Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 7, Issue 1, 2012

The eight individual papers that is our pleasure to highlight in the April, 2012 issue of “Recent Patents on Cardiovascular Drug Discovery” integrate state-of-the-art advances in basic vascular biology with the translational impact of relevant recent patents focusing on improved clinical outcomes. A major challenge for the contributing Authors of this issue was to present the critical underlying pathophysiologic features typical of a spectrum of cardiovascular diseases in a comprehensive, yet critical, forum whereby treatment innovations could be communicated to both the basic and clinical science communities. In this regard, the most recent issue of “Recent Patents on Cardiovascular Drug Discovery” has not only achieved this goal but also provides a dynamic platform for the exchange of ideas and concepts in the context of the next generation of translationallyrelevant scientific advances, many of which are garnered from the current patent portfolio. This was a difficult task but one that the Authors and Editors did well attesting to the unique value of this issue that spans the spectrum from basic to translational to clinical utility. The important contributions to this issue include: 1. The role of the adenosine receptor A3AR as a clinically-relevant cardioprotective target (Nizhat et al). 2. Novel treatment strategies for ischemic stroke focusing on new fibronolytic agents, sonothrombolysis therapy and clot retrieval as therapeutically-useful modalities (Calabro et al). 3. Vaso-protective effects of the incretin system and medications that mimic or increase gucagon-like peptide-1 activity on the treatment of diabetic vascular disease (Motta et al). 4. The impact of peroxisome proliferators-activated receptor-γ modulation as an approach to reduce cardiovascular risk and disease in the context of insulin resistance (Yew et al). 5. Asrpin as a therapy in cardiovascular disease (Ugurlucan et al). 6. A focus on the short- and long-term efficacy of anti-coagulants in the treatment and prevention of venous thrombosis in heart failure patients (Shariff et al). 7. A critical analysis of the pathophysiology of atherosclerosis-associated endothelial dysfunction and recent developments in treatment options to reverse disease progression (Briasoulis et al). 8. The role of stem/progenitor cells and advances in biocompatible materials as novel components and vehicles in the creation of cardiovascular implants with enhanced functional and self-renewal characteristics (Cheema et al). As Co-Editor-in-Chief, a position with which it is my pleasure to share with Dr. Raouf Khalil, I wish to express my particular thanks to Bentham Science for their on-going commitment to the highest quality science, to Sumaiya Azhar, our Publication Manager, and the entire Bentham Editorial Staff that have done an exceptional job in insuring the highest standards of peer review. I would like to particularly acknowledge the untiring contributions of our distinguished cadre of Editorial Board Members who do the lion's share of the reviews and are largely responsible for the exceptional quality of the current and past issues. I also wish to thank all our readers; your comments and submissions significantly contribute to the success of this series. I encourage all of you to contact me directly with your suggestions, criticisms and ideas that will help us all make “Recent Patents on Cardiovascular Drug Discovery” meet the expectations that it is meant to do.

The incidence of type 2 diabetes (T2DM) is increasing rapidly worldwide and is a strong risk factor for cardiovascular disease (CVD) events. Although hyperglycemia is associated with increased CVD, intensive glycemic control with current diabetes medications has failed in recent large clinical trials to reduce macrovascular disease, demonstrating that intensive glucose control alone is insufficient to reduce major CVD events. A new approach to lowering glucose takes advantage of the incretin system and medications that raise or mimic glucagon-like peptide-1 (GLP-1). These agents not only improve glycemic control by mechanisms that minimize hypoglycemia, but also improve lipoprotein profiles, blood pressure control and weight loss. There is also increasing evidence that at least pharmacologic concentrations of GLP-1 or GLP-1 mimetics may improve endothelial function and have direct vascular-protective effects. Importantly, these benefits transpired even before the improvements in weight and overall glucose control occurred. It remains to be seen whether the chronic effects of GLP-1 activity on glucose, CVD risk factors and vascular function will lead to lasting beneficial effects on CVD risk. If preliminary findings on the vasculoprotective effects of GLP-1 agents are validated and confirmed in longitudinal clinical trials, this class of drugs may represent a paradigm shift in the treatment of vascular disease in both patients with diabetes and in non-diabetic individuals at high risk for CVD. Recent patents regarding GLP-1 agents are discussed in this review article.

The use of stem and progenitor cells in cardiovascular therapy has been proposed as a feasible option to promote repair of tissue damage by ischemia, or to devise definitive artificial tissue replacements (valves, vessels, myocardium) to be surgically implanted in patients. Whereas in other medical branches such as dermatology and ophthalmology the use of ex vivo grown tissues is already accessible to a large degree, the use of bio-artificial implants in cardiovascular surgery is still marginal. This represents a major limitation in cardiovascular medicine at present. In fact, the limited durability and the lack of full compatibility of current implantable devices or tissues prevent a long-term resolution of symptoms and often require re-intervention thereby further increasing the economic burden of the cardiovascular disease. Stem cell technology can be of help to derive tissues with improved physiologic function and permanent durability. Specifically, the intrinsic ability of stem cells to produce tissue-specific “niches”, where immature cells are perpetuated while differentiated progenitors are continuously produced, makes them an ideal resource for bioengineering approaches. Furthermore, recent advancements in biocompatible material science, designing of complex artificial scaffolds and generation of animal or human-derived natural substrates have made it feasible to have ex vivo reproduction of complex cellenvironment interactions - a process necessary to improve stem cells biological activity. This review focuses on current understanding of cardiovascular stem cell biology as well as tissue engineering and explores their interdisciplinary approach. By reviewing the relevant recent patents which have enabled this field to advance, it concentrates on various design substrates and scaffolds that grow stem cells in order to materialize the production of cardiovascular implants with enhanced functional and self-renewal characteristics.

