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Patients with previously untreated pulmonary arterial hypertension who were randomly assigned to combination therapy with ambrisentan and tadalafil had a significantly lower risk of a composite clinical failure outcome at 20 months than did the pooled monotherapy group. Regardless of the initiating trigger, pulmonary arterial hypertension results in the altered synthesis of a variety of vasoactive substances derived from the endothelium. 1 Current therapies for pulmonary arterial hypertension 2 target abnormalities in one of three intracellular pathways with signaling dysfunction: the prostacyclin, nitric oxide, or endothelin pathway. 1 However, no single class of drug is consistently effective in treating all patients, which suggests that no single pathway plays a dominant pathogenic role. 3 , 4 Combination therapy with agents that target several different pathways may potentially increase the overall therapeutic effect on the mechanisms of this disease 5 and provide additional clinical benefits. 6 – . . .

Pulmonary arterial hypertension (PAH) is a life-threatening disease that typically causes shortness of breath and exercise intolerance. Combination therapy with ambrisentan and tadalafil has proven to be more effective at preventing clinical failure events in patients with PAH than either drug alone. The aim of this study was to evaluate the bioequivalence of an ambrisentan/tadalafil fixed-dose combination (FDC) compared with co-administration of the 2 monotherapies. This 3-part, randomized, single-dose, open-label crossover study was conducted in healthy volunteers. The first part of the study consisted of a 5-way crossover that compared the relative bioavailability of 4 FDC formulations (10-mg ambrisentan + 40-mg tadalafil) with co-administered reference monotherapies. One formulation was selected and its relative bioavailability was assessed when produced in 3 different granulation sizes during the second part of the study. In the third part of the study, the bioequivalence of the candidate FDC with the reference monotherapies was evaluated for the 10-mg/40-mg dose strength, in addition to 2 other dose strengths (5 mg/20 mg and 5 mg/40 mg). For all parts of the study, blood samples were taken at regular intervals after each dose, ambrisentan and tadalafil concentrations determined, and pharmacokinetic (PK) parameters (Cmax, AUC0–∞, and AUC0–t) obtained. Test/reference ratios of the geometric means of PK parameters were used to evaluate bioequivalence. Safety and tolerability were assessed by recording adverse events and monitoring vital signs, ECGs, and clinical laboratory data. Of the 174 subjects screened for eligibility, 112 were allocated to a randomized treatment sequence across all study parts, and 100 completed their full assigned treatments. All 4 FDC formulations tested during part 1 of the study yielded PK parameters similar those of the reference treatments. In part 2, granulation size was found to not affect the relative bioavailability of the selected formulation. In part 3, the selected FDC was found to be bioequivalent to co-administration of the monotherapies in both the fasted and fed states. The FDC was also found to be bioequivalent to the reference treatments at the 2 additional dose strengths. All but one of the adverse events was mild to moderate in intensity, and no serious adverse events were reported. An ambrisentan/tadalafil FDC was bioequivalent to concurrently administered monotherapies and therefore represents a viable alternative treatment to co-administration. Use of an FDC is likely to be associated with reduced costs and improved patient compliance. ClinicalTrials.gov identifier: NCT02688387.

Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension. This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (≥130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369. All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0·0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events. Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed. Gilead Sciences.

Saroglitazar is a dual PPAR-α/γ agonist approved for the treatment of diabetic dyslipidemia. In addition to reduction in atherogenic lipids, it may also contribute to improvement in insulin sensitivity through PPAR-α/γ agonism, which remains unexplored. We conducted a randomized, double-blind, placebo-controlled trial in treatment-naive T2DM individuals with serum triglyceride >150 mg/dL. Participants were randomized to receive either saroglitazar 4 mg or placebo (1:1) daily for 4 months (n = 30). Insulin sensitivity (SI clamp ) was studied using hyperinsulinemic-euglycemic clamp at baseline and at 4 months. We observed a significant reduction in TG (p = 0.001), HbA1c (p = 0.019) and fasting plasma glucose (p = 0.019) and significant increase in HDL-C levels (p < 0.01) with saroglitazar compared to placebo. Further, patients on saroglitazar had a greater improvement in SI clamp (p = 0.026) with the effect persisting despite adjusting for baseline weight, TG, HDL-C and HbA1c (p = 0.002). This was accompanied with significant increase in HOMA-β (p = 0.01) in the saroglitazar group and change in HOMA-β showed a trend towards significance with SI clamp (r = 0.503, p = 0.056). However, change in SI clamp did not significantly correlate with reduction in HbA1c and TG. We conclude that saroglitazar effectively reduces hypertriglyceridemia and improves insulin sensitivity along with β-cell function by reduction in gluco-lipotoxicity and possibly directly through PPAR-γ agonism in patients ofT2DM with hypertriglyceridemia.

