Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 2, Issue 2, 2007

Low density lipoproteins (LDL) size seems to be an important predictor of cardiovascular events and progression of coronary artery disease and the predominance of small dense LDL have been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. We recently showed increased LDL size or higher levels of small, dense LDL in different categories of patients at higher cardiovascular risk, such as those with coronary (including acute myocardial infarction) and non-coronary (including carotid disease, abdominal aortic aneurysm and peripheral arterial disease) forms of atherosclerosis or metabolic diseases (including type-II diabetes, polycystic ovary syndrome and growth hormone deficiency). Screening for the presence of small, dense LDL may potentially identify those with even higher risk and may contribute in directing specific treatments in order to prevent new cardiovascular events. This seems particularly true for statins and fibrates. Promising data are available for rosuvastatin, the latest statin molecule introduced in the market, and ezetimibe, a cholesterol absorption inhibitor. The most recent patents regarding these two hypolipidemic agents include the antiinflammatory, antithrombotic and antiplatelet activity (EP1626716B1 and CN1794987A for rosuvastatin) and the potential use for treatment of cholesterol-associated benign and malignant tumors and diabetes (US7098198 and US7071181 for ezetimibe).

Advanced glycation endproducts (AGEs) are unavoidable byproducts of various metabolic pathways. They are formed by reactive metabolic intermediates such as methylglyoxal (MG), glyoxal, and 3-deoxyglucosone. These reactive intermediates bind to proteins, DNA, and other molecules and disrupt their structures and functions, which leads to different diseases such as vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, and aging. In recent years, more compounds that prevent the formation of AGEs or degrade the existing AGEs have been produced and patented. They include: 1) aminoguanidine, 2) drugs used in the treatment of type 2 diabetes such as metformin and pioglitazone (patented), 3) angiotensin receptor blockers and angiotensin converting enzyme inhibitors, 4) pentoxyfylline (patented), 5) metal ion chelators desferoxamine and penicillamine, 6) antioxidants such as vitamin C or E, 7) amino group capping agents such as aspirin, 8) enzymes that cause deglycation of Amadori products, the Amadoriases, 9) compounds that mostly break α-dicarbonyl cross-links such as phenacylthiazolium bromide and its stable derivative ALT-711 (Alagebrium), and 10) derivatives of aryl ureido and aryl carboxaminido phenoxy isobutyric acids (patented). While some of these anti-AGE compounds are being used in clinical practice (such as metformin, pioglitazone, pentoxyfylline and aspirin) or tested in clinical trials (such as aminoguanidine and ALT-711), most of them are commonly used as experimental tools to investigate the role of AGEs in different disease conditions.

Obesity is an increasing health problem not only in the industrialized western countries but, also in the developing countries like India. The adipose tissue specific obese (ob) gene and its peptide product leptin were discovered in 1994. Leptin binding to specific receptors in the hypothalamus results in altered expression of orexigenic and anorexigenic neuropeptides that regulate neuroendocrine functions and energy homeostasis. Recent patents and experimental evidence suggest that leptin plays an important role in the pathogenesis of obesity and eating disorders. Central leptin action also includes regulation of blood pressure, bone mass, and immune function. Peripherally also, leptin plays an important role in direct regulation of immune cells, pancreatic beta cells, adipocytes and muscle cells. Leptin receptors are present on human endothelial cells, and it has been shown to induce angiogenesis both in vitro and in vivo. Further, leptin appears to be a potential pressure and volume regulating factor and may function pathophysiologically as a common link to obesity and hypertension. Obesity is also a risk factor for several other cardiovascular diseases like myocardial hypertrophy, myocardial infarction, coronary atherosclerosis and increased cardiovascular morbidity and mortality. Recent progress in understanding central and peripheral leptin receptor signaling pathways may provide potential new targets to combat obesity, hypertension etc.

