Assessment of the implementation of risk minimization measures for bosentan: a retrospective study.

BACKGROUND: Bosentan is associated with adverse hepatic effects. To minimize such risk, regulators implemented risk minimization measures (RMMs), including testing for liver injury biomarkers (alanine and aspartate transaminase and bilirubin) prior to therapy initiation and monthly throughout therapy. This study aimed to examine the adherence to hepatic monitoring requirements. RESEARCH DESIGN AND METHODS: This retrospective cohort study collected data about bosentan new-users from the Real-world Evidence Research Network from 2016 to 2022. We ascertained hepatic tests from laboratory files. Adherence to RMM definition was performing the required tests within 90 days before initiation and categorized adherence to monthly testing requirement based on the expected number of tests throughout therapy as low (<50%), moderate (50-74%), and high (≥75%). RESULTS: One hundred patients entered the study cohort and 71% were females, with a median age of 25 years. Adherence to testing prior to bosentan initiation was 60%. Adherence to monthly testing was low in the majority of patients (58.2%). CONCLUSIONS: Adherence to bosentan RMMs relevant to minimizing risk of hepatotoxicity either before starting or throughout therapy was low. Our findings could be used as a baseline for monitoring trends in implementation of RMMs over time or to compare performance of various minimization strategies.

Bosentan and Pulmonary Hypertension Caused by COVID-19: A Pilot Randomized Double-blind Clinical Study.

INTRODUCTION/OBJECTIVE: Coronavirus disease 2019 (COVID-19) has been the biggest pandemic in history, with severe complications, such as acute respiratory distress syndrome and pulmonary hypertension (PH). An endothelin-1 (ET-1) receptor antagonist, such as bosentan, may be beneficial in treating elevated ET-1 levels. Hence, our study aimed to evaluate the therapeutic effects of bosentan in patients with COVID-19-induced PH. METHODS: A single-centre, randomized, double-blind study involving 72 participants was carried out; 36 received bosentan and the other 36 received a placebo. Pulmonary arterial pressure, tricuspid valve pressure gradient, and right atrial pressure were measured using echocardiography. The Cox proportional hazards regression model was used to investigate the impact of bosentan and patients' age on mortality during a 6-month follow-up period. RESULTS: In-hospital mortality was significantly lower in the case group (13%) compared with the control group (33.3%) (P=0.003). Additionally, bosentan improved echocardiographic parameters, such as systolic pulmonary artery pressure and tricuspid regurgitation gradient (P=0.011 and P=0.003, respectively). Bosentan use was a significant predictor of long-term mortality rates for 600 days [age-adjusted hazard ratio of 5.24 (95% CI 1.34 to 20.46)]. CONCLUSION: This study provided a mixed perspective on the use of bosentan therapy in patients with COVID-19-related PH. Bosentan effectively reduced in-hospital mortality and improved echocardiographic measures. However, the treatment group showed an increased requirement for supplemental oxygen therapy and long-term mortality. Further studies with larger sample sizes are necessary to elucidate the effects of bosentan in PH following COVID-19.

The Anti-Atherosclerotic Effects of Endothelin Receptor Antagonist, Bosentan, in Combination with Atorvastatin-An Experimental Study.

Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.

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).

Simple Determination of Bosentan in Plasma Samples by Reversed-Phase High-Performance Liquid Chromatography.

Background: In order to measure the plasma levels of Losartan and Bosentan, a sensitive Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) technique was developed. Methods: To compare bioavailability, the Area Under the Curve (AUC), peak plasma concentration (Cmax), and time to Cmax (Tmax) were employed. The standard curve (150-2400 ng/ml) was linear (R2=0.999), relative errors were between 2.4 to 10.05% and the coefficient of variation (CV%) ranged from 1.52 to 10.88. A single dosage (test and reference) was used for the in vivo investigation, which involved 16 healthy individuals. Results: The AUC0-48, AUC0-, Cmax, and Tmax of the test and reference had no statistically significant differences. The Cmax and 95% confidence intervals of the ratio of Cmax of the two formulations were 0.93-0.96 and 97.6-135%, respectively. Conclusion: Therefore, it was established that generic Bosentan was equivalent to Bosentan from Actelion and that both medications could be regarded as equally effective in clinical settings. The blood level of Bosentan could be measured using this straightforward procedure in all hospital laboratories.

