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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.

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. [ABSTRACT FROM AUTHOR]

Background: Persistent pulmonary hypertension (PPHN) is a life-threatening condition in neonates. In developing countries, mortality is estimated to be around 10%–20% due to lack of access to the main drug, inhaled nitric oxide. Bosentan as an endothelin type A and B receptor antagonist and sildenafil as a phosphodiesterase inhibitor type 5 are effective in reducing pulmonary vascular resistance and pulmonary artery pressure (PAP). Materials and Methods: A double-blind clinical trial was conducted at the intensive care unit of Akbarabadi Hospital Tehran between October 2017 and September 2019. The efficacy, safety, and possible side effects of bosentan and sildenafil were evaluated in neonates suffering from PPHN. Echocardiographic findings, duration of oxygen dependency, invasive ventilation support requirement, duration of medication, short-term outcomes including blood pressure, white blood cell, and hemoglobin counts were compared between the two groups. Results: Bosentan is as effective as sildenafil in reducing PAP and improving cardiac output. The duration of treatment with bosentan was significantly shorter than that of sildenafil (P = 0.002). The time of oxygen demand was similar between both the groups, ranging from 15 to 17 days (P = 0.198). The need for invasive ventilation support was similar in both the groups (P = 0.989). Although PAP and the severity of tricuspid valve insufficiency were higher before treatment, the third echocardiographic findings such as pulmonic insufficiency (P = 0.194), tricuspid regurgitation (P = 0.368), and ejection fraction (P = 0.160) were similar in bosentan and sildenafil groups. The need for supportive inotropic drugs was similar in both the groups. There was no statistically significant difference in the mean of blood pressure, white blood cell, and hemoglobin counts between the two groups.Conclusion: Bosentan is effective in the treatment of PPHN in neonates and reduces it over a shorter period of time. It is more efficient in reducing PAP and decreases the severity of tricuspid valve insufficiency in a shorter time compared to sildenafil. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the role of endothelin 1 (ET-1) in human breast cancer proliferation and migration and antagonism of endothelin receptor A (ETAR) and endothelin receptor B (ETBR) by using the non-selective dual ETA/ETB receptor antagonist bosentan and determine its anti-proliferative, anti-metastatic, and apoptotic effects demonstrated by nuclear factor kappa B (NF-kB), vascular endothelial growth factor (VEGF), Caspase 3 and Caspase 9 expression on endothelin-induced proliferation of MCF-7 cell line in vitro. Materials and Methods: A total of 8,000 cells were seeded into e-plates 24 hours after the cells were incubated with or without 10-4 M BOS (1 hour before ET-1 treatment); 10-7, 10-8, and 10-9 M ET-1 for 1-4 days. Results: Whether ET-1 is present or not in the tumor area, bosentan exerts anti-proliferative effect on breast cancer. However, ET-1 and bosentan group showed important inhibitory effect on tumor migration compared to bosentan alone, which can be attributed to increased activity of ET-1 axis in the presence of ET-1. The imbalance among the NF-kB, caspases, and VEGF, which are predictive factors of carcinogenesis significantly improved after bosentan administration. Conclusion: Our study definitely demonstrated ET-1 and its critical role in cancer progression with apoptotic and anti-apoptotic pathways (NF-κB) and VEGF expression, and migration analyses were also performed. The second major finding was that bosentan inhibited ET-1-mediated effects on tumor proliferation and migration. [ABSTRACT FROM AUTHOR]

PurposePlastic bronchitis is the occlusion of the major bronchial airways by a firm, gelatinous mucoid cast. It is a rare condition, which while classically described in asthma and sickle cell disease has greater mortality in patients with congenital heart disease. The management of this disease is obscure given the lack of clinical data regarding treatment therapies.MethodsWe describe a case of an 11-year-old female status after Fontan surgery who presented with respiratory distress secondary to atelectasis of the right lung.ResultsA bronchoscopy was performed demonstrating an obstructing bronchial cast with successful extraction. The plastic bronchitis continued to recur and she was placed on multiple inhaled mucolytics as well as inhaled tissue plasminogen activator with temporary resolution. Further evaluation of the etiology of her casts revealed that she had elevated pulmonary arterial pressures. Repeated bronchoscopic removal of the casts was utilized as well as continuation of the aggressive airway clearance. Ultimately fenestration of her Fontan was performed along with treatment of pulmonary vasodilators sildenafil and bosentan. Although there was improvement of the cast formation, her airway clearance could only be weaned to four times a day therapy with which she was discharged home after a 3-month hospitalization. She continues to remain on this therapy and has not required hospitalization since the initial incident over 1 year ago.ConclusionsPlastic bronchitis in a patient with Fontan physiology presents a treatment dilemma that may require comprehensive therapy in severe cases such as described.