Background and Objectives Dyslipidaemia is a major cardiovascular risk factor associated with type 2 diabetes mellitus. Saroglitazar (ZYH1) is a novel peroxisome proliferator-activated receptor (PPAR) agonist with predominant PPARα and moderate PPARγ activity. It has been developed for the treatment of dyslipidaemia and has favourable effects on glycaemic parameters in type 2 diabetes mellitus. The objective of this phase 1 study was to evaluate the pharmacokinetics, safety and tolerability of saroglitazar in healthy human subjects. Methods This was a randomized, double-blind, placebo-controlled, single-centre, phase I study in healthy human volunteers, and was performed in two parts; part I evaluated single ascending oral doses of saroglitazar (0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg) in healthy subjects, and part II measured the effects of food and sex on the pharmacokinetics of 1 mg saroglitazar, the human equivalent efficacy dose derived from pre-clinical studies. A total of 96 subjects were enrolled in the study, which included 88 healthy male subjects in part I and 16 healthy subjects (8 males from part I of the study and 8 females) in part II. Results Saroglitazar was rapidly and well absorbed across all doses in the single-dose pharmacokinetic study, with a median time to the peak plasma concentration ( t max ) of less than 1 h (range 0.63–1 h) under fasting conditions across the doses studied. The maximum plasma concentration ranged from 3.98 to 7,461 ng/mL across the dose range. The area under the plasma concentration–time curve increased in a dose-related manner. The average terminal half-life of saroglitazar was 5.6 h. Saroglitazar was not eliminated via the renal route. There was no effect of sex on the pharmacokinetics of saroglitazar, except for the terminal half-life, which was significantly shorter in females than in males. Food had a small effect on the pharmacokinetics; however, it was not consistent in males and females. Single oral doses of saroglitazar up to 128 mg were well tolerated. No serious adverse events were reported. Adverse events were generally mild and moderate in nature. Saroglitazar did not show any clinically relevant findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms. Conclusion The highest dose of saroglitazar evaluated in this study was 128 mg, several times the estimated therapeutic doses (1–4 mg). The pharmacokinetics of saroglitazar support a once daily dosage schedule. Saroglitazar was found to be safe and well tolerated in this study.

The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model. Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens, produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling. These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN.

BackgroundPatients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.ObjectiveTo explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.MethodsThis was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).ResultsIn the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.ConclusionsThis post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.Trial registration number NCT01178073, post results.

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

Background The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. Methods In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. Results A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: − 1.38 ± 1.99 for saroglitazar 2 mg; − 1.47 ± 1.92 for saroglitazar 4 mg and − 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE’s were ‘mild’ to ‘moderate’ in severity and were resolved by the completion of the study. Conclusions Saroglitazar effectively improved glycemic control and lipid parameters over 56 weeks in patients of T2DM receiving background metformin therapy and has a promising potential to reduce the cardiovascular risk in T2DM patients. Trial registration CTRI/2015/09/006203, dated 22/09/2015

The variations in the chemical composition, and consequently, on the biological activity of the propolis, are associated with its type and geographic origin. Considering this fact, this study evaluated propolis extracts obtained by supercritical extraction (SCO2) and ethanolic extraction (EtOH), in eight samples of different types of propolis (red, green and brown), collected from different regions in Brazil. The content of phenolic compounds, flavonoids, in vitro antioxidant activity (DPPH and ABTS), Artepillin C, p-coumaric acid and antimicrobial activity against two bacteria were determined for all extracts. For the EtOH extracts, the anti-proliferative activity regarding the cell lines of B16F10, were also evaluated. Amongst the samples evaluated, the red propolis from the Brazilian Northeast (states of Sergipe and Alagoas) showed the higher biological potential, as well as the larger content of antioxidant compounds. The best results were shown for the extracts obtained through the conventional extraction method (EtOH). However, the highest concentrations of Artepillin C and p-coumaric acid were identified in the extracts from SCO2, indicating a higher selectivity for the extraction of these compounds. It was verified that the composition and biological activity of the Brazilian propolis vary significantly, depending on the type of sample and geographical area of collection.