Effect of off-label targeted drugs on long-term survival in chronic thromboembolic pulmonary hypertension: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Off-label pulmonary arterial hypertension (PAH)-targeted drugs are commonly prescribed for non-operated chronic thromboembolic pulmonary hypertension (CTEPH), but their effect on the long-term prognosis of CTEPH remains unknown. This study investigated the effect of off-label PAH-targeted drugs on the long-term survival of CTEPH patients. METHODS: CTEPH patients were enrolled from a prospective multicentre national registry. Except for licensed riociguat and treprostinil, other PAH-targeted drugs were off-label. In the original and propensity score-matched (PSM) samples, five-year survival was compared in two groups: (a) patients not receiving off-label PAH-targeted drugs (control) versus (b) patients receiving off-label PAH-targeted drugs (treatment). The latter group was investigated for the effect of started off-label PAH-targeted drugs at baselines (initial) or during follow-up (subsequent). RESULTS: Of 347 enrolled patients, 212 were treated with off-label PAH-targeted drugs initially (n = 173) or subsequently (n = 39), and 135 were untreated. The 1-, 2-, 3- and 5-year survival of the treatment group was significantly higher than that of the control group (97.1% vs. 89.4%, 92.3% vs. 82.1%, 83.2% vs. 75.1% and 71.1% vs. 55.3%, respectively, log-rank test, p = 0.005). Initial treatment was correlated with better 5-year survival after excluding patients with subsequent treatment to reduce the immortal-time bias (hazard ratio: 0.611; 95% CI: 0.397-0.940; p = 0.025). In PSM samples, patients given initial treatment showed significantly better 5-year survival than untreated patients (68.9% vs. 49.3%, log-rank test, p = 0.008). CONCLUSION: Off-label targeted drugs contributed to improved long-term survival in CTEPH patients receiving pharmacotherapies.

Impact of a Moderate CYP3A4 Inducer (Bosentan) on Lurbinectedin Pharmacokinetics and Safety in Patients with Advanced Solid Tumors: An Open-Label, Two-Way, Crossover, Phase Ib Drug-Drug Interaction Study.

This open-label, two-way, crossover, phase Ib drug-drug interaction study investigated whether the pharmacokinetics (PKs) and safety profile of lurbinectedin (LRB) are affected by co-administration of a moderate CYP3A4 inducer (bosentan, BOS) in adult patients with advanced solid tumors. Eleven patients were randomly assigned to Sequence 1 (LRB + BOS in Cycle 1 [C1] and LRB alone in Cycle 2 [C2]) or Sequence 2 (LRB alone in C1 and LRB + BOS in C2), and finally, eight patients (four per sequence) were considered evaluable for PK assessment. LRB (3.2 mg/m2, 1 h [h], intravenous) was administered alone or combined with multiple BOS administration (125 mg/12 h oral; 5.5 days). Co-administration with BOS decreased the systemic total exposure (area under the curve, AUC) of LRB by 21% for AUC0-t and 20% for AUC0-∞ and increased clearance by 25%. Co-administration with BOS did not significantly modify the unbound plasma LRB PK parameters. BOS increased the conversion of LRB to its metabolite M1, with no changes on its metabolite M4. The LRB safety profile was consistent with the toxicities previously described for this drug. No differences in terms of toxicity were found between LRB with and without BOS. In summary, the magnitude of the observed changes precludes a clinically relevant effect of BOS co-administration on LRB exposure and its safety profile.

