Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 13, Issue 2, 2015

The prevalence of atrial fibrillation (AF) increases with age and two-thirds of patients with AF aged over 75 years. In addition, comorbidities are frequent in the elderly and worsen the prognosis. There are poorer quality of life, increased number of hospitalizations and cardiovascular events. The annual death rate was 8% in patients older than 75 years, and higher among women. There is a significant association between AF and cognitive disorders. Despite highest stroke risk, elderly have been paradoxically less likely to receive oral anticoagulation. This review summarizes available data on the epidemiology, risk factors, and scores of bleeding and systemic embolism, evolution and the approach of elderly patients with AF.

The prevalence of cardiovascular disease is one of the major causes of overall mortality. It kills almost 18-19 million individuals annually. There are a number of synthetic drug departures but the major effects are hemorrhagic impact, immunogenicity, and high price, due to restricted applications. Actinomycetes are the most economically and biotechnologically valuable prokaryotes. They are known to be responsible for the production and successful exploitation as a source of secondary metabolites, and are found to be abundant and active in marine sediments. Natural thrombolytic drugs are increasingly reported as safer, more fascinating and less costly. Actinokinase is a serine protease which cleaves α-chain, β-chains and γ-chains of fibrinogen. Hence, such mechanistic property makes actinokinase an interesting feature. These microbial fibrinolytic proteases are used for therapeutic approach of medical interest and have biotechnological applications to treat cardiovascular diseases.

Objectives: The efficacy and safety of fondaparinux, an emerging therapeutic option for heparin-induced thrombocytopenia (HIT), remain unclear in cardiac surgery patients with HIT. Methods: Using several search criteria, we reviewed all cases of fondaparinux use in patients who developed HIT after any cardiovascular intervention and were indexed in MEDLINE by August 2014. Based on pre-specified criteria, cases were divided into confirmed HIT, probable HIT and possible HIT. The outcome of fondaparinux use in each group was compared using Chi-square test. Results: Of 43 total cases, 22 had confirmed HIT and 21 had possible HIT. Valve replacement or repair (39%) and heart transplant or ventricular assist device placement (21%) were the most common preceding cardiovascular interventions. Creatinine clearance <30 ml was present in 27% and 52% of confirmed and possible HIT respectively. Overall the risk of new thrombosis and bleeding with fondaparinux were 4.6% and 7% respectively, without any differences in the two subgroups. The majority (86%) of cases improved clinically; of the remainder patients, similar percentage of cases with possible HIT and confirmed HIT died (24% vs. 5%; p= 0.102). None of the deaths were attributed to HIT or complications of bleeding. Conclusion: Within the limitations of this study, the risk of thrombosis and bleeding with fondaparinux use in cardiac surgery patients with HIT are low and largely comparable to outcomes reported in literature with other agents.

Objective: Drugs currently in use for the management of heparin-induced thrombocytopenia (HIT) have their limitations. Several new oral anticoagulants (NOACs) such as dabigatran, rivaroxaban and apixaban may offer attractive therapy options for HIT. Although the clinical data are sparse on this topic, we have summarized the available clinical data, discussed pertinent in-vitro studies and provided the rational and advantages of using NOACs in patients with suspected or confirmed HIT. We have also reviewed the safety and efficacy of these NOACs in patients with HIT based on published literature. Methods: We reviewed all suspected or confirmed HIT cases treated with NOACs and indexed in English language in MEDLINE and EMBASE by July 2015. The bibliography of each relevant article was searched for additional reports. In-vitro studies and other pertinent literature were briefly discussed. Results: A total of 36 HIT patients were treated with the following NOACs: rivaroxaban (50%), dabigatran (36%) and apixaban (14%). Sixty-one percent of patients received argatroban bolus before NOACs and 3% received rivaroxaban after a lack of response with three-day course of fondaparinux. Three percent (n=1) received rivaroxaban after the patient responded to intravenous immunoglobulin for 2 days, following a lack of response to fondaparinux and bilvalirudin. In another 3% (n=1), prophylactic dose of rivaroxaban was used for 21 days and then changed to dabigatran because of persistent thrombocytopenia. All cases responded with early signs of clinical improvement and increase in platelet counts. A follow-up after a median 47 days (range 4- 450) reported no bleeding or thrombotic complications. Conclusion: In this review, all patients with HIT treated with NOACs responded without any bleeding or thrombotic complication. Although the argatroban bolus might have contributed to a response in some patients, response to NOAC alone in other patients and in-vitro studies provide a proof of principle that NOACs can be effective in the management of HIT. Additionally, properties such as rapid onset of action, oral administration, ease of use and a lack of need for monitoring make these drugs attractive options for HIT. However, given several limitations of prior reports, further confirmation of the results are desirable.

