Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 4, Issue 3, 2009

Obesity is a risk factor for complications of atherosclerotic vascular disease such as myocardial infarction. Recent studies and several patents have demonstrated that the cardiovascular risk associated with obesity is correlated particularly with visceral adiposity. Excess visceral adiposity may increase vascular risk due to secretion of cytokines and chemokines by cellular constituents of the adipose tissue. The secretory profile of various adipose depots may be regulated by the influx of macrophages that has been shown to occur with expansion of fat stores. This macrophage infiltration may lead to a chronic low grade, systemic, inflammatory state. Since circulating markers of inflammation are associated with cardiovascular events, the inflammation triggered by visceral fat may contribute to an increased risk for vascular complications. While the vasculopathic effects of central obesity may be best treated by weight loss, long term weight loss is difficult to achieve, even with currently available pharmacotherapies. Therapies that target macrophage accumulation in fat or secretory products of adipose tissue may be potentially beneficial in reducing the vascular risk associated with obesity. A potential therapeutic target is monocyte chemoattractant 1 (MCP-1), which is a potent chemokine that is elevated in obesity. Since MCP-1 promotes atherosclerosis, inhibition of MCP-1 may be effective in reducing the vascular risk associated with obesity.

Despite the progress accomplished in the field of off-pump heart surgery, the vast majority of cardiac operations are still performed with the use of extracorporeal circulation, otherwise known as “heart-lung machine.” This valuable tool, however, is connected with various complications, partly deriving from the application of intravenous heparin, necessary for the extracorporeal circuits to function. In order to deal with these complications, which among others include postoperative hemorrhage and systemic inflammatory response, several extracorporeal circulation systems, which contain a heparin-coating on their blood-contacting surfaces, have been developed with patents. The philosophy behind the creation of these systems is that with the controlled absorption and interaction of this heparin with the blood elements, adequate intraoperative anticoagulation with lower doses of systemic heparin and fewer systemic complications can be achieved. The idea of the use of heparin coatings has also been applied in other settings, such as in renal dialysis catheters, ECMO (extracorporeal membrane oxygenation), MECC (minimized extracorporeal circulation) and left ventricle assist devices.

Calcineurin (Cn), a serine/threonine phosphatase, plays a crucial role in the development of myocardial hypertrophy. Cn is a cytosolic phosphatase which dephosphorylates various target molecules, e.g. the transcriptional factor nuclear factor of activated T cells (NFAT), thereby enabling its nuclear translocation. Recently, it was demonstrated that not only NFAT, but also Cn is translocated into the nucleus. The nuclear coexistence of Cn and NFAT is important for the full transcriptional activity of the Cn-NFAT signalling cascade. Once Cn and NFAT have entered the nucleus of cardiomyocytes, the transcription of genes characteristic for myocardial hypertrophy (e.g. BNP, ANP) is initiated. The nuclear localization sequence (NLS), a region spanning amino acids 172-183 of calcineurin Aβ (CnAβ) is essential for recognition and shuttling of Cn into the nucleus by importinβ1. A synthetic import blocking peptide (IBP) that mimics the NLS of Cn was tested recently. The NLS analogon IBP saturates the Cn binding site of importinβ1 thereby preventing binding of Cn and importin. This inhibits the translocation of Cn into the nucleus. Inhibiting the Cn/importin interaction with competing synthetic peptides is one of several new approaches to prevent the development of myocardial hypertrophy. Several patents have also been filed on molecules related to inhibition of Cn-NFAT signalling.

Cardiac transplantation is a time-honored therapy for end stage heart disease for a select group of patients. The advances in recent years have increased mean survival to 12 and 13 years. The probability of survival after heart transplantation at one, five and ten years are 80%, 70% and 60% respectively. Calcineurin-inhibitors (CNIs) based regimes have been the corner stone of medical therapy in these patient populations. They have reduced the amount of rejections but with considerably increased toxicities to therapies that decreases long-term patient survival. Proliferation Signal Inhibitors or mammalian target-of-rapamycin inhibitors (PSI/mTOR) are a new class of agents that have been extensively used recently to limit these toxicities. Sirolimus and Everolimus are two such drugs. PSI/mTOR work syngeristically with CNIs or have been as primary immunosuppressant’s for patients who do not tolerate or have developed side effects to calcineurin inhibitors. This current article will discuss about sirolimus and its use in heart transplant patients along with outlining some recent patents.

