Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 11, Issue 4, 2013

Cardiovascular diseases are an important public health problem because they represent a major cause of death worldwide. The pathophysiology of these chronic diseases is defined, among others, by an excess of reactive oxygen species production, a defect of endothelium-dependent vasodilation, a high blood pressure or a modification of platelet function. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruits and vegetables are, in part, mediated by their flavonoid content, with particular benefits provided by members of this family such as epigallocatechin gallate, quercetin or delphinidin. Many studies show that these phytochemicals are promising natural compounds to prevent cardiovascular diseases associated with endothelial dysfunction. Mechanistically, shortterm effects on endothelium-dependent vasodilation following the consumption of these flavonoids have been linked to an increased nitric oxide bioactivity. Moreover, besides their well-described antioxidant properties, these flavonoids are able to prevent endothelial cell apoptosis and to modulate various signaling pathways leading to inflammation. Therefore, this review attempts to outline our understanding about the pleiotropic beneficial effects of epigallocathecin gallate, quercetin or delphinidin on cardiovascular diseases associated with endothelial dysfunction. Furthermore, this review aims to identify the potential protective vascular effects of these flavonoids and their therapeutic value in cardiovascular medicine.

Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial myelosuppression and infection. Treatment of CLL is now moving towards targeted therapy. The success of new class of agents such as monoclonal antibodies, proteasome inhibitors and immunomodulatory derivatives has sparked further search for treatment agents with novel targets to inhibit. The B cell receptor activating pathway involving the Bruton’s tyrosine kinase (BTK) is crucial in B cell production and maintenance and is an attractive therapeutic target. Ibrutinib is an oral covalent inhibitor of the BTK pathway that induces apoptosis of B cells. Early phase studies with Ibrutinib either as a single agent or in combination regimens have shown promising results with an excellent safety profile in patients with high-risk, refractory or relapsed CLL and elderly treatment-naïve patients. This review summarizes the current knowledge of Ibrutinib in the treatment of CLL.

Obesity, classified by the American Medical Association in 2013 as a disease, is an epidemic that is drawing serious global attention. It is the most common preventable disease and the most common modifiable risk factor for several chronic diseases. It is an independent cause of increased morbidity and mortality. Obesity is spreading across most countries, socio-economic strata, age groups, gender groups, and races, albeit to variable degrees. It is concerning that both adults and children are increasingly afflicted by obesity. Both incidence and prevalence of the disease are on the rise. The direct and indirect costs attributable to obesity have reached billions of US dollars. Obesity management involves a multi-disciplinary approach that includes the patient and his or her family, the primary care provider, a dietician or nutrition specialist and physical trainer. It may also require specialist care in the use of pharmacological and surgical interventions. Currently available anti-obesity drugs are indicated for those who are obese (BMI of 30 kg/m2) or overweight (BMI of 27 kg/m2) with at least one weight-related comorbid condition. This article focuses on the FDA-approved antiobesity drugs, their mechanisms of action, chemical structures, efficacy, safety profiles and known side effects.

PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) protein plays an important role in LDL cholesterol (LDL-C) metabolism, due to its role in the degradation of the LDL receptor. Preliminary clinical data of PCSK9 inhibition are quite promising and indicate that PCSK9 inhibition may be a novel strategy for the treatment of dyslipidemia particularly for those with refractory hypercholesterolemia, statin intolerance, or an elevated lipoprotein (a) level and associated cardiovascular diseases. Furthermore, development of PCSK9 inhibitor is an excellent example of “bench to bedside” concept where discovery of a genetic mutation was translated into a novel therapy to address unmet clinical needs. Although several approaches have been attempted to inhibit PCSK9 activity including small molecules, gene silencing and inhibitory antibodies, the most promising approach appears to be the use of monoclonal antibodies with a 50 -70% LDL cholesterol reduction on top of maximal doses of statins. In this article, we review the pharmacology of PCSK9 and summarize findings from key clinical studies using PCSK9 inhibitors.

Over the last decade advanced therapies for the management of pulmonary arterial hypertension have been introduced. These agents have also been effective in reducing pulmonary vascular resistance in patients with Eisenmenger syndrome. Specific guidelines focusing on modern therapies for Eisenmenger syndrome however do not exist to date. More recently, clinical trials in patients with Eisenmenger syndrome demonstrated a significant clinical improvement with favorable safety and tolerability profile. This review aims to summarize newly reported pharmacological agents used in patients with Eisenmenger syndrome.