Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 5, Issue 2, 2010

The role of percutaneous coronary intervention (PCI) in the treatment of coronary artery disease has grown at an astronomical pace. Drug eluting stents (DES) offer advantages over bare metal stents (BMS) such as reduction in early in-stent restenosis rates. However, they have disadvantages like increased late stent thrombosis when compared with BMS. Furthermore, recent data suggest endothelial dysfunction in the DES stented segments of the arteries. Currently, bioabsorbable stents are under development to avert the complications of DES such as stent thrombosis via degradation of the stent over time. The hypothetical advantage of leaving behind a natural vessel and restoring vasoreactivity may be the most normal physiology which can be achieved after an intervention with a stent. The ABSORB and the PROGRESS AMS are two of the recent clinical trials that have looked at the outcomes of using bioabsorbable stents. So far, data from these and other studies has yielded mixed results in terms of angiographic and clinical outcomes. Newer stents such as REVA and WHISPER are presently being tested in preclinical and clinical trials. The landscape for bioabsorbable stents is constantly evolving through continued improvisation of existing technology and emergence of new technology. Large scale randomized trials are needed with adequate long term follow-up for safety and benefits to have mainstream application in coronary artery disease, bioabsorbable stents are a promising innovation in the field of PCI. We review some of the patents and the data that is emerging on bioabsorbable stents in addition to currently ongoing clinical trials.

The circulating anion nitrite (NO2¯) has long been considered an inert oxidative metabolite of nitric oxide (NO). Over the last decade several studies have identified inorganic nitrite as a key player in many biological processes because it acts both as a principal storage source of NO and as a signalling molecule distinct from its link with NO. This new field of research involves the exploration of the molecular, biochemical, and physiological activities of nitrite under a variety of physiological and pathophysiological states. As a signalling molecule, nitrite is involved in various biological responses, including hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion and regulation of protein and gene expression. As a stored form of NO, since the cardiovascular system is under an important NO-mediated autocrine-paracrine control, intensive investigations involve nitrite effects on vessel and heart regulation. Recently, some authors have reported that nitrite, through both direct and indirect pathways, plays a fundamental role in vascular homeostasis and cardiac function not only in mammals but also in non-mammalian species (fish, amphibians). This review highlights some patents and the importance of the signalling properties of nitrite anion in a comparative vertebrate context for providing significant insights on “ancestral” functions of the nitrite-NO system, which may facilitate its potential use as a therapeutic agent of cardiovascular disease.

Resveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. Considering the central role of mitochondria in cell signaling, growth and death, in the present paper we have tried to summarize the present data including patents and discuss the beneficial effects of resveratrol on cardiovascular diseases from the mitochondria perspective.

Contrast echocardiography is a safe, accurate, and reproducible method to assess left ventricular volumes and function. Based on current guidelines, ultrasound contrast is indicated for left ventricular opacification at rest in patients with suboptimal echocardiographic images, and in stress echocardiography when ≥ 2 adjacent segments are poorly visualised. Adding contrast for assessment of regional myocardial perfusion expands the use of echocardiography in ischemic heart disease from detection of left ventricular dysfunction at rest or during stress to assessment of myocardial ischemia, extent of myocardial necrosis and re-flow after coronary revascularisation. Myocardial perfusion also adds prognostic information to that given by structural and functional assessment alone and may reduce the need for more time-consuming, expensive cardiac imaging procedures associated with radiation as well as coronary angiography with the risk of vascular complications. This article gives an overview of ultrasound contrast agents and their impact on echocardiographic assessment of ischemic heart disease also discussing recent patents.

Interruption of the Renin-Angiotensin-Aldosterone System (RAAS) with Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin-Receptor Blockers (ARBs), alone or in combination, has become a leading therapeutic strategy to slow down the progression of chronic kidney disease. Nevertheless, a considerable proportion of patients progress despite this therapy. New alternative arms are available today to treat hypertension in uncontrolled patients that might have a role in renoprotection. The role of aliskiren, the recently available renin inhibitor may be assumed, based on the pathophysiology of RAAS related renal damage and from data derived on experimental and clinical studies in-patient with type 2 diabetes related nephropathy. The review focuses on the potential consequences of (pro)renin blockade in glomerular hypertension and renal scarring along with some patented treatment methods. The benefit of this additional therapy is still only hypothetical. Ad hoc clinical trials have been conducted to confirm the expected results. Finding that prolonged inhibition of renin vasoconstrictor effect, suppression of plasma renin activity and a more effective RAAS blockade, in patients with chronic RAAS inhibition may help to achieve a sustained reduction of proteinuria, would suggest that renin inhibitors may represent a new weapon to fight progressive nephropathies.

