Group 5 Pulmonary Hypertension Associated With T-Cell Large Granular Lymphocytic Leukemia: Hemodynamics and Treatment.

Group 5 pulmonary hypertension (PH) encompasses diverse diseases, with a few cases linking it to T-cell large granular lymphocytic (LGL) leukemia. We report a case of a 76-year-old woman, diagnosed with LGL leukemia and concomitant PH, treated with oral triple pulmonary arterial hypertension (PAH) therapy. She initially presented with dyspnea on exertion; evaluation revealed severe precapillary PH. Implementing cyclophosphamide for leukemia along with tadalafil and macitentan for PH led to sustained symptomatic and hemodynamic improvement for over 3 years. At that time, deterioration in PH prompted the addition of selexipag, resulting in sustained clinical improvement for an additional 5 years. This case exemplifies the potential for sustained benefits of PAH therapy in leukemia-associated PH and highlights the need for continued research on the mechanistic relationship between LGL leukemia and PH, with the hope of identifying new management strategies.

Improvement in idiopathic interstitial pneumonia by adding macitentan to a patient unresponsive to nintedanib.

A 69-year-old woman was diagnosed with idiopathic interstitial pneumonia (IIP). The patient underwent a combination therapy of steroid therapy and intravenous cyclophosphamide, long-term oxygen therapy, and the initiation of Nintedanib. However, there was no improvement in IIP, and as a result, the activities of daily living also declined. As one of the various examinations conducted, the results of the right heart catheterization diagnosed the patient with mild pulmonary hypertension, and Macitentan therapy was initiated. The subsequent clinical course appeared to show an improvement in Idiopathic Interstitial Pneumonia (IIP) by adding Macitentan therapy to Nintedanib therapy.

Initial combination therapy with macitentan and tadalafil in patients with pulmonary arterial hypertension, with and without cardiac comorbidities.

AIMS: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities. METHODS AND RESULTS: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups. CONCLUSIONS: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups.

Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed-dose combination tablets versus the use of single-component tablets in healthy subjects.

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

Study on the comparison between Bosentan and Macitentan in the treatment of persistent pulmonary hypertension of the newborns, simultaneously on sildenafil: A randomized double-blinded non-inferiority parallel clinical trial.

BACKGROUND: Persistent Pulmonary Hypertension of the newborn (PPHN) is characterized by sustained elevated Pulmonary Artery Pressure (PAP). Drug resistance and the adverse effects of current therapeutic agents warrant investigation of other targeted therapies. Bosentan has shown benefits in affected neonates. However, trials reported the association with unwanted effects. Thus, in this study, we assess another agent in the same family, Macitentan. However, its efficacy in the treatment of PPHN is not yet reported. Hence, this study evaluated the effect of Macitentan compared to Bosentan in terms of efficacy and safety in the treatment of PPHN. METHODS: This randomized, double-blinded non-inferiority clinical trial was conducted in Shahid Akbar Abadi hospital, Tehran, Iran. Sixty clinically stable neonates with signs suggestive of PPHN were randomly allocated into two groups (n = 30 in each group) and they received either Bosentan 1 mg/kg/dose BD (twice daily) or Macitentan 1 mg/kg/dose BD simultaneously with sildenafil. The echocardiographic and laboratory indices of efficacy and safety were compared between groups. SPAP (systolic pulmonary artery pressure) was used to assess the non-inferiority of the Macitentan compared to the Bosentan in their respective doses used in the study. RESULTS: Participants' mean (SD) age was 3.53 (1.21) days, and 55% were female. No mortality case occurred. SPAP was reduced in both Bosentan and Macitenan groups with the mean difference in SPAP of 9 (95% CI: 7.34-10.65) in Bosentan and SPAP mean difference of 14 (95% CI: 12.12-15.86) in Macitentan group. Categorical comparison of primary outcome improvement showed that Macitentan was superior to Bosentan with a 10% non-inferiority margin. Similar results were obtained in other echocardiographic indices. Also, no significant alterations were observed in laboratory safety parameters. CONCLUSION: Macitentan 1 mg/kg/dose BD (twice daily) is non-inferior to Bosentan 1 mg/kg/dose BD in improving echo outcomes of PPHN and it was even more effective in improving some of these. Also, it is non-inferior to Bosentan in terms of safety. TRIAL REGISTRY NUMBER: (IRCT20160120026115N9).

