Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 4, Issue 2, 2009

It is now widely accepted that redox signaling is a key feature in vascular homeostasis. Reactive oxygen species are generated by a wide range of enzymatic systems located in both vascular endothelium and vascular wall. Further, to their role as cytotoxic molecules produced by immune system, free radicals play critical signaling roles in the vascular wall. By regulating several redox-sensitive transcription pathways, free radicals play a key role in the synthesis of inflammatory mediators in both vascular endothelium and vascular wall, with important role in the overall vascular dysfunction. The well-established role of redox state in vascular disease mandates that development of newer therapeutic strategies should be able to alter redox-sensitive intracellular signaling events. Widely used cardiovascular agents like statins or angiotensin receptor blockers have well documented beneficial effects on vascular redox state, reflected also in clinical outcome improvement. Newer promising strategies along with recent patented inventions may also include thiazolidinediones, folates, tetrahydrobiopterin, cyclopentone prostaglandins and aldose reductase inhibitors with well known effects on vascular redox, but with still unclear results on clinical outcome. Better understanding of redox-sensitive intracellular signaling pathways could indicate the critical steps to intervene with newer agents to reverse vascular dysfunction, inhibiting atherosclerosis progression and potentially improve clinical outcome.

Inflammatory cardiomyopathy (ICMP) is characterized by myocarditis associated with cardiac dysfunction. Clinical presentation may include acute heart failure and cardiogenic shock, chronic heart failure, ventricular tachyarrhythmias or may mimic an acute coronary syndrome. Inspite of the recent improvements in non-invasive diagnostic techniques, such as cardiac magnetic resonance, the diagnostic gold standard is still the endomyocardial biopsy. In the last years, classical histological Dallas criteria have been significantly improved by the introduction of immunohistochemical and molecular biology techniques. Recent findings using these new diagnostic tests resulted in increased interest in ICMP and a better understanding of its pathophysiology, the recognition in overlap of virus-mediated damage, inflammation, and autoimmune dysregulation. Moreover, there is growing evidence that the treatment of these patients with specific strategies may be effective only if based on their immunological and virological characterization. Several studies suggest that patients with autoimmune ICMP can benefit from immunosuppressive treatment and immunoadsorption, as well as high dose immunoglobulins, showing a significant improvement of left ventricular function and heart failure symptoms. On the other hand, immunosuppressive treatment can be deleterious for ICMP patients with evidence of viral persistence, while antiviral treatments have been proven effective in this subgroup. The present review summarizes the recent advances in the diagnosis and risk stratification of ICMP, and reviews patents and treatment options for these patients.

In patients with cardiovascular diseases, platelet aggregation plays an important role in development of cardiovascular events and hence its inhibition is important in prevention and treatment of these events. Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome and in those who undergo percuatneous coronary intervention. Currently dual antiplatelet therapy with aspirin and clopidogrel is the standard of care in such patients and has been associated with improved cardiovascular outcomes. However, a significant number of patients experience recurrent cardiovascular events despite being on dual antiplatelet therapy. At present there is growing evidence that these events may be associated with poor response to these antiplatelet drugs and has been commonly called as antiplatelet drug resistance. The exact mechanisms leading to antiplatelet drug resistance are not very well understood but are likely multifactorial. Although the precise definition of antiplatelet drug resistance is lacking, but there is sufficient evidence to support that persistence of enhanced platelet reactivity persists despite use of aspirin and clopidogrel and is associated with adverse cardiovascular outcomes. In this paper, we will review the mechanisms, clinical relevance, methods to evaluate, controversies surrounding the definition along with some recent patents and current and future directions for management of antiplatelet drug resistance.

MicroRNAs are key, recently discovered, regulators of gene expression. They are involved in many physiological cellular pathways so it is not surprising that an altered microRNA expression pattern can be involved in the pathogenesis of many disease states. The possibility to manipulate microRNAs to obtain a therapeutical effect is very attractive since they represent specific targets in a particular cellular pathway and because it is quite easy to synthesize short oligonucleotides with the ability to interfere with microRNA mechanism of action. The main problem for microRNA-based therapy is represented by delivery. In the last two years many studies have underlined the involvement of microRNAs in many aspects of ischemic heart disease, the leading cause of morbidity and mortality in the Western World. MiR-29 is involved in fibrotic reaction after myocardial infarction while miR-21 may exert a fundamental role in post-angioplasty restenosis. MiR-208 is involved in the shift toward a fetal gene expression pattern in contractile proteins in heart failure. MiR-1 influences susceptibility to cardiac arrhythmias after myocardial infarction. This review will focus on microRNAs involvement in multiple aspects of ischemic heart disease and on their promising novel therapeutic applications including some recent patents.

