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Background: Access to inhaled nitric oxide (iNO) is limited in low resource settings due to non-availability and high cost. There is a need for research on low-cost alternative therapies for management of persistent pulmonary hypertension of the newborn (PPHN). We aimed to compare oral sildenafil and bosentan as monotherapy in the treatment of neonates with PPHN., Study Design: In this single-centre open-label randomized controlled trial (RCT), term and late preterm neonates with PPHN, defined as pulmonary arterial systolic pressure (PASP) > 35 mmHg and requiring fraction of inspired oxygen (FiO 2 ) > 0.21, were randomized to receive oral sildenafil and bosentan. The primary outcome was reduction of PASP by 25% within 48 h after start of drug., Results: Thirty-six neonates were analyzed (18 in each group). Initial PASPs were similar in both groups. The median (IQR) time for the primary outcome (PASP to reduce by 25% within 48 h) was 36 (24-48) h and 96 (48-120) h in sildenafil and bosentan groups respectively (p = 0.008). There was also a higher need to add other pulmonary vasodilators in bosentan group as compared to sildenafil group (p = 0.006)., Conclusion: Sildenafil was associated with quicker reduction of PASP and FiO 2 in neonates with PPHN, as compared to bosentan. Large multicentre blinded trials to assess efficacy and safety of bosentan in comparison with other pulmonary vasodilators would help to get a clearer understanding of its role in the management of PPHN, particularly for use in resource-limited settings that lack iNO., Clinical Trial Registration: https://ctri.nic.in/Clinicaltrials/rmaindet.php? trialid=63997&EncHid=39716.16132&modid=1&compid=19[CTRI/2022/06/043328]., (© 2024. The Author(s).)

Hypothesis: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs., Experiments: The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs., Findings: It was shown that binary formulations in which bosentan was molecularly dispersed in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

What Is Known and Objective: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH., Methods: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index., Results: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02)., What Is New and Conclusion: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH., (© 2021 John Wiley & Sons Ltd.)

Bosentan is a high-affinity antagonist of endothelin receptors and one of the earliest examples for target-mediated drug disposition [a type of nonlinear pharmacokinetics (PKs) caused by saturable target binding]. The previous physiologically based PK (PBPK) modeling indicated that the nonlinear PKs of bosentan was explainable by considering saturable hepatic uptake. However, it remained unexamined to what extent the saturable target binding contributes to the nonlinear PKs of bosentan. Here, we developed a PBPK model incorporating saturable target binding and hepatic uptake and analyzed the clinical bosentan PK data using the cluster Gauss-Newton method (CGNM). The PBPK model without target binding fell short in capturing the bosentan concentrations below 100 nM, based on the PK profiles and the goodness-of-fit plot. Both global and local identifiability analyses (using the CGNM and Fisher information matrix, respectively) informed that the target binding parameters were identifiable only if the observations from the lowest dose (10 mg) were included. By analyzing blood PK profiles alone, the PBPK model with target binding yielded practically identifiable target binding parameters and predicted the maximum target occupancies of 0.6-0.8 at clinical bosentan doses. Our results indicate that target binding, albeit not a major contributor to the nonlinear bosentan PKs, may offer a prediction of target occupancy from blood PK profiles alone and potential guidance on achieving optimal efficacy outcomes, under the condition when the high-affinity drug target is responsible for the efficacy of interest and when the dose ranges cover varying degrees of target binding. SIGNIFICANCE STATEMENT: By incorporating saturable target binding, our physiologically based pharmacokinetic (PBPK) model predicted in vivo target occupancy of bosentan based only on the blood concentration-time profiles obtained from a wide range of doses. Our analysis highlights the potential utility of PBPK models that incorporate target binding in predicting target occupancy in vivo., (Copyright © 2021 The Author(s).)

