Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 14, Issue 2, 2016

Anticoagulation therapy is indicated for management of various clinical conditions to prevent adverse events and introduction of direct oral anticoagulants (DOACs) has ushered in a new era in anticoagulation therapy. Major advantages of DOACS include fewer drug interactions and that they do not need periodic monitoring. Several patients who were not on anticoagulation before due to older age, polypharmacy/drug interaction concerns, and logistics of periodic monitoring are now on anticoagulation with DOACs. Despite their many advantages, a challenge while prescribing DOACs is very limited availability of specific reversal agents and lack of understanding or guidance about the treatment strategy in case of major life threatening bleeding or need for urgent surgery. So far only one reversal agent has been approved by the Food and Drug Administration (FDA), idarucizumab for one of the DOACs i.e., dabigatran. Several other reversal agents are under final phases of development such as andexanet alfa and PER977 (ciraparantag) and will help in developing specific strategies for reversal of these agents. In this article, we review current strategies to manage bleeding with DOACs and provide guidance to clinicians of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection.

Vitamin D deficiency is common in metropolitan cities of India and worldwide due to faulty life style. The prevalence of vitamin D deficiency has tremendously increased in India despite the fact that it is located between 8.4° and 37.6° north latitude and majority of the Indian population exposed to ample sunlight throughout the year. From published data regarding vitamin D deficiency in India estimated prevalence of vitamin D deficiency is 70%-100% in the adult population. The main identified reason for vitamin D deficiency is the lack of appropriate sunlight exposure and no consumption (in case of vegetarian population) or less consumption of vitamin D containing diet (e.g. fish, cod liver oil, beef liver and eggs). Mild to moderate vitamin D deficiency is identified as a risk factor for type 2 diabetes, due to its protective role against development of type 2 diabetes mellitus and its complications. Vitamin D may affect glucose homeostasis through increasing insulin resistance and reducing insulin secretion from beta cells of the pancreas. Vitamin D plays an important role against oxidative stress, because of its antioxidant property. Till date very few studies determined the link between vitamin D and oxidative stress in type 2 diabetes mellitus and its complications. However, more studies are needed to evaluate an underlying mechanism of vitamin D in amelioration of the oxidative stress in type 2 diabetes mellitus.

Pressure sores are a major complication in the bed-ridden older patient. In this report, we present the case of platelet rich plasma (PRP) application for the treatment of a pressure sore in an 88-year-old female affected by transfusion-dependent chronic inflammatory disease anemia associated with the congenital and inherited condition of thalassemic trait carrier. A weekly application schedule was planned athome, given the patient’s debilitation and her decreased performance status as well as personal and family difficulties to go as outpatients at our treatment center. After 9 PRP applications, a remarkable sore improvement was achieved so that PRP was discontinued; nevertheless, sore rapidly improved until the full resolution and the complete closing after 4 months from the start of PRP treatment. Noteworthy, transfusion support was interrupted and a significant recovery and a sustained stabilization of hemoglobin (Hb) level at 1 year after ulcer healing were observed. The present case suggests that PRP application, performed athome in our case, is a feasible and effective treatment for pressure sores and related complications.

Statins are the most widely prescribed drugs to reduce serum low density lipoprotein cholesterol (LDL-C) by inhibiting 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. LDL-C reduction is associated with a decreased risk of atherosclerotic cardiovascular disease (ASCVD), including cardiovascular disease (CVD) and stroke. Statins reduce LDL-C by 30 to 40%, and the combination with other lipid-lowering agents such as ezetimibe leads to a further reduction by 20 to 25%. However, even the combination of these two agents might not be sufficient in high risk patients to require aggressive LDL-C reduction. Therefore, starting from observations on individuals with loss-of-function in proprotein convertase subtilisin/kexin type 9 (PCSK9), which was associated with lower LDL-C levels and CVD rates, monoclonal antibodies (mAbs) against PCSK9 were developed. To date, two mAbs, alirocumab and evolocumab, have received approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In the present review we give an overview about pathophysiological and clinical aspects as well as evidence for these drugs with respect to cerebrovascular events.

Cancer-associated thrombosis (CAT) accounts for about 20% of all thrombosis worldwide. It is the second leading cause of death in cancer patients. The risk of venous thromboembolism (VTE) is 4 -7 times higher and the risk of recurrent VTE three times higher in the cancer patients, compared to the non-cancer patients. The survival of cancer patients with VTE is lower than that of patients without VTE. In the last two decades, the incidence of CAT has risen in the ambulatory patients than in the inpatient setting. While the role of pharmacologic thromboprophylaxis (PTP) is established in the hospitalized cancer patients, ambulatory PTP is not, except in patients with multiple myeloma and myeloproliferative neoplasms. In the last decade, the low-molecular-weight heparin (LMWH) has emerged as the standard of care for the treatment of acute cancer-associated VTE. Many questions remain unanswered with regards to the optimal duration of LMWH therapy in the CAT, the role of direct oral anticoagulants (DOACs) in CAT, and the optimal anticoagulation management in thrombocytopenic cancer patients. Research trials are necessary to define a subset of ambulatory solid tumor patients who may benefit from PTP and to define the role of DOACs in the prevention and treatment of CAT.

