Recent patents on cardiovascular drug discovery最新文献

Antifibrinolytic agents are often used in different clinical situations, especially in cardiac surgery. During several years, aprotinin was the drug of choice because more than antifibrinolytic properties, aprotinin offers a direct effect on kallikrein and inflammatory pathways. In 2008, The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) initiated a discussion about real risks associated with aprotinin administration. Tranexamic acid and epsilon-aminocaproic acid appear to be interesting alternatives in our daily practice. The exact mechanism of action, the pharmacokinetic parameters, the efficacy, and the safety profile need to be clarified for lysine analogs. In this review, the different antifibrinolytics will be described with a special interest into the route of work, and recent patents. Current studies about the pharmacokinetic and the pharmacodynamic profile will be described, and finally the benefit-to-risk balance in patients undergoing cardiac surgery with cardiopulmonary bypass will be discussed.

Unlabelled: Coronary heart disease (CHD) is the leading cause of morbidity and mortality across the entire world, in which reversion of angina or improvement of ECG remains an unrealistic therapeutic option for most patients, suggesting that microvascular dysfunction or impaired oxygen delivery might be critical factors in CHD. This research article, thus presents the rationale basis, clinical and experimental, for the first therapeutic innovation addressing the role of red blood cell (RBC) H/K and O2/CO2 exchanges in CHD. It is followed by a randomized single-blind trial of Amiloride and Optimal Medical Therapy (OMT, n=35 cases) vs OMT alone (n=35 cases) in patients having angina, ST-T alteration and a defective RBC-K transport. All patients had serial clinical evaluation, Ion Transport Studies, ECGs and non-invasive aortic waveform and cardiovascular hemodynamic recordings. Statistical analysis was performed by SAS.

Results: Amiloride rapidly improved RBC-K (93.5 ±4 vs 84.5 ±4 mmol/lc, p= < 0.001), angina (80% of cases, 1.5 ±0.3 weeks, CI:1.72 to 1.45), CCS Class (1.3 ±0.5 vs 3.1 ±0.8, p < 0.001) vs patients with OMT alone CCS Class (3.2 ± 0.4 vs 3.3 ± 0.5, p =0.21). Reversion of angina was sustained through the next 6-months (87% vs 26 % in OMT, RR 2.1, odds ratio 6.31, Pearson x2 34.6,p < 0.0001 at 95% CI) and 1-year (85% vs 37% OMT). At 6-months of amiloride, ECG became normal (29% vs 0%, RR ∞ uncalculated-time, odds ratio ∞, Pearson x2 42.4 at 95% CI, p < 0.0001), improved (55% vs 29%; RR2.1, odds ratio 3.16, 95% CI, p < 0.0001) or unchanged (15% vs 67% OMT). At 1-year, seven patients on amiloride (18%) exhibited evidence of electrical regeneration of the heart, not observed with placebo.

In conclusion: This therapeutical innovation of amiloride improves RBC H/K and O2/CO2 function, and reverses angina, ST-T alterations while inducing electrical regeneration of the heart, in patients receiving optimal medical treatment for angina. The article has short discussion on the relevant patents to the topic.

We have demonstrated that entire oxytocin (OT) system is synthesized in the rat and human heart and this hormone is implicated in several cardiac functions including stem cells differentiation into cardiomyocytes. These observations led us to the invention of OT as an inducer of cardiomyogenesis (US20060205636A1). We also proposed the use of OT, its functional derivatives, and/or physiological precursors as well as nucleic acids capable of encoding OT as cell-differentiating and useful agents for treating or preventing diseases, such as heart diseases associated with loss of cardiomyocytes. The invention is relevant to the use of OT or OT-related compounds. OT is claimed as an inducer that promotes the differentiation of non-cardiomyocytes (e.g. stem/progenitor cells) in situ, which can be used to repair, restore or fortify damaged cardiac tissue or in cell culture in order to provide material for cell or tissue grafting in the heart. Recent reports documented the significant progress in the research on the role of OT in cardiovascular regulation. Most of the results are consistent with the postulated cardioprotective role of OT. In this review, new data are discussed in the context of the main points presented in the invention.