Introduction :Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening neonatal condition, mostly treated with inhaled nitric oxide (iNO), intravenous prostaglandins, oral bosentan, sildenafil and tadalafil. However, the utility of non-oral agents is limited in PPHN for their side effects and inconvenient deliveries. Therefore, oral agents such as bosentan, sildenafil and tadalafil are becoming appealing for their satisfactory efficacy, easy mode of administration and acceptable side effects. Areas covered : We conducted a comprehensive search on Pubmed, Scopus, Web of Sciences concerning the use of bosentan, sildenafil and tadalafil to treat PPHN and summarized their efficacy, safety and pharmacokinetics. Expert opinion : Current randomized controlled trials (RCTs) have demonstrated the favorable responses and tolerable side effects of bosentan and sildenafil. Nevertheless, those RCTs are small and only one study has described the pharmacokinetics of sildenafil in neonates. Accordingly, bosentan, sildenafil and tadalafil remain off-label in clinical use. More well-designed RCTs with large samples and long-term follow-up and pharmacometrics studies are needed to demonstrate the efficacy, safety and pharmacokinetics of bosentan, sildenafil and tadalafil in PPHN.

Traumatic brain injury (TBI) is induced by the immediate physical disruption of brain tissue. TBI causes disruption of the blood-brain barrier (BBB) and brain edema. In the cerebrospinal fluid (CSF) of TBI patients, endothelin-1 (ET-1) is increased, suggesting that ET-1 aggravates TBI-induced brain damage. In this study, the effect of bosentan (ET A /ET B antagonist) and ambrisentan (ET A antagonist) on BBB dysfunction and brain edema were examined in a mouse model of TBI using lateral fluid percussion injury (FPI). FPI to the mouse cerebrum increased the expression levels of ET-1 and ET B receptors. Administration of bosentan (3 or 15 mg/kg/day) and ambrisentan (0.1 or 0.5 mg/kg/day) at 6 and 24 h after FPI ameliorated BBB disruption and cerebral brain edema. Delayed administration of bosentan from 2 days after FPI also reduced BBB disruption and brain edema, while ambrisentan had no significant effects. FPI-induced expression levels of ET-1 and ET B receptors were reduced by bosentan, but not by ambrisentan. In cultured mouse astrocytes and brain microvessel endothelial cells, ET-1 (100 nM) increased prepro--ET-1 mRNA, which was inhibited by bosentan, but not by ambrisentan. FPI-induced alterations of the expression levels of matrix metalloproteinase-9, vascular endothelial growth factor-A, and angiopoietin-1 in the mouse cerebrum were reduced by delayed administration of bosentan, while ambrisentan had no significant effects. These results suggest that ET antagonists are effective in improving BBB disruption and cerebral edema in TBI patients and that an ET A /ET B non-selective type of antagonists is more effective., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Patent ductus venosus (PDV) is a rare and critical disease, and the majority of patients present with pulmonary arterial hypertension (PAH) or hepatopulmonary syndrome due to congenital portosystemic shunt. We reported that both PAH and hypersplenism were major complications of PDV in this case. This case report can assist the treatment and recovery of the patients with similar symptoms., Patient Concerns: A 4-year-old male patient presented to our institution with a history of recurrent respiratory infections accompanied by leukocytopenia, thrombocytopenia and presented with tachypnoea. upon mild exertion., Diagnosis: A wide communication, 10 mm in diameter, between the portal vein and inferior vena cava was identified in the subcostal echocardiogram and computed tomography images. Echocardiography showed an estimated systolic pulmonary artery pressure of 106 mm Hg. Right-sided cardiac catheterization indicated a mean pulmonary arterial pressure of 30 mm Hg and a pulmonary vascular resistance of 3 Wood units. Chest X-ray revealed cardiomegaly with a prominent pulmonary segment., Interventions: The patient was treated with combination pharmacotherapy of bosentan and tadalafil and PDV ligation., Outcomes: A year later, the boy showed normal exercise tolerance and weight gain. Liver and spleen parameters, liver function, blood cells and the general condition of the boy improved., Conclusion: Initial combination therapy of bosentan and tadalafil is safe and effective in children with PAH associated with PDV. When PDV banding test shows normal portal pressure, PDV ligation is considered acceptable in children with PAH and hypersplenism associated with PDV.

