Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125 mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30 L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3-5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15-30 mL/min) and mild hepatic impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and beta-hydroxyacid simvastatin) and (R)- and (S)-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.
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PMID:Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. 1556 89

(1) Pulmonary hypertension is a progressive disorder characterised by abnormally high pulmonary artery pressure, leading to right ventricular failure and death, generally after a few years. (2) Treatment usually combines an anticoagulant, oxygen therapy, a diuretic and, sometimes a calcium channel blocker. Efficacy is poorly documented but appears to be limited. Long-term treatment with epoprostenol (prostacyclin), given as a continuous intravenous infusion via a central catheter and pump improves the quality of life of patients with severe pulmonary hypertension (NYHA classes III and IV, associated with discomfort during daily activities or even at rest). The impact of this treatment on survival seems to depend on the type of pulmonary hypertension: benefits were seen in a trial in patients with idiopathic pulmonary hypertension, while there was no effect in another trial in patients with pulmonary hypertension associated with scleroderma. Epoprostenol causes numerous adverse effects, some of which can be severe. (3) Marketing authorisation was recently granted in Europe for oral bosentan therapy for pulmonary arterial hypertension severe enough to restrict daily activities. (4) Two placebo-controlled trials lasting 12 to 16 weeks included 32 and 213 patients who responded inadequately to calcium channel blockers. They showed that the 6-minute walking distance improved by a median of 76 metres and 44 metres, respectively. In the trial with 213 patients, 42% of patients in the bosentan group and 30% of those in the placebo group were improved according to the NHYA scale. No impact on survival was observed in these short trials. (5) A trial in 33 patients showed no difference in symptom improvement between groups treated with intravenous epoprostenol + oral bosentan or intravenous epoprostenol + oral placebo. (6) Two adverse effects require monitoring, namely anemia and elevated transaminase activity. Bosentan carries a risk of multiple pharmacokinetic interactions and is teratogenic in animals. Women taking bosentan cannot use hormone-based contraception, because of a pharmacokinetic interaction. (7) In practice, oral bosentan improves symptoms in patients whose daily activities are restricted by pulmonary arterial hypertension. Bosentan is easy to use, making it an option before continuous intravenous epoprostenol infusion, even though it may not be as effective.
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PMID:Bosentan: new preparation. Pulmonary hypertension: an option before epoprostenol infusion. 1587 38

Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcomes. Bosentan is an oral endothelin-1 receptor antagonist (ERA) that has been shown in a large randomized placebo-controlled trial (BREATHE-1) to be effective at improving exercise tolerance in patients with PAH in functional class III and IV. Further studies have been conducted showing: benefit in smaller subgroups of PAH, eg, congenital heart disease, efficacy in combination with other PAH therapies, eg, sildenafil, improved long-term survival compared with historical controls. More recently, controlled trials of new ERAs have included patients with milder symptoms; those in functional class II. Analysis of the functional class II data is often limited by small numbers. These trials have generally shown a similar treatment effect to bosentan, but there are no controlled trials directly comparing these new ERAs. The EARLY trial exclusively enrolled functional class II patients and assessed hemodynamics at 6 months. Though significant, the reduction in pulmonary vascular resistance is merely a surrogate marker for the intended aim of delaying disease progression. Significant adverse effects associated with bosentan include edema, anemia and transaminase elevation. These may preclude a long duration of treatment. Further studies are required to determine optimum treatment strategy in mild disease.
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PMID:Bosentan in the treatment of pulmonary arterial hypertension with the focus on the mildly symptomatic patient. 1968 1