-
Heart Disease (Hagerstown, Md.) 2003Bosentan is the first endothelin (ET) receptor antagonist approved by the Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). In... (Review)
Review
Bosentan is the first endothelin (ET) receptor antagonist approved by the Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). In patients with World Health Organization Class III and IV PAH, bosentan has demonstrated improvement in dyspnea and exercise tolerance. ET also plays an important role in the pathophysiology of different vascular diseases. Therefore, bosentan also may have the potential to alter the outcome of many other diseases, such as heart failure, hypertension, ischemic heart disease, and renal disease, as well as cerebrovascular disorders. Because of the rarity and the poor prognosis of patients with PAH, as well as the requirement of close monitoring of bosentan (due to its potential of causing liver dysfunction and its teratogenic effects), bosentan is currently available only through a special access program and is distributed by certain selected pharmacies. Patients who are receiving bosentan should be taught to recognize early signs and symptoms of liver dysfunction and possible pregnancy. In addition, bosentan is not only a substrate but also an inducer of CYP3A4 and CYP2C9. Therefore, it is anticipated that numerous drug interactions may occur. Patients should be advised to consult their physicians or pharmacists should they need to consume other prescription or nonprescription medications.
Topics: Antihypertensive Agents; Bosentan; Drug Labeling; Endothelin Receptor Antagonists; Heart Failure; Humans; Hypertension; Myocardial Ischemia; Sulfonamides
PubMed: 12713683
DOI: 10.1097/01.hdx.0000061696.83820.51 -
Journal of Clinical Hypertension... 2002
Review
Topics: Antihypertensive Agents; Bosentan; Humans; Sulfonamides
PubMed: 11821645
DOI: 10.1111/j.1524-6175.2002.00748.x -
Current Opinion in Investigational... Nov 2008Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis of lung fibrosis, therefore it was hypothesized that the oral dual endothelin receptor antagonist bosentan may have efficacy for the treatment of IPF. The BUILD-1 study evaluated the efficacy, safety and tolerability of bosentan in patients with IPF. Bosentan was associated with a trend toward delayed time to disease progression or death and improvement in quality-of-life, both of which were more pronounced in patients with a biopsy-confirmed IPF diagnosis. These observations are being investigated in the ongoing BUILD-3 trial.
Topics: Animals; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Pulmonary Fibrosis; Randomized Controlled Trials as Topic; Sulfonamides
PubMed: 18951296
DOI: No ID Found -
Future Cardiology Jan 2011Pulmonary hypertension is a severe progressive disease with a marked morbidity and a high mortality attributed to right heart failure. Bosentan, a dual endothelin... (Review)
Review
Pulmonary hypertension is a severe progressive disease with a marked morbidity and a high mortality attributed to right heart failure. Bosentan, a dual endothelin receptor antagonist, is an effective and well-tolerated oral therapy for the management of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension). Bosentan improves cardiopulmonary hemodynamics, exercise capacity, WHO functional class and quality of life, as well as delaying time to clinical worsening in patients with PAH. This article reviews the role of endothelin-1 in the pathogenesis and progression of PAH, the diagnosis of PAH and the pharmacology of bosentan, and summarizes the current available evidence for the safety and efficacy of bosentan for the treatment of PAH as a monotherapy and combination therapy, as well as its role in the management of other forms of pulmonary hypertension.
Topics: Antihypertensive Agents; Bosentan; Comorbidity; Disease Progression; Endothelin Receptor Antagonists; Endothelin-1; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Prognosis; Quality of Life; Receptors, Endothelin; Sulfonamides
PubMed: 21174507
DOI: 10.2217/fca.10.114 -
Expert Review of Cardiovascular Therapy Dec 2009Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and underdiagnosed disease characterized by progressive hypertension secondary to organized thrombi in... (Review)
Review
Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and underdiagnosed disease characterized by progressive hypertension secondary to organized thrombi in pulmonary vessels. The arteriolar lesions of CTEPH are similar to those seen in idiopathic pulmonary arterial hypertension (PAH). Surgical disobliteration of the vessels by pulmonary endarterectomy is the therapy of choice but this is not suitable for all cases. To date, there is no licensed specific drug for CTEPH. Endothelin-1, a vasoconstrictor and promoter of cell proliferation, is involved in the pathogenesis of both CTEPH and PAH. Bosentan, the first oral dual endothelin receptor antagonist, has been shown to be effective in PAH. Preliminary uncontrolled and/or unblinded studies reported efficacy of bosentan in CTEPH, and the only randomized, controlled trials showed a positive hemodynamic effect but failed its other co-primary end point, namely the improvement of 6-min walking distance. Nevertheless, bosentan has been shown to be safe and the data from most literature encourage its use for inoperable CTEPH. However, further randomized controlled trials are needed to definitively establish bosentan as a standard drug for CTEPH.
