Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 2, Issue 1, 2007

Natriuretic peptides (BNP and pro-BNP) represent useful biomarkers in heart failure diagnosis and risk stratification, more recently their clinical use has been applied in Acute Coronary Syndrome (ACS) with and without ST elevation. Few studies demonstrated that hormones dosage could add clinical and prognostic information respect to the traditional laboratory analysis (i.e. Troponin, MB-creatinkinase, C-reactive protein). In fact, natriuretic peptides appear able to predict left ventricular enlargement and dysfunction after coronary episode and high plasma levels seem related to future cardiac events and poor prognosis at early and late time. Therefore, data from both experimental and clinical studies suggest that BNP and pro-BNP levels may reflect the size and severity of the ischemic insult, even in the absence of myocardial necrosis. On the basis of these reports, we describe below the potential clinical application and prognostic information of natriuretic peptides in patients affected to non-ST elevation coronary disease. Some recent patents discuss the role of cardiac hormones, especially focus on natriuretic peptide for the treatment of acute coronary syndrome.

Erythropoietin (EPO), a renal cytokine, regulates proliferation, differentiation and maturation of erythroid cells. Recombinant human erythropoietin (rH-EPO) is well known to correct anemia in patients with chronic renal failure undergoing dialysis. Recent studies have reported several non-hematopoietical effects of EPO. Erythropoietin receptors have been discovered in a variety of tissues, including the cardiovascular system. Recently published data including recent patent documented an enhancement of cardiac function in patients with heart failure receiving EPO treatment. Furthermore, experiments carried out in animal models of ischemia/reperfusion (IR) injury have shown a significant reduction in infarct size following EPO treatment. Other beneficial effects of EPO are related to its pro-angiogenic action on endothelial cells, which might be of potential value in patients with ischemic heart disease. Taken together, these findings suggest that EPO may be clinically useful as an adjunct in the treatment of different cardiovascular conditions, besides the simple correction of anemia. This review will focus on the pleiotropic effects of EPO in the cardiovascular system and its promising novel applications.

ω-3 and ω-6 Polyunsaturated fatty acids (PUFA) are the major families of PUFA that can be found as components of the human diet. After ingestion, both ω-3 and ω-6 PUFA are distributed to every cell in the body where they are involved in a myriad of physiological processes, including regulation of cardiovascular, immune, hormonal, metabolic, neuronal, and visual functions. At the cell level, these effects are mediated by changes in membrane phospholipids structure, interference with eicosanoid intracellular signaling, and regulation of gene expression. Two longchain ω-3 PUFAs, the docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid, are found in fatty fish and other marine sources and might be the putative dietary components thought to modify the cardiovascular risk in subjects consuming high amounts of such food. Evidence of an inverse relationship between fatty fish intake and cardiovascular risk has, in fact, emerged in studies performed more than twenty years ago in Eskimos and has been subsequently confirmed in other ethnic groups. The benefits of ω-3 PUFA might relate principally to prevention of coronary heart disease, coronary artery restenosis after angioplasty, and sudden arrhythmic death. In this brief review, we will cover the general biochemical aspects of ω-3 PUFA, summarize the evidence relating these fatty acids with control of cardiovascular risk factors and prevention of cardiovascular events, and overview the most recent and relevant patents that are related to these issues. More specifically, we will deal with the possibility to use PUFA in association with other molecules that can potentiate their antiinflammatory and antiatherogenic effects.

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction. Ang II with AT 1 receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT1 receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT1 receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT1 receptor enhances the activation of nuclear factor NF-κB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT1 receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT1 receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.

Vascular calcification is a very common event in patients affected by diabetes and chronic kidney disease (CKD). Recently, it has been well documented that abnormalities in mineral and bone metabolism in CKD patients associate with increased morbidity and mortality. Elevated serum phosphate and calcium-phosphate product levels play an important role in the pathogenesis of vascular mineralization in uremic patients and also appear to be associated with increased cardiovascular mortality. Together with classical passive precipitation of calcium-phosphate in soft tissues, during the last decade it has been demonstrated that inorganic phosphate may cause extraskeletal calcification directly through a real “ossification” of the tunica media in the vasculature of CKD patients. Therefore, control of phosphate retention is now an even more crucial target of treatment in patients affected by chronic kidney disease. The “classical” treatment of secondary hyperparathyroidism and hyperphosphatemia in CKD patients consists of either calcium or aluminium based phosphate-binders and calcitriol administration. Unfortunately, this “old generation” therapy is not free of complications.Patents are also reported discussing the role of derivatives of Lanthanum carbonate hydrates are also used for the treatment of hyperphosphataemia in patients with renal failure. New calcium- and aluminium-free phosphate binders, such as sevelamer hydrochloride and lanthanum carbonate, can be used to treat hyperphosphatemia and secondary hyperparathyroidism, reduce atherosclerotic process, and prevent vascular calcification in CKD patients.

