Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 15, Issue 1, 2017

Background: Neo-angiogenesis, a key step in cancer progression, is a highly regulated process, in which Vascular Endothelial Growth Factor (VEGF) plays a fundamental role, thus representing the most suitable anti-angiogenic target. In the last year, a number of anti-VEGF drugs have been developed and approved for therapeutic use, especially in combination with standard chemotherapy. VEGF, however, is not only crucial for physiological and pathological angiogenesis, but also for the maintenance of vascular homeostasis, at a point that its pharmacological blockade may lead to endothelial dysfunction and adverse vascular effects, such as venous thromboembolism. The picture is further complicated by the understanding that the amount of VEGF production is influenced by genetic factors, with environmental ones accounting only for 20-30% of its variations. This has recently prompted the design of various pharmacogenetic studies to investigate the role of VEGF polymorphisms in determining the pharmacological response and safety profile of various anti-angiogenic drugs, suggesting that the analysis of VEGF genetic variants in cancer patients may further help personalize anti-angiogenic pharmacological strategies. Conclusion: In this review, we initially focused on the biological mechanisms involved in vascular maintenance and angiogenesis. Then, discussed the efficacy and toxicity profile of some of the antiangiogenic drugs most commonly used in the treatment of solid cancer, with a particular focus on the thromboembolic complications of anti-angiogenic treatments in cancer patients. Finally, the impact of VEGF gene polymorphisms on clinical outcome and toxicity was briefly reviewed.

Background: Pernicious Anemia (PA), the most common cause of cobalamin deficiency anemia worldwide, is an autoimmune disease of multifactorial etiologies involving complex environmental and immunological factors. Although it was first reported by Addison in 1849 with subsequent advances in understanding of pathogenesis and molecular biology, diagnosis of PA is still challenging for clinicians because of its complexity and diverse clinical presentations. Conclusion: Herein, we provide an overview of PA, mainly focusing on its scientific and practical aspects in diagnosis. We also discuss the limitations of currently available diagnostic tools for the evaluation of cobalamin deficiency and PA.

Background: Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at a high risk of severe Adverse Drug Reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreatitis and hypersensitivity. However, TPMT-deficient patients can successfully be treated with decreased thiopurine doses if enzyme status is identified by a prior testing. TPMT status identification is a pioneering experience in application of pharmacogenetic testing in clinical settings. 4 TPMT (*2, *3A, *3B, *3C) alleles are known to account for 80-95% of a decreased enzyme activity, and therefore, identifying the presence of these alleles supported by phenotypic measurement of the enzyme activity can reveal patient’s TPMT status. Evaluation of the levels of thiopurine metabolites further supports the practice of appropriate dose adjustment by providing the efficient monitoring of drug cytotoxicity. Conclusion: We hereby review the thiopurine pharmacogenetics and the methods applied in common practice to evaluate patient’s TPMT status.

Background: Polypharmacy is now a frequent aspect and reality of current medicine practice, driven by managing multiple comorbidities, especially in older adults. However and unfortunately, polypharmacy can expose patients to adverse drug reactions, and drug-drug or drug-disease interactions. On the other hand, clinicians are often hesitant to add new drugs to complex regimens even when recommended by evidence-based medicine and guidelines. In addition, there is frequently a failure to assess which medications might not be beneficial and may therefore be stopped. Method: Cardiovascular disease prevalence is increasing despite the efforts to prevent this with pandemics of obesity and diabetes as leading causes. The healthcare system is facing an increasing number of cardiovascular diseases in older patients with multiple comorbidities. New cardiovascular guidelines encourage multiple drug use to control these conditions and improve mortality and morbidity. However, use of multiple drugs can lead to inappropriate drug interactions and increased adverse outcomes. On the other hand, the so-called polypill has been proposed as a means to decrease the burden of multiple medications as well as increase cardiovascular disease prevention. Conclusion: This review discusses multiple issues of polypharmacy and its challenges, with a focus on cardiovascular diseases.

Background: Direct inhibition of coagulation factor XIa (FXIa) carries a significant promise for developing effective and safe anticoagulants. Method: In this report, we studied 4-methyl-2-oxo-2H-chromen-7-yl furan-2-carboxylate 1, a coumarin derivative, for direct FXIa inhibition. Results: This small molecule was found to inhibit FXIa with an IC50 value of 0.77 μM. Coumarin 1 also displayed a moderate-to-high selectivity for FXIa inhibition over other coagulation, digestive, and fibrinolysis serine proteases. Coumarin 1 selectively doubled APTT of human plasma at a concentration of 72 μM. Insights about the structural features that contribute to the unique potential of such small molecule were deduced by profiling similar molecules in PubChem Open Chemistry Database as well as by performing a computational docking exercise. Conclusion: Overall, chromen-7-yl furan-2-carboxylate 1 is expected to serve as an excellent fragmental lead for further anticoagulant design and development.

Background: Kenaf (Hibiscus cannabinus Linn, Pundi), Chick pea (Cicer arietinum Linn, Chana) and Prickly lettuce (Lactuca scariola Linn, Hattaraki) leaves are a few of indigenous plants which are routinely consumed by the people of north Karnataka in the diet. Studies on these plants showed some potential anti-diabetic efficacies. Objectives: To examine the effect of leaves extracts of Hibiscus cannabinus Linn, Cicer arietinum Linn and Lactuca scariola Linn on cardiovascular integrity, glucose homeostasis and oxygen sensing cell signaling mechanisms in alloxan induced diabetic rats. Method: In vitro and in vivo tests on glucose regulatory systems and molecular markers such as - NOS3, HIF- 1α and VEGF were conducted in alloxan induced diabetic rats supplemented with all the three plant extracts. Electrophysiological analysis (HRV, LF: HF ratio, baroreflex sensitivity, BRS) and histopathogy of myocardial tissues and elastic artery were evaluated in diabetic rats treated with L. scariola linn. Results: Out of these three plant extracts, Lactuca scariola Linn supplementation showed significant beneficial effects on glucose homeostasis and oxygen sensing cell signaling pathways in alloxaninduced diabetic rats. Furthermore, effects of sub chronic supplementation of Lactuca scariola Linn aqueous extracts showed significant improvement in sympatho-vagal balance in diabetic rats by increase of Heart Rate Variability (HRV) and regaining of Baroreflex Sensitivity (BRS). These results were also corroborated with myocardial and elastic artery histopathology of Lactuca scariola Linn supplemented diabetic rats. Conclusion: These findings indicate an adaptive pathway for glucose homeostasis, oxygen sensing cell signaling mechanisms and cardio protective actions in alloxan – induced diabetic rats supplemented with Lactuca scariola Linn extracts.

Objective: The study aims to determine the association between apo B levels in mothers and their pre-school offspring. Methods: Anthropometric measurement (e.g. BMI), lipids, lipoproteins, and apolipoproteins (e.g. apo B) levels in mothers and their children were obtained in November 2015 in Buenos Aires. Results: Eighty-four children (42M) aged 5.3±1.6 years and their mothers aged 33.8±7.2 years were examined. The prevalence of overweight was 39.2 % (33) in mothers and 22.6 % (19) in children, and the prevalence of obesity was 38.1% (32) in mothers and 10.7% (9) in children. Multiple linear regression analysis showed that maternal apo B levels were associated with apo B levels in their offspring, adjusted for confounding variables (Beta=0.29; p=0.03; R2=0.25). Furthermore, offspring born to mothers with high apo B levels were six times likelier to have high apo B levels (OR), 5.7; (95% CI 1.3-25.5). Conclusion: This study suggests that maternal apo B levels were significantly associated with apo B concentration in their pre-school age children.