Background: Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan.Objective: To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms.Methods: 27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients.Results: Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms.Conclusions: Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood.

BackgroundThree oral drugs (ambrisentan, bosentan, and sildenafil) have been widely used to treat patients with pulmonary arterial hypertension (PAH). 1) There are no studies that directly compare the safety and efficacy of these three drugs. Existing studies could not meet the physician’s need to select the most beneficial drugs for patients. 2) Principal component analysis is mainly used for scale analysis and has not been reported in clinical field. 3) When the results of the indirect meta-analysis were not satisfactory, no new solutions have been proposed in existing meta-analysis studies.MethodsThe overall process of this study is divided into 4 steps 1) literature search and data extraction; 2) principal component analysis; 3) common reference-based indirect comparison meta-analysis; 4) formal adjusted indirect comparison.ResultsNine randomized controlled trials (RCTs) experiments and eight long-term experiments were selected. The main influencing factors are mortality, 6-min walk distance (6MW), mean pulmonary arterial pressure (PAP), cardiac index (CI) by principal component analysis. There was no significant heterogeneity among the indirect meta-analysis of three drugs. But in the formal adjusted indirect comparison 1) the level of PAP of sildenafil group (60.5 ± 22.35, 220) was higher than that of the other three groups, placebo (53.5 ± 17.63, 507) (p < 0.001), ambrisentan (49.5 ± 15.08, 130) (p < 0.001), and bosentan (54.6 ± 118.41, 311) (p < 0.001); 2) the level of CI of sildenafil group (54 ± 18, 311) was higher than that of the other three groups, placebo (2.7 ± 1.09, 518) (p < 0.001), ambrisentan (2.5 ± 0.75, 130) (p < 0.001), and bosentan (2.5 ± 1.06, 333) (p < 0.001). In addition, sildenafil significantly improved the survival rate comparing with ambrisentan and bosentan.ConclusionsThe results of this study suggest that sildenafil might be more suitable for long-term treatment of PAH patients than ambrisentan and bosentan. In order to enable clinicians to draw conclusions more quickly and directly in the data-rich literature, we suggest the use of principal component analysis combined with formal adjusted indirect comparison to compare the efficacy and safety of drugs.

At the present time evidential base on bosentan use comprises more randomized control trials results compared with other Lag-specific medications. Bosentan can be successfully used as monotherapy of in combination with medications of other groups in patients with idiopathic pulmonary hypertension (PH), pulmonary arterial hypertension (PAH) comorbid with connective tissue disease (PAH-CTD), HIV (PAH-HIV), congenital heart disorders (systemic-to-pulmonary shunts) - PAH-CHD, and also in PH treatment and for disease progression delay in patients with unimpaired functional class. It is the only Lag-specific medication approved for use in children and the only medication of this group included in the list of essential medicines. The articles presents literature review of clinical trials on bosentan and discusses indications, contradictions and side effects of its use.

At the present time evidential base on bosentan use comprises more randomized control trials results compared with other Lag-specific medications. Bosentan can be successfully used as monotherapy of in combination with medications of other groups in patients with idiopathic pulmonary hypertension (PH), pulmonary arterial hypertension (PAH) comorbid with connective tissue disease (PAH-CTD), HIV (PAH-HIV), congenital heart disorders (systemic-to-pulmonary shunts) – PAHCHD, and also in PH treatment and for disease progression delay in patients with unimpaired functional class. It is the only Lag-specific medication approved for use in children and the only medication of this group included in the list of essential medicines. The articles presents literature review of clinical trials on bosentan and discusses indications, contradictions and side effects of its use.

Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

Pulmonary arterial hypertension (PAH) is a progressive and irreversible disease characterized by a steady increase in pulmonary vascular resistance (PVR) and death. Introduction of current PAH-specific drugs has not solved the problem of follow-up of critical patients with PAH associated with systemic sclerosis (SSc). Clinical trials have shown that 1-, 2- and 3-year survival rates are 77, 46, and 33%, respectively. Arguments in favor of starting triple PAH-specific therapy that substantially improves the prognosis of this critical group of patients are being accumulated. The paper describes Russia’s first clinical case of successful up-front triple combination therapy (iloprost, bosentan and sildenafil) in a 40 year old female with SSc and diagnosed functional class (FC) IV PAH. There were clinical, laboratory, and hemodynamic improvements already at 2 weeks after therapy initiation. Thirty-month therapy resulted in a reversal of FC from IV to II, relieved the signs of right ventricular failure, complete right ventricular reverse remodeling and subnormalization of hemodynamic parameters. Hemodynamic improvement including reductions in right atrial pressure to 4 mm Hg, mean pulmonary arterial pressure to 26 mm Hg, and PVR to 2.2 Wood units and an increase in cardiac output up to 7.4 l/min, despite preserved elevated uric acid levels (432 μmol/l). The intriguing feature of this case is critically low values of % predicted/carbon monoxide lung diffusion capacity, which rose from 17% to only 22%, in the presence of positive changes. This clinical case demonstrates the predictive capabilities of up-front triple combination therapy for severe PAH associated with SSc.

Background: Persistent pulmonary hypertension of the newborn (PPHN) contributes to neonatal hypoxemia and is associated with a high mortality. Some PPHN patients are unresponsive to inhaled nitric oxide (iNO). Bosentan, an oral endothelin-1 receptor antagonist, reduces pulmonary vascular resistance and hence may play a role in the treatment of PPHN. Methods: A retrospective medical records review was performed in newborns who received oral bosentan as an adjunctive therapy for treatment of PPHN between January 2013 and February 2016 at the neonatal intensive care unit of Songklanagarind Hospital. The main outcomes were the effect of bosentan on oxygenation and hemodynamic status after commencement of treatment and the safety of bosentan. Results: Forty neonates at a median (IQR) gestation of 38 (36.8–40) weeks and an initial median (IQR) oxygen index (OI) of 29.2 (13.4–40.1) received bosentan therapy. Oral bosentan was commenced at a median (IQR) age of 27 (14.5–40.2) hours and the mean (SD) duration of treatment was 6.2 (3.1) days. The OI, alveolar-arterial oxygen difference (AaDO2) and oxygen saturation (SpO2) improved significantly at 2 h after treatment (p = 0.002, p = 0.01 and p

Drug-induced liver injury, including cholestasis, is an important clinical issue and economic burden for pharmaceutical industry and healthcare systems. However, human-relevant in vitro information on the ability of other types of chemicals to induce cholestatic hepatotoxicity is lacking. This work aimed at investigating the cholestatic potential of non-pharmaceutical chemicals using primary human hepatocytes cultured in 3D spheroids. Spheroid cultures were repeatedly (co-) exposed to drugs (cyclosporine-A, bosentan, macitentan) or non-pharmaceutical chemicals (paraquat, tartrazine, triclosan) and a concentrated mixture of bile acids for 4 weeks. Cell viability (adenosine triphosphate content) was checked every week and used to calculate the cholestatic index, an indicator of cholestatic liability. Microarray analysis was performed at specific time-points to verify the deregulation of genes related to cholestasis, steatosis and fibrosis. Despite the evident inter-donor variability, shorter exposures to cyclosporine-A consistently produced cholestatic index values below 0.80 with transcriptomic data partially supporting its cholestatic burden. Bosentan confirmed to be hepatotoxic, while macitentan was not toxic in the tested concentrations. Prolonged exposure to paraquat suggested fibrotic potential, while triclosan markedly deregulated genes involved in different types of hepatotoxicity. These results support the applicability of primary human hepatocyte spheroids to study hepatotoxicity of non-pharmaceutical chemicals in vitro.