Objective: Safety and efficacy of therapeutic agents used for heparin-induced thrombocytopenia are not established in pregnancy. Methods: MEDLINE database was searched in November 2014 to identify all patients who received therapy for HIT during pregnancy. Results: A total of 12 patients with the median age of 28 years (range 21-39) were diagnosed with HIT at the median gestational age of 20 weeks (range 5-34). Clinical probability (4T) score for HIT was high (50%) or intermediate (50%) and associated with thrombosis in 50%. Patients were initially managed with lepirudin (33%), argatroban (25%), danaparoid (25%) or fondaparinux (17%) and ultimately bridged to vitamin K antagonist or maintained on lepirudin. All patients had resolution of HIT. Complications included therapeutic abortion prior to valve replacement for valve thrombosis (8%), preterm delivery (18%) and preeclampsia (8%). Except for one instance of hypoplastic lung related to preterm delivery, none of the other newborns had any complications during delivery. Conclusion: Confirmed cases of HIT in pregnant patients appear to be rare. Within the limits of retrospective analysis, the use of argatroban, danaparoid, fondaparinux and lepirudin may be effective in preventing the thrombotic complications of HIT in pregnancy. The effect of HIT or its therapy on obstetrical complications cannot be determined based on this study since many of the obstetrical complications are common in otherwise healthy pregnancies. Although this study did not identify any fetal teratogenicity except hypoplastic lung related to preterm delivery, small number of cases treated with various therapies precludes any definite conclusion.

Edoxaban is a factor Xa inhibitor that is approved for prevention of stroke in individuals with atrial fibrillation and treatment of venous thromboembolic disease at once daily 60 mg dose for individuals with normal renal function. A decrease of dose to 30 mg is recommended for those with moderate renal insufficiency, weight ≤ 60 kg or simultaneous administration of strong P-glycoprotein inhibitors. At this time, it is not recommended for use in persons with either end stage renal disease or with GFR exceeding 95 mL/min. Shorter half-life averaging 8-10 hours may translate into a safer profile. With a fast onset of action of ~1.5 hours and relatively high bioavailability, edoxaban is an alternative for patients who may not be good candidates for warfarin therapy due to multiple limitations that vitamin K anticoagulation entails. No clear benefits of edoxaban have been reported to date compared to the other available factor Xa inhibitors.

Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of anti-diabetic medications. Canagliflozin was the first drug approved in this group in 2013 and subsequently dapagliflozin was approved in January 2014 and empagliflozin was approved in August 2014. Preclinical studies have demonstrated safety, tolerability, and efficacy in terms of glycemic control and HbA1c level in type 2 diabetes mellitus (T2DM) patients in comparison to other anti-diabetic drugs. The U.S. Food and Drug Administration (FDA) recently released a warning that some of the patients who used SGLT2 inhibitors developed diabetic ketoacidosis (DKA). Empagliflozin has showed safety in type 2 diabetics with renal impairment. Each of these medications can be used as a single treatment or in combination with other anti-diabetic medications.

Prolylcarboxypeptidase (PRCP) regulates plasma prekallikrein/high molecular weight kininogen/bradykinin axis. It also modulates angiotensin II (Ang II), angiotensin III (Ang III), and alpha-melanocyte stimulating hormone (α-MSH) physiological effects. Study suggests that increased plasma PRCP level is associated with cardiovascular risk factors, such as atherosclerosis, inflammation, and diabetes. Since expression pattern of PRCP in Zucker diabetic fatty (ZDF) rat vascular tissue remain unproved, we aimed to study its expression in the heart and kidney. The purpose of the present study was also to obtain systemic information of inflammation status with regard to PRCP expression and function in a high-fat diet (HFD)- fed ZDF rats. The ZDF rats were divided into 2 groups, which were fed a high-fat diet for 16 weeks or 32 weeks. Differential expression and pathological significance of PRCP expression during the consecutive stages of renal disease development were identified. After 16 weeks, ZDF rats exhibited early transiently altered PRCP expression in the heart and kidneys. After 32 weeks, ZDF rats showed continuously altered expression in PRCP and inflammatory markers, which was linked to severe hyperglycemia and nephropathy. Altered expression of PRCP associated with inflammatory mediators was illustrated to be functionally relevant. In further support of an important role of PRCP, we found PRCP protein to be highly elevated in rat plasma and in human plasma and the anti-diabetic agents reversed it. These findings indicate that impairment of tissues within the cardiovascular system influences PRCP expression and suggest that pathogenic mechanisms of deregulated PRCP expression warrant further investigation.

