Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 16, Issue 1, 2018

Heart Failure (HF) is one of the main healthcare burdens in the United States and in the world. Many drugs are approved and used in practice for management of this condition; including beta blockers, diuretics, aldosterone antagonists, Angiotensin Converting Enzyme Inhibitors (ACEI's), and Angiotensin Receptor Blockers (ARBs). Recently, the Food and Drug Administration (FDA) approved a drug with brand name Entresto (Sacubitril/Valsartan or LCZ696), an angiotensin receptor neprilysin inhibitor for the use in Heart Failure with Reduced Ejection Fraction (HFrEF) patients instead of ACEI's and ARBs. The drug works through angiotensin receptor blockage via valsartan as well as neprilysin inhibition with sacubitril. This represented a new milestone in managing heart failure patients and provided yet another therapy in our armamentarium. This article reviews the stages that led to the development of this drug, the failure of its preceding agents, the lessons we have learnt, and the current trials of Entresto for new indications.

Cardiovascular disease is one of the most important risk factors for mortality and morbidity in patients with Chronic Kidney Disease (CKD). This systematic review focuses on the protective effects of diuretics against the development of cardiovascular disease in patients with CKD. Among various kinds of diuretics, spironolactone, a mineralocorticoid receptor antagonist, has been shown to have protective effects against cardiovascular disease in patients with all stages of CKD, including predialysis, hemodialysis, and peritoneal dialysis. Low-dose loop diuretics have also been shown to have cardioprotective effects in patients with CKD during the pre-dialysis and hemodialysis stages; however, high-dose loop diuretics have failed to show these cardioprotective effects. The protective effects of other classes of diuretics, including thiazide and tolvaptan, against cardiovascular diseases in patients with CKD remain unclear.

Metabolic syndrome induces an increased cardiovascular morbidity and mortality. Most importantly, the prevalence of metabolic syndrome in adult population is expanding. Both clinical and preclinical studies indicate that increased Free Fatty Acids (FFAs) are involved in the pathogenesis of insulin resistance and subsequent development of metabolic syndrome. The relevance of FFAs in protecting and restoring tissue function is quite vast. The search to correlate the functional deterioration of the tissues within the cardiovascular system and increased plasma concentrations of FFAs has been reported. The importance of reduction in the consumption of dietary fatty acids along with the identification of dysregulated genes responsible for persistent increased FFAs uptake and mitochondrial β-oxidation has been increasingly recognized. This review discusses the current empirical understanding of the different types of fatty acids and their metabolism and functions both in physiological and pathophysiological conditions. We also discuss in detail about the molecular and pathophysiological basis of increased FFAs, which augments Cardiovascular Disease (CVD).

Background: Obesity, diabetes and dyslipidemica are the key pathogenic stimulus that enhances progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Coagonist of Glucagon Like- Peptide-1 (GLP-1) Receptor (GLP-1R) and Glucagon Receptor (GCGR) are being evaluated for obesity and diabetes. GLP-1 analogs have shown to reverse diabetes and obesity. Glucagon treatment reduces lipids after acute and chronic treatment. Objective: In this study, we have investigated the effect of co-agonist on the prevention of NAFLD induced by long-term feeding of High Fat Diet (HFD). Method: We have used HFD to induce NAFLD after chronic feeding in mice. Co-agonist treatment (150 μg.kg-1, s.c.) was initiated with induction of HFD, which was continued for 40 weeks. Body weight, food intake, glucose homeostasis, lipid profile, inflammatory and fibrotic markers were assessed at the end of treatment. Results: Co-agonist treatment prevented body weight gain, glucose intolerance and insulin resistance. Treatment with co-agonist reduced NEFA, increased FGF21 and adiponectin levels. Co-agonist increased glycerol release and energy expenditure, while decreased respiratory quotient. Co-agonist reduced lipids in circulation and liver. Expression of SREBP-1C, SCD-1, ACC and FAS were decreased, while ACOX1 and CPT1 were increased after co-agonist treatment. Inflammatory cytokine TNF-α and IL-6 in plasma and expression of MCP-1, TGF- MMP-9, TNF-α, TIMP-1, α-SMA, and COL1A1 were decreased after co-agonist treatment. Plasma transaminases, hepatic TBARS, hepatic hydroxyproline and relative liver weight were suppressed after co-agonist treatment. Fat accumulation, inflammation and fibrosis were reduced in histological assessment of liver in co-agonist treated animals. Conclusion: Co-agonist prevented development of HFD-induced NAFLD by ameliorating obesity, diabetes, inflammation and fibrosis.