AIM: This study aims to compare the protective effects of ambrisentan, a selective endothelin typeA receptor antagonist, and bosentan, a dual endothelin typeA/B receptor antagonist, on experimental renal ischemia reperfusion injury. METHOD: The study sample consisted of 21 female rats, which were divided into 3 groups: Control, Ambrisentan and Bosentan. For the ischemia-reperfusion injury model, left-kidney nephrectomy was performed after sacrificing the animals. In the immunohistochemical examination, caspase-3 was examined, and then the apoptotic index was determined. In the biochemical examination, the activities of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, and the levels of nitrite (NOx), TNF-a, and IL-1ß were determined. RESULTS: There were statistically significant differences between the groups in terms of total injury score grade in range of 0 3 (p=0.001). The glomerular and tubular apoptotic indices were higher in the control group as compared to those of the ambrisentan and bosentan groups (p=0.001). There were no statistically significant differences in terms of SOD, CAT, GPx, MDA, IL-1ß and TNF-a measurements among the groups (p>0.05). CONCLUSIONS: In the experimentally created renal ischemia reperfusion model, both ambrisentan and bosentan increased the NOx level, decreased the apoptosis, and protected the kidney from renal ischemia reperfusion injury. However, no significant superiority was found between ambrisentan and bosentan in terms of their protective effects (Tab. 3, Fig. 2, Ref. 31). [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma is currently one of the leading causes of cancer-related death worldwide. The high rate of mortality in pancreatic cancer patients is due to the inability to detect early-stage disease and the disease being highly refractory to therapy. Gemcitabine has been the standard chemotherapy for advanced pancreatic cancer patients for the last two decades. However, gemcitabine resistance develops within a few weeks of treatment, and the associated mechanism remains poorly understood. Therefore, a novel therapeutic strategy is needed to overcome the limited clinical efficacy of gemcitabine in pancreatic adenocarcinoma. In this study, we demonstrated that ET-1/ETAR axis gene expression was upregulated in pancreatic cancer cells after treatment with gemcitabine. Additionally, ETAR expression was significantly higher in tumor tissues than in normal tissues, and patients with high ETAR expression had a notably worse overall survival rate than those with low ETAR expression. Furthermore, our results revealed that bosentan, an ETAR antagonist, enhanced the growth-inhibiting and proapoptotic effects of gemcitabine on pancreatic cancer cells. Thus, our findings indicate that blockade of the ET-1/ETAR axis signaling pathway promotes the antiproliferative effect of gemcitabine on pancreatic cancer. Therefore, combination of ETAR blockade and gemcitabine serves as an effective therapeutic approach to achieve clinical benefits in pancreatic adenocarcinoma patients. • Gemcitabine promoted ET-1/ETAR axis signaling in pancreatic cancer cells. • ETAR overexpression is correlated with a poor prognosis in pancreatic cancer patients. • ETAR antagonist enhanced the growth-inhibiting effect of gemcitabine on pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Objective: Digital ulcers related to systemic sclerosis (SS) are associated with disability and mortality in the progression of the disease. In our study, we investigated the duration of treatment and drug-related side effects on patients, who were started bosentan for the treatment of digital ulcers. Methods: SS patients with digital ulcers, who had a follow-up period in outpatient and inpatient clinics of Rheumatology Department, were included in our study. Duration of treatment and drug-related side effects were retrieved from the patient’s files. For the patients who did not come to the clinic in the last 6 months, visits were made over the phone. Results: A total of 30 patients were included in the study. The mean age of SS diagnosis was 37.5±14.7 years and 25 of these patients were female. The distribution of disease patterns was limited cutaneous for 25 patients and diffuse cutaneous for 5 patients. The median length of bosentan treatment was 31.0±23.9 months. Five patients required the discontinuation of bosentan due to adverse events including toxic hepatitis (2 patients) and headache (3 patients). Also, 3 patients discontinued the treatment on their own, despite the absence of adverse effects or toxicity. Conclusion: Bosentan, used for the treatment of digital ulcers in SS patients, has been shown to have an acceptable side-effect profile. [ABSTRACT FROM AUTHOR]