Dual antiplatelet therapy has been the standard therapy in the management of patients with acute coronary syndrome. It involves the use of aspirin along with a thienopyridine, like clopidogrel. However, it has been found that these patients had recurrent ischemic attacks even when on the dual therapy and hence a congener was introduced known as prasugrel which is a third generation thienopyridine. This has recently been approved by United States Food and Drug Administration (FDA). Although structurally similar to clopidogrel, it is found to be more potent, rapidly acting and with better levels of platelet inhibition. Unlike clopidogrel, it promises less inter patient variability in its responsiveness. It is a prodrug which is converted to its active metabolite in liver and only then it can combine with its P2Y12 receptor on the platelet surface to further inhibit the adenosine-diphosphate induced platelet aggregation. But the main limitation of prasugrel has been the increased incidence of bleeding which when compared with clopidogrel was significant. This article focuses on pathophysiology of thrombosis and role of prasugrel along with recent patents in preventing atherothrombotic events including its pharmacological aspects and key clinical trials.

Recently, regenerative medicine using the transplantation of embryonic stem cells and bone marrow stem cells has been a great success but still has many unconfirmed problems including its clinical evaluation. The aim of this article is to review current literature and some patents regarding molecular therapeutic agents including using MAP kinase TNNI3K for the treatment and diagnosis of acute myocardial ischemia or infarction. TNNI3K is a novel cardiac troponin I-interacting kinase gene and its overexpression may promote cardiac myogenesis, improve cardiac performance, and attenuate ischemia-induced ventricular remodeling. The modulation of embryonal stem cells with high TNNI3K activity using a TNNI3K active peptide could be a useful therapeutic approach for ischemic cardiac diseases. For overexpressing TNNI3K or enhancing TNNI3K activity in cardiac precursor cells, the engraftment of bone marrow cells or embryonic stem cells can effectively promote cardiac myogenesis, beating frequency, and contractile functions, and decrease “silent” (no contraction) cardiac cells after cell transplantion, indicating that the overexpression of TNNI3K can increase the success rate of transplanting embryonic stem cells or bone marrow cells into ischemic hearts for the treatment of ischemic cardiac diseases. Although previous investigations showing that TNNI3K may be involved in the development of cardiac hypertrophy, it is still unclear whether TNNI3K has a role in cardiac hypertrophy or what mechanism is involved in the effects of TNNI3K. To confirm this, further investigations need to be undertaken.

A thoracic aortic aneurysm is a potentially life-threatening condition that involves a structural weakness of the aortic wall, which can lead to aneurysm, rupture, or dissection. Optimal treatment strategies for lesions of the thoracic aorta are still controversial. Open surgery is complex and is associated with significant morbidity and mortality. Endovascular stenting has emerged as an alternative to open repair in patients requiring surgery for thoracic aortic pathology. Endovascular treatment of vascular disease involving the descending thoracic aorta can be performed safely. It is an alternative option to open repair, less invasive, and carries a relatively low risk. Due to the low morbidity and mortality of endovascular repair, this option has become attractive to many surgeons lately. Stent grafting has become the first-line approach to traumatic thoracic aortic transections in some trauma centers. However, the challenges of accurate placement within an angulated arch, size of the delivery system, and uncertainty regarding long-term durability have been cited as reasons for caution. Major challenges are the technical aspects of the procedure and the learning curve to handle the delivery system and the variability in the anatomy of the aorta. The goal of this article is to review endovascular repair of the thoracic aorta in the current literature outlining some recent patents.

The field of neurovascular ultrasound is growing rapidly with new applications. While ultrasound contrast agents were initially used to overcome poor transcranial bone windows for identification of cerebral arteries, newgeneration microbubbles in combination with innovative contrast-specific ultrasound techniques now enable potential therapeutic procedures. This article will provide a review of recent and emerging developments along with patents in ultrasound technology and contrast-specific therapeutic techniques for cerebrovascular patients.

Coronary artery disease (CAD) is a leading cause of mortality and morbidity in most developed countries. Gender-related differences have been found in the presentation, prevalence, and clinical outcomes of CAD in many studies. Compared to women, men present with ST-segment elevation myocardial infarction more often and have a higher prevalence of CAD. These findings indicate that gender may have an important influence on CAD. Appropriate diagnosis, prevention, recent patent inventions, and treatment will improve the care of all patients. It is therefore necessary to consider the differences in the features of ischemic heart disease between men and women when examining patients. Novel drugs for tailor-made therapy based on gender differences should be developed for the treatment of CAD in future.

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