Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 6, Issue 3, 2011

To determine self-reported sleep quality-related differences in physical activity (PA) and health-related quality of life (HRQOL) and target values of PA for high-quality sleep in chronic heart failure (CHF) outpatients, 149 CHF outpatients (mean age 58 years) were divided into two groups by sleep-quality level determined via self-reported questionnaire: shallow sleep (SS) group (n = 77) and deep sleep (DS) group (n = 72). Steps were assessed by electronic pedometer, HRQOL was assessed with the Short Form 36 (SF-36) survey, and data were compared between groups. PA resulting in high-quality sleep was determined by receiver-operating characteristics curves. All SF-36 subscale scores except that of bodily pain were significantly decreased in the SS versus DS group. A cutoff value of 5723.6 steps/day and 156.4 Kcal/day for 1 week were determined as target values for PA. Sleep quality may affect PA and HRQOL, and attaining target values of PA may improve sleep quality and HRQOL of CHF outpatients. Patents relevant to heart failure are also discussed in this article.

More than 250,000 patients undergo cardiac surgery every year. Although advances in surgical techniques have reduced the peri-operative morbidity and mortality in these patients, atrial fibrillation persists to commonly occur following these surgeries. Traditional therapies have reduced their occurrence; however there are still a significant number of patients who develop this complication. Newer and non-conventional medications are being studied to reduce this cardiac arrhythmia. This review will elaborate on the patho-physiology, and prevention of this arrhythmia. We also aim to summarize recent investigated and patented medications which may result in more effective strategies for prophylaxis against this cardiac arrhythmia.

β-adrenergic blocking agents have been in use for nearly 40 years. β-blockers have been more thoroughly studied in the past twenty years as they have become commonly prescribed to heart failure patients. The class of β-blockers has grown considerably and has many pharmaceutical applications in patients with heart failure. Carvedilol has been the most effective beta-blocker in the treatment of the systolic heart failure. Carvedilol is a non-selective β- and α-blocker enantiomer with antioxidant effects that are attributed to its carbazole moiety. Carvedilol is taken twice daily because it is extensively metabolized and therefore loses its effectiveness due to a short half-life. Recently a long acting carvedilol has become available, as Coreg CR. Coreg CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate. The subject of the current report is to design a new structural analog of carvedilol that incorporates a protecting group such as a fluorine atom at position 8 of the carbazole ring for the purpose of blocking a critical metabolic pathway thus increasing its half life. This will follow discussion regarding current carvedilol patents. We believe that carvedilol activity will remain unchanged. The synthesis of 8-Fluoro-1, 2, 3, 9- tetrahydro-4H-carbazol-4-one, a key synthetic intermediate of the designed carvedilol analog, was carried out and successfully characterized.

Pulmonary arterial hypertension (PAH) is a rare, but serious condition which, if untreated, is associated with a poor survival. Currently, even if several trials have led to the approval of many drugs for PAH, there is no established cure for this disease. However, approved drugs for PAH have contributed to significantly improve symptoms, exercise capacity, quality of life and survival of these patients. The aim of this review is to overview the standard treatment of PAH and to give some insights about new treatments that are currently under investigation along with the discussion of recent patents.

Recent studies have significantly advanced our understanding of arteriogenesis, raising hope that therapies to increase collateral arterial formation may become important new tools in the treatment of ischemic disease. The most important initiating trigger for arteriogenesis is the marked increase in shear stress which is sensed by the endothelium and leads to characteristic changes. Intracellularly, it was shown that platelet endothelial cell adhesion molecule (PECAM-1) becomes tyrosine-phosphorylated in response to increased shear stress, suggesting a role as a possible mechanoreceptor for dynamic and continual monitoring of shear stress. The signal generated by PECAM-1 leads to the activation of the Rho pathway among others. More than 40 genes have been shown to have a shear stress responsive element. The Rho pathway is activated early and appears to be essential to the arteriogenic response as inhibiting it abolished the effect of fluid shear stress. Overexpression of a Rho pathway member, Actin-binding Rho protein (Abra), led to a 60% increase in collateral perfusion over simple femoral artery occlusion. A patent for the Abra gene has been filed recently. It may be a harbinger of a future where collateral arteries grown on demand may become an effective treatment for ischemic vascular disease.

