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The European Respiratory Journal Feb 2008The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together... (Review)
Review
The endothelin (ET) system, especially ET-1 and the ET(A) and ET(B) receptors, has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Together with prostanoids and phosphodiesterase 5 inhibitors, ET receptor antagonists have become mainstays in the current treatment of PAH. Three substances are currently available for the treatment of PAH. One of these substances, bosentan, blocks both ET(A) and ET(B) receptors, whereas the two other compounds, sitaxsentan and ambrisentan, are more selective blockers of the ET(A) receptor. There is ongoing debate as to whether selective or nonselective ET receptor blockade is advantageous in the setting of PAH, although there is no clear evidence that receptor selectivity is relevant with regard to the clinical effects of these drugs. For the time being, other features, such as safety profiles and the potential for pharmacokinetic interactions with other drugs used in the treatment of PAH, may be more important than selectivity or nonselectivity when selecting treatments for individual patients.
Topics: Animals; Bosentan; Clinical Trials, Phase III as Topic; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Isoxazoles; Phenylpropionates; Prognosis; Pyridazines; Randomized Controlled Trials as Topic; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Severity of Illness Index; Sulfonamides; Survival Rate; Thiophenes; Treatment Outcome
PubMed: 18238950
DOI: 10.1183/09031936.00078207 -
Kidney International Jan 2000Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
UNLABELLED
Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A.
BACKGROUND
Endothelins may play an important role in cyclosporine A (CsA)-induced renal vasoconstriction. Therefore, the effects of a mixed endothelin A and B receptor antagonist, bosentan (BO), on CsA were studied.
METHODS
BO was given either alone or combined with CsA to healthy subjects in a double-blind, placebo-controlled, cross-over study. Standardized renal hemodynamics took place after a single dose of BO or placebo and after seven days of regular intake of CsA + BO or CsA + placebo. CsA was administered as a dose-adjusted regimen to achieve predetermined target trough levels. A pharmacokinetic study of CsA and BO was performed.
RESULTS
A single dose of BO did not affect renal hemodynamics. After seven days of coadministration with CsA, BO significantly attenuated both the overall CsA-induced fall of renal plasma flow (RPF; placebo, 594 +/- 85; CsA + placebo, 490 +/- 93; CsA + BO, 570 +/- 106* mL/min, *P < 0.01) and the maximal RPF fall (P < 0.01) observed five hours after CsA intake. The CsA-induced rise of blood pressure and the decrease of glomerular filtration rate (GFR) were not influenced by comedication with BO. After seven days of CsA + BO, the area under the curve (AUC) of BO was nearly doubled compared with the AUC after a single dose of BO (P < 0.05). To reach the CsA target trough levels after seven days, the average CsA dose was increased by 35% when given with BO, as compared with placebo (P = 0.01). CsA exposure (trough levels, AUC) was not statistically different after CsA + placebo and after CsA + BO.
CONCLUSIONS
Assuming CsA nephrotoxicity is mainly due to vasoconstriction, BO has the potential to attenuate the CsA renal toxicity by markedly blunting the renal hypoperfusion effect of CsA. A complex drug interaction between BO and CsA was observed.
Topics: Adult; Blood Pressure; Bosentan; Cyclosporine; Double-Blind Method; Endothelin Receptor Antagonists; Humans; Kidney; Male; Placebos; Reference Values; Sulfonamides
PubMed: 10620203
DOI: 10.1046/j.1523-1755.2000.00838.x -
Drug Design, Development and Therapy 2016The objectives of this study were to prepare bosentan hydrate (BST) microparticles as dry powder inhalations (DPIs) via spray drying and jet milling under various...
The objectives of this study were to prepare bosentan hydrate (BST) microparticles as dry powder inhalations (DPIs) via spray drying and jet milling under various parameters, to comprehensively characterize the physicochemical properties of the BST hydrate microparticles, and to evaluate the aerosol dispersion performance and dissolution behavior as DPIs. The BST microparticles were successfully prepared for DPIs by spray drying from feeding solution concentrations of 1%, 3%, and 5% (w/v) and by jet milling at grinding pressures of 2, 3, and 4 MPa. The physicochemical properties of the spray-dried (SD) and jet-milled (JM) microparticles were determined via scanning electron microscopy, atomic force microscopy, dynamic light scattering particle size analysis, Karl Fischer titration, surface analysis, pycnometry, differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. The in vitro aerosol dispersion performance and drug dissolution behavior were evaluated using an Anderson cascade impactor and a Franz diffusion cell, respectively. The JM microparticles exhibited an irregular corrugated surface and a crystalline solid state, while the SD microparticles were spherical with a smooth surface and an amorphous solid state. Thus, the in vitro aerosol dispersion performance and dissolution behavior as DPIs were considerably different due to the differences in the physicochemical properties of the SD and JM microparticles. In particular, the highest grinding pressures under jet milling exhibited excellent aerosol dispersion performance with statistically higher values of 56.8%±2.0% of respirable fraction and 33.8%±2.3% of fine particle fraction and lower mass median aerodynamic diameter of 5.0±0.3 μm than the others (<0.05, analysis of variance/Tukey). The drug dissolution mechanism was also affected by the physicochemical properties that determine the dissolution kinetics of the SD and JM microparticles, which were well fitted into the Higuchi and zero-order models, respectively.
