Frontiers in Cardiovascular Drug Discovery

Ranolazine is approved for symptomatic stable angina patients on standard antianginal therapy. It inhibits myocardial late sodium current (INa) and partially inhibits fatty acid oxidation. INa is increased in the pathological conditions of ischemia and heart failure. Ranolazine changes myocardial fatty acid beta-oxidation to glucose oxidation, making the heart more oxygen efficient in ischemia. Thus, ranolazine improves myocardial desynchrony, mechanical dysfunction, diastolic depolarization, and action potential duration during ischemia. The book chapter focuses on salient features of ranolazine with emphasis on its indication in cardiovascular medicine, the knowledge gap in its translational research, and future scope. One of the important findings of the review is that ranolazine is a versatile cardiovascular medicine with effects on angina, heart failure, arrhythmia, and cardiomyopathy. Most animal studies of ranolazine had a correlation with human trials. Ranolazine, with its current cost and side effects profile, could be a second-line medication for angina, heart failure, and arrhythmia, specifically for patients having intolerance or side effects to first-line medications. Ranolazine as a pain modulator in angina, myotonia, and claudication needs to be further studied. Ranolazine may improve cardioversion rates in cardioversion and treatment-resistant patients with paroxysmal atrial fibrillation. Ranolazine is an option for preventing recurring shocks in patients with defibrillators who have recurrent ventricular tachycardias. Diabetes, hibernating myocardium and reperfusion injury are major modulators of ranolazine’s treatment outcomes. Subsequently, better outcomes are seen in the presence of these pathologies. Ranolazine has similar efficacy as most oral hypoglycemics, and long-term studies are needed to evaluate its outcomes in diabetics with angina.

Since Madaule and Axel first discovered Rho gene in 1985, Rho and its signal transduction pathway have been extensively studied. Rho protein family belongs to the small GTP binding protein of Ras super-family, whose molecular weight is between 20kd-30kd. As a molecular switch, Rho protein family controls many signal transduction pathways in eukaryotic cells. There are two states of Rho protein, one is the inactivation state bound to GDP (GDP Rho), the other is the activation state bound to GTP (GTP Rho). In the resting state, the GDP Rho dissociation inhibitor (rho GDI) is bound to the GDP Rho and located in the cytoplasm. GTP was substituted for GDP to activate Rho protein by guanosine exchange factor (GEFs). GTP Rho interacts with the downstream effector Rho kinase (ROCK). There are two types of ROCK: ROCK1 and ROCK2. The activation of ROCK can inhibit the activity of myosin phosphorylated light chain phosphatase (MYPT1), thus increasing the level of myosin phosphorylated light chain (MLC) in cells, leading to increased sensitivity of vascular smooth muscle cells to Ca2+ and vasoconstriction. Previous studies have shown that Rho/ROCK signaling pathway not only plays an important role in vasoconstriction, but also regulates cell movement, proliferation, adhesion, activation of cytokines and migration of inflammatory cells. At the molecular level, the expression of ROCK upregulates various factors that promote oxidative stress, inflammation, thrombosis and fibrosis, and down-regulates endothelial nitric oxide synthetase. At the cellular level, it is involved in many cell functions such as gene expression, cytokinesis, cell adhesion and migration. It has been found that Rho/Rho kinase is related to cardiovascular diseases, such as coronary atherosclerotic heart disease, hypertension, heart failure and so on. Fasudil, a potent and selective inhibitor of ROCK, can treat many cardiovascular diseases and has been used in clinical practice. This article reviews the relationship between Rho/Rho kinase and many system diseases.

The decline in deaths from cardiovascular diseases in line with scientific developments between 1950-2010 was impressive. Despite these significant advances, cardiovascular (CV) diseases remain the leading cause of death worldwide. According to the World Health Organization (WHO) data, 17.9 million people die due to CV diseases every year, which corresponds to 31% of the total deaths worldwide. Therefore, for many CV diseases, there is still a need for improved treatment, and this is only possible with the development of new drugs.

Although investments in the previous decade have resulted in the development of many innovative drugs in the treatment of CV diseases, today, pharmaceutical companies are less enthusiastic about developing CV drugs, mainly due to financial and regulatory difficulties. Indeed, today, institutes, associations and even organizations such as WHO are taking over the sponsorship role that pharmaceutical industry players have abandoned. In parallel, cardiovascular pipeline activity is shifting from large pharmaceutical companies to small and medium-sized companies and from fastfollowing drugs to first-in classes. This transformation in CV drug discovery and development reveals significant challenges that require square up to. The aim of this chapter is to discuss the global challenges faced in CV drug discovery and development to find effective solutions.

Thienopyridine-derived clopidogrel, prasugrel, cyclopentyltriazole pyrimidine-derived ticagrelor, and non-thienopyridine-derived ATP analogue cangrelor block the P2Y12 component of ADP receptors on the platelet surface. This prevents activation of the GPIIb/IIIa receptor complex, thereby reduces platelet aggregation. The platelet activation pathway caused by ADP is blocked by P2Y12, and therefore, these drugs have a crucial role in preventing ischemic complications in patients undergoing acute coronary syndrome, including unstable angina, myocardial infarction, and percutaneous coronary intervention. In addition, the use of P2Y12 inhibitors for secondary prevention has also been focused on in clinical studies. The results of recent studies show a lot of variances in terms of duration of use, dosage, and individualized treatment management.

The main concern in the clinical use of P2Y12 is dual antiplatelet therapy (with aspirin and a P2Y12 receptor blocker) following intracoronary stenting to prevent stent thrombosis. However, there are also other multifactorial variables in terms of P2Y12 inhibitor use. In this chapter, current and precise medicines regarding P2Y12 inhibitor use are evaluated, from gene testing to escalation and de-escalation strategies. Taking all these into account, providing appropriate drugs selection considering treatment time, onset time, duration of use, side effect profile, treatment limitations, and evaluating and interpreting differences in clinical use based on randomized trials will shed light on coronary heart disease treatment choice.

The cardiovascular system mainly involves blood circulation to transport oxygen, nutrients and metabolic compounds throughout the body. The blood is also used to transport different endocrine hormones (for example, insulin) from the pancreas to various cells in response to blood glucose levels. Unfortunately, any imbalance in glucose and insulin levels may help to develop diabetes mellitus (DM) and increase the risk of developing cardiovascular diseases (CVD) complications such as atherosclerosis, hypertension, and myocardial infarction. Obesity plays a crucial role in developing atherosclerotic plaques and other cardiovascular diseases. It is also responsible for the inappropriate secretion of endocrine factors, resulting in metabolic impairment of insulin target tissues and eventually failure of insulin-producing β-cells. It has been found that 65% of diabetic patients develop cardiovascular problems. Therefore, to know the underlying etiological factors, it is essential to study the molecular mechanisms behind cardiovascular complications from diabetes. Understanding the mechanisms and biomarkers of heart disease in diabetes research can bridge the knowledge gap between diabetes and cardiovascular diseases.