Background: Three oral drugs (ambrisentan, bosentan, and sildenafil) have been widely used to treat patients with pulmonary arterial hypertension (PAH). 1) There are no studies that directly compare the safety and efficacy of these three drugs. Existing studies could not meet the physician's need to select the most beneficial drugs for patients. 2) Principal component analysis is mainly used for scale analysis and has not been reported in clinical field. 3) When the results of the indirect meta-analysis were not satisfactory, no new solutions have been proposed in existing meta-analysis studies. Methods: The overall process of this study is divided into 4 steps 1) literature search and data extraction; 2) principal component analysis; 3) common reference-based indirect comparison meta-analysis; 4) formal adjusted indirect comparison. Results: Nine randomized controlled trials (RCTs) experiments and eight long-term experiments were selected. The main influencing factors are mortality, 6-min walk distance (6MW), mean pulmonary arterial pressure (PAP), cardiac index (CI) by principal component analysis. There was no significant heterogeneity among the indirect meta-analysis of three drugs. But in the formal adjusted indirect comparison 1) the level of PAP of sildenafil group (60.5 ± 22.35, 220) was higher than that of the other three groups, placebo (53.5 ± 17.63, 507) (p < 0.001), ambrisentan (49.5 ± 15.08, 130) (p < 0.001), and bosentan (54.6 ± 118.41, 311) (p < 0.001); 2) the level of CI of sildenafil group (54 ± 18, 311) was higher than that of the other three groups, placebo (2.7 ± 1.09, 518) (p < 0.001), ambrisentan (2.5 ± 0.75, 130) (p < 0.001), and bosentan (2.5 ± 1.06, 333) (p < 0.001). In addition, sildenafil significantly improved the survival rate comparing with ambrisentan and bosentan. Conclusions: The results of this study suggest that sildenafil might be more suitable for long-term treatment of PAH patients than ambrisentan and bosentan. In order to enable clinicians to draw conclusions more quickly and directly in the data-rich literature, we suggest the use of principal component analysis combined with formal adjusted indirect comparison to compare the efficacy and safety of drugs. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a rare and complex autoimmune disease associated with poor vital and functional outcomes. The functional hindrance in patients derives from various disease-specific manifestations, including Raynaud's phenomenon and digital ulcers (DUs). Bosentan is an endothelin receptor antagonist capable of preventing the appearance of new DUs in patients with scleroderma. The present study aimed to evaluate the effects of Bosentan on the severity of Raynaud's phenomenon, DU-related symptoms and functional impairment during the first year of treatment. A prospective study that included adult patients with SSc admitted to the Rheumatology Department between January 2016 and January 2017 that were candidates for Bosentan therapy, was performed. All patients were asked to evaluate the burden of symptoms secondary to Raynaud's and DUs using a visual analogue scale (VAS), whereas functional hindrance was assessed via Health Assessment Questionnaire Disability Index (HAQ-DI). The outcomes were assessed at baseline and every 3 months during 1 year of therapy. Among the 41 patients included initially, 2 participants discontinued the treatment after 1 month due to adverse events (elevation of liver enzymes). The study cohort exhibited a significant improvement in HAQ-DI, VAS-R and VAS-DU scores in response to Bosentan therapy over the 1-year follow-up period. Higher scores at baseline predicted a weaker treatment-related improvement, with the risk of a poor outcome being increased by 220% for VAS-R, 116% for VAS-DU, whereas no increase was observed for HAQ-DI. The post-treatment improvement in VAS-DU levels was associated with a better outcome for HAQ-DI (R=0.44; P=0.005). This association was not identified for VAS-R (R=0.24; P=0.137). Throughout the follow-up period, patients with dyspnea presented with significantly higher HAQ-DI scores compared with non-dyspneic patients. Bosentan therapy may indirectly influence functionality and quality of life in patients with scleroderma by reducing the burden of Raynaud's and DU-related symptoms. Nonetheless, patients with SSc with a decreased symptom burden at baseline exhibited improved outcomes. [ABSTRACT FROM AUTHOR]

