Activation of the Mas receptors by AVE0991 and MrgD receptor using alamandine to limit the deleterious effects of Ang II-induced hypertension.

The MrgD receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin-angiotensin system. We evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II-induced hypertension in rats. Sprague Dawley rats were subject to 4-week subcutaneous infusions of Ang II (80 ng/kg/min) or saline after which they were treated with ALA (50 µg/kg), AVE0991 (576 µg/kg), or ALA+AVE0991 during the last 2 weeks. Systolic blood pressure (SBP) and heart rate (HR) values were recorded with tail-cuff plethysmography at 1, 15, and 29 days post-treatment. After euthanization, the heart and thoracic aorta were removed for further analysis and vascular responses. SBP significantly increased in the Ang II group when compared to the control group. Furthermore, Ang II also caused an increase in cardiac and aortic cyclophilin-A (CYP-A), monocyte chemoattractant protein-1 (MCP-1), and cardiomyocyte degeneration but produced a decrease in vascular relaxation. HR, matrix metalloproteinase-2 and -9, NADPH oxidase-4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviated vascular responses. The inflammatory and oxidative stress related to cardiac MCP-1 and CYP-A levels decreased in the Ang II+ALA+AVE0991 group. Vascular but not cardiac angiotensin-converting enzyme-2 levels decreased with Ang II administration but were similar to the Ang II+ALA+AVE0991 group. Our experimental data showed the combination of ALA and AVE0991 was found beneficial in Ang II-induced hypertension in rats by reducing SBP, oxidative stress, inflammation, and improving vascular responses.

Dose-dependent subacute cardiovascular effects of modafinil in rats.

Modafinil is used for the treatment of various sleep disorders; however, its usage among healthy individuals is also increasing. There are a limited number of cardiovascular side effects, including ischemic T-wave changes, dyspnea, hypertension, and tachycardia in the literature. Our research aimed to investigate the dose-dependent subacute cardiovascular effects of modafinil in rats. Thirty-two rats were randomly and equally assigned to a control group (vehicle-treated for 14 days), a subacute low-dose group (SALD, 10 mg/kg for 14 days), a subacute moderate-dose group (SAMD, 100 mg/kg for 14 days), and a subacute high-dose group (SHD, 600 mg/kg for 14 days). The cardiovascular effects of modafinil were evaluated using hemodynamic, biochemical, electrocardiographic, electrophysiologic, and histopathologic parameters. In terms of hemodynamic parameters, heart rate, and systolic/diastolic/mean blood pressure levels, electrophysiological parameters did not reach statistical significance among the groups (p > 0.05). The incidence of T-wave negativity in SAMD and SAHD groups was 25 and 37.5%, respectively. Moreover, one rat per group was affected by an atrioventricular blockage. Malondialdehyde, superoxide dismutase, catalase, and reduced glutathione levels in the heart and vascular tissues, serum troponin-I, and creatine kinase levels were similar between the modafinil-administered groups and the control group (p > 0.05); this indicates that modafinil activated neither oxidative stress nor antioxidant pathway. Also, there was no difference in histopathological parameters between groups (p > 0.05). Supratherapeutic doses of modafinil may have the potential to cause ischemic cardiac damage and atrioventricular blockage, despite inconsistency with literature findings; however, this does not pertain to hemodynamic changes.

Protective effects of naringin on valproic acid-induced hepatotoxicity in rats.

Valproic acid (VPA) is mainly prescribed to treat epilepsy. VPA has been reported to be associated with many adverse effects, including hepatotoxicity. Naringin (NRG) is a natural, therapeutically active flavanone glycoside with anti-inflammatory, anti-apoptotic, and antioxidant. The current study was therefore designed to investigate the protective effect of NRG against the VPA-induced experimental hepatotoxicity model. For this purpose, 24 Wistar albino rats were randomly divided into three groups as control (Vehicle), VPA (500 mg/kg), and NRG + VPA (100 mg/kg NRG + 500 mg/kg VPA) groups. The agents were administered via oral gavage for 14 days. Blood and liver tissue samples were taken on the end of the experiment. Biochemical analyzes were performed on the blood and liver samples. Also, malondialdehyde (MDA), superoxide dismutase (SOD) enzyme, glutathione (GSH) content, catalase (CAT) enzyme levels were examined in the liver tissue samples. Histopathological changes (hydropic degeneration and congestion) in the VPA group were increased significantly when compared to the control group (p < 0.05). We also found a decrease in enzymes of serum liver function in the VPA group. However, NRG has been shown not to prevent histopathological changes in the VPA group. According to our results with this experiment protocol, NRG could not exert sufficient protection against VPA-induced hepatotoxicity.

The efficacy of voxelotor, 900 mg in patients with sickle cell anaemia: A meta-analysis of the randomised controlled trials.

OBJECTIVE: Sickle cell anaemia (SCA), an inherited chronic hematological disease affecting hundreds of thousand people worldwide, causes significant morbidity and reduced life expectancy about two or three decades. This study aimed to conduct a meta-analysis of the efficacy of voxelotor, 900 mg in patients with SCA. METHODS: The research protocol was registered at the International Register of Prospective Systematic Reviews (PROSPERO), under the registration number: CRD42020147796. ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Conference Abstracts, Google Scholar, Ovid Medline, Scopus, Web of Science, and Wiley Online Library from 2015 through July 25, 2019, and bibliographies of review articles and eligible studies. Eleven eligible studies that evaluated the effectiveness of voxelotor, 900 mg in SCA. Based on pre-specified inclusion and exclusion criteria, 2 randomized, placebo-controlled studies were included in the meta-analysis. RESULTS: The primary outcome measured was hemoglobin elevation, assessed in a highly similar fashion in both trials. There was a significant difference between voxelotor and placebo in haemoglobin change from baseline (mean difference [MD]: 0.87, 95% confidence interval [CI]: 0.67-1.06). Voxelotor also reduced markers of haemolysis, MD: -36.79, 95% CI: (-75.05) to 1.48 for unconjugated bilirubin that changes from baseline; MD: -19.09, 95% CI: (-44.06) to 5.88 for the percentage of reticulocytes that change from baseline and MD: -23.29, 95% CI: (-65.14) to 18.55 for LDH that change from baseline) but the difference was not statistically significant. CONCLUSIONS: As a conclusion, voxelotor, 900 mg use significantly increased hemoglobin levels which of 1 g/dL elevation predicts a reduced risk of stroke (41%), albuminuria (53%), pulmonary arterial hypertension (57%), and mortality (64%) in recent studies. Voxelotor also reduced markers of hemolysis but failed to reach statistically significance in current evidence. Multicenter, randomized, placebo-controlled studies are on the way and will provide more evidence to see the potential of disease-modifying effects of voxelotor.