Recent advances in cardiovascular drug discovery最新文献

Atrial fibrillation (AF) is the commonest cardiac arrhythmia currently affecting 1-2% of the general population, with stroke being one of its most fearsome complications. Dose-adjusted warfarin is an established treatment for reduction of thromboembolic risk but mandates dietary restrictions and need for routine blood monitoring. Novel oral anticoagulants (Dabigatran - patent: US20110082299A1, manufactured by Boehringer Ingelheim; Rivaroxaban - patent: US20150175590A1, manufactured by Bayer; Apixaban - patent: US20140335178A1, manufactured jointly by Pfizer and Bristol-Myers Squibb; Edoxaban - patent: WO2013026553A1, manufactured by Daiichi Sankyo) have recently been introduced that might provide at least equal reduction in thromboembolic risk to patients; negating the need for dietary restrictions and routine blood tests. The most recent National Institute of Health and Care Excellence, UK guidelines from August 2014 suggest consideration of one of the novel oral anticoagulants if the time in therapeutic range is less than 65%. In this study, the evidence for four novel oral anticoagulants is reviewed and the anticoagulation success with warfarin with atrial fibrillation and mechanical heart valves assessed in a large UK District General Hospital. Fifty-eight patients were identified with mechanical heart valve and 2737 patients with atrial fibrillation. Patients with atrial fibrillation had a significantly better TTR when compared with the patients included in the NOAC trials. Our results were similar with the Auricula registry. However, 25% of patients had TTR<65% and they would need to be considered for NOACs. Our data suggest that the degree of benefit seen in the NOAC trials might not be expected in our cohort of patients with atrial fibrillation. Interestingly, our patients with atrial fibrillation had a much better mean TTR of 76.4% and required less INR tests (12/year) compared to patients with mechanical heart valve who had a mean TTR of 61.4% and required more INR tests (26/year).

Accumulation of fibrin in blood vessels significantly increases thrombosis, leading to myocardial infraction and other cardiovascular diseases. Microbial enzymes are one option for curing this pathological condition. Fibrinolytic enzymes such as urokinase (UK), tissue type plasminogen activator (t-PA) and streptokinase (SK) attracted much attention for thrombolytic therapy. Among them SK is preferable in low-resource settings because it is cost-effective. Therefore, the purpose of this review is to summarize recent patents related to the occurrence, mechanism of action, physico-chemical properties, cloning and expression, production, structure, immunogenicity, chemical modification, in vivo application and clinical trials of SK. This patent review considers the properties and characteristics of SK that make it a preferred agent for thrombolytic therapy.

Poor prognosis is strongly associated with Acute Coronary Syndrome (ACS) and, even though a number of treatment strategies are available, the incidence of subsequent serious complications after an acute event is still high. Statins are hypolipidemic factors and recent studies have demonstrated that they have a protective role during the process of atherogenesis and that they reduce mortality caused by cardiovascular diseases. This review tries to reveal the function of the statins as a component of the primary and secondary action of acute coronary syndrome and to describe the lifestyle changes that have the same effect as the use of statins.

The large research series has become known to the international scientific community 1986 after a publication in The Lancet (2:595). In short, cultures of smooth muscle cells from the human aortic intima or blood-derived monocytes/macrophages were used for measurements of ability of drugs and plant substances to induce or prevent cholesterol deposition in the cells, cultured with the sera from atherosclerosis patients, which was interpreted as pro- or anti-atherogenic effects. However, as discussed previously, the relationship between the uptake of lipids by cultured cells and atherogenesis in vivo must be inverse rather than direct. The up-regulation of lipoprotein receptors is one of the action mechanisms of some cholesterol-lowering drugs. Accordingly, if a drug lowers the uptake of lipids by cultured smooth muscle cells or macrophages, it should be expected to elevate the blood cholesterol level in vivo. Nevertheless, following their concept of blood atherogenicity, the same researchers started to apply apheresis (extracorporeal perfusion of patients' blood for 2 hours through a column with immobilized LDL) aimed at a removal of non-lipid atherogenicity factors. In conclusion, validity of the cell culture method of serum atherogenicity measurement, and testing of pro- or antiatherogenic effects of drugs and dietary supplements is questionable. It would be useful to reproduce some of the cell culture experiments discussed in this letter in an independent laboratory. Verification is necessary prior to preclinical studies in animals and then humans of reportedly anti-atherogenic substances, detected by the cell culture method.

Acute coronary syndrome (ACS) constitutes a group of pathophysiological entities resulting from reduced blood flow in the coronary arteries leading to decreased or improper functioning or death of heart muscle. Such patients are usually prescribed combination antiplatelet drug therapy, containing acetylsalicylic acid (aspirin) and an adenosine diphosphate receptor inhibitor to prevent recurrence of ischemic events. The combination prophylactic therapy to certain extend has been successful in preventing secondary complications including ischemic/thrombotic events in these patients. However, research is still on for newer advances in anti-thrombotic therapy that can further prevent secondary complications of Acute Coronary Syndrome. Vorapaxar is a newer drug recommended along with aspirin or clopidogril for prevention of recurrence of cardiac events. Vorapaxar, a thrombin receptor antagonist acts by reversible inhibition of the protease-activated receptor-1 (PAR-1). PAR-1 is expressed on platelets, and it inhibits platelet aggregation, both thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced. Various trials world -wide have documented its efficacy as an anti-platelet agent for preventing recurrent cardiovascular ischemic events but at the expense of increased bleeding complications including intracranial haemorrhage (ICH), when compared to standard therapy alone. For the same reason, vorapaxar is contraindicated in patients with prior stroke, transient ischemic attack and ICH. U.S. Food and Drug Administration (FDA) approved vorapaxar in May 2014 as an antiplatelet agent along with standard anti-platelet therapy for the reduction of recurring thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Vorapaxar is developed and marketed by Merck Sharp Dohme and is available by the brand name 'Zontivity' as 2.5 mg oral tablet equivalent to 2.08 mg of vorapaxar sulfate. There are two patents protecting this drug.

Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acid of the ω-3 family of polyunsaturated fatty acids (PUFA) are abundant in fatty fish and other marine sources. Their consistent consumption has been related to an improved cardiovascular risk especially in high risk patients and populations. In this review, we presented major findings about potential mechanisms of action and clinical evidence regarding ω-3 PUFA effect on the control and prevention of cardiovascular disease. This review is an update of our previous review (Colussi et al. Recent Pat Cardiovasc Drug Discov 2007;2:13-31) in which we additionally summarize and comment new literature of the past few years. Despite clinical studies have been significantly increased in the last years, the evidence in support of a beneficial role of ω-3 PUFA in cardiovascular prevention is still relatively weak. The growing improvement of medical interventions for cardiovascular prevention might explain why these molecules appear to have limited impact on the cardiovascular risk.