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Clinical use of macitentan in the treatment of connective tissue disease-associated pulmonary arterial hypertension.

Background: Connective tissue disease (CTD) is the second most common cause of the pulmonary arterial hypertension (PAH). Currently, clinical data concerning CTD-PAH is scarce. Our study aimed to assess the efficacy and safety of macitentan in the treatment of CTD-PAH. Methods: In this retrospective study, patients diagnosed with CTD-PAH at The First Affiliated Hospital of Soochow University from April 2020 to November 2021 were included. Of the patients, 9 were switched to macitentan monotherapy whereas 23 received initial combination therapy. The mean follow-up time was 24 weeks. Six-minute walking distance (6MWD), World Health Organization functional class (WHO-FC), serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiography parameters before and after medication were assessed. Adverse reactions were also recorded and compared. Results: After 24 weeks of treatment, 6MWD, NT-proBNP, systolic pulmonary artery pressure (sPAP) estimated by ultrasound, tricuspid regurgitation pressure gradient (TRPG) and tricuspid annular plane systolic excursion (TAPSE) in the macitentan monotherapy group revealed significant differences (Z=-2.67, Z=-2.67, t=6.20, t=5.60, t=-3.04, P<0.05). There were no statistically significant differences in right ventricular diameter (RVD), right atrial diameter (RAD), ascending aortic root inner diameter (AAO) and left ventricular end-diastolic diameter (LVEDd) (P>0.05). After 24 weeks of medication, the number of patients with WHO-FC grade III/IV symptoms decreased from 6 to 3, 1 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 2, 2 to 4 respectively(P<0.05). After 24 weeks of treatment, 6MWD, NT-proBNP, LVEDd, sPAP and TRPG in the macitentan combined with sildenafil treatment group revealed statistically significant differences (Z=-4.11, Z=-3.74, Z=-3.83, t=6.88, t=6.54, P<0.001). Significant differences in RVD, RAD, and TAPSE were found (t=3.46, t=3.69, t=-3.12, P<0.05). There were no statistically significant variances in AAO between the groups (P>0.05). The number of patients with WHO-FC grade III/IV symptoms decreased from 16 to 8, 5 to 0 respectively (P<0.05), and that of patients with WHO-FC grade I/II symptoms increased from 0 to 1, 2 to 14 respectively (P<0.001). There were no statistically significant differences before and after treatment in 6MWD, NT-proBNP, RVD, RAD, AAO, LVEDd, sPAP, TRPG and TAPSE between the two groups (P>0.05). There were no statistically significant differences in alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Scr) and hemoglobin (Hb) between 0 and 24 weeks (P>0.05). Conclusions: Exercise tolerance and cardiac function in patients with CTD-PAH were significantly improved after treatment with macitentan, which was well tolerated. Therefore, macitentan may be an effective and safe targeted drug for CTD-PAH.

Macitentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease (CTD-PAH): Real-World Evidence from the Combined OPUS/OrPHeUS Dataset.

INTRODUCTION: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). RESULTS: The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). CONCLUSIONS: Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov Graphical abstract available for this article.

Safety of Macitentan for the Treatment of Portopulmonary Hypertension: Real-World Evidence from the Combined OPUS/OrPHeUS Studies.

INTRODUCTION: Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS. RESULTS: The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58 years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events. CONCLUSION: There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov .

Effect of Macitentan in Pulmonary Arterial Hypertension and the Relationship Between Echocardiography and cMRI Variables: REPAIR Echocardiography Sub-study Results.