Background: Recently published meta-analyses did not discriminate between drug agents used for initial and sequential combination therapy. Objective: To assess the comparative efficacy of drugs specific for the treatment of pulmonary arterial hypertension (PAH) as add-on therapies based on 6-minute walk distance (6MWD), all-cause mortality, and discontinuation due to adverse events (AEs). Methods: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched until December 9, 2018, for the randomized, placebo-controlled clinical trials (RCTs) conducted on primarily adult patients diagnosed with PAH. Data extracted from applicable RCTs were as follows: for 6MWD mean change from baseline, the total number of patients, and the number of patients with events, per treatment. Network meta-analysis (NMA) was conducted in a Bayesian framework. Results: A total of 16 RCTs were eligible for analysis, with 4112 patients. Add-on therapy with tadalafil or inhaled treprostinil performed better than endothelin receptor antagonists alone [27 m; 95% credible interval (CrI): (11, 43); and 19 m; 95% CrI: (10, 27); respectively]. Add-on therapy with macitentan or bosentan performed better than phosphodiesterase type 5 inhibitors alone [26 m; 95% CrI: (6.4, 45); and 22 m; 95% CrI: (5.1, 38); respectively]. Differences in all-cause mortality and discontinuation due to AEs were nonsignificant. Conclusion and Relevance: Our NMA evaluated efficacy and safety of add-on therapies in patients with PAH. None of the previous meta-analyses evaluated RCTs focusing solely on patients pretreated with another PAH-specific drug therapy. Our results support guideline recommendations on combination therapy in PAH patients and add the quantitative perspective on which sequential therapy demonstrated the greatest effect size.

Prenatal closure of foramen ovale without CHD is a rarely reported entity. Therefore, clinical and echocardiographic findings are poorly defined in these patients. We report a patient with prenatal closure of foramen ovale that presented with severe pulmonary hypertension of the newborn and left ventricular failure. Judicious management strategies were utilised to successfully treat both life-threatening conditions.

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.

Purpose: Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis., Methods: PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach., Results: Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs., Conclusion: The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.

Background: Bronchopulmonary dysplasia (BPD) remains an important cause of morbidity and mortality in premature infants. There is currently no proven effective treatment modality for BPD, and inflammation and oxidative injury play an important role in the pathogenesis of this disease. This study investigated the histopathological and biochemical effects of bosentan, which is a non-specific endothelin receptor antagonist with known antioxidant and anti-inflammatory properties, on hyperoxia-induced lung injury (HILI) in neonatal rats., Methods: The experiment was performed on newborn rats from the 3rd to the 13th postnatal day. The rats were randomly divided into six groups: Group 1 (air-exposed + saline, n = 6); Group 2 (HILI, n = 8); Group 3 (air-exposed + bosentan, n = 7); Group 4 (HILI + saline, n = 7); Group 5 (HILI + early bosentan-treated group, n = 6), and Group 6 (HILI + late bosentan-treated group, n = 7). Bosentan was administered (30 mg/kg/day) intraperitoneally. The histopathological effects of bosentan on lung tissue were assessed by their alveolar surface area, fibrosis, and smooth muscle actin (SMA) scores, and the biochemical effects on lung tissue were assessed by interleukin-1 beta (IL-1β), IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)., Results: The alveolar surface area and fibrosis scores were found to be significantly higher in HILI groups compared with Group 1 (P < 0.01). The SMA scores in HILI groups were also significantly higher than Group 1 (P < 0.01). Bosentan treatment, especially late therapy, reduced all of these histopathological scores and the levels of IL-6 and TNF-α in the hyperoxia groups (P < 0.01)., Conclusion: This experimental study showed that bosentan had a protective effect on hyperoxic lung injury through its anti-inflammatory properties., (© 2019 Japan Pediatric Society.)

The aim of this study was to evaluate the participation of the endothelin ET A and ET B receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1 mg/kg of oxaliplatin intravenously, twice a week for 5 weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ET A and ET B receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10 nmol in 30 μL, intraplantarly) and non-selective (bosentan, 100 mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56 days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ET A receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ET B receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ET A and ET B receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ET A and ET B receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.

