Pulmonary arterial hypertension bosentan

Example 7.3 Bosentan therapy in pulmonary arterial hypertension... 

In a double-blind, placebo-controlled study, the Bosentan Randomized trial of Endothelin Antagonist Therapy for Pulmonary Arterial I lypertension (BREATHE-2), 33 patients took epoprostenol (2 ng/kg/ min initially, increasing to a mean dosage of 14 ng/kg/min at week 16) and were then randomized for 16 weeks in a 2 1 ratio to bosentan (62.5 mg bd for 4 weeks then 125 mg bd) or placebo (11). There was a non-significant trend towards hemodynamic and clinical improvement with to the combination. There were several early and late major complications (four withdrawals with bosentan + epoprostenol two deaths due to cardiopulmonary failure, one clinical worsening, and one increase in hepatic transaminases and one withdrawal due to increased hepatic transaminases with placebo + epoprostenol. Power was the major limitation of this study, in which only 33 patients were enrolled, and the results should be interpreted with caution. Additional information is needed to evaluate the benefit to harm balance of combined bosentan + epoprostenol therapy in pulmonary arterial hypertension. 

Ivy DD, Doran A, Clausen L, Bingaman D, Yetman A. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan. Am J Cardiol 2004 93 943-6. 

Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension BREATHE-2. Eur Respir J 2004 24 353-9. 

The effects of bosentan (62.5 mg bd for 4 weeks followed by either 125 or 250 mg bd for a minimum of 12 weeks) have been studied in a double-blind, placebo-controUed trial in 213 patients with pulmonary arterial hypertension (2). The patients who took bosentan had improved exercise capacity, less dyspnea, and delayed worsening. There were similar results in 32 patients who took bosentan for a minimum of 12 weeks (62.5 mg bd for 4 weeks then 125 mg bd) (4). Bosentan significantly reduced pulmonary vascular resistance. The number and nature of adverse events were similar with bosentan and placebo. 

Rubin LJ, Badesch DB, Barst RJ, Gahe N, Black CM, Keogh A, Puhdo T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002 346(12) 896-903. 

Badesch DB, Bodin F, Channick RN, Frost A, Rainisio M, Robbins IM, Roux S, Rubin LJ, Simonneau G, Sitbon O, Tapson VF. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Curr Ther Res Clin Exp 2002 63 227M6. 

Ahmadi-Simab K, Lamprecht P, Hellmisch B, Gross WL. Treatment of pulmonary arterial hypertension (PAH) with oral endothelin-receptor antagonist bosentan in systemic sclerosis BREATHE-1 trial and clinical experience. Z Rheumatol 2004 63(6) 495-7. [Article in German]... 

Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J 2007 29(3) 469-75. 

Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002 346 896-903. 

McLaughlin VV, Oudiz RJ, Frost A, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006 174 1257-63. 

Bosentan is an endothelin receptor antagonist. It antagonized endothelin (ET) receptor by binding to ET and ETg receptors in the endothelium and vascular smooth muscle. Bosentan is indicated in treatment of pulmonary arterial hypertension in patients with WHO class III and IV symptoms, to improve exercise ability, and decrease the rate of clinical worsening. 

Example bosentan In 2004 in Australia, the price of bosentan for pulmonary arterial hypertension was linked to the survival of patients followed in an observational study. 

Bosentan The pharmacokinetic interaction of sildenafil and the dual endotheUn receptor antagonist bosentan, both of which are marketed for the treatment of pulmonary arterial hypertension, has been studied in 55 healthy men [31 ]. Bosentan reduced the Cnmx and AUCx of sildenafil, and sildenafil increased the corresponding values of bosentan. The clinical implications for combined therapy are not known. 

Liver The availability of ambrisentan in patients with pulmonary artery hypertension who have previously discontinued other endothelin receptor antagonists because of liver function abnormalities provides an important option for patients who have had adverse reactions to bosentan or sitaxsentan [76 ]. Ambrisentan is a... 

The use of bosentan in patients with mildly symptomatic pulmonary arterial hypertension has been studied in a multicenter, double-blind, randomized, placebo-con-trolled trial (the EARLY study) [85 ]. Patients over 12 years of age ( = 185) with less functional compromise (WHO functional class 2) were randomized to bosentan or placebo and followed for 6 months double-blind, followed by an open extension period. Adverse events were common in both groups and included nasopharyngitis and abnormal liver enzymes in the bosentan arm. Laboratory tests identified increases in aminotransferases of more than three times the upper limit of normal in 12 (13%) patients taking bosentan compared with two (2%) patients taking placebo. Liver enzyme abnormalities invariably resolved on dose reduction or drug withdrawal. 

Observational studies STRIDE-2X is the 1-year open extension study of the 18 week STRIDE-2 (Sitaxsentan To Relieve ImpaireD Exercise) investigation that followed patients taking sitaxsentan or bosentan for pulmonary artery hypertension [87 ]. As well as efficacy measures, the researchers included time to withdrawal because of adverse events and time to rises in hepatic aminotransferases in the outcome measures. For the analysis population, the risk of raised aminotransferases to more than 3 times the upper limit of normal at 1 year was 6% with sitaxsentan 100 mg/day and 14% with bosentan. The cumulative risk of withdrawal at 1 year with raised aminotransferases was 3% with sitaxsentan 100 mg/day and 9% with bosentan. Other adverse events were peripheral edema, nasopharyngitis, dyspnea, and cough, consistent with previous trials in pulmonary artery hypertension. The overall withdrawal rates at 1 year were 15% with sitaxsentan 100 mg/ day and 30% with bosentan. Sitaxsentan therefore seems to have similar efficacy to bosentan and from this evidence may have the advantage of causing fewer hepatic adverse events in longer-term treatment (but see below). 

McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin W, Gerber MJ, Dufton C, Despain DJ, Rubin LJ. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009 135(1) 122-9. 

Beghetti M, Hoeper MM, Kiely DG, Carlsen J, Schwierin B, Segal ES, Humbert M. Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension results from the European Postmarketing Surveillance program. Pediatr Res 2008 64(2) 200-4. 

Degano B, Yaid A, Le PJ, Savale L, Jais X, Camara B, Humbert M, Simonneau G, Sitbon O. Long-term effects of bosentan in patients with HIV-associated pulmonary arterial hypertension. Eur Respir J 2009 33(1) 92-8. 

Galie N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi A, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study) a double-blind. 

Neurological Neuropsychiatric effects have been reported in a man receiving telaprevir based triple therapy, raltegravir, emtricitabine (FTC)/tenofovir (TDF) and bosentan for pulmonary arterial hypertension (PAH) with hepatitis C (HCV), hepatitis B (HBV) and HIV coinfection [81 ]. 

The endothelins interact with two endothelin receptors, ETa and ETb. Endothelins are highly potent vasoconstrictors and endothelin antagonists have the potential to be used clinically to treat pulmonary arterial hypertension (PAH), congestive heart failure, stroke, kidney failure, asthma, pain, and cancer. The small molecule bosentan (Tracleer) interacts with both ETa and ETb receptors and was the first endothelin antagonist to be used clinically for the treatment of PAH. Additional compounds are in clinical development or have reached the market. ... 

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