Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 4, Issue 1, 2009

The zebrafish is a well established model of vertebrate development, but has recently emerged as a powerful tool for cardiovascular research and in vivo cardiovascular drug discovery. The zebrafish embryo's low cost, small size and permeability to small molecules coupled with the ability to generate thousands of embryos per week, and improved automation of assays of cardiovascular development and performance allow drug screening for a number of cardiovascular effects. Such studies have already led to discovery of novel cardiovascular drugs with potentially clinically beneficial effects. In this review we summarise the advantages and disadvantages of the zebrafish for drug discovery using some patents, previous literature on zebrafish-based drug screening and assess where the zebrafish will fit into existing drug discovery programmes.

Systemic vascular disease is the greatest cause of mortality in the western world. Treatment options have been preventative with medical therapy or curative with surgical bypass. Recently, there has been an increase in the use and popularity of minimally invasive endovascular techniques, particularly angioplasty and stent insertions. The short-term results of these techniques have been demonstrated to be superior in a number of studies when compared with conventional surgery, which itself carries high mortality and morbidity. The long-term outcomes of endovascular treatments have not been as impressive, due to vascular restenosis caused mainly by intimal hyperplasia. There have been a large number of studies and therapeutic trials to discover a solution to restenosis, but to date success has not been reached. Cilostazol is a phosphodiesterase inhibitor licensed for treating patients suffering from intermittent claudication. Recent clinical trials have shown the effects of cilostazol in also preventing coronary artery restenosis post-endovascular treatments. These results have recently been repeated for peripheral vascular stents. This review discusses the pharmacology of cilostazol, peripheral vascular disease, mechanisms of intimal hyperplasia causing vascular restenosis. We also discuss the use of cilostazol and other current patents of novel targets and therapeutics, for preventing restenosis of both coronary and peripheral arterial disease following endovascular therapies.

An elevated plasma level of homocysteine (HCY) is associated with increased risk of thrombotic and atherosclerotic vascular disease. Several studies and recent patents have demonstrated that hyper-homocysteinemia (HHCY) is an indipendent risk factor for vascular disease. An elevated homocysteine level has been also reported to be a risk factor for the development of congestive heart failure (CHF) in individuals free of myocardial infarction. Animal studies showed that experimental HHCY induces systolic and diastolic dysfunction, as well as an increased BNP expression. Moreover, hyperhomocysteinemic animals exhibit an adverse cardiac remodeling characterized by accumulation of interstitial and perivascular collagen. The mechanisms leading from an elevated HCY level to reduced pump function and adverse cardiac remodeling are a matter of speculation. Existing data indicate that direct effects of HCY on the myocardium, as well as nitric oxide independent vascular effects, are involved. Preliminary data from small intervention trials have initiated the speculation that HCY lowering therapy by micronutrients may improve clinical as well as laboratory markers of CHF. In conclusion, HHCY might be a potential etiological factor in CHF. Future studies need to explore the exact pathomechanisms of HHCY in CHF. Moreover, larger intervention trials are needed to clarify whether modification of plasma HCY by B-vitamin supplementation improves the clinical outcome in CHF patients.

Acute heart failure is a common clinical problem faced in cardiac surgery operating rooms and intensive care units. Levosimendan, an inotropic and vasodilating agent used widely in cases of acute heart failure for “cardiological” patients, has not gained global acceptance in its application for heart-operated ones. Herein, we are presenting a series of studies and patents concerning this medication, which, in general, support the use of levosimendan during and after heart surgery, despite the relatively high cost of administration. However, trials with larger samples of patients have to be performed in order to definitively establish this medication as a routinely administered drug for acute congestive heart failure after heart surgery.

Atherothrombosis and the resulting coronary heart disease and stroke, are the most common causes of death in developed countries. The molecular basis of the pathophysiology of atherothrombosis remains largely unknown. As a consequence, although cardiovascular medicine has been able to reduce the incidence of this disorder, it still fails to avoid the development of acute vascular events, such as stroke and acute coronary syndromes (ACS). In the last years, there has been an explosion in the search for novel biomarkers that may help the clinician to predict the probability of recurrence of atherothrombosis. The classical way to address the study of this disorder and the development of new biomarkers was to focus in one, two or a few candidate molecules. However, the arrival of new proteomic techniques into the field of cardiovascular research will allow analyzing the expression of multiple proteins at once. Using proteomic techniques, it is possible to study the proteome of cells involved in atherosclerosis with different approaches. We have analyzed the proteome of the supernatant of cultured atherosclerotic plaques and from circulating monocytes in subjects with an acute coronary syndrome. Other authors have also studied the proteome of cultured cells involved in this disorder. The results of these approaches are lists of proteins differently expressed in atherothrombosis. The involvement of these molecules in this disorder should be addressed in functional studies in vitro and in experimental models. Those proteins related to the pathophysiology of atherothrombosis also displaying stable plasma levels should be good candidates to be patented as potential biomarkers and tested in large populations.