Bosentan in the treatment of persistent pulmonary hypertension in newborns: a systematic review and meta-analysis.

BACKGROUND: Persistent pulmonary hypertension of the newborn is a life-threatening condition that affects about 1-2 per 1,000 live births worldwide. Bosentan is an oral dual endothelin receptor antagonist that may have a beneficial effect on persistent pulmonary hypertension of the newborn by reducing pulmonary vascular resistance and improving oxygenation. However, its role in persistent pulmonary hypertension of the newborn remains unclear. OBJECTIVES: To systematically evaluate the efficacy and safety of bosentan as an adjuvant therapy for persistent pulmonary hypertension of the newborn in newborns. METHODS: We searched six English and two Chinese databases from their inception to 1 January 2023 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomised controlled trials and retrospective studies that compared bosentan with placebo or other drugs for persistent pulmonary hypertension of the newborn in newborns. We performed a meta-analysis using random-effects models and assessed the risk of bias and heterogeneity in the included studies. RESULTS: We included 10 studies with a total of 550 participants. Bosentan significantly reduced the treatment failure rate (relative risk = 0.25, P < 0.001), pulmonary artery pressure (mean difference = -11.79, P < 0.001), and length of hospital stay (mean difference = -1.04, P = 0.003), and increased the partial pressure of oxygen (mean difference = 10.02, P < 0.001) and blood oxygen saturation (SpO2) (mean difference = 8.24, P < 0.001) compared with a placebo or other drugs. The occurrence of adverse reactions was not significantly different between bosentan and a placebo or other drugs. CONCLUSIONS: Bosentan is effective in the treatment of persistent pulmonary hypertension of the newborn but adverse reactions such as abnormal liver function should be observed when using it.

Correlation between right atrial function parameters and prognosis in patients with chronic obstructive pulmonary disease complicated with pulmonary hypertension / 中国医师进修杂志

Objective:To explore the correlation between right atrial function parameters and prognosis in patients with chronic obstructive pulmonary disease(COPD) complicated with pulmonary hypertension.Methods:Eighty-four patients with COPD combined with pulmonary arterial hypertension treated with bosentan combined with milrinone admitted to the First Affiliated Hospital of Xinjiang Medical University during the period of February 2020 to June 2022 were selected as the study subjects, and they were divided into the effective group (63 cases) and the ineffective group (21 cases) according to the treatment effect. Right cardiac function parameters were measured by Philips iE33 color ultrasonography before treatment and 72 h after treatment. Logistic regression was used to analyze the risk factors affecting the treatment outcome of patients, and receiver operating characteristics (ROC) curve was used to analyze the predictive value of right atrial function parameters in the poor prognosis of patients with COPD complicated with pulmonary hypertension.Results:The main pulmonary artery diameter (MPA), right ventricular base transverse diameter (RVd1), right ventricular middle transverse diameter (RVd2), right atrial diameter (RAd) and right ventricular free wall thickness (RVWT) in the effective group were lower than those in the ineffective group: (2.65 ± 0.23) cm vs. (2.90 ± 0.44) cm, (3.46 ± 0.43) cm vs. (3.76 ± 0.72) cm, (3.48 ± 0.42) cm vs. (3.88 ± 0.69) cm, (3.53 ± 0.81) cm vs. (4.03 ± 1.20) cm, (0.63 ± 0.12) cm vs. (0.72 ± 0.21) cm; end-diastolic to end-systolic tricuspid ring displacement (TAPSE) was higher than that in the ineffective group: (2.08 ± 0.32) cm vs. (1.82 ± 0.46) cm, there were statistical differences( P<0.05). Logistic regression analysis showed that RVd1 increased ( OR = 3.717, P<0.05), RVd2 increased ( OR = 2.162, P<0.05), RAd increased ( OR = 2.838, P<0.05) and TAPSE reduction ( OR = 1.704, P<0.05) were risk factors for treatment failure in patients. The results of ROC curve showed that the area under the curve of RVd1, RVd2, RAd, TAPSE in predicting the therapeutic effect of COPD patients with pulmonary hypertension were 0.820, 0.831, 0.872, 0.909, respectively. Conclusions:The independent influencing factors of ineffective patients with COPD combined with pulmonary arterial hypertension treated with bosentan combined with milrinone are the increase of structural parameters of the right heart and the decrease of systolic function parameters. The therapeutic effect of patients can be evaluated clinically according to the level of each parameter.