Recently, there is a growing interest in the cardiovascular beneficial effects of green tea. Epidemiological and clinical studies have suggested that consumption of green tea is inversely associated with the risk of developing cardiovascular diseases. Catechins, the major flavonoid constituents of green tea, exert cardioprotective effects through diverse mechanisms that include reversal of endothelial dysfunctions, decreasing inflammatory biomarkers, and providing antioxidant, antiplatelet and antiproliferative effects. Moreover, dietary consumption of green tea catechins has beneficial effects on blood pressure and lipid parameters. This review will focus on discussing the latest research on the cardioprotective effects of green tea catechins and their underlying molecular mechanisms. Several recent patents pertinent to green tea and cardiovascular health will also be discussed. It is noteworthy that clinical studies involving green tea are fraught with multiple complexity and confounding factors. Therefore, a rigorous assessment of the effects of green tea catechins in well-controlled human trials will be required for better understanding of the effects of green tea in cardiovascular health.

Percutaneous coronary intervention (PCI) has been increasingly used in the last years during interventional procedures in patients with acute coronary syndromes (ACS) including ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). In patients with either STEMI, NSTEMI, high risk ACS with EKG changes or cardiac enzymes rises; PCI with bare metal stent (BMS) implantation has been associated with a significant improvement in clinical outcome. Therefore, BMS implantation during primary PCI in STEMI has become a standard of practice. With the introduction of drug eluting stents (DESs) in this decade, the use of these new devices instead of BMSs in patients with STEMI has emerged as a rational PCI alternative in this particular subgroup of patients. In spite of the unquestionable benefits of DESs in terms of reduction of restenosis and TVR, specific concerns have arisen with regard to their long-term safety. High incidence of very late stent thrombosis has been described with these devices, and special attention should be paid in patients with unstable coronary lesions, in which plaque composition and remodeling may play a main role in their safety and long-term outcome. Intraluminal thrombus caused by plaque rupture is the most frequent mechanism of STEMI, in which the necrotic core and thin fibrous cap play a major role. In this context, the use of first DESs designs may be futile or even unsafe because delayed healing may further contribute to plaque instability. Adjunctive invasive imaging tools can improve stent deployment and safety outcome in these lesions with intravascular findings of plaque instability. Recently, other players such as new dedicated antithrombotic BMS designs, including selfexpanding stents or drug-eluting coated balloons, are exploring their potential indications in patients with ACS and myocardial infarction. This paper reports and discusses new stent devices and adjunctive pharmacologic agents. It also mentions and describes the recent patents of devices invented to use in these complex lesions subsets.

Multiple cell types in the vascular wall rely upon the rho-kinase (ROCK) signaling pathway for homeostatic function and response to injury. These cell types include endothelial and vascular smooth muscle cells, inflammatory cells, and fibroblasts. Rho is a guanosine triphosphate binding protein that activates its downstream target rho-kinase, in response to activation of a variety of G-protein coupled receptors. When activated, ROCK inhibits myosin phosphatase and conversely upregulates the ezrin-radixin-moesin family of kinases. In vitro activation of these signaling cascades results in modulation of multiple cellular processes, including enhanced vasoconstriction, proliferation, impaired endothelial response to vasodilators, chronic pulmonary remodeling, and upregulation of vasoactive cytokines via the NF-κB transcription pathway. ROCK activity has also been linked specifically to a number of known effectors of pulmonary arterial hypertension (PAH), including endothelin-1, serotonin, and endothelial nitric oxide synthase, among others. Recently, elevated ROCK activity has been demonstrated in various animal models of PAH with ROCK inhibitors associated with pulmonary vasodilatation and regression of PAH. ROCK inhibitors are a new class of agents which may be beneficial in the treatment of PAH. Fasudil (Daiichi Chemical and Pharmacological Company, Ibaragi, Japan), a first generation ROCK inhibitor, has been widely studied. Emerging evidence from both animal and human studies suggests that fasudil can promote vasodilation independent of the mechanism that induces vasoconstriction and will be useful in conditions in which endothelial function is impaired including PAH. Several recent patents have described fasudil as a potential therapeutic option in PAH. This article provides an overview of the role of ROCK in the pathogenesis of PAH and discusses the clinical efficacy of fasudil as a therapeutic option for treating PAH.