Human embryonic stem cells, hES, and the recently created human induced pluripotent stem cells, hiPS, have a multitude of uses in cardiovascular drug discovery with a significant patent coverage for most applications. The research involving hiPS and hES cells may be subdivided into two main areas: one utilizing undifferentiated cells, and the other using hES and hiPS for in vitro differentiation of mature cell types. Both areas are of use in basic discovery, high throughput screening, and toxicology research. A number of methods have been developed to differentiate stem cells to mature cardiac cell types and to obtain pure populations of cardiomyocytes. This review will discuss three major aspects of stem cell patent landscape: 1) patents pertaining to the basic methodology of obtaining hES and hiPS cells, 2) patents pertaining to the methods of hiPS and hES differentiation to cardiovascular cell types, and 3) patents concerned with the applied uses of differentiated cardiac cells.

Platelet activation and aggregation are key events in the pathophysiological process of thrombosis, and vascular occlusions. Antiplatelet therapy has proven to be crucial for managing patients with acute coronary syndromes, coronary artery disease and in patients undergoing percutaneous coronary interventions. However, residual platelet reactivity on antiplatelet treatment confers a five-fold increased risk of major adverse cardiovascular events which indicates a need for more effective antiplatelet medications to address the substantial burden of cardiovascular disease. This article reviews the P2Y12 receptor antagonists with regards to pharmacologic and pharmacogenetic differences and their clinical implications along with the discussion of recent patents.

Chronic stable angina affects 6-7 million Americans and contributes to a significant reduction in quality of life and life expectancy. Current pharmacotherapy for reducing episodes of exertional angina includes β-blockers, calcium channel blockers and long-acting nitrates. Patients may have contraindications to the use of one or more of these agents or be unable to tolerate initial or larger therapeutic doses. As a result of the inability of current management strategies to optimally control episodes of chronic angina, new therapies have been investigated that do not have some of the limitations of current therapies. New therapies for chronic stable angina are based on a mechanism involving membrane current such as the funny current and the late Na current. Ranolazine (Ran) is an antianginal drug acting on I(Na). After its current indication in the chronic stable angina, the role of this molecule is still being studied for prophylaxis of certain arrhythmias and treatment of heart failure. Moreover, have been recently developed new interesting patents of novel pharmaceutical effects and derivates of Ran.

Oxidative stress in the cardiovascular system, including brain microvessels and/or parenchymal cells results in an accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) compounds thus promoting leukocyte adhesion and increasing endothelial permeability. The resulting chronic injury stimulus results in progressive cellular hypometabolism. We propose that hypometabolism, coupled with oxidative stressors, is responsible for most Alzheimer disease (AD) and cerebrovascular accidents (CVAs) and appears to be a central initiating factor for vascular abnormalities, mitochondrial damage and an imbalance in the activity of vasoactive substances, such as different isoforms of nitric oxide synthase (NOS), endothelin-1 (ET-1), oxidative stress markers, mtDNA and mitochondrial enzymes in the vascular wall and in brain parenchymal cells. At higher concentrations, ROS induces cell injury and death, which occurs during the aging process, where accelerated generation of ROS and a gradual decline in cellular antioxidant defense mechanisms, especially in the mitochondria. Vascular endothelial and neuronal mitochondria are especially vulnerable to oxidative stress due to their role in energy supply and use, which can cause a cascade of debilitating factors such as the production of giant and/or vulnerable young mitochondrion who's DNA has been compromised. Therefore, mitochondrial DNA abnormalities such as overproliferation and or deletion can be used as a key marker for diseases differentiation and effectiveness of the treatment. We speculate that specific antioxidants such as acetyl-L-carnitine and R-alpha lipoic acid seem to be potential treatments for AD. They target the factors that damage mitochondria and reverse its effect, thus eliminating the imbalance seen in energy production and restore the normal cellular function, making these antioxidants very powerful alternate strategies for the treatment of cardiovascular cerebrovascular as well as neurodegenerative diseases including AD. Future potential exploration using mtDNA markers can be considered more accurate hallmarks for diagnosis and monitoring treatment of human diseases. The present article discusses some of the patents regarding the oxidative stress.

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.....