Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 6, Issue 2, 2011

THE ROLE OF REDOX STATE IN VASCULAR FUNCTION During the last few years, the progress in molecular cardiology allowed the in-depth study of the mechanisms involved in atherogenesis [1]. Importantly, this is now considered to be an inflammatory disease that is highly regulated by complex biological networks inside the human vascular wall [1]. In these mechanisms, oxidative stress plays a central role [2]. Reactive oxygen species (ROS) such as superoxide anions (O2 -.), hydroxyl radicals (OH-), peroxynitrite (ONOO-), are molecules with important role in host defence mechanisms of the human immune system [3] and key signalling molecules involved in the physiology of the human vascular wall [4, 5]. SOURCES OF ROS IN THE VASCULAR WALL Vascular bioavailability is there if ROS is dependent on the balance between its biosynthetic rate by various enzymatic sources in the vascular wall (such as NADPH-oxidase, Nitric oxide synthases (NOSs), xanthine oxidase (XO), mitochondrial oxidases and others) and their “deactivation” by the endogenous antioxidant defence systems (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/ peroxiredoxin, catalase and paraoxonase) [6]. When this balance is disturbed (e.g. in the presence of atherosclerosis risk factors such as hypertension, dyslipidaemia, smoking, obesity, etc), then these ROS trigger a number of pathophysiological processes that eventually lead to atherogenesis [6]. ROS induces the oxidation of LDL at the subendothelial space, resulting in the formation of oxidised LDL (ox-LDL). This is a highly proatherogenic molecule that induces the release of multiple chemotactic signalling mediators promoting migration of more monocytes to the sub-endothelial space. Eventually, ox-LDL is up-taken up by the resident macrophages leading to the formation of foam cells, that will form the lipid core of atheromatous plaque [7]. Importantly, ROS and ox-LDL activate a number of proinflammatory redox-sensitive transcriptional pathways (such as nuclear factor kappa B (NF-kappaB) and activating protein -1 (AP-1)), inducing the expression of various pro-atherogenic, pro-inflammatory genes and promoting atherogenesis [7]. A summary of these mechanisms is provided in the Fig. (1).

Recently, adipose tissue has been implicated in the regulation of vascular function in humans. This regulatory function is mediated via the release of vasoactive cytokines called adipokines. Adiponectin is an adipokine with powerful anti-inflammatory and antioxidant properties being dysregulated in obesity and in insulin resistance states. In both in vitro and in vivo models adiponectin has been shown to increase nitric oxide bioavailability, improve endothelial function, and exert beneficial effects on vascular smooth muscle cell function. Strategies to upregulate adiponectin expression or to potentiate adiponectin signalling may favourably modulate vascular redox state and therefore reduce cardiovascular risk. Various drug classes such as glitazones, newer sulfonylureas, angiotensin receptor blockers, ACE inhibitors and nicotinic acid exert beneficial effects on insulin resistance partly by increasing plasma adiponectin levels. Others such as tetrahydrobiopterin or certain antioxidants are also promising in normalizing plasma adiponectin levels. Given the central role of adiponectin in vascular disease states and obesity-related metabolic disorders, improving adiponectin vascular or systemic bioavailability via existing drugs or novel therapeutic strategies may be valuable in the prevention of cardiovascular disease in humans. The discussion of recent patents for the adiponectin as a regulator of vascular redox state is also included in this review article.

Oxidative stress, resulting from a deregulated equilibrium between superoxide and nitric oxide (NO) production, contributes to the progression of different vascular diseases such as atherosclerosis, hypertension, ischemia/reperfusion injury and restenosis. Despite disappointing results of various oral antioxidant treatment trials, promising findings have been reported using gene delivery of enzymes to improve NO bioavailability and decrease oxidative stress in animal models for vascular diseases. NO production can be increased by overexpression of endothelial NO synthase (eNOS) in the vascular wall. However, the complex regulation of NOS needs to be carefully considered in the context of gene therapy along with the availability of its cofactor tetrahydrobiopterin and eNOS uncoupling. Furthermore, preclinical studies demonstrated that gene delivery of antioxidative vascular wall-specific enzymes, such as heme oxygenase-1, superoxide dismutase, catalase and glutathione peroxidase, has the potential to attenuate oxidative stress and inhibit atherosclerosis. Another option is to transfect vascular disease patients with secreted antioxidants such as high density lipoprotein-associated enzymes or soluble scavenger receptors. The advantage of the latter is that gene delivery of these enzymes and receptors does not need to be endothelium specific. Nonetheless, techniques to deliver genes specifically to the vascular wall are under development and hold interesting perspectives for the treatment of vascular diseases in the future. The patents relevant to gene delivery are also discussed in this review article.

Cardiovascular risk factors, such as hypertension, hypercholesterolemia, diabetes mellitus, or chronic smoking, stimulate the production of reactive oxygen species (ROS) in the vascular wall. Oxidative stress and endothelial dysfunction in the coronary and peripheral circulation have important prognostic implications for subsequent cardiovascular events. The pathophysiologic causes of oxidative stress are likely to involve changes in a number of different enzyme systems. Reactive oxygen species (ROS) are produced by various oxidase enzymes, including nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, uncoupled endothelial NO synthase (eNOS), cyclooxygenase, glucose oxidase, and lipooxygenase, and mitochondrial electron transport. Decreased NO production due to changes in the expression and activity of eNOS and increased degradation of NO, by reaction with superoxide account for the reduction in endothelium- dependent vascular relaxation. Recently, a variety of antioxidants have been extensively studied in clinical trials for the prevention and treatment of atherosclerosis. In small clinical studies both vitamins C and E may improve endothelial function in high-risk patients. However, larger interventional trials have been controversial, suggesting potential harm in certain high-risk populations. Antihypertensive and hypolipidemic medications exhibit well-documented antioxidant effects and improve endothelial function. However, the discussion of recent patents with the novel antioxidant strategies are required to clarify the role of antioxidant intervention in vascular diseases.