Kids Mod PAH trial: A multicenter trial comparing mono- versus duo-therapy for initial treatment of pediatric pulmonary hypertension.

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network.

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.

Cost-utility of ambrisentan and bosentan for pediatric pulmonary arterial hypertension.

INTRODUCTION: Despite the increasing evidence supporting the efficacy of ambrisentan and bosentan in improving functional classes among pediatric patients with pulmonary arterial hypertension (PAH), there is a lack of information regarding their cost implications. Therefore, the objective of this study is to assess the cost-utility of bosentan compared to ambrisentan for the treatment of pediatric patients with PAH in Colombia. METHODS: We employed a Markov model to estimate the costs and quality-adjusted life-years (QALYs) associated with the use of ambrisentan or bosentan in pediatric patients diagnosed with pulmonary arterial hypertension (PAH). To ensure the reliability of our findings, we conducted sensitivity analyses to assess the robustness of the model. In our cost-effectiveness analysis, we evaluated the outcomes at a willingness-to-pay (WTP) threshold of US$5,180. RESULTS: The expected annual cost per patient receiving ambrisentan was estimated to be $16,055 (95% CI 15,937 -16,172), while for bosentan it was $14,503 (95% CI 14,489 -14,615). The QALYs per person estimated for ambrisentan were 0.39 (95% CI 0.381-0.382), whereas for bosentan it was 0.40 (95% CI 0.401-0.403). CONCLUSION: Our economic evaluation shows that ambrisentan is not cost-effective regarding bosentan to in treating pulmonary arterial hypertension in C.

Development and pharmacokinetic evaluation of Neusilin® US2-based S-SNEDDS tablets for bosentan: Fasted and fed states bioavailability, IVIS® real-time biodistribution, and ex-vivo imaging.

The study reported here aimed to develop and optimize the S-SNEDDS tablet of bosentan (BOS) and to investigate its pharmacokinetic and biodistribution properties. The BOS-loaded SNEDDS have been developed and characterized in a previous study. The BOS-loaded SNEDDS formulation was converted to S-SNEDDS using Neusilin® US2. The S-SNEDDS tablets were obtained using the direct compression technique, and in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies of the tablets were performed. The S-SNEDDS tablet and reference tablet (Tracleer®) were administered to male Wistar rats at 50 mg/kg dose by oral gavage in fasted and fed state conditions. The biodistribution of the S-SNEDDS tablet was investigated in Balb/c mice using fluorescent dye. The tablets were dispersed in distilled water before administration to animals. The relationship between in vitro dissolution data and in vivo plasma concentration was examined. The S-SNEDDS tablets showed 2.47, 7.49, 3.70, and 4.39 increases in the percentages of cumulative dissolution in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively, when compared to the reference, and increased the Cmax and AUC 2.65 and 1.28-fold and 4.73 and 2.37-fold in fasted and fed states, respectively, when compared to the reference. S-SNEDDS tablets also significantly reduced interindividual variability in both fasted and fed states (p < 0.05). The XenoLight™ DiR and VivoTag® 680XL labeled S-SNEDDS tablet formulation increased the real-time biodistribution in the body by factors of 2.4 and 3.4 and organ uptake and total emission increased by factors of 2.8 and 3.1, respectively. The IVIVR has been successfully established for S-SNEDDS tablets (R2 > 0.9). The present study confirms the potential of the S-SNEDDS tablet to enhance the in vitro and in vivo performance of BOS.

Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension.

Since decades, bosentan has been in use for the treatment of pulmonary arterial hypertension (PAH). However, chronic exposure to bosentan leads to the development of resistance, tolerance, and serious adverse effects that have restricted its usage in clinical practices. To surmount these limitations, some new bosentan derivatives have been synthesized and evaluated for their therapeutic efficacy in PAH. Molecular docking analyses of all the synthesized derivatives were carried out using the endothelin (ET) receptor. In addition, the inhibitory ability of synthesized derivatives was determined in in vitro assay employing an ET-1 human ELISA kit. Among the synthesized derivatives, three derivatives namely 17d, 16j, and 16h with higher docking scores and lower IC50 values were selected for determination of the magnitude of the binding force between the derivative and ET receptor using molecular dynamics (MD) simulations study. Further, these derivatives were subjected to in vivo studies using monocrotaline (MCT) induced PAH in rat model. Results of in vivo studies inferred that the derivatives exhibit impressive ability to reduce PAH. Besides, its protective role was also evidenced in hemodynamic and right ventricular hypertrophy analyses, histological analysis, cardiac biomarkers, hypoxia-inducible factor 1 alpha (HIF1α) levels, and biochemical studies. Furthermore, gene quantification by quantitative RT-PCR and Western blot analysis was also performed to examine its effect on the expression of key proteins in PAH. Notably, amongst three, derivative 16h exhibited the most encouraging results in molecular docking analysis, in vitro, in vivo, histopathological, biochemical, protein expression, and MD studies. Besides, derivative 16h also showed impressive pharmacokinetic features in ADMET analysis. In conclusion, derivative 16 h could act as a reliable ET receptor antagonist and requires further exploration to attain its therapeutic utility in PAH management.

Macitentan for the Treatment of Refractory Digital Ulcers in Patients With Connective Tissue Diseases.

Systemic sclerosis (SSc) is a chronic autoimmune disease with complex pathogenesis, characterized by vascular dysfunction and fibrosis. Digital ulcers (DUs) are a common and severe complication in SSc patients, negatively impacting their quality of life. This retrospective study evaluates the use of macitentan, an endothelin receptor antagonist, in six female patients with connective tissue disease (CTD) and sclerodermiform features (five SSc and one mixed connective tissue disease) for the treatment of refractory DUs. Macitentan demonstrated a safe and effective alternative to bosentan, reducing DU relapses, hospitalizations, and the use of systemic prostaglandin therapy. The findings suggest that macitentan may be a valuable therapeutic option in specific cases of recurrent or refractory DUs and warrant further investigation in larger, long-term studies.

High energy ball milling vs. nano spray drying in the development of supersaturated systems loaded with bosentan.

In this study, high energy ball milling and nano spray drying were used to prepare amorphous solid dispersions of bosentan in copovidone for the first time. In particular, the impact of this polymer on the bosentan amorphization kinetics was investigated. Copovidone was shown to facilitate the amorphization of bosentan upon ball milling. As a result, bosentan was dispersed in copovidone at the molecular level, forming amorphous solid dispersions, regardless of the ratio of the compounds. The similarity between the values of the adjustment parameter that describes the goodness of fit of the Gordon-Taylor equation to the experimental data (K = 1.16) and that theoretically calculated for an ideal mixture (K = 1.13) supported these findings. The kind of coprocessing method determined the powder microstructure and the release rate. The opportunity to prepare submicrometer-sized spherical particles using nano spray drying was an important advantage of this technology. Both coprocessing methods allowed the formation of long-lasting supersaturated bosentan solutions in the gastric environment with maximum concentrations reached ranging from four (11.20 µg/mL) to more than ten times higher (31.17 µg/mL) than those recorded when the drug was vitrified alone (2.76 µg/mL). Moreover, this supersaturation lasted for a period of time at least twice as long as that of the amorphous bosentan processed without copovidone (15 min vs. 30-60 min). Finally, these binary amorphous solid dispersions were XRD-amorphous for a year of storage under ambient conditions.