In excitable cells such as skeletal and cardiac myocytes excitation-contraction coupling is an important intermediate step between initiation of the action potential and induction of contraction. This process is predominantly controlled by Ca2+ release from the sarcoplasmic reticulum via the ryanodine receptor. This very large protein (MW 560 kDa) exists as a homotetramer (∼2.2 MDa) and is expressed in three isoforms: RyR1, expressed in skeletal muscle; RyR2, expressed in cardiac muscle; and RyR3, expressed in various cells at lower levels than the other isoforms. Release of Ca2+ via RyR2 is induced by Ca2+ influx through L-type Ca2+ channels and is modulated by multiple factors, including phosphorylation of RyR2 protein by protein kinase A, calmodulin kinase II and FKBP12.6, and stimulation via the β-adrenergic receptor signaling pathway. Hyperphosphorylation of RyR2 induces Ca2+ leak during diastole, which can cause fatal arrhythmias and lead to heart failure. This makes RyR2 an important therapeutic target. Although there are few commercially available drugs that inhibit Ca2+ leak from RyR2, K201 (JTV-519), a benzothiazepine derivative, has emerged as a new ryanodine receptor-selective agent that prevents atrial fibrillation, ventricular arrhythmias, heart failure and exercise-induced sudden cardiac death. In this review, we discuss recent advances in our understanding of the basic structure and function of ryanodine receptors, their involvement in heart disease, and the development of drugs to prevent ryanodine receptor malfunction and recent patents.

In recent years male sexual research has increasingly centered on molecular mechanisms operating from the central nervous system to peripheral end-organ levels involved in the penile erectile response. Major progress has been made in the field, and currently a whole host of neurotransmitters, chemical effectors, growth factors, second-messenger molecules, ions, intercellular proteins, and hormones have been characterized as components of the complex physiology of erectile function. Foremost among these mediators is nitric oxide (NO), which was initially characterized as a locally released physiologic mediator of the erectile response. Impaired formation and action of NO is closely associated with erectile dysfunction (ED), which may be caused by a variety of pathogenic factors. The impact of this knowledge has been substantial, leading to the development of several NO-based medical approaches for the treatment of ED. This review will focus on recent patents and current clinical trials involving innovative pharmacological and gene therapies in the field of male ED, particularly targeting the NO/intracellular cyclic GMP pathway, which still represents the most promising therapeutic approach to treat patients with ED.

The heart is an aerobic organ, and most of the energy required for the contraction and maintenance of ion gradients comes from oxidative phosphorylation. Oxidative stress caused by free radicals plays a crucial role in the pathophysiology associated with atherosclerosis, neoplasia and neurodegenerative diseases. Therefore, a great deal of attention has focused on the naturally occurring antioxidant phytochemicals as potential therapy for cardiovascular diseases. One of the most recognized and widely studied compounds is resveratrol, a member of a family of polyphenols called viniferins. Although resveratrol was first isolated in 1940 from the roots of white hellebore (Veratrum grandiflorum), the importance of resveratrol was recognized only after the widely publicized historic “French Paradox” associated with drinking of red wine. Both epidemiological and experimental studies have revealed that drinking wine, particularly red wine, in moderation protects cardiovascular health; however, the experimental basis for such an action is not fully understood. A growing body of evidence supports the role of resveratrol as evidence based cardiovascular medicine. Resveratrol protects the cardiovascular system by multidimensional way. The most important point about resveratrol is that at a very low concentration, it inhibits apoptotic cell death, thereby providing protection from various diseases including myocardial ischemic reperfusion injury, atherosclerosis and ventricular arrhythmias. Both in acute and in chronic models, resveratrol-mediated cardioprotection is achieved through the preconditioning effect (the state-of-the-art technique of cardioprotection), rather than direct effect as found in conventional medicine. The same resveratrol when used in higher doses, it facilitates apoptotic cell death, and behaves as a chemo-preventive alternative. Resveratrol likely fulfills the definition of a pharmacological preconditioning compound and gives hope for the therapeutic promise of alternative medicine. The purpose of this review is to provide evidence in favor of resveratrol to be used as a preventive medicine and related patents for the maintenance of healthy heart.