In our search for new compounds among the structural analogues of the Picotamide acting on antiplatelet aggregation activities, a new series 2 of 4-ethoxyisophthal-amides were synthesized and their in vitro anti-platelet aggregation activities were evaluated by Born’s test in comparison with their structural analogues of the series 1 of 4-methoxyisophthal-amides. The results revealed, among the series 2, six compounds 200, 2a, 2k, 2n, 2q and 2r displayed good antiplatelet aggregation activities in vitro induced by 5.0 mM ADP with IC50 values ranging over 0.35 μM - 0.77 μM. And of which, compound 2a exhibited the highest in vitro activity superior than two control drugs Picotamide and Aspirin. From a structure-affnity-’Relationship (SAR) pointed of some insight in the view of the role played by 4-ethoxy derivatives.

Background: Epidemiological studies have suggested an inverse association between circulating levels of vitamin D and cardiovascular disease risk biomarkers, including an atherogenic lipid profile. Objective: To compare the prevalence and the distribution of lipid levels among vitamin D supplemented Argentinean indigenous San Antonio de los Cobres (SAC) children with a nonsupplemented Buenos Aires (BA) mixed population group. Methods: A group of indigenous children from SAC with hypovitaminosis D supplemented with vitamin D; and a nonsupplemented group from a BA mixed population were compared via a cross sectional study. Anthropometric measures, glucose, lipids, vitamin D, and insulin were measured. Results: The mean ages were 10.3 + 2.3 in SAC and 8.7 ± 1.8 years in BA children. There was a lower prevalence of overweight 7.9%(15/192) vs 17.8% (23/129); and of obesity 1.6% (3/192) vs 30.2% (39/129) in SAC vs. BA respectively. Approximately half of the SAC children versus 30% from BA had optimal vitamin D levels (≥30ng/mL). There was a significantly higher prevalence of high triglycerides (TG) (27.6%vs 4.6%) and low HDL-C (21.3% vs 5.4%) in SAC vs BA children, respectively. In separate linear regression models, we found that despite effective vitamin D repletion, SAC children had higher TG and TG/HDL-C values, whereas HDL-C levels were lower than those of BA children adjusted for age, gender, BMI, and insulin levels. Conclusion: Indigenous Argentinean children have a higher risk for dyslipidemia in comparison with BA children, even after vitamin D treatment, suggesting that dyslipidemia could be related to diet or ethnic backgrounds.

Objective: To determine whether vitamin D supplementation improves non-traditional cardiovascular risk factors such as Apo B levels among indigenous children. Methods: A prospective two-year study evaluated a treated cohort of 190 children (104 males) aged 9.4+ 2.2 years. Children were divided into group A (n=104; 54.7%) and group B (n=86; 45.3%). Both groups received vitamin D supplementation with 100,000 u/year; group B was treated in 2013 and group A in 2014. All subjects were evaluated at the end of each treatment and anthropometric measures, lipids and vitamin D levels between the two groups were compared. Results: Changes in vitamin D levels were significantly higher in Group A, which was supplied in 2014, than in group B, which was not supplied in 2014 (6.8 vs 0.96 ng/dL; respectively). Levels of LDL-C and Apo B were improved in group A versus B: LDL-C (-5.7 vs 6.9 mg/dL respectively) and Apo B (-0.9 vs 11. mg/dL respectively). Several multiple regression linear analyses showed that changes in vitamin D were significantly associated with lower LDL-C levels (Beta- 0.41, p<0.01; R2 0.07); and with lower Apo B levels (Beta-0.37, p<0.01; R2 0.17). Conclusion: Vitamin D supplementation among indigenous children could improve Apo B levels.