Aims: To evaluate the pharmacokinetics and safety of once-daily (QD) tadalafil in paediatric patients with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further research., Methods: This was an open-label, multicentre, international, multiple-ascending-dose study. Patients aged ≥2 years were enrolled into 1 of 3 cohorts based on body weight: heavy-weight (≥40 kg), middle-weight (25 to <40 kg), and light-weight (<25 kg). Each patient received tadalafil QD for 10 weeks: 5 weeks at a low dose, then 5 weeks at a high dose. The doses for each cohort were intended to produce plasma tadalafil concentrations within the range produced by 5-10 mg (for the low dose) or 20-40 mg (for the high dose) of tadalafil in adults with PAH. Area under the plasma concentration-time curve during 1 dosing interval (AUC τ ), maximum concentration, and apparent clearance were assessed throughout the trial, as were safety and tolerability., Results: The study enrolled 19 patients aged 2-17 years, weighing 9.9-76.0 kg. Tadalafil's median (range) steady-state AUC τ at the high dose was 7243 (3131-13 088) ng•h/mL across all patients. Concentrations were higher in no bosentan-treated patients than in bosentan-treated patients, but both populations were within the range of respective adult patients taking 20-40 mg QD. Tadalafil had an acceptable safety profile consistent with the known safety profile of tadalafil in adults., Conclusions: Tadalafil 40 mg QD for patients ≥40 kg, and 20 mg QD for patients <40 kg and aged ≥2 years, are suitable for further research in paediatric patients with PAH., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The amphiphilic propyl Karaya gum (KG) with a degree of propyl group substitution of 3.24 was synthesized to design self-assembled nanogels as carriers for bosentan monohydrate, a poorly soluble antihypertensive drug. The drug was physically hosted into the hydrophobic core of the micellar nanogels by solvent evaporation method. TEM images revealed spherical shape and core-shell morphology of the nanogels. Depending upon polymer: drug weight ratio, the drug entrapment efficiency of >85% was attained. The carriers had hydrodynamic diameter in the range of 230-305 nm with narrow size distribution. The zeta potential of -23.0 to -24.9 mV and low critical association concentration (CAC) of 8.32 mg/l provided evidence that the colloidal nanogel system was physically stable. Thermodynamics of the propyl KG system in water favored spontaneous self-assembly of propyl KG. FTIR, thermal and x-ray analyses suggested that the drug was compatible in the hydrophobic confines of the nanogels. The micellar nanogels liberated their contents in simulated gastrointestinal condition in a pH-dependent manner over a period of 10 h. Peppas-Sahlin modeling of in vitro drug release data suggested that the polymer relaxation/swelling mechanism dominated the drug release process. Pre-clinical testing of the mucoadhesive nanogel formulations exhibited that the system could monitor the anti-hypertensive activity for a prolonged period. Overall, this propyl KG micellar nanogel system had a great potential and splendid outlook to serve as novel oral controlled release carriers for poorly soluble drugs with outstanding pharmacodynamics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The present study was aimed to explore the role of endothelins in remote preconditioning (RP)-induced myocardial protection in ischemia-reperfusion (IR) injury. RP stimulus was given by subjecting hind limb to four cycles of ischemia and reperfuion (5 minutes each) using blood pressure cuff in male rats. Following RP, hearts were isolated and subjected to 30 minutes of ischemia and 120 minutes of reperfusion on Langendorff apparatus. The extent of myocardial injury was determined by measuring the levels of LDH-1, CK-MB and cardiac troponin T (cTnT) in coronary effluent; caspase-3 activity and Bcl 2 expression in heart (apoptosis); infarct size by triphenyl tetrazolium chloride and contractility parameters including left ventricular developed pressure, dp/dt max dp/dt min and heart rate. RP reduced ischemia reperfusion-induced myocardial injury, increased the levels of endothelin 1 (in blood), Akt-P, GSK-3β-P and P-connexin 43 (in hearts). Pretreatment with ET A receptor antagonist, BQ 123 (1 and 2 mg/kg), ET B receptor antagonist, BQ 788 (1 and 3 mg/kg) and dual inhibitor of ET A and ET B receptor, bonsentan (25 and 50 mg/kg) abolished these effects of RP. However, the effects of bonsentan were more pronounced in comparison to BQ 123 and BQ 788. It is concluded that RP stimulus may release endothelin 1 in the blood, which may activate myocardial ET A and ET B receptors to trigger cardioprotection through connexin 43 and Akt/GSK-3β pathway.