Topics: Aerosols; Bosentan; Chemistry, Physical; Chromatography, High Pressure Liquid; Dosage Forms; Dry Powder Inhalers; Molecular Structure; Particle Size; Sulfonamides; Surface Properties
PubMed: 28008226
DOI: 10.2147/DDDT.S120356 -
Vascular Health and Risk Management Mar 2010Raynaud's phenomenon is a common condition characterized by vasospasm of the digital arteries and resulting cyanosis and redness. It often does not require pharmacologic... (Review)
Review
Raynaud's phenomenon is a common condition characterized by vasospasm of the digital arteries and resulting cyanosis and redness. It often does not require pharmacologic management, but in some cases symptoms are severe and pharmacologic management is necessary. Calcium channel blockers are often used first-line, but in some patients are ineffective. Patients with severe symptoms or intolerance to available therapies have prompted exploration of alternative therapies, including endothelin antagonists, phosphodiesterase-5 inhibitors, antioxidants, newer vasodilators, statins, and botulinum toxin. These newer therapies provide the focus for this review.
Topics: Antioxidants; Bosentan; Botulinum Toxins, Type A; Calcium Channel Blockers; Endothelin Receptor Antagonists; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Iloprost; Phosphodiesterase 5 Inhibitors; Raynaud Disease; Serotonin Antagonists; Selective Serotonin Reuptake Inhibitors; Sulfonamides; Vasodilator Agents
PubMed: 20448801
DOI: 10.2147/vhrm.s4551 -
European Respiratory Review : An... Dec 2012The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few... (Review)
Review
The long-term prognosis for patients with pulmonary arterial hypertension (PAH) remains poor, despite advances in treatment options that have been made in the past few decades. Recent evidence suggests that World Health Organization functional class I or II patients have significantly better long-term survival rates than patients in higher functional classes, thus providing a rationale for earlier diagnosis and treatment of PAH. However, early diagnosis is challenging and there is frequently a delay between symptom onset and diagnosis. Screening programmes play an important role in PAH detection and expert opinion favours echocardiographic screening of asymptomatic patients who may be predisposed to the development of PAH (i.e. those with systemic sclerosis or sickle cell disease), although current guidelines only recommend annual echocardiographic screening in symptomatic patients. This article reviews the currently available screening programmes, including their limitations, and describes alternative screening approaches that may identify more effectively those patients who require right heart catheterisation for a definitive PAH diagnosis.
Topics: Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Early Diagnosis; Echocardiography, Doppler; Exercise Test; Humans; Hypertension, Pulmonary; Mass Screening; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Practice Guidelines as Topic; Purines; Respiratory Function Tests; Risk Factors; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents
PubMed: 23204118
DOI: 10.1183/09059180.00005112 -
International Heart Journal 2020Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to...
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.
Topics: Administration, Oral; Adult; Aged; Bosentan; Case-Control Studies; Endothelin Receptor Antagonists; Female; Hemodynamics; Humans; Japan; Male; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Placebos; Prostaglandins I; Pulmonary Arterial Hypertension; Pulmonary Wedge Pressure; Pyridazines; Pyrimidines; Retrospective Studies; Sulfonamides; Treatment Outcome; Vascular Resistance
PubMed: 32728000
DOI: 10.1536/ihj.20-173 -
Journal of Gastrointestinal and Liver... Mar 2011Bosentan is an endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension. Mild liver reactions occur in about 10% of treated patients but... (Review)
Review
Bosentan is an endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension. Mild liver reactions occur in about 10% of treated patients but severe hepatotoxicity is rare. We present clinical data and treatment outcome of a severe drug induced liver injury due to bosentan in a patient with non-cirrhotic portopulmonary hypertension. After 18 months of uncomplicated therapy with bosentan 125 mg b.i.d., the patient developed a severe mixed hepatic injury. Serum levels of bilirubin were 316 µmol/l (ref. value <20 micromol/l), AST 14 µkat/l (ref. value < 0.9 µkat/l), ALT 10 µkat/l (ref. value < 0.9 µkat/l), ALP 8 µkat/l (ref. value <1.8 µkat/l) and INR 1.8 (ref. value 0.9-1.1). Complete diagnostic work-up disclosed no other cause of hepatotoxicity. Treatment with prednisolone 40 mg/day in tapering doses was ultimately added and the patient made a full recovery. Subsequent treatment with sildenafil and ambrisentan for pulmonary arterial hypertension was well tolerated and liver function tests have remained normal during 12 months' follow-up. A review of the literature revealed three other women with severe hepatotoxicity due to bosentan. Bosentan may cause severe liver injury, even after long uneventful therapy, and current recommendations on regular monitoring of liver function tests are reinforced. Ambrisentan may be a therapeutic alternative in patients with pulmonary arterial hypertension and hepatotoxicity by bosentan.