Topics: Antihypertensive Agents; Bosentan; Chronic Disease; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Sulfonamides; Thromboembolism
PubMed: 19954311
DOI: 10.1586/erc.09.148 -
Bioorganic & Medicinal Chemistry Letters Aug 2016The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular... (Review)
Review
The endothelin peptides bind to two receptors found on cells of vasculature and in tissues. While the endothelin-A (ETA)-receptor is predominantly expressed in vascular smooth muscle cells, the endothelin-B (ETB)-receptor is also found in endothelial cells, fibroblasts, and neuronal cells. Activation of the endothelin system plays a driving role in several chronic cardiovascular diseases and several endothelin receptor antagonists (ERAs) (bosentan (6), ambrisentan (83) and macitentan (43)) have successfully been introduced as oral treatments for the life threatening condition of pulmonary arterial hypertension (PAH). This digest highlights the medicinal chemistry of the pyrimidine based ERAs 6 and 43 and describes the story that started with bosentan and culminated in macitentan (43). A condensed overview of the competitive landscape in the field of ERAs puts the different strategies and tactics applied by the medicinal chemists involved in this endeavor into perspective.
Topics: Bosentan; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrimidines; Receptors, Endothelin; Structure-Activity Relationship; Sulfonamides
PubMed: 27321813
DOI: 10.1016/j.bmcl.2016.06.014 -
Current Vascular Pharmacology Apr 2009In order to provide an overview of current knowledge, the literature was systematically examined for clinical studies, which evaluate the safety and effectiveness of... (Review)
Review
OBJECTIVE
In order to provide an overview of current knowledge, the literature was systematically examined for clinical studies, which evaluate the safety and effectiveness of bosentan in pediatric pulmonary arterial hypertension (PAH).
SOURCES
3 databases (MEDLINE, EMBASE and BIOSIS) were searched for the period January 2000 - October 2007 using the key words 'pulmonary arterial hypertension', 'bosentan', and 'pediatric patients/children'.
RESULTS
Of 165 identified publications, 21 clinical studies were selected: 1 interventional prospective, 6 observational prospective, 5 observational retrospective, and 9 case reports/case series. In the absence of controlled trials, these 21 studies represent the current evidence on the effectiveness and safety of bosentan in the treatment of pediatric PAH. Bosentan appears to improve long-term functional status and hemodynamics in children with PAH but improvement in exercise capacity is not consistently demonstrated. Promising results are reported for the combination of bosentan with other PAH-specific treatments although guidelines for instituting combination therapy have not been defined. Overall, no safety concern is raised by these studies; adverse events, including liver enzyme elevations, appear to be less frequent than reported in the adult PAH clinical trials.
CONCLUSION
Recent experience, although uncontrolled, suggests that bosentan is a well-tolerated and effective therapy for pediatric PAH.
Topics: Adolescent; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Clinical Trials as Topic; Drug Therapy, Combination; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Sulfonamides
PubMed: 19356006
DOI: 10.2174/157016109787455653 -
The Journal of Pharmacology and... Oct 2021Bosentan, a well-known cholestatic agent, was not identified as cholestatic at concentrations up to 200 µM based on the drug-induced cholestasis (DIC) index value,...
Bosentan, a well-known cholestatic agent, was not identified as cholestatic at concentrations up to 200 µM based on the drug-induced cholestasis (DIC) index value, determined in a sandwich-cultured human hepatocyte (SCHH)-based DIC assay. To obtain further quantitative insights into the effects of bosentan on cellular bile salt handling by human hepatocytes, the present study determined the effect of 2.5-25 µM bosentan on endogenous bile salt levels and on the disposition of 10 µM chenodeoxycholic acid (CDCA) added to the medium in SCHHs. Bosentan reduced intracellular as well as extracellular concentrations of both endogenous glycochenodeoxycholic acid (GCDCA) and glycocholic acid in a concentration-dependent manner. When exposed to 10 µM CDCA, bosentan caused a shift from canalicular efflux to sinusoidal efflux of GCDCA. CDCA levels were not affected. Our mechanistic model confirmed the inhibitory effect of bosentan on canalicular GCDCA clearance. Moreover, our results in SCHHs also indicated reduced GCDCA formation. We confirmed the direct inhibitory effect of bosentan on CDCA conjugation with glycine in incubations with liver S9 fraction. SIGNIFICANCE STATEMENT: Bosentan was evaluated at therapeutically relevant concentrations (2.5-25 µM) in sandwich-cultured human hepatocytes. It altered bile salt disposition and inhibited canalicular secretion of glycochenodeoxycholic acid (GCDCA). Within 24 hours, bosentan caused a shift from canalicular to sinusoidal efflux of GCDCA. These results also indicated reduced GCDCA formation. This study confirmed a direct effect of bosentan on chenodeoxycholic acid conjugation with glycine in liver S9 fraction.