Heparin, low molecular weight heparin (LMWH) and warfarin are well-established anticoagulants still in widespread use despite their well known drawbacks. Heparin requires continuous monitoring, has serious side-effects such as haemorrhage, thrombosis and osteoporosis, and lacks an oral route of administration. LMWH is a safer, more convenient anticoagulant to use but it cannot be given orally, does not have an antidote and may be difficult to administer in patients with renal failure. Warfarin has a narrow therapeutic window, interacts with other drugs and foods and requires monitoring like heparin. The limitations of all three of these established anticoagulants have prompted the search for better more convenient agents. The major examples of these newer anticoagulants are the direct and indirect factor Xa inhibitors and the direct thrombin inhibitors. These new agents tend to have more predictable pharmacokinetic properties, superior efficacy and safety and some can be administered orally. In this review, we summarise the advantages and disadvantages of three established anticoagulants (heparin, LMWH and warfarin) and the most promising new anticoagulants (fondaparinux, idraparinux, rivaroxaban, apixaban, dabigatran and ximelagatran) by discussing their pharmacodynamics and pharmacokinetics. We also discuss recent patents in the field of anticoagulation, which aim to improve the safety and effectiveness of antithrombotic agents currently in use or offer alternative ways for anticoagulation.

Cardiovascular diseases account for more deaths worldwide than any other illness. Myocardial ischemia, a common finding in cardiovascular diseases, lowers cellular energy levels, which affects a cell's integrity and function. Pre-clinical animal studies have reported lower cellular energy levels with an associated decreased function following myocardial ischemia. Recently, scientists have reported that the failing heart is energy starved and yet no pharmaceuticals have been able to address this issue with satisfactory results. Over decades, researchers have explored the use of various metabolites to replenish deficient cellular energy levels following induced ischemia with mixed results. However, D-ribose, a natural occurring carbohydrate, has demonstrated significant enhancing abilities in replenishing deficient cellular energy levels following myocardial ischemia, as well as improving depressed function in numerous animal investigations. Subsequent clinical trials have further substantiated these benefits of D-ribose in patients afflicted with ischemic cardiovascular disease and those carrying the diagnosis of congestive heart failure. The future of effective therapies for ischemic heart disease and congestive heart failure must strongly consider novel pharmaceuticals directed at replenishing cellular energy levels. Intellectual property and the represented patents in this paper emphasize the use of D-ribose for its cellular energy enhancing potential, reflected in both objective and subjective clinical improvements; therefore, substantiating its value in patients with ischemic cardiovascular diseases.

Lipid profiles were evaluated for 281 dyslipidemia patients treated with HMG-CoA reductase inhibitors (statins) for 2 years. The efficacy and safety of ezetimibe 10mg/day one-year add-on therapy were also retrospectively evaluated. The results show that in 281 dyslipidemia patients with a mean low-density lipoprotein-cholesterol (LDL-C) level of 120mg/dl or greater, ezetimibe 10mg/day administration reduced LDL-C levels to 90mg/dl or below. Patients who had been treated with one of six statins (pravastatin, simvastatin, fluvastatin, pitavastatin, atorvastatin, and rosuvastatin) for one year were given ezetimibe add-on therapy for one year, which reduced their LDL-C levels by 18% (pravastatin), 25% (simvastatin), 27% (fluvastatin), 30% (pitavastatin), 29% (atorvastatin), and 31% (rosuvastatin). Also, during the one-year add-on therapy, no severe adverse event was detected. An analysis of associations among lipids during a two-year lipid-lowering pharmacotherapy revealed correlations in a single patient. The correlation was between LDL-C and small, dense LDL as well as mid-band lipoprotein cholesterol. In conclusion, ezetimibe 10mg/day add-on therapy may be safe and effective for treating dislipidemia patients who have been treated with a statin. Moreover, this article discusses the disappearance thresholds for small, dense LDL and intermediate-density lipoprotein (IDL) by using the quantitative analysis of densitometric pattern based on genetic algorithm, which indicated that the major eight subspecies of lipoproteins (VLDL1, VLDL2, IDL1, IDL2, LDL1, LDL2, LDL3, HDL). The threshold for small, dense LDL indicates the IDL1 plus IDL2 plus LDL1 when LDL2 and LDL3 were not detectable, while the threshold for IDL indicates the LDL1 when IDL1, IDL2, LDL2 and LDL3 were not detectable.

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.