Chronic Angina resistant to medical treatment with hemodynamically acting agents is a major problem in clinical setup. For such patients, large number of clinical trials have documented the beneficial effect of Ranolazine. It acts as an anti-anginal agent that controls myocardial ischemia through intracellular metabolic changes. Ranolazine is a partial fatty acid oxidation inhibitor which shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation. Since the oxidation of glucose requires less oxygen than the oxidation of fatty acids, ranolazine can help maintain myocardial function in times of ischemia. In addition, ranolazine has minimal effect on blood pressure and heart rate. Ranolazine, by inhibiting cellular ionic channels, prolongs the corrected QT interval. However, ranolazine has not yet been associated with any incidences of ventricular arrhythmia. Other possible mechanism by which Ranolazine could act is by reducing the formation of reactive oxygen species (ROS) and improves reperfusion mechanical function. Ranolazine has been approved by US FDA for the treatment of chronic angina pectoris in combination with amlodipine, β-blockers or nitrates in patients who do not show adequate response to other anti-anginals. Ranolazine is a metabolic modulator that is being developed by CV Therapeutics (CVT), under license from Roche (formerly Syntex), as a potential treatment for angina. Ranolazine is available as brand name ‘Ranexa’ as extended release oral tablets. This review focuses on the clinical effects, the mechanism of actions, drug interactions and beneficial effects of Ranolazine in chronic angina and other cardiometabolic disorders.

Microparticles are a heterogeneous population of small membrane-coated vesicles released by several cell lines upon activation or apoptosis. Microparticle generation seems to be a well regulated process, although these vesicles are highly variable in size, composition and function. Despite being previously considered inert debris without specific function, recent data demonstrated important pathophysiologic mechanisms orchestrated by microparticles in vascular diseases associated with endothelial dysfunction. These vesicles have been implicated, among others, in the pathogenesis of thrombosis, diabetes, inflammation, atherosclerosis and vascular cell proliferation. In addition to microparticles, circulating activated cells release smaller vesicles denominated exosomes that can also participate in vascular derangement. This mechanistic role of microparticles and exosomes in mediating vascular dysfunction indicates that they may represent novel pathways in short or long-distance paracrine transcelular signaling in vascular environment. The most recent patents regarding microparticles and exosomes are related to their procoagulant potential (U.S. Pat. No. 7005271), role in immune activation of T or B cells (Eurasian Pat. No. 0002827B1) and role in peptide vaccination (World Pat. No. 9705900A1). These commercial applications of microvesicles will be discussed in this review, as well as mechanisms involved in their origin, composition and participation in the pathogenesis of cardiovascular diseases.

Intensified treatments with multi-drug regimens are responsible for the continuously increasing survival of children with acute lymphoblastic leukaemia. However, together with the widespread use of central venous lines, they are also considered the main risk factors for the growing number of thromboembolic complications in this population. The rate of thrombosis that was observed in 17 prospective studies was 5.2%. Due to the high survival rate, it is relevant to apply strategies to the long term survivors who overcome the disease but who experience thromboembolic complications. Specific treatment includes anticoagulants, especially unfractionated heparin and low molecular weight heparins, and thrombolytic drugs in few cases. Guidelines for the treatment of thrombosis in childhood only became available recently, but they do not include specific clinical subsets such as children with acute lymphoblastic leukaemia. The problems involved in scheduling thrombosis treatment in children with malignancy have recently been discussed, however the paper does not provide practical diagnostic schemes or treatment schedules. Some important questions regarding optimal prevention and treatment are still unanswered. Moreover, antithrombotic therapy in these patients is quite challenging owing to the higher risk of bleeding. We believe it would be possible to propose reasoned appropriate recommendations for treating thrombosis in children with acute lymphoblastic leukaemia, looking forward for the effects of recent patents. This paper is an attempt to provide a practical guide to the diagnosis and treatment of thrombotic events in children with acute lymphoblastic leukaemia, and it is aimed at physicians who have no specific knowledge of the diagnosis and management of thrombosis and haemostasis alterations in children.

Technical advances in cardiovascular magnetic resonance (CMR) T2-weighted imaging have allowed in-vivo visualization and accurate quantification of myocardial edema, a substantial feature of myocardial ischemic/reperfusion injury. In acute myocardial infarction, myocardial edema imaging can be used to differentiate acute from chronic irreversible injury. This can also be of particular importance in the sub-acute phase in which laboratory markers are equivocal or in the setting of missed infarction. Furthermore, CMR-T2-weighted edema imaging identifies the area at risk and thus can be used to quantify the area of salvaged myocardium after coronary reperfusion by comparing the area of irreversible injury to that of the myocardium at risk. Another exciting area of research employs edema imaging to monitor the effect of interventions that target reduction of myocardial edema. The premise is that myocardial edema results in vascular compression, and may thus contribute to failure of myocardial tissue reperfusion even after reestablishing the patency of the infarct related coronary artery. This can be used to monitor the efficiency of novel therapeutic strategies targeting post-infarction myocardial edema. This mini review will address the pathophysiological, clinical and some technical issues related to edema imaging in acute myocardial infarction. Some recent patents on myocardial edema, Magnetic resonance imaging and myocardial infarction are also addressed.

Objective: To investigate the role of infrasound aortic pressure waves (IPW) in atherosclerotic plaque rupture. Methods: Atherosclerotic plaques have been simulated partly, in two dimensions, as being short or long Conical Intersections (CIS), that is to say elliptic, parabolic or hyperbolic surfaces. Consequently, the course and reflection of the generated aortic pressure wave (infrasound domain-less than 20Hz) has been examined around the simulated plaques. Results: The incidence of IPW on plaque surface results both in reflection and “refraction” of the wave. The IPW course within tissue, seems to be enhanced by high Cu-level presence at these areas according to recent evidence (US2003000388213). The “refracted”, derived wave travels through plaque tissue and is eventually accumulated to the foci of the respective CIS-plaque geometry. Conclusions: The foci location within or underneath atheroma declares zones where infrasound energy is mostly absorbed. This process, among other mechanisms may contribute to plaque rupture through the development of local hemorrhage and inflammation in foci areas.In future, detection of foci areas and repair (i.e. via Laser Healing Microtechnique) may attenuate atherosclerotic plaque rupture behavior.