Pyrethroids, such as deltamethrin, are toxic substances that lead to generation of reactive oxygen species, which harm living organisms. We assessed the level and patterns of imbalance evolved by a single dose of 2 microg/L deltamethrin on the lipid peroxidation (LPO) and the antioxidant defense system of Carassius auratus gibelio liver and intestine, and monitored the recovery dynamics of these parameters during a 14-day post-exposure period. LPO and antioxidative defense mechanisms displayed different responses in the investigated tissues. Sudden increase of LPO in the liver, persisting at this elevated level throughout the test period, was observed on the third day post-exposure, while in the intestine significant enhancement of this parameter was recorded from the seventh day. Reduced glutathione (GSH) showed a transient increase in the liver, and was depleted in the intestine by the second day of exposure, with signs of recovery by the end of the experimental tenure. In the liver of fish a temporary inhibition of superoxide dismutase (SOD) and catalase (CAT) activity, and activation of glutathione peroxidase (GPX), glutathione transferase (GST), and glutathione reductase (GR) enzymes was observed, with maximum thresholds recorded on the third and second days, respectively. In the intestine a relevant increase in CAT and GST activity up to the second day and almost complete recovery by the end of the experiment was recorded, while for GR a continuous enhancement was apparent.
Rationale Initial combination therapy with ambrisentan and tadalafil has been demonstrated superior to either agent alone in pulmonary arterial hypertension (PAH). This study sought to examine the efficacy, tolerability and safety of another combination of endothelin receptor antagonist and phosphodiesterase 5-inhibitor, macitentan and tadalafil, as initial therapy for PAH. Methods This single centre, retrospective cohort study identified adult patients newly diagnosed with PAH between January 2014 and December 2017 who were started on macitentan and tadalafil as initial combination therapy. Patients were retrospectively followed for one year. Efficacy was evaluated via change from baseline in disease risk profile based on a score incorporating World Health Organization (WHO) functional class (FC), 6-minute walk distance, B-type natriuretic peptide and hemodynamics on follow-up right heart catheterization, including right atrial pressure, cardiac index, and mixed venous oxygen saturation. Each variable was assigned a score based on the 2015 European Respiratory Society risk assessment table (low risk, 1; intermediate risk, 2; high risk, 3) and overall risk was determined by the average score rounded to the nearest integer. Secondary endpoints included mean change from baseline in 6MWD and hemodynamic variables. Drug tolerability and adverse events were assessed. Results From January 2014 to December 2017, 46 patients were identified. Median age was 56 years and 84.8% were female. Twenty-three patients had idiopathic PAH, 19 associated with connective tissue disease, 3 congenital heart disease and 1 HIV. The majority were WHO FC III at baseline (78.3%). A total of 8 patients did not tolerate the combination therapy and discontinued one of the two study drugs within one month due to adverse events, including peripheral edema (macitentan, 3), headache (tadalafil, 2), transaminitis (macitentan, 1), nausea (macitentan, 1), and epistaxis (tadalafil, 1). Two of these 8 patients had progressive disease and died within 1 year. Of 38 patients who tolerated macitentan and tadalafil, 14 of 36 individuals (38.9%) improved from baseline intermediate or high to low risk profile after 6 months of treatment (Table A). No patients worsened to high risk. One patient remained high risk despite therapy and died within 1 year. Change in secondary endpoints of 6MWD and hemodynamic variables are summarized below (Table B). Conclusion In a real-world setting, macitentan and tadalafil as initial combination therapy for PAH was generally well tolerated and yielded significant clinical benefits. Nearly 40% of patients improved to a low risk profile, which has been associated with excellent 5-year transplant-free survival.
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