The mechanisms for decreased tolerance to ischemia in the aging hearts have not been fully explored but they appear to be multifactorial. The elderly patients most often meet classification of “no-option” patients who suffer from symptoms of chronic recurrent myocardial ischemia without good options for intervention. As such these patients are in greatest need of alternative therapies for revascularization such as angiogenesis. Not only does aging and their co-morbid conditions such as hypercholesterolemia and diabetes impair the endogenous angiogenesis response but there may be decreased responsiveness to exogenous angiogenic therapies. Enhancing the effectiveness of angiogenic therapy in this ever increasing subgroup of cardiovascular patients is as yet unmet. One such promising avenue involves sirtuins. Herein, we review the effect of aging on the processes of angiogenesis and explore the implications for successful clinical treatment of myocardial ischemia with angiogenesis therapy, with particular focus on modification of sirtuins and their targets by resveratrol along with some recent patents.

The Seventh Joint National Committee on the Prevention, Detection, Evaluation and Treatment of Hypertension (VII JNC) introduced the term “prehypertension” to designate individuals whose systolic blood pressure (BP) levels are in the range of 120 to 139 mmHg and diastolic BP between 80 and 89 mm Hg. The decision to establish this new BP category was based on a rate of progression to hypertension, its prevalence and association with other cardiovascular disease (CVD) risk factors, its relationship to the development of CVD, and its therapy. So, the prehypertension term was established to focus attention on a segment of the population who is at higher-than-normal CVD risk and in whom therapeutic approaches to prevent or delay the onset of hypertension would be of value. The VII JNC report has recommended the adoption of healthy lifestyles to achieve BP goals except in prehypertensive subjects with diabetes or chronic renal disease in whom drug treatment is also advocated. The treatment with antihypertensive drugs to prehypertension has been the subject of recent debate. The decision to use antihypertensive drug treatment should be based on global CVD risk rather than on specific levels of BP alone. This review article discusses the background, risk factors, treatment options and some recent patents related to hypertension.

New treatment options have improved the prognosis of patients with pulmonary arterial hypertension. However, drugs such as prostanoids, PDE5 inhibitors and endothelin receptor antagonists mainly act as vasodilating agents. Recently, it has become clear that pulmonary arterial hypertension is an inflammatory and vasoproliferative disease. Therefore new anti-inflammatory and antiproliferative treatments are needed. This review will focus on the pathogenesis of inflammation and vasoproliferation in pulmonary hypertension. In addition, an overview on possible new antiinflammatory and antiproliferative drugs in pulmonary hypertension (e.g. Rho-kinase inhibitors, imatinib mesylate. HMG-CoA reductase inhibitors) will be given along with recent patents.

Abdominal aortic aneurysm (AAA) is a very significant health problem in the United States. Current therapeutic options are surgery or endovascular stenting. Medical treatment is not very effective and there is no medical therapy that can effect the regression of AAA. Surgical or endovascular intervention for many older patients will be unnecessary if medications could prevent or reduce the progression rate of small AAA by 50%. Basic research has helped to determine the molecular basis of pathogenesis in AAA. Mediators of aortic damage include angiotensin II, leukotriene- LT4, prostaglandin- PGE2, interleukins, tumor necrosis factor, tissue plasminogen activator, c-Jun N-terminal Kinase, NF-κB, Rho kinases, osteoprotegerin and chymases. They work in concert to activate matrix metalloproteinase, serine proteases and cysteine proteases. The result is degradation of aortic wall proteins, extracellular matrix and apoptosis of vascular smooth muscle cells. An enhanced understanding of the pathogenetic pathways has led to significant research and development of new molecules, which can inhibit these pathways and delay the expansion of AAA. We discuss newly patented agents that may have a beneficial role in preventing the progression of AAA.

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