1. This study aimed to investigate the inhibitory effect of azole antifungal agents, including ketoconazole, voriconazole, fluconazole, and itraconazole, on the pharmacokinetics of bosentan (BOS) and its active metabolite hydroxy bosentan (OHBOS) in Sprague–Dawley (SD) rats. 2. A total of 25 healthy male SD rats were divided into five groups and treated with various azole antifungal agents by gavage, followed by a single dose of BOS after 30 min. 3. The study found that ketoconazole led to a significant increase (5.1-fold) in the AUC(0-t) of BOS, associated with a 5.8-fold elevation in the Cmax, which was greater than that for fluconazole (2.6- and 2.9-fold) and voriconazole (1.1- and 1.7-fold). Accordingly, the Vz/F and CLz/F of BOS reduced by 89.2% and 83.7%, respectively, on administering ketoconazole concomitantly. However, fluconazole caused a decrease in Vz/F and CLz/F by 77.4% and 72.2%, respectively, compared with voriconazole that exhibited a decrease in CLz/F by 51.7% with a negligible change in Vz/F. Also, obvious differences were observed in the pharmacokinetic parameters of OHBOS between the control and treated groups. 4. Collectively, treatment with ketoconazole resulted in a prominent inhibitory effect on the metabolism of BOS, followed by treatment with fluconazole, voriconazole, and itraconazole. Therefore, these details of animal studies may help draw more attention to the safety of BOS while combining it with ketoconazole, voriconazole, fluconazole, or itraconazole clinically. [ABSTRACT FROM AUTHOR]

Introduction:  Bosentan is an endothelin-1 receptor antagonist with anti-inflammatory, antioxidant, and antiproliferative effects. We aimed to evaluate its effects on lung tissue in a pulmonary contusion (PC) model.Materials and Methods:  The rats were randomly divided into five groups: PC3: PC evaluated on the 3rd day (n = 8), PC-B3: PC enteral bosentan 100 mg/kg/day, for 3 days (n = 8), PC7: PC evaluated on the 7th day (n = 7), PC-B7: PC 7 days bosentan 100 mg/kg/day, for 7 days (n = 8), C: control (n = 6). Unilateral lung contusion was created by dropping a metal weight onto the chest. The rats were sacrificed on the 3rd or the 7th days. The lung tissue was evaluated histopathologically for alveolar edema, congestion, and leukocyte infiltration, biochemically for malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels, and immunohistochemically for inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and apoptosis scores.Results:  Alveolar edema, congestion, and leukocyte infiltration scores were increased in all groups compared with the control group (p < 0.05) and decreased in bosentan-treated groups compared with the relevant nontreated groups (p < 0.05). Fibrosis was observed only in PC7 and PC-B7 groups. Bosentan did not have any effect on fibrosis development. iNOS and eNOS levels were higher in all groups compared with the control (p < 0.05) without a difference in the nontreated versus treated groups (p > 0.05). Bosentan treatment caused decreased MDA and increased SOD levels in comparison to the nontreated groups (p < 0.05). Tissue NO levels did not show any significant difference among groups. PC groups had higher levels of apoptosis compared with the control group (p < 0.05). The degree of apoptosis decreased in bosentan-treated groups compared with the nontreated groups (p < 0.05).Conclusion:  PC causes progressive lung tissue damage. Bosentan reduced leukocyte infiltration and alveolar edema and congestion caused by PC. It also decreased MDA levels and increased SOD levels. Bosentan prevents tissue damage by inhibiting acute inflammatory response and reduces oxidative stress secondary to inflammation. It has therapeutic effects on apoptosis. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome is characterized by dyspnea at presentation, tachypnea on physical examination, findings of bilateral infiltration in chest radiography, refractory hypoxia, and high mortality. Although the main treatment approach is to address the underlying disease, there are also pharmacological and nonpharmacological options for supportive treatment. There is currently no pharmacological agent with proven efficacy in this syndrome, and many drugs are being studied for this purpose. One of these is the endothelin receptor antagonist bosentan. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a rare genetic disease. Precapillary pulmonary hypertension (PH) with NF1 is an extremely severe complication. A 65-year-old woman was admitted in our hospital with 3-year history of gradually worsening dyspnea on exertion (New York Heart Association functional class III-IV). Considering her clinical feature and examination findings, she could be diagnosed as PH associated with NF1. She was treated with endothelin receptor antagonist. However her dyspnea was not significantly improved. This is the first Korean case of NF1 patient with PH which confirmed with right heart catheterization.