Unlabelled: Slow flow and no-reflow phenomenon (SF-NR) in saphenous vein grafts (SVG) stenting is related to the occurrence of distal plaque embolization, platelet activation and microvascular vasospasm. Our article discusses few of the patents related to strategies for preventing slow-flow/no-reflow phenomenon in SVG percutaneous coronary intervention (SVG PCI).

Methods: Data from 163 consecutive patients who underwent PCI of SVG lesions without visible macro-thrombus without use of distal embolic protection device over a 10-year period were reviewed. Patients in the novel strategy group received prophylactic intra-graft administration of abciximab and verapamil followed by direct stenting (n=91). The control group (n=72) comprised of patients who had undergone conventional PCI technique before the routine availability of distal embolic protection devices, with balloon pre-dilatation of the target lesion followed by stent deployment and optional use of intragraft verapamil or intravenous abciximab. Patients with visible macro-thrombus in the vein graft were excluded from the study, since these patients underwent PCI with use of the distal embolic protection (filter).

Results: SF-NR (TIMI 0-1 flow) occurred more frequently in the control group compared to the novel strategy group (18% vs. 1%, P=0.0001). One patient in the control group died after developing persistent SF-NR and acute MI post-PCI. No death was reported in the novel strategy group. In the control group, 13% patients developed cardiac enzyme elevation 3 times more than normal after the PCI as compared to 1% in the novel strategy group (P < 0.05).

Conclusions: In recent years several distal embolic protection devices have been granted patents for minimizing the chance of slow-flow/no-reflow phenomenon. In carefully selected subgroup of SVG lesions without visible macrothrombus, a strategy of prophylactic intra-graft administration of abciximab and verapamil, combined with direct stenting of the graft lesion without pre-dilatation, can be safely accomplished without any significant risk of slow-flow/no-reflow phenomenon. We propose a patent to this 3-step strategy of percutaneous coronary intervention of SVG lesions not associated with thrombus.

Aortic root aneurysm and dissection are potentially life-threatening conditions that involve a structural weakness of the aortic wall. Management of aortic root aneurysm (with or without aortic insufficiency) has recently been the subject of much scholarly discussion which resulted in some modifications. The current trend is a valve-sparing root repair or replacement as well as preserving or restoring the diameter of the aortic annulus and sinutubular junction. This manuscript reviews the etiology and diagnosis of aortic root aneurysm or dilated aortic annulus as well as a novel treatment approach. A newly patented apparatus that restores and repairs the aortic annulus and sinotubular junction is reviewed.

HMG-CoA reductase inhibitors have consistently demonstrated a relative risk reduction of death and myocardial infarction ranging between 29 and 35%. Nevertheless, in spite of significant improvement in prevention, cardiovascular disease remains the main cause of morbidity and mortality in industrialized countries. This significant residual risk observed in approximately 70% of patients under optimal anti-atherosclerotic therapies, warrants the exploration and development of alternative cardiovascular drugs. Specifically, HDL-C levels have been inversely correlated with the incidence of cardiovascular disease and an estimated 1 mg/dl higher HDL-C is associated with a 2% lower risk for men and a 3% lower risk for women. However, HDL-C-C pharmacological induced increases presented contradicting results regarding atherosclerotic development and in some cases increased cardiovascular mortality. In this review, we will focus on the structure and metabolism of HDL-C and patents related to HDL-C levels and cardiovascular disease along with the possible role of HDL-C increasing therapies in the future primary and secondary prevention of cardiovascular disease.