Effectiveness of bosentan in the treatment of systemic sclerosis-related digital ulcers: Systematic review and meta-analysis.

Background: The aim of the present systematic review and meta-analysis was to evaluate the therapeutic efficacy of bosentan, a dual endothelin receptor antagonist, for systemic sclerosis (SSc) patients with digital ulcers (DUs). Materials and Methods: A systematic search of MEDLINE, Embase, Web of Science, and Scopus was done using appropriate keywords till September 2021. Weighted mean difference (WMD) as the effect of therapeutic efficacy of bosentan on continuous outcomes was an estimate. Furthermore, the pooled prevalence of diffuse SSc and limited SSc was computed. Fixed or random effects models when appropriate were used for data synthesis. Results: Totally, 469 patients, with a mean age ranging from 48.1 to 63.7 years, from 8 studies were included in the systematic review and meta-analysis. The pooled frequency of diffuse SSc and limited SSc was 56% (95% confidence interval [CI]: 39%, 73%) and 44% (95% CI: 27%, 61%). The pooled prevalence of new DUs following bosentan treatment was 21% (95% CI: 10%, 33%). The results of the meta-analysis showed a pooled mean decrease of WMD: -0.09 (95% CI: -0.020, 0.02, P = 0.10), WMD: -2.82 (95% CI: -5.91, 0.27, P = 0.07), and WMD: -6.65 (95% CI: -9.49, -3.82, P < 0.001) in mean SSc-Health Assessment Questionnaire, pain, and Rodnan score, respectively. Our meta-analysis also indicated a significant pooled decrease in the number of new DUs in SSc patients compared to placebo subjects (WMD: -0.89 [95% CI: -1.40, -0.37; P = 0.001]) and baseline values (WMD: -1.34 (95% CI: -1.95, -0.73; P < 0.001). Conclusion: Bosentan possibly is an efficacious treatment option for SSc-related DUs. Although further large-scale randomized clinical trials are required to confirm the preliminary finding and underlying mechanisms of action.

Endothelin-1 Induces Cell Proliferation and Myofibroblast Differentiation through the ETAR/Gαq/ERK Signaling Pathway in Human Cardiac Fibroblasts.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of cardiac fibrosis. Stimulation of endothelin receptors (ETR) with ET-1 leads to fibroblast activation and myofibroblast differentiation, which is mainly characterized by an overexpression of α-smooth muscle actin (α-SMA) and collagens. Although ET-1 is a potent profibrotic mediator, the signal transductions and subtype specificity of ETR contributing to cell proliferation, as well as α-SMA and collagen I synthesis in human cardiac fibroblasts are not well clarified. This study aimed to evaluate the subtype specificity and signal transduction of ETR on fibroblast activation and myofibroblast differentiation. Treatment with ET-1 induced fibroblast proliferation, and synthesis of myofibroblast markers, α-SMA, and collagen I through the ETAR subtype. Inhibition of Gαq protein, not Gαi or Gßγ, inhibited these effects of ET-1, indicating the essential role of Gαq protein-mediated ETAR signaling. In addition, ERK1/2 was required for ETAR/Gαq axis-induced proliferative capacity and overexpression of these myofibroblast markers. Antagonism of ETR with ETR antagonists (ERAs), ambrisentan and bosentan, inhibited ET-1-induced cell proliferation and synthesis of α-SMA and collagen I. Furthermore, ambrisentan and bosentan promoted the reversal of myofibroblasts after day 3 of treatment, with loss of proliferative ability and a reduction in α-SMA synthesis, confirming the restorative effects of ERAs. This novel work reports on the ETAR/Gαq/ERK signaling pathway for ET-1 actions and blockade of ETR signaling with ERAs, representing a promising therapeutic strategy for prevention and restoration of ET-1-induced cardiac fibrosis.