Hypothenar Hammer syndrome' (HHS) describes the symptoms and signs produced by thrombosis or aneurysm of the ulnar artery as a consequence of repeated blunt trauma to the hypothenar eminence [1]. We describe a case report of a man presenting with symptoms of ulnar artery thrombosis as result of blunt trauma secondary to his occupation and related patents. Radiological findings and management options are briefly discussed.

Objective: To establish a yielding criterion for porcine thoracic aorta. Methods: The thoracic aortas of three healthy pigs were used in order to form three testing groups: Group D, included aortic Dactyl tissues (n=8); Group C, included aortic Circumferential tissues (n=8); and Group L included aortic Longitudinal tissues (n=8). These groups were tested in a uniaxial tension device in order to determine the mechanical properties of the vessel. Results: Stress-Strain analysis of testing groups showed that for Low strain level (e=0.5) Stress of D group (S-D) was statistically (S, p<0.01) greater than that of C and L groups (S-D>S-C and S-D>S-L, S); for medium strain level (e=1, S-D>S-L, S); for high strain level (e=1.5, S-D>S-C, S-D>S-L, S-C>S-L,S); and for yielding strain level e=2.1 (S-D>S-C, S-D>S-L, S-C>S-L,S). Additionally, mathematical elaboration of yielding data produced a criterion defined as: S-C∧2+S-L∧2=(S-C+S-L)/3*S-D. Conclusions: Although the derived yielding criterion refers to healthy porcine thoracic aorta, however, it predicts that tensile stresses, compressive stresses or a combination of them may simultaneously be present in physiological and pathological situations (i.e. atherosclerosis). Thus, it should be taken into account that patients with seemingly, trivial atherosclerotic stenoses deserve early treatment because certain minor events (i.e. blood pressure fluctuations) may trigger a fatal stress combination that could make aortic wall yield. Since the increased Cu concentration in aortic tissue results in diminished elastic properties of the vessel, it is obvious that, the present outcome along with recent evidence-regarding the effect of high Cu level in atherosclerosis (US2003000388213)-may also contribute to a deeper understanding of plaque rupture behavior.

The human lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that has been implicated in the pathogenesis of atherosclerosis. LOX-1 activation is an important mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Association studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. In particular, previously we demonstrated that intronic SNPs associated to susceptibility to myocardial infarction, regulate the expression of a new functional splicing isoform of the OLR1 gene, called LOXIN. The ratio OLR1/LOXIN mRNA is increased in subjects carrying the risk haplotype. On this basis, we developed a genetic kit named “LOXIN test” that allows the rapid identification of ORL1 genotypes and therefore establish the susceptibility risk to atherosclerosis and myocardial infarction. The recent patents related to OLR1, SNPs and LOXIN are also discussed in this article.

Although their specific mechanisms of action are incompletely understood, beta blockers are most likely lower blood pressure and provide target organ protection by several different mechanisms, including inhibition of renin-angiotensine system by decreasing renin release by the jugstaglomerular cells of the kidney, central inhibition of sympathetic nervous system outflow and slowing of heart rate with a decrease in cardiac output. These agents are widely recommended as important parts of antihypertensive regimens and as well as preferred therapies for patients at high risks of coronary heart disease, and including those with angina pectoris, myocardial infarction or heart failure. The third generation beta blockers are distinguished from the earlier class of beta blockers by their vasodilating activity. Labetalol, carvedilol and bucindolol appear to provide a vasodilation primarily through their blockade of alpha-1 rerceptors. Nebivolol is a lipophilic beta reseptor blocker of third generation with distinct beta-1 with selective and vasodilating properties. A number of experimental and human pharmological studies suggest that the vasodilatation is triggered via increasing vascular NO bioavailabilty which is a consequence of stimulation of NO release and antioxidant properties of this compound. The pharmocological profile is characterised by the significant antihypertensive effect as well as lowering of cardiac pre and after load. Nebivolol is well tolerated and does not appear to significantly influence glucose or plasma lipid metabolism. It is devoid of intrinsic sympathomimetic activity (ISA). This article will review patents, novel composition, pharmacology, haemodynamics, antihypertensive efficiency, metabolic effect and tolerability of nebivolol.

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