Pulmonary arterial hypertension (PAH) is a life threatening syndrome, which is characterized by a progressive increase in pulmonary vascular resistance (PVR), medium pulmonary artery pressure and functional disorders and morphological changes of pulmonary arteries. Despite the relative abundance of PAH-specific drugs, the choice of a suitable agent for the treatment of a particular patient remains challenging. One of the most important parameters measured in clinical studies is patient survival or, in some cases, mortality. Survival or mortality as secondary or components of the primary endpoint one way or another has been studied in clinical trials of drugs for the treatment of PAH. For tablets drugs for the treatment of some forms of PAH (sildenafil, riociguat, bosentan, macitentan, ambrisentan) currently available data studies, which studied the survival.

Background: Pulmonary Arterial Hypertension (PAH) carries a poor prognosis in both adult and pediatric patients. It is a life-threatening condition in newborns. Current recommendations advocate the use of targeted monotherapy as a first-line approach for the treatment of Persistent Pulmonary Hypertension of the Newborn (PPHN). In case of an inadequate clinical response to treatment, an addition of a second or third agent is considered. PAH is usually managed with a phosphodiesterase 5 inhibitor or an endothelin receptor blocker. There are limited pediatric studies that address questions like which class of therapy should be initiated first or if a combination should be initiated together. With this background, the present study was initiated to compare the efficacy, safety, and tolerability of bosentan as an adjuvant to sildenafil and sildenafil alone in PPHN. Results: A total of 40 patients were enrolled in the study. Out of them, 26 were males (65%) and 14 were females (35%). PPHN was most commonly seen in the 29 (72.5%) of participants with a history of first order birth. Mean duration of symptoms was 14.05 ± 2.06 days. The participants were randomized to two groups. Group A consisted of total 25 participants that received both bosentan and sildenafil and group B had 15 participants that received sildenafil alone. Both groups were comparable in terms of birth weight and present weight, consanguinity, and mode of delivery. Efficacy was determined by the reduction in mean baseline Pulmonary Artery Systolic Pressure (PASP). PASP in group A was 75.56 ± 10.62mm Hg and in group B was 64.86 ± 12.25mm Hg which was not statistically significant (P > 0.05). PASP on the third and seventh day in group A were 43.72 ± 8.63 and 24.47 ± 3.52mm Hg compared to 42.28 ± 9.43 and 27.276 ± 8.38 respectively in group B which was statistically significant (P < 0.05). There were two deaths each in both groups. Two participants in Group A developed liver function abnormalities. None of the participants in Group B had adverse effects. Conclusion: Most common clinical manifestations were nonspecific. Cardiovocal syndrome was common in PPHN. We conclude that oral sildenafil treatment is a safe, simple and effective treatment for persistent pulmonary hypertension in newborn. Combination of bosentan with sildenafil is more effective and safe in reducing pulmonary artery (PA) pressures in high-risk patients with PPHN. [ABSTRACT FROM AUTHOR]

Objective: Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH. Methods: All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation. Results: In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56–6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962–4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up. Conclusion: CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Amorphous bosentan alone lacks dissolution flux that could enhance its bioavailability. Its coamorphization with hydrophilic copovidone (1:1) enables to improve wettability and dissolution rate, but fine amorphous particles are prone to moisture uptake. Water sorbed on the surface of this amorphous solid dispersion can considerably alter its physical properties annihilating benefits of coamorphization. The gravimetric measurements of water uptake, the solid state 1H NMR spectroscopy and relaxometry enabled us to describe for the first time, phase changes initiated by hydration in amorphous bosentan systems. The properties of copovidone greatly impacted water uptake in bosentan solid dispersions. A nonlinear reduction of the Tg upon water sorption resulted in the transformation of the glassy state into the rubbery state at ambient temperature. The state diagrams were developed for optimization of manufacturing conditions, selection of suitable packaging material and storage temperature, ensuring long-term stability of amorphous bosentan products. [Display omitted] • Polarity of copovidone enhances bosentan wettability and dissolution flux. • Copovidone load correlates with moisture uptake in coamorphous bosentan systems. • Hydration of amorphous bosentan samples is reversible (physisorption). • Sorbed water transforms glassy state into rubbery state at ambient temperature. • Solid state diagrams enable to optimize amorphous drug manufacturing and storage. [ABSTRACT FROM AUTHOR]