INTRODUCTION: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function. METHODS: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses. RESULTS: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of - 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR. CONCLUSIONS: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up. TRIAL REGISTRATION NUMBER: REPAIR NCT02310672.

Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

Stability Indicating RP-HPLC-DAD method for simultaneous estimation of tadalafil and macitentan in synthetic mixture for treatment of pulmonary arterial hypertension.

OBJECTIVE: High Performance liquid chromatography is an integral analytical tool in assessing drug product stability. A simple, selective, precise, accurate and stability indicating RP-HPLC method was developed and validated for analysis of Tadalafil and Macitentan in synthetic mixture. MATERIAL AND METHOD: Chromatographic separation was performed using Phenomex Gemini C18 (25cm×4.6nm, 5µm) Column. The mobile phase consists of (10mM Ammonium Acetate in water and [Methanol: ACN 20: 80% v/v]) (40: 60% v/v). The flow rate was set to be 1.0mL/min. The injection volume was 10.00µL. The detection was carried out at 260nm at column temperature 35°C. RESULTS: The method was validating according to ICH Q2R1 guideline for accuracy, precision, reproducibility, specificity, robustness and detection and quantification limits. Stability testing was performed on Tadalafil and Macitentan and it was found that these degraded sufficiently in all applied chemical and physical conditions. Linearity for Tadalafil and Macitentan was observed 0.4-100µg/mL and 0.1-25µg/mL with correlation coefficient at 0.9999. LOD and LOQ 0.008µg/mL and 0.024µg/mL and 0.001µg/mL and 0.0029µg/mL for Tadalafil and Macitentan respectively. CONCLUSION: The developed RP-HPLC method was found to be suitable for the determination of both the drugs.

Macitentan Administration for Pulmonary Hypertension Due to ß-thalassemia with Multiple Organ Failure: A Case Report.

A 51-year-old Thai woman diagnosed with ß-thalassemia underwent regular blood transfusion and iron-chelating therapy. However, after voluntarily discontinuing treatment, the patient developed progressive dyspnea and was diagnosed with pulmonary hypertension following right heart catheterization. Despite resuming blood transfusions, her condition did not improve. Because the patient had a history of multiple organ failure, curative treatment for ß-thalassemia was not feasible, and macitentan was administered. Despite experiencing hypotension as an adverse event, her condition remained stable during macitentan treatment. Thus, macitentan may be well tolerated in patients with pulmonary hypertension caused by ß-thalassemia with multiple organ dysfunction.

Benefits of Macitentan in Patients with Pulmonary Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: This systematic review and meta-analysis aimed to determine the efficacy of macitentan in patients with pulmonary hypertension (PH). Methods: A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with macitentan, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs). Results: Six RCTs (enrolling 1,003 participants) met the inclusion criteria. Macitentan showed significant effects on 6-min walk distance (6MWD) (WMD 12.06 m, 95% CI 2.12 to 21.99 m), pulmonary vascular resistance (PVR) (WMD -186.51 dyn·s/cm-5, 95% CI -232.72 to -140.29 dyn·s/cm-5), mean pulmonary artery pressure (mPAP) (WMD -3.20 mmHg, 95% CI -5.93 to -0.47 mmHg), N-terminal pro-brain natriuretic peptide (NT-proBNP) (WMD -232.47 ng/L, 95% wCI -318.22 to -146.72 ng/L), and cardiac index (WMD 0.39 L/min/m2, 95% CI 0.20 to 0.58 L/min/m2). Conclusion: Macitentan significantly improved 6MWD, PVR, mPAP, NT-proBNP, and cardiac index in patients with PH. Macitentan should be further validated in patients with PH.

Current Status of Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension: A Combined Study Results and Pharmacology-Based Review.