Topics: Antihypertensive Agents; Bile Acids and Salts; Bosentan; Cells, Cultured; Culture Media; Dose-Response Relationship, Drug; Extracellular Fluid; Hepatocytes; Humans
PubMed: 34349015
DOI: 10.1124/jpet.121.000695 -
International Journal of Pharmaceutics Jun 2022New clinical indications for an orphan drug bosentan are prompting the improvement of the drug formulation. Since bosentan is available as monohydrate, the information...
New clinical indications for an orphan drug bosentan are prompting the improvement of the drug formulation. Since bosentan is available as monohydrate, the information on its anhydrous form together with the assessment of its glass forming ability is necessary when developing enabling formulations. The aim of this research was, therefore, to analyze the phenomena occurring upon dehydration and amorphization of bosentan. The anhydrous form was obtained by a thermal treatment of the monohydrate and characterized for the first time using DSC and XRD. Two stable amorphous forms were prepared by cooling of the melt and high energy ball milling (Tg = 82 ⁰C). The chemical stability of milled bosentan was evaluated using ATR-IR and H NMR as well. The kinetics of bosentan amorphization was established. It was stated that bosentan could be easily amorphized. Importantly, even if the system was semiamorphous, there was no recrystallization while heating. The concentration-time curves recorded in biorelevant media, confirmed the beneficial effect of amorphization on the dissolution of bosentan. Yet, the amorphous form recrystallized into the monohydrate form in the gastric milieu. This phenomenon was accompanied by a reversible color change from yellow, which is typical of bosentan glass, to creamywhite that is characteristic of the crude crystalline drug.
Topics: Bosentan; Dehydration; Drug Compounding; Drug Repositioning; Drug Stability; Humans; Kinetics; Solubility; X-Ray Diffraction
PubMed: 35609831
DOI: 10.1016/j.ijpharm.2022.121846 -
Pediatric Pulmonology Mar 2021Persistent pulmonary hypertension of the newborn (PPHN) is a significant clinical problem characterized by refractory and severe hypoxemia secondary to elevated... (Review)
Review
Persistent pulmonary hypertension of the newborn (PPHN) is a significant clinical problem characterized by refractory and severe hypoxemia secondary to elevated pulmonary vascular resistance resulting in right-to-left extrapulmonary shunting of deoxygenated blood. PPHN is associated with diverse cardiopulmonary disorders and a high early mortality rate for infants with severe PPHN. Surviving infants with PPHN have an increased risk of long-term morbidities. PPHN physiology can be categorized by (1) maladaptation: pulmonary vessels have normal structure and number but have abnormal vasoreactivity; (2) excessive muscularization: increased smooth muscle cell thickness and increased distal extension of muscle to vessels that are usually not muscularized; and (3) underdevelopment: lung hypoplasia associated with decreased pulmonary artery number. Treatment involves adequate lung recruitment, optimization of cardiac output and left ventricular function, and pulmonary vasodilators such as inhaled nitric oxide. Infants who fail to respond to conventional therapy should be evaluated for lethal lung disorders including alveolar-capillary dysplasia, T-box transcription factor 4 gene, thyroid transcription factor-1, ATP-binding cassette A3 gene, and surfactant protein diseases.
Topics: Bosentan; Epoprostenol; Humans; Hypertension, Pulmonary; Hypoxia; Infant; Infant, Newborn; Infant, Premature; Lung; Milrinone; Nitric Oxide; Oxygen; Persistent Fetal Circulation Syndrome; Pulmonary Alveoli; Pulmonary Surfactants; Risk; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents
PubMed: 32930508
DOI: 10.1002/ppul.25073