Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 3, Issue 1, 2008

The research, development and use of natural products as therapeutic agents, especially those derived from plants, have been increasing in recent years. There has been great deal of focus on the naturally occurring antispasmodic phytochemicals as potential therapy for cardiovascular diseases. Naturally occurring diterpenes exert several biological activities such as anti-inflammatory action, antimicrobial and antispasmodic activities. Several diterpenes have been shown to have pronounced cardiovascular effects, for example, grayanotoxin I produces positive inotropic responses, forskolin is a well-known activator of adenylate cyclase, eleganolone and 14-deoxyandrographolide exhibit vasorelaxant properties and marrubenol inhibits smooth muscle contraction by blocking L-type calcium channels. In the last few years, we have investigated the biological activity of kaurane and pimarane-type diterpenes, which are the main secondary metabolites isolated from the roots of Viguiera robusta and V. arenaria, respectively. These diterpenoids exhibit vasorelaxant action and inhibit the vascular contractility mainly by blocking extracellular Ca2+ influx. Moreover, kaurane and pimarane-type diterpenes decreased mean arterial blood pressure in normotensive rats. Diterpenes likely fulfil the definition of a pharmacological preconditioning class of compounds and give hope for the therapeutic use in cardiovascular diseases. This article will review patents, structure-activity relationship, pharmacology, antihypertensive efficiency, and the vascular mechanisms underlying the effects of diterpenes. Careful examination of the cardiovascular effects exhibited by kaurane and pimarane-type diterpenes will be provided.

Ischemia and reperfusion (I/R) injury develops when blood flow is interrupted for a long period of time and then restarted. In the liver, this type of damage occurs in clinical settings such as liver transplantation and hepatic resection. Given the shortage of donor organs it is essential to maximize the use of sub-optimal organs, those previously rejected due to elevated risk of malfunction, and to increase split-liver transplantation interventions. Therefore, the development of strategies that preserve organ viability and promote liver regeneration is urgently needed. As observed for other organs, a brief period of ischemia followed by short reperfusion before the surgical procedure significantly increases liver resistance towards prolonged periods of ischemia. This phenomenon is known as ischemic preconditioning, and is the only protective strategy that has reached clinical practice. Recently, intensive research has improved our understanding of the mechanisms involved in I/R liver injury, and the biologic bases of ischemic preconditioning. This knowledge has generated relevant patented advances in the field, including the targeted inhibition of pro-apoptotic pathways, the interference with neutrophil activation, and the identification of cytoprotective cytokines. Here, we briefly review the mechanisms of hepatic ischemic damage, and present the most promising pharmacologic approaches against I/R injury. This article also includes recent patents on this topic.

Interest in the role of thyroid hormones (TH) in heart failure is steadily increasing due to evidence for a physiological, homeostatic role of TH and the effects of altered TH metabolism on the cardiovascular system, particularly in presence of heart failure. Experimental studies have shown that altered TH metabolism modifies cardiovascular homeostasis by inducing alterations of cardiac histology, cardiomyocyte morphology and gene expression and consequently, of diastolic and systolic myocardial function. Clinical studies have shown that mild forms of thyroid dysfunction, both primary (subclinical hypothyroidism and subclinical hyperthyroidism) and secondary (low T3 syndrome) have negative prognostic impact in patients with heart failure. In these patients, the administration of synthetic triiodothyronine (T3) was well tolerated and induced significant improvement in cardiac function without increased heart rate and metabolic demand. Large multicenter, placebo-controlled prospective studies are necessary to evaluate the safety and prognostic effects of chronic treatment with TH replacement therapy in patients with heart failure. The article also discusses recent patents in this field.

Cardiovascular anesthesiologists have traditionally resorted to using intravenous therapy in the operating room to manipulate hemodynamics and the determinants of cardiac output and systemic vascular resistance during cardiac surgery. General anesthesia involves the administration of both intravenous and inhaled drug therapy to achieve the desired goals, i.e. analgesia, amnesia, muscle relaxation and blockade of autonomic activity. Anesthesiologists are the experts in the use and titration of drugs that are administered through the inhaled route. However, this method of drug delivery presents many challenges, notably timing, dosage accuracy, rapid titratability and consistency of drug delivery. Arguably the most rapid method of treating acute reactive pulmonary vasculature would be by drugs that directly act upon the pulmonary endothelium. In the operating room, pulmonary hypertension and right ventricular failure are high predictors of morbidity and mortality and present significant challenges to the anesthesiologist. In this article, we will focus on advances in inhaled therapy of these conditions, including concerned recent patents. This review will focus on some of the advances in the pharmacology of inhaled drugs that are being used to treat pulmonary hypertension, right and left ventricular failure in the perioperative setting.

Heart failure is a major healthcare problem and leading cause of death in Western countries. Growing evidence has shown recent improvements in pharmacological therapy, such as receptor-regulating agents, in treating heart failure; however, the morbidity and mortality of heart failure is still high. More recent studies have suggested the presence of additional molecular targets for treating heart failure. Several key molecules in the beta adrenergic receptor signaling pathway play an important role in the progression of heart failure, and transgenic mice studies supported beneficial effects of controlling such molecules in heart failure. In addition, molecules in the renin-angiotensin system or calcium signaling pathway may also be potential targets for treating heart failure. In this review, we focused on putative mechanisms underlying the beneficial effects of regulating these molecules on the progression of heart failure including relevant patents on this topic.

Urokinase (UK) [EC 3.4.99.26] is a serine protease that activates plasminogen to plasmin, which in turn degrades fibrin clots. Hence, UK finds its value as an important anti-thromboembolic drug. Plasmin has diverse physiological roles apart from its fibrinolytic role in the regulation of blood clotting. It has been implicated in complement activation, cell migration, wound healing, and generation of localized extracellular proteolysis during tissue remodelling, pro-hormone conversion, carcinogenesis and neoplasia. Among the plasminogen activators, UK provides a superior alternative for the simple reasons of its being more potent as compared to tissue-plasminogen activator and non-antigenic by virtue of its human origin unlike streptokinase. Based on these observations, UK is a very popular cardiovascular agent. Hence, UK, as one of the most potent plasminogen activators is attracting a great deal of attention. We will summarize recent patents related to the occurrence, mechanism of action, structure and function, physico-chemical properties, in vitro production, cloning and expression, purification and applications of UK.

Chronic heart failure has emerged as a leading cause of morbidity and mortality worldwide. Conceptually, replacement of akinetic scar tissue by viable myocardium and improvement of neovascularization should improve cardiac function and impede progressive left ventricular remodelling. Experimental and clinical studies suggest that transfer or mobilization of stem and progenitor cells can have a favourable impact on tissue perfusion and contractile cardiac performance. The aim of the present review was to screen various available patent data bases to give an overview on different patent applications of cell-based and non-cell based therapies in regenerative cardiovascular medicine. The first part describes cell based methods and use of growth factors to improve cardiovascular function. Secondly, patents on methods to improve angiogenesis, re-endothelialization and vascular function are presented. Finally, we describe patents describing methods for improved differentiation of stem cells to cardiovascular cells, including the generation of cardiomyocytes from embryonic or adult stem cells. A systematic overview on the current patent situation about use of stem cells in cardiovascular medicine should facilitate future decision making in the development of novel therapeutic strategies in regenerative medicine.

Full text available