It is well established that RAS plays a key role in the development of hypertension, cardiovascular and renal disease. On the other hand oxidative stress is a key feature in vascular homeostasis. Many of the cellular effects of Ang II appear to be mediated by ROS generated by NAD(P)H oxidase. In this review, we provide an overview of ROS physiology in human vessels especially in relation with RAS. We also discuss how therapeutic interventions on RAS affect redox signaling in the vascular wall at a clinical level with the discussion of recent patents.

Minocycline is a semi-synthetic tetracycline that inhibits bacterial protein synthesis and hence is used for the treatment of many infectious diseases. Over the years, many other interesting properties of minocycline have been identified and been used to make patents which include anti-inflammatory, anti-apoptotic, matrix metalloproteinase inhibitor and free oxygen radical scavenger activity. Ischemia-reperfusion injury is a concern for almost every clinical specialty and minocycline seems to be an attractive cytoprotective agent that can ameliorate the damage due to these properties. Ischemia-reperfusion injury is a complex process and involves various pathways that lead to cell death. This review focuses on the body of evidence describing various proposed mechanisms of action of minocycline and its current experimental use in various animal models of ischemia-reperfusion injury.

To examine differences in objective and subjective outcomes in outpatients undergoing percutaneous coronary intervention (PCI) performed for acute myocardial infarction versus cardiac surgery (CS) following a phase II cardiac rehabilitation (CR). Longitudinal observational study of 437 consecutive cardiac outpatients after 8 weeks of phase II CR. Patients were divided into the PCI group (n = 281) and CS group (n = 156). Handgrip and knee extensor muscle strength, peak oxygen uptake (VO2), upper- and lower-body self-efficacy for physical activity (SEPA), and physical component summary (PCS) and mental component summary (MCS) scores as assessed by Short Form-36 were measured at 1 and 3 months after PCI or CS. All outcomes increased significantly between months 1 and 3 in both groups. However, increases were greater in the CS versus PCI group in handgrip strength (+12.3 % vs. +8.1%, P > 0.01), knee extensor muscle strength (+19.3% vs. +17.5%, P = 0.008), peak VO2 (+20.9% vs. +16.9%, P > 0.01), upper-body SEPA (+27.7% vs. +9.2%, P = 0.001), and PCS score (+6.5% vs. +4.1%, P = 0.001). Although this relatively short-term phase II CR increased all outcomes for both groups, outcomes showed the recovery process was different between the PCI and CS groups, slightly favoring CS patients. Furthermore, patents in the field of CR are presented.

Vitamin D has an important role in bone mineralization and maintenance of calcium homeostasis. Thus, vitamin D deficiency is better characterized in the situations that involve the musculoskeletal system and bone metabolism. Recently, there is an interest in the association of vitamin D deficiency with the presence of metabolic syndrome, diabetes mellitus, cardiovascular disease and arterial hypertension. The mechanism underlying the inverse relationship between vitamin D levels and blood pressure is not completely understood, but it seems to involve several systems. Clinical and experimental studies suggest that vitamin D may influence blood pressure by regulating reninangiotensin system, improving endothelial function, blunting cardiomyocyte hypertrophy, improving insulin sensitivity, reducing the concentrations of serum free fatty acids and regulating the expression of the natriuretic peptide receptor. In accordance with recent clinical studies and meta-analyses, the association between blood 25-hydroxyvitamin D concentrations and hypertension is controversy. There is no doubt about the role of vitamin D in skeletal health. However, the vitamin D supplementation to prevent or treat hypertension has been the subject of recent debate. Thus, the decision to use supplementation with vitamin D would be important in patients with vitamin D deficiency. This review article discusses the association between vitamin D and hypertension, vitamin D supplementation and some recent patents related to vitamin D and hypertension.

Heparin which is desulfated at the 2-O and 3-O positions (ODSH) has reduced anti-coagulant properties, and reduced interaction with heparin antibodies. Because of the reduced anti-coagulant effect, ODSH can be safely administered to animals and humans intravenously at doses up to 20 mg/kg, resulting in a serum concentration of up to 250 μg/ml. Administration of ODSH causes a 35% reduction in infarct size in dogs and pigs subjected to coronary artery occlusion and reperfusion when given 5 min before reperfusion. ODSH has anti-inflamatory effects, manifest as a decrease in neutrophil infiltration into ischemic tissue at high doses, but this effect does not entirely account for the reduction in infarct size. ODSH decreases Na+ and Ca2+ loading in isolated cardiac myocytes subjected to simulated ischemia. This effect appears due to an ODSH-induced reduction in an enhanced Na+ influx via the Na channel in the membrane of cardiac myocyes caused by oxygen radicals generated during ischemia and reperfusion. Reduction in Na+ influx decreases Ca2+ loading by reducing Ca2+ influx via Na/Ca exchange, thus reducing Ca2+ - dependent reperfusion injury. ODSH does not appear to interact with antibodies to the heparin/platelet factor 4 complex, and does not cause heparin-induced thrombocytopenia. Because of these therapeutic and safety considerations, ODSH would appear to be a promising heparin derivative for prevention of reperfusion injury in humans undergoing thrombolytic or catheter-based reperfusion for acute myocardial infarction. The review article discussed the use of heparin and the discussion of some of the important patents, including: US6489311; US7478358; PCTUS2008070836 and PCTUS2009037836.

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