Hypovitaminosis D is a worldwide clinical problem, affecting populations in numerous ways. Several factors seem to affect vitamin D metabolism, including the suggestion that therapy with the lipid lowering HMG-CoA inhibitors might modulate vitamin D levels. However, the relationship between statins intake and serum levels of vitamin D is still controversial. The present work aimed to add new insights on the association between statins therapy, and more specifically the generation of statins, and the lipid profile in a population of 106 subjects treated with these HMG-CoA inhibitors. Data showed that despite a higher prevalence of hipovitaminosis D in subjects treated with statins, there is no association between statin generation, total and LDL cholesterol and vitamin D levels. Moreover, second generation statins, the most common treatment of hypercholesterolemia in the studied population, promoted the remodelling of serum fatty acids that was characterized by the increase of arachidonic acid (AA) relative levels without affecting eicosapentaenoic acid (EPA) levels. Among statin treated subjects, vitamin D levels did not affect serum fatty acid profile. The statin-related increased ratio AA/EPA suggests a pro- inflammatory status, whose long-term impact should be better clarified in the future.

Back ground: One of the most prevailing diseases that required effective drug as therapeutic purposes is cardiac related illness includes myocardial infarction Current scenario makes enzyme to raises their sector towards therapeutic as effective active component for such diseases. Objectives: The main aim of the study was to isolate, screen, characterize and produce an extracellular thrombolytic protease from marine actinomycetes. Methods: Marine actinomycete was isolated and characterized on the basis of morphological, biochemical, and molecular characterization. The primary screening for protease activity was done by casein hydrolysis method followed by radial caseinolytic assay. The actinoprotease was partially purified using ammonium sulfate precipitation technique followed by dialysis and Sephadex G-50 gel permeation chromatography. Results: 16srDNA sequencing and BLAST search analysis of the sequence revealed close affiliation with Streptomyces genera and identified as Streptomyces violaceus VITYGM with 99% similarity. The specific activity of purified protease was found to be 1437 units/mg along with purification fold up to 1.5 times. The blood clot lysis activity was compared with the standard and found to lyse the blood clot with 97.43%. Till now very less evidences have been reported on actinoprotease. A single peak at retention time 0.9 min observed on high performance liquid chromatography (HPLC) confirmed the homogeneity of the preparation. Conclusion: This is the first study to report on actinoprotease from Streptomyces violaceus VITYGM. This study emphasizes the potency of novel actinoproteases as active compound in drugs for the treatment of cardiovascular diseases.

Background: There are data indicating that several azonine-derivatives may exert effects on some biological systems; however, there is very low information on the biological activity induced by these compounds on left ventricular pressure. Objective: The aim of this study was to synthesize and evaluate the biological activity of new triazoninederivative on left ventricular pressure. Material and Methods: The first stage involved: 1) preparation of two azepine-benzamide derivatives (Z or E) by reaction of the nitrobenzoyl azide with adrenosterone; and 2) reaction of (Z)-azepine-benzamide derivative with ethylenediamine to form the triazonine derivative. The structure of compounds was confirmed by spectroscopy and spectrometry data. The second stage involved the biologic activity on left ventricular pressure was evaluated in a model of rat heart isolated. In addition, some physicochemical parameters were evaluated to characterize the possible molecules involved in its effect. Results: The results showed that only the triazonine increased left ventricular pressure via androgen receptor. Conclusions: In conclusion, this phenomenon is conditioned by the functional groups involved in the chemical structure of triazonine derivative and their interaction with residues of amino acids involved on the androgen receptor surface.

Background: Non-traditional risk factors including low levels of magnesium and high levels of uric acid have been associated with central obesity and cardiovascular disease. Objective: To determine the association between waist circumference (WC) and non-traditional risk factors such as magnesium, phosphorus, and uric acid in indigenous children living at high altitudes. Methods: A total of 354 (166 M) indigenous school children, aged 9.6 + 2.3 years, were enrolled in a cross-sectional study in November 2011. Central obesity was defined as WC ≥ 90th percentile according to age and sex. Low magnesium and phosphorus levels were defined as serum magnesium <1.8 mg/dL and phosphorus <2.4 mg/dL. Hyperuricemia was defined as serum uric acid > 7 mg/dL. Results: The prevalence of central obesity was 6.8% (24/354). None of the children had hyperuricemia or low phosphorus levels. Hypoagnesemia was identified in 21.7% (57/263). There was a significant association between WC (z-score) and magnesium (r-015), uric acid (r0.28), phosphorus (r-0.30), HOMAIR (r0.49), triglycerides (r0.24), and HDL-C (r0.24). However, calcium, sodium, and potassium were not significantly associated with WC. As z-WC quartiles increased magnesium and phosphorus levels significantly decreased, whereas uric acid levels increased. Multiple linear regression analysis showed that z-WC was associated significantly and directly with uric acid (B0.31), triglycerides (B0.004), and HOMA-IR (B0.35); and inversely with magnesium (B-0.83) and phosphorus (B-0.25), adjusted for confounding variables (R2 0.34). Conclusion: Our results indicate that central obesity was associated significantly and inversely with magnesium and phosphorus and directly with uric acid in indigenous school children. Supplementation with magnesium and/or phosphorus could prevent future cardiovascular disease. Prospective and randomized studies should be performed to confirm these findings.