Frontiers in Cardiovascular Drug Discovery

Aspirin is known to have inter-individual variability in its pharmacodynamic response. Clinical investigators continue their empirical search for the optimum aspirin dose to safely prevent athero-thrombosis. Several patient populations have an accompanied accelerated platelet turnover that is associated with a time-dependent loss of aspirin efficacy. Increasing the dosing frequency has been shown to elicit better and more sustained platelet inhibition compared to a dose increase in these patient populations. This review explores the role of accelerated platelet turnover in aspirin pharmacodynamics and the benefits of multiple daily aspirin dosing.

The signaling nucleoside adenosine is produced intra- and extracellularly under physiologic and, more importantly, under pathologic conditions. Adenosine modulates cellular functions involved in injury, metabolic derangement, energy perturbations, and inflammation. The biologic effects of adenosine are mediated by four adenosine receptor (AR) subtypes of the G-protein coupled receptors (GPCRs) family: A₁AR, A_2AAR, A_2BAR and A₃AR. In the cardiovascular (CV) system, adenosine and its receptors are intricately involved in the regulation of myocardial contraction, heart rate, sympathetic control, conductivity, vascular tone, cardiac and vascular growth, inflammation, injury and apoptosis. As such, the modulation of the adenosinergic system has therapeutic potential for cardiovascular diseases (CVDs) such as metabolic disorders, atherosclerosis, hypertrophy, ischemic heart diseases, and heart failure. Nevertheless, despite the many years of investigation and experimentation only a few drugs targeting the adenosinergic system were developed and actually have reached clinical application. This chapter outlines the unique role adenosine plays in the CV system in physiology, pathology, and potentially therapeutic pharmacology. It also presents an updated review of the different adenosine receptors ligands, and their clinical potential in different CVDs.

Objective: To study platelet reactivity at different times while on dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel in patients treated with bioactive stents (TITAN₂ ^®) or everolimus-coated stents (XIENCE V^®) and one month after clopidogrel cessation.

Background: Coronary intervention damages the endothelium and causes platelet response leading to thrombotic occlusion, which is prevented with DAPT.

Methods: We studied 20 patients with bioactive stent and stable ischemia (BAS-SI group); 31 patients with bioactive stent and acute coronary syndrome (BAS-ACS group) and 31 patients with stable ischemia and everolimus-coated stent (EVE group). DAPT was administered (ASA 100 mg/day and clopidogrel 75 mg/day) for one year in BAS-ACS and EVE groups and for 1 month in BAS-SI group. Platelet aggregation induced by different agonists and platelet recruitment were analyzed at different times of DAPT and 1 month after clopidogrel cessation.

Results: After one month of DAPT, platelet aggregation showed no difference between groups; at 12 months of DAPT, the response to collagen and ADP increased in EVE group. Platelet recruitment at 1 month was higher in the BAS-ACS than the other groups; after 12 months, recruitment increased in the EVE group with respect to BASACS. Platelet aggregation and recruitment in diabetics were significantly higher in all situations than in non-diabetic patients. Clopidogrel withdrawal increased ADPinduced aggregation and collagen-induced aggregation and recruitment.

Conclusion: Platelet reactivity in patients with DAPT varies with time, depending on the subset of patients, the type of the stent implanted and the time after implantation.

Congestive heart failure affects 23 million people worldwide [1]. Cardiac transplantation provides a lifesaving treatment for patients with end-stage heart disease. It offers a longer life with a higher quality to those who have no other treatment alternative. Although cardiac transplantation offers a relief from heart immunosuppression. The goal of immunosuppression immediately following surgery is to prevent hyperacute and acute rejections. Transplantation immunosuppression must be balanced in order to prevent rejection while minimizing the serious adverse effects of therapy including life-threatening infections and malignancies. Immunosuppressive regimens are classified as induction, maintenance, or anti-rejection regimens. Induction regimens consist of intense early post-operative immunosuppression while maintenance regimens are used indefinitely for prevention of acute and chronic rejection. This chapter will review the induction and maintenance immunosuppressive regimens used in heart transplantation with summaries of selected literature as well as the most common complications of these therapies and significant drug-drug interactions.

Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increase, thus uptaking and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance between PCSK9 and LDLR regulates the intracellular concentration of cholesterol and in consequence has impact on circulating LDL-cholesterol.

This chapter reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the pcsk9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published.

Since evolocumab clinical research program has completed and published their phases I, II and III results including its cardiovascular outcomes trial, this chapter is focused in reviewing the results of evolocumab clinical research program. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAb-PCSK9, AMG-145 (evolocumab) produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I study with evolocumab versus placebo were reported; this program informed very significant reductions in LDLcholesterol in healthy subjects and patients with familial and non-familial hyper-cholesterolemia treated without/with statins; tolerability and safety of evolocumab were similar to placebo. With this evidence, the phase II and III investigations with evolocumab initiated; four years later, the OSLER trial allowed us to envisage the following scenario: MAb-PCSK9 evolocumab have a favorable effect on LDLcholesterol, other apo-B100 lipoproteins and overall mortality and myocardial infarction; all the aforementioned with a very favorable safety and tolerability profile. In the same direction, in 2016 was published the GLAGOV trial, wich demonstrates for the first time that the addition of a non-statin therapy -evolocumab- to the optimal treatment with statins is associated with atheroregression; and finally, in 2017, the FOURIER and the EBBINGHAUS trials were presented, wich confirmed that the addition of evolocumab to the optimal treatment with statins is associated with an additional and significant 20% relative risk reduction -26 months of follow-up- for cardiovascular mortality, myocardial infarction and/or ischemic stroke, all without neurocognitive risk.

Beyond the currently approved indications by regulatory agencies, considering the high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, for now and before definitive and necessary cost-effectiveness analysis and price optimization are in place, evolocumab is recommended in specific clinical scenarios reviewed in this chapter.