2 promotes atherogenesis in mice. Journal of the American Heart Association.
2012;2(3):e000201. [Pubmed]

Farhat N, Thorin-Trescases N, Voghel G, et al. Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic
smokers. Canadian Journal of Physiology and Pharmacology. 2008;86(11):761–9. [Pubmed]