Endothelial dysfunction reflected by reduced nitric oxide (NO) availability is certainly the causative factor or promoting mechanism of atherosclerosis. It is necessary to detect endothelial dysfunction at an early stage using appropriate methods, and to choose a treatment for the recovery of endothelial function. There are nonpharmacological and pharmacological therapies to attain endothelial repair. The latter includes the use of renin-angiotensin system inhibitors, statins, erythropoietin, tetrahydrobiopterin, and antioxidants. The pharmacologic therapies are intended to increase NO synthase activity and NO release, inhibit NO degradation, and enhance the activity of endothelial progenitor cells. This article reviews the current knowledge of the pathophysiological events contributing to endothelial dysfunction as well as several established and novel treatment options to reverse those changes along with the discussion of recent patents.

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone improve glucose homeostasis through activation of peroxisome proliferator-activated receptor (PPAR)-γ. Their use, however, has been limited due to adverse effects that include body weight gain and edema leading to congestive heart failure. Selective PPAR-γ modulators (SPPARMs) are second generation PPAR-γ ligands designed to improve insulin sensitivity with minimal undesirable effects associated with first generation PPAR-γ agonists. INT131 is one of the first SPPARMs to reach human trials. Early phase human studies with INT131 look promising with changes in plasma lipids and glucose being equal or better than what is seen with rosiglitazone and pioglitazone treatment but without evidence of edema. This profile of improved glucose homeostasis, improved plasma lipids, and reduced inflammation in the absence of edema would be expected to reduce cardiovascular risk in patients with Type 2 diabetes mellitus. Recent patents of novel approaches for the use of PPAR-γ related compounds with the potential for this improved risk-benefit ratio are discussed.

Stroke is the third leading cause of death and the main cause of permanent disability in western countries. Reperfusion within 3 hours of symptoms-onset is the most beneficial of all therapeutic strategies for acute ischemic stroke. Alteplase has been the first thrombolytic treatment approved by FDA. However, its use is still limited to specific patient subgroups and may be complicated by severe side effects, including massive cerebral hemorrhages. This review is aimed at investigating the current and future treatment strategies in ischemic stroke, including new fibrinolytic drugs, sonothrombolysis, mechanical clot retrievals, and recent patents.

Heart failure (HF) is a common clinical syndrome characterized by high morbidity and frequent hospitalizations. HF is an independent and major risk factor for venous thromboembolism (VTE) and VTE occurring in patients with HF carries a worse prognosis. The present review will focus on short and long term role of anti-coagulants in prevention of venous thrombosis in HF patients. We will also be discussing the recently investigated and patented anti-coagulants which could have a role in this specific population.

Diabetes mellitus categorized as type I and II, is a disease of pancreatic insulin, affecting blood glucose level in the body. Recent evidence suggests that cardiac diseases such as hypertension, coronary artery disease, congestive heart failure, and diabetic cardiomyopathy are associated with diabetes and hyperglycemia. The adenosine receptors (AR) have been reported to play an important role in the regulation of these diseases. Four adenosine receptors have been cloned and characterized from several different mammalian species. The receptors are named adenosine A1, A2A, A2B, and A3. The A2A and A2B receptors preferably interact with members of the Gs family of G proteins and the A1 and A3 receptors with Gi/o proteins. The ubiquitous levels of adenosine are found in each cell in normal conditions but in disease conditions its level has been shown to increase and activate G-protein mediated signaling pathway leading to artery constriction in cardiovascular diseases and diabetes. Various studies have demonstrated that A3AR is a potent cardioprotectant during myocardial ischemeia/ischemic reperfusion. Role of A3AR receptor as a possible cardioprotectant in diabetes is under investigation and studies have verified the involvement of cyclooxygenases (COXs) and NADPH oxidase pathways. This review summarizes the possible role of A3AR in cardiovascular disease and discusses advancement in the development of therapeutic agents targeting cardioprotection with discussion on recent patents on A3 agonists that are being utilized in the clinical setting. We anticipate that detailed pharmacological studies of adenosine A3 receptors could help in understanding the link between cardiovascular disease and diabetes and this can be utilized to develop newer therapies that selectively target A3 receptor to overcome cardiac challenges.

Aspirin is one of the oldest medicines. Due to its wide range usage in different fields of medicine, we aimed to present the history, effects and different uses of aspirin in this review. Furthermore, recent patents of novel pharmaceutical interventions in the field of acetylsalicylic acid, expanding treatment options are presented. Literature search was performed in order to reach data and present information about aspirin from a historical perspective. Since its first use as a pain killer, aspirin has found a broad range of use in general medicine, cardiovascular medicine, neurology, obstetrics and gynecology, dentistry, gastroenterology, oncology with its different effects. Aspirin, a painkilling gift of history to mankind, with a history dating back to BC and various healing effects, promises to be of greater use in different fields of medicine with the light of recent studies, inspiring more research and gaining more popularity.

The patents annotated in this section have been selected from various patent databases. These recent patents are relevant to the articles published in this journal issue, categorized by therapeutic areas/targets and therapeutic agents related to cardiovascular drug discovery.