Topics: Adult; Antihypertensive Agents; Bosentan; Chemical and Drug Induced Liver Injury; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Sulfonamides
PubMed: 21451802
DOI: No ID Found -
Arthritis Research & Therapy Oct 2016Systemic sclerosis (SSc) is characterized by early vascular abnormalities and subsequent fibroblast activation to myofibroblasts, leading to fibrosis. Recently,...
BACKGROUND
Systemic sclerosis (SSc) is characterized by early vascular abnormalities and subsequent fibroblast activation to myofibroblasts, leading to fibrosis. Recently, endothelial-to-mesenchymal transition (EndoMT), a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype, has been reported in SSc. In the present study, we evaluated the ability of endothelin-1 (ET-1) dual receptor antagonists bosentan (BOS) and macitentan (MAC) to antagonize EndoMT in vitro.
METHODS
Ten women with limited SSc were enrolled. They underwent double skin biopsy (affected and nonaffected skin). Fibroblasts and microvascular endothelial cells (MVECs) were isolated from biopsies. We performed mono- or coculture of MVECs (isolated from nonaffected skin) with fibroblasts (isolated from affected skin and stimulated with ET-1 and transforming growth factor beta [TGF-β]). In cocultures, the MVEC layer was left undisturbed or was preincubated with BOS or MAC. After 48 h of coculture, MVECs were analyzed for their tube formation ability and for messenger RNA and protein expression of different vascular (CD31, vascular endothelial growth factor-A [VEGF-A], VEGF-A165b) and profibrotic (alpha-smooth muscle actin [α-SMA], collagen type I [Col I], TGF-β) molecules.
RESULTS
After 48 h, MVECs showed a reduced tube formation ability when cocultured with SSc fibroblasts. CD31 and VEGF-A resulted in downregulation, while VEGF-A165b, the antiangiogenic isoform, resulted in upregulation. At the same time, mesenchymal markers α-SMA, Col I, and TGF-β resulted in overexpression in MVECs. Tube formation ability was restored when MVECs were preincubated with BOS or MAC, also reducing the expression of mesenchymal markers and restoring CD31 expression and the imbalance between VEGF-A and VEGF-A165b.
CONCLUSIONS
With this innovative EndoMT in vitro model realized by coculturing nonaffected MVECs with affected SSc fibroblasts, we show that the presence of a myofibroblast phenotype in the fibroblast layer, coupled with an ET-1-TGF-β synergic effect, is responsible for EndoMT. BOS and MAC seem able to antagonize this phenomenon in vitro, confirming previous evidence of endothelium-derived fibrosis in SSc and possible pharmacological interference.
Topics: Adult; Aged; Blotting, Western; Bosentan; Cell Transdifferentiation; Cells, Cultured; Coculture Techniques; Endothelial Cells; Endothelin Receptor Antagonists; Female; Fibroblasts; Humans; In Vitro Techniques; Middle Aged; Myofibroblasts; Pyrimidines; Real-Time Polymerase Chain Reaction; Scleroderma, Systemic; Sulfonamides
PubMed: 27716320
DOI: 10.1186/s13075-016-1122-y -
Rheumatology (Oxford, England) Dec 2023To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines.
OBJECTIVE
To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines.
METHODS
A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data.
RESULTS
Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs.
CONCLUSION
There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.
Topics: Adult; Humans; Skin Ulcer; Fingers; Scleroderma, Systemic; Bosentan
PubMed: 37335850
DOI: 10.1093/rheumatology/kead289 -
The European Respiratory Journal Jan 2013Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial...
Data on treatment of patients with portopulmonary hypertension (PoPH) are limited, as they are usually excluded from randomised controlled trials with pulmonary arterial hypertension (PAH)-specific therapies. This study investigated the short- and long-term efficacy/safety of bosentan in these patients, as well as its pharmacokinetics. All 34 consecutive patients with PoPH treated with first-line bosentan (December 2002 to July 2009) were retrospectively evaluated. Assessments included the New York Heart Association functional class (NYHA FC), blood tests, haemodynamics, 6-min walk distance (6MWD) and event-free status. The pharmacokinetics of bosentan in five patients with Child-Pugh (C-P) class B cirrhosis were compared with idiopathic PAH patients. Significant improvements from baseline were observed in NYHA FC, 6 MWD and haemodynamics, and were largely maintained during follow-up. Patients with C-P class B cirrhosis (n=9) had significantly larger haemodynamic improvement after mean ± SD 5 ± 2 months. Mean follow-up time was 43 ± 19 months; four patients died and seven patients had significant elevation of liver enzymes (annual rate 5.5%). Plasma concentrations of bosentan were higher in patients with C-P class B cirrhosis than those observed in idiopathic PAH. These data confirm the benefit of bosentan treatment for patients with PoPH. Haemodynamic improvements were particularly pronounced in patients with more severe cirrhosis. The safety profile of bosentan was consistent with previous studies.
Topics: Antihypertensive Agents; Bosentan; Female; Humans; Hypertension; Hypertension, Pulmonary; Male; Middle Aged; Portal System; Retrospective Studies; Sulfonamides
PubMed: 22653773
DOI: 10.1183/09031936.00117511