Pulmonary arterial hypertension (PAH) affects a wide range of people globally and has a poor prognosis despite many advancements in available treatment options. Among the available treatments, endothelin receptor antagonists (ERA) are among the most widely used drugs. These drugs have been evaluated in scientific trials. We included free full texts in the English language from the last ten years and reviewed them. We are writing this review to amalgamate the pharmacological aspects and the previous studies on ERAs to demonstrate a comprehensive overview of the current status of ERAs for PAH treatment. We focused on the structure, pharmacodynamics, pharmacokinetics, and efficacy and safety of the three most widely used ERAs: Bosentan, Ambrisentan, and Macitentan. These drugs have different receptor affinities, bioavailability, excretion routes, and different levels of safety profiles. There are three available studies, the RCT, the ARIES series, and the SERAPHIN studies, for assessing the safety and efficacy of Bosentan, Ambrisentan, and Macitentan, respectively. All the studies and some additional studies for combination therapy have proven all three drugs effective in treating PAH. The side effects (SE) varied from headache and hepatic enzyme elevation to worsening the PAH status of varied severities. Although these studies provided valuable insight into the role of ERAs, there is still enough scope for more studies on ERAs, both as monotherapy and combination therapy for PAH.

Inhaled nintentanib, pirfenidone and macitentan for pulmonary fibrosis: a laboratory experiment.

Aim: Idiopathic pulmonary fibrosis is a rare disease with few efficient drugs in the market. The consequences of this disease are mainly respiratory failure and pulmonary hypertension. Materials & methods: In our experiment we used the drugs pirfenidone, nintetanib and macitentan. We performed nebulization experiments with three jet nebulizers and three ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5 µm in mass median aerodynamic diameter. Results: Pirfenidone versus nintetanib had smaller droplet size formation at both inhaled technologies (1.37 < 2.23 and 1.92 < 3.11, jet and ultrasound respectively). Discussion: Pirfenidone and nintetanib can be administered as aerosol in any type of nebulization system.

Efficacy and safety of the endothelin-1 receptor antagonist macitentan in epicardial and microvascular vasospasm; a proof-of-concept study.

Background: Treatment of patients diagnosed with angina due to epicardial or microvascular coronary artery spasm (CAS) is challenging because patients often remain symptomatic despite conventional pharmacological therapy. In this prospective, randomized, double-blind, placebo-controlled, sequential cross-over proof-of-concept study, we compared the efficacy and safety of macitentan, a potent inhibitor of the endothelin-1 receptor, to placebo in symptomatic patients with CAS despite background pharmacological treatment. Methods: Patients with CAS diagnosed by invasive spasm provocation testing with >3 anginal attacks per week despite pharmacological treatment were considered for participation. Participants received either 10 mg of macitentan or placebo daily for 28 days as add-on treatment. After a wash-out period patients were crossed over to the alternate treatment arm. The primary endpoint was the difference in anginal burden calculated as [1] the duration (in minutes) * severity (on a Visual Analogue Scale (VAS) pain scale 1-10); and [2] the frequency of angina attacks * severity during medication use compared to the run-in phase. Results: 28 patients of whom 22 females (79%) and a mean age of 55.3 ± 7.6 completed the entire study protocol (epicardial CAS n = 19 (68), microvascular CAS n = 9 (32)). Change in both indices of anginal burden were not different during treatment with add-on macitentan as compared to add-on placebo (duration*severity: -9 [-134 78] vs -45 [-353 11], p = 0.136 and frequency*severity: -1.7 [-5.8 1.2] vs -1.8 [-6.2 0.3], p = 0.767). The occurrence and nature of self-reported adverse events were closely similar between the treatment phase with macitentan and placebo. Conclusion: In patients with angina due to epicardial or microvascular CAS despite background pharmacological treatment, 28 days of add-on treatment with the ET-1 receptor antagonist, macitentan 10 mg daily, did not reduce anginal burden compared to add-on treatment with placebo.Trial Registrationhttps://trialsearch.who.int/, Identifier: EUCTR2018-002623-42-NL. Registration date: 20 February 2019.