Pulmonary hypertension: Hemodynamic assessment and response to vasodilators
Debabrata Mukherjee, Eric R. Bates, Marco Roffi, Richard A. Lange, David J. Moliterno, Nadia M. Whitehead in Cardiovascular Catheterization and Intervention, 2017
Bosentan, a nonselective endothelin receptor blocker, was the first orally available therapy approved for PAH. It was studied in two placebo-controlled, randomized trials of FC III or IV patients.123, 124 In the pivotal Bosentan: Randomized Trial of Endothelin Receptor Antagonist Therapy for Pulmonary Hypertension 1 (BREATHE-1) trial, bosentan improved the primary endpoint of 6MWD by 36 m, whereas placebo patients deteriorated by 8 m (P = 0.0002). Bosentan also improved the composite endpoint of time to clinical worsening, which was defined as death, initiation of IV epoprostenol, hospitalization for worsening PAH, lung transplantation, or atrial septostomy. Long-term observational results have shown improved survival compared with expected outcome based on the NIH registry equation.125 Bosentan was shown to be effective in mildly symptomatic patients in the Treatment of Patients with Mildly Symptomatic Pulmonary Arterial Hypertension with Bosentan (EARLY) study, a 6-month, multicenter, placebo- controlled trial, which enrolled 168 FC II PAH patients.126 The results demonstrated a significant decrease in PVR, which was the primary endpoint to evaluate treatment effects on vascular remodeling, and a significant delay in clinical worsening.
Control of blood vessels: intrinsic control
Neil Herring, David J. Paterson in Levick's Introduction to Cardiovascular Physiology, 2018
Hypoxia stimulates ET production, so plasma levels increase with altitude and may contribute to high-altitude pulmonary hypertension. Plasma ET is also raised in pre-eclamptic toxaemia, the acute hypertension of pregnancy. ET makes a small contribution to essential hypertension (Chapter 18). In heart failure, a raised plasma ET also contributes to the characteristic renal and peripheral vasoconstriction. Consequently, bosentan significantly increases peripheral blood flow, dilates veins and reduces BP in heart failure patients. Subarachnoid haemorrhage, ischaemic strokes and brain trauma raise the ET content of cerebrospinal fluid, contributing to the cerebral vasospasm associated with these conditions. Cerebral vasospasm is ameliorated by bosentan.
The Patient with Non-Group 2 Pulmonary Hypertension
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Bosentan is an endothelin 1 antagonist that blocks both ETA and ETB receptors by binding to them. Bosentan treatment is initiated at a dose of 62.5 mg twice daily for four weeks and then the dose is increased to the approved maintenance dose of 125 mg twice daily. In the BREATH-1 trial, patients in the bosentan arm showed a significant improvement in the 6-minute walk test distance and WHO functional class compared with the placebo arm42 In mildly symptomatic PAH, improvements in pulmonary vascular resistance and delayed time to clinical worsening vs placebo were observed in the EARLY study.43 Bosentan was also evaluated with respect to response of other forms of PAH, such as Eisenmenger syndrome (BREATH-5 study),44,45 in pediatric patients,46 HIV-related PAH,47 and in those with porto-pulmonary hypertension.48 Monitoring of liver transaminases is required in patients treated with bosentan as elevated aspartate aminotransferase or alanine aminotransferase levels more than three times the upper limit of normal subject are not uncommon during therapy and may necessitate dose reduction or treatment discontinuation.
Systemic capillary leak syndrome following bosentan treatment in a patient with systemic sclerosis
Published in Scandinavian Journal of Rheumatology, 2019
J Vikse, LG Gøransson, KB Norheim
The pathophysiology of SCLS is not completely understood, but a role of endothelial cell apoptosis and elevated levels of vascular endothelial growth factor, angiopoietin-2, and pro-inflammatory cytokines has been hypothesized (2, 3). While vasculopathy and capillary leakage are involved in the pathophysiology of SSc (4), only a couple of cases with SSc and SCLS have been reported (5–7). Drugs may trigger SCLS, but bosentan-induced SCLS has not previously been reported. Bosentan is a dual endothelin receptor antagonist (ERA), which inhibits binding of endothelin-1 (ET-1) to endothelin receptor A and B (ETA, ETB). The endothelin system is involved in regulation of vasomotor tone, vascular permeability, and fluid homeostasis, and fluid retention and oedema are commonly reported adverse events of ERAs (8).
Phase three clinical trials in idiopathic pulmonary fibrosis
Published in Expert Opinion on Orphan Drugs, 2021
Giacomo Sgalla, Marialessia Lerede, Luca Richeldi
Bosentan, an ETa and ETb endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension, was tested in 2008 with a phase III randomized, double blind placebo-controlled trial (ClinicalTrials.gov Identifier NCT00071461) called BUILD-1 (Bosentan Use in Interstitial Lung Disease). The administration of an oral daily dose of bosentan for 12 months in mild-moderate IPF patients did not meet the primary outcome of improvement in exercise tolerance (expressed as change from baseline in the 6-minute walking distance). On the other hand, Bosentan showed positive results with regards to a few secondary endpoints, including time to death or disease progression and dyspnea scores in a subgroup of randomized subjects with histological IPF diagnosis [37,[38]. Nevertheless, a second phase III trial with the same design (BUILD-3, ClinicalTrials.gov Identifier NCT00391443) published in 2011 did not show any efficacy of Bosentan in reducing morbidity and mortality in IPF patients [39].
Oral drugs used to treat persistent pulmonary hypertension of the newborn
Published in Expert Review of Clinical Pharmacology, 2020
Wei Zhang, Yue-E Wu, Xiao-Yan Yang, Jing Shi, John van den Anker, Lin-Lin Song, Wei Zhao
Due to the low prevalence and scarce RCTs of PPHN, the results of ADE might be underestimated. Drug-induced liver injury is the most common adverse effect of bosentan in adults [74]. However, the present literature did not report any liver injury in neonates [11,28,35–38,100]. Moreover, an internet-based post-marketing surveillance study showed that the incidence of hepatotoxicity appears to be lower in children than adolescents and adults. A couple of reasons may explain this phenomenon: the dose used in children leads to slightly lower concentrations; children have fewer comorbidities and might be treated in the early phase [101]. Since most aminotransferase elevations happen during the first 6 months of the treatment and less likely to occur after 1 year, a monthly check of liver enzymes should be performed during the treatment with bosentan [74,102]. Notably, the liver injury is usually reversible and often decreases with dose reduction, or therapy discontinuation [103]. Other major ADEs we found were red blood cell transfusion, anemia and edema, probably because bosentan represses the role of ET-1 in erythrocyte survival protection and natriuresis [104,105].
Related Knowledge Centers
- Edema
- Endothelin Receptor Antagonist
- Glibenclamide
- Liver Disease
- Pulmonary Hypertension
- Systemic Scleroderma
- Hemoglobin
- Hormonal Contraception
- Elevated Transaminases
- Pulmonary Venoocclusive Disease