This study aimed to explore the potential of polyacrylamide-gel disc electrophoresis (PAGE) for lipoprotein profiling in clinical practice. Blood samples were collected from 146 patients with type 2 diabetes mellitus and lipid parameters were assayed by PAGE, including small, dense low-density lipoprotein (LDL) (n = 41), and triglyceride-rich lipoprotein remnant cholesterol (n = 37). We also used a commercial kit to measure small, dense LDL (n = 41). By PAGE, we obtained the percentage of the area under the curve (AUC %) of each peaks and calculated respective AUC% x total cholesterol (AUC%xTC) values. The calculated values of LDL-AUC%xTC, small LDL-AUC%xTC, and HDLAUC% xTC values were correlated well with values from homogeneous assay for LDL-cholesterol, small, dense LDLcholesterol, and HDL-cholesterol assays (r = 0.94, 0.81, and 0.89, respectively). PAGE combined with measurement of total cholesterol and triglycerides provides a rapid evaluation of anti- or pro-atherogenic lipoproteins and a simple profiling system for both the “quantity” and “quality” of lipoproteins, allowing a better assessment of the risk of coronary artery diseases. This article discusses several methods for simple and rapid lipid profiling and outlines some recent patents relevant to the methods.

Vitamin B deficiency causes many diseases, which may be improved by vitamin B supplementation. Homocysteine, a sulphur aminoacid, is frequently increased in patients with vitamin B deficiency, chronic renal failure and metabolism disorders. Bone and cardiovascular disease is often detected in patients with renal disease or homocystinuria. This review shows the most important discoveries, including recent patents, about vitamin B therapy not only in hyperhomocysteinemic patients but also in the general population. Vitamin B supplementation may be useful to reduce bone and cardiovascular events, but until now prospective intervention studies have given uncertain results. We need well-done randomized controlled trials to verify the effects of vitamin B treatment on these hard end-points.

The purpose of this study was to present results of special examination and prospective observation of patients with coronary artery disease (CAD) and angina pectoris (AP) in practical cardiology. Except standard cardiological methods, we used high-resolution rhythmocardiography and apparatus-program complex for registration and analysis of the heart rate variability. There was an evaluation of the autonomic and humoral-metabolic regulative influences on pacemaker activity of the heart sinus node in 273 patients selected by criteria of including-excluding patients with CAD and AP. It was determined by high-resolution HRV-analysis that ischemic heart disease is accompanied by the sinus node autonomic and humoral disregulation. Angina pectoris was correlated to HRV-stabilization on the rhythmocardiogram during ischemic episodes. Duration and frequency of these HRV-stabilization episodes permit to describe different peculiarities of the angina pectoris in every case, to predict the complication, for example, acute coronary syndrome, to define risk of lethal outcome, to study autonomic efficacy of the same drug (nitroglycerin). Prospective observations of patients with CAD permitted to create ischemic cascade in HRV-symptoms. The following conclusion can be made. Highresolution HRV analysis is an informative and perspective method in the diagnosis and management of CAD and AP. Recent patents have also disclosed methods and apparatus to reduce heart rate variability and assessment of cardiovascular risks.

The role of antiplatelet therapy in the management of coronary artery disease and its sequalae is of great significance. Acetil Salycilic Acid (ASA) has continued to dominate the field as a potent antiplatelet agent, due to its ease of use and cost effectiveness. In addition to this, clopidogrel has also been widely used with better long term administration results in patients with atherosclerotic disease. However, interpatient variability and resistance to clopidogrel has opened the doors for further investigative research to find another agent which potentially meets the pharmacokinetic demands whilst having a satisfactory safety profile. Prasugrel and other novel nonthienopyridine derivatives are currently under investigation, with previous trials showing very reassuring outcomes. Patented inventions along with large trials have shown that prasugrel significantly reduces ischemic end points, ultimately resulting in a decrease in Myocardial infarctions, thromboocculusive episodes and death. Further studies are required to support these findings before we are aware of all clinical effects of Prasugrel.

Ivabradine (a compound of the benzocyclobutane) is a highly selective If current inhibitor acting directly on the sino-atrial node, induces a rapid, sustained and dose-dependent reduction of heart rate at rest and during exercise without a significant effect on atrio-ventricular conduction, left ventricular contraction/relaxation or vascular tissues. These properties associated with an improvement in left ventricular loading related to bradycardia resulted in an increase in stroke volume and preservation in cardiac output even during exercise. Various experimental and clinical studies showed the efficacy of ivabradine in patients with chronic stable angina, on heart rate reduction, on ventricular remodelling after acute myocardial infarction and on coronary blood flow. The safety of ivabradine has been documented in several studies and clinical trials, in contrast to beta-blockers, no significant side effects were expressed in the literature. The aim of our review is to describe ivabradine and its cardiovascular effects and outline some recent patents and the results of the most important trials.

Neurocardiogenic syncope is one of the most common types of syncope, characterized by arterial vasodilatation with or without bradycardia. The regulation of blood pressure and heart rate is the result of a complex reaction between the central and peripheral nervous system with the circulatory system. Multiple therapies, pharmaceutical and interventional, have been applied without any proven effect. The initial positive reports on pacing were not demonstrated in enough number of controlled studies. Neurocardiogenic syncope continues to remain a clinical problem in terms of understanding its underlying mechanisms and therapy needs to be enlightened by future studies. This article provides a background of diagnosis and therapy of neurocardiogenic syncope and reviews some related patents.

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