Introduction: Fibrinolytic enzymes must currently originate a significant product in the arena of medical research. Very limited studies are stated on fibrinolyticenzyme production from actinomycetes. Methods: Streptomyces sp. isolated from marine soil was chosen to optimize its fibrinolytic protease production.16s rRNA sequencing confirmed the isolated potent strain to be Streptomyces rubiginosus VITPSS1. A fibrinolytic protease was then purified from Streptomyces rubiginosus VITPSS1, with the target of producing a cost effective feasible enzyme from a potential actinomycete. Results: SDS-PAGE results exhibited a protein band of about 45 kDa and the fibrinolytic band was detected by zymography. Optimization of physical and nutritional parameters for fibrinolytic protease production from a marine soil isolate Streptomyces strain was done by response surface methodology. The optimal cultural condition for fibrinolytic protease production was obtained with response surface methodology was based on OFAT results, it was inferred that glycerol, Soyabean meal, pH 7.2 and temperature 37°C. The optimization of the production of fibrinolytic protease with response surface methodology bring about two-folds increase in production by Streptomyces rubiginosus VITPSS1. Conclusion: Thus, this study presents its novelty by highlighting the potential of marine Streptomyces as a significant source for fibrinolytic enzyme production.

Introduction: The argan tree (Argania spinosa L.) is an endemic species from south-western Morocco. Argan-based preparations have been widely used in Moroccan traditional medicine for their biological properties including diabetes especially argan oil. However, the antihypergycemic effect of the pericarp of A. spinosa fruit has never been evaluated. Objective: The purpose of this study was to investigate the effect of a single dose and daily oral administration for seven days of aqueous extract of pericarp of Argania spinosa fruit (A.E.P.F.A.S) in normal and streptozotocin (STZ) diabetic rats. Methods: The effect of A.E.P.F.A.S. (10 mg/kg) on blood glucose levels, plasma Total Cholesterol (TC) and triglyceride concentrations were measured in both normal and diabetic rats. The antioxidant capacity of the A.E.P.F.A.S was also demonstrated using test of DPPH (1-1-diphenyl 2-picryl hydrazyl). The histopathological changes in liver and pancreas have been evaluated in both normal and STZ diabetic rats. A preliminary phytochemical screening for various bioactive constituents and the antioxidant capacity were realized. Results: Single oral administration of A.E.P.F.A.S reduced blood glucose levels p 6 h after administration in STZ diabetic rats. Furthermore, blood glucose levels were decreased in STZ diabetic rats after seven days of treatment. According to the oral glucose tolerance test, the A.E.P.F.A.S. was shown to prevent significantly the increase in blood glucose levels in diabetic treated rats after glucose administration when compared to the control group. Moreover, A.E.P.F.A.S showed antioxidant activity and revealed the inhibitory concentration of 50% of free radicals (IC50) of 279.16 μg/ml. Conclusion: This study demonstrates antihyperglycemic, lowering plasma cholesterol levels and antioxidant effects of A.E.P.F.A.S. in the severe diabetic state. Further investigations are needed to elucidate the mechanism( s) of action of A.E.P.F.A.S. and the active constituent(s) of the extract.

Background: Warionia saharae is a medicinal plant used in the Morocco for the treatment of diabetes mellitus. Objective: The aim of the study was to assess the effect of the aqueous extract of this plant on blood glucose levels in diabetic rats. Method: The current study was carried out to investigate the effect of a single dose and daily oral administration for 15 days of the Aerial Part Aqueous Extract (A.P.A.E) of Warionia saharae (W. saharae) at a dose of 5 mg/kg body weight on blood glucose levels and the histopathological changes in liver and pancreas both in normal and streptozotocin-induced diabetic rats (STZ). Also, the effect of this extract to improve glucose tolerance in normal rats was demonstrated. Results: Single oral administration of W. saharae A.P.A.E reduced blood glucose levels 6 h after administration in normal rats and in STZ-induced diabetic rats. Furthermore, blood glucose levels were decreased in normal and STZ-induced diabetic rats after 15 days of treatment. The aqueous extract of W. saharae was shown to improve the increase on blood glucose levels in normal treated rats significantly (p< 0.001) 90 min after glucose administration as compared to the control groups. Conclusion: In conclusion, the results show that APAE of W. saharae possesses significant antihyperglycemic and hypoglycemic activity.