***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospect i ve , r and omized trial to improve survival . METHODS We conducted a 12-week prospect i ve , r and omized , multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol ( formerly called prostacyclin ) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension ( New York Heart Association functional class III or IV ) . RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol ( median distance walked in six minutes , 362 m at 12 weeks vs. 315 m at base line ) , but it decreased in the 40 patients treated with conventional therapy alone ( 204 m at 12 weeks vs. 270 m at base line ; P < 0.002 for the comparison of the treatment groups ) . Indexes of the quality of life were improved only in the epoprostenol group ( P < 0.01 ) . Hemodynamics improved at 12 weeks in the epoprostenol-treated patients . The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and + 3 percent , respectively ( difference in mean change , -6.7 mm Hg ; 95 percent confidence interval , -10.7 to -2.6 mm Hg ; P < 0.002 ) , and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and + 9 percent , respectively ( difference in mean change , -4.9 mm Hg/liter/min ; 95 percent confidence interval , -7.6 to -2.3 mm Hg/liter/min ; P < 0.001 ) . Eight patients died during the study , all of whom had been r and omly assigned to conventional therapy ( P = 0.003 ) . Serious complications included four episodes of catheter-related sepsis and one thrombotic event . CONCLUSIONS As compared with conventional therapy , the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement , as well as improved survival in patients with severe primary pulmonary hypertension Background — Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease . Because Eisenmenger syndrome is associated with increased endothelin expression , patients may benefit from endothelin receptor antagonism . Theoretically , interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia . Methods and Results — The Bosentan R and omized Trial of Endothelin Antagonist Therapy-5 ( BREATHE-5 ) was a 16-week , multicenter , r and omized , double-blind , placebo-controlled study evaluating the effect of bosentan , a dual endothelin receptor antagonist , on systemic pulse oximetry ( primary safety end point ) and pulmonary vascular resistance ( primary efficacy end point ) in patients with World Health Organization functional class III Eisenmenger syndrome . Hemodynamics were assessed by right- and left-heart catheterization . Secondary end points included exercise capacity assessed by 6-minute walk distance , additional hemodynamic parameters , functional capacity , and safety . Fifty-four patients were r and omized 2:1 to bosentan  ( n=37 ) or placebo ( n=17 ) for 16 weeks . The placebo-corrected effect on systemic pulse oximetry was 1.0 % ( 95 % confidence interval , −0.7 to 2.8 ) , demonstrating that bosentan did not worsen oxygen saturation . Compared with placebo , bosentan reduced pulmonary vascular resistance index ( −472.0 dyne · s · cm−5 ; P=0.0383 ) . The mean pulmonary arterial pressure decreased ( −5.5 mm Hg ; P=0.0363 ) , and the exercise capacity increased ( 53.1 m ; P=0.0079 ) . Four patients discontinued as a result of adverse events , 2 ( 5 % ) in the bosentan group and 2 ( 12 % ) in the placebo group . Conclusions — In this first placebo-controlled trial in patients with Eisenmenger syndrome  , bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation Background — Pulmonary hypertension ( PH ) is associated with restricted physical capacity , limited quality of life , and a poor prognosis because of right heart failure . The present study is the first prospect i ve r and omized study to evaluate the effects of exercise and respiratory training in patients with severe symptomatic PH . Methods and Results — Thirty patients with PH ( 21 women ; mean age , 50±13 years ; mean pulmonary artery pressure , 50±15 mm Hg ; mean World Health Organization [ WHO ] class , 2.9±0.5 ; pulmonary arterial hypertension , n=23 ; chronic thromboembolic PH , n=7 ) on stable disease-targeted medication were r and omly assigned to a control ( n=15 ) and a primary training ( n=15 ) group . Medication remained unchanged during the study period . Primary end points were the changes from baseline to week 15 in the distance walked in 6 minutes and in scores of the Short Form Health Survey quality -of-life question naire . Changes in WHO functional class , Borg scale , and parameters of echocardiography and gas exchange also were assessed . At week 15 , patients in the primary and secondary training groups had an improved 6-minute walking distance ; the mean difference between the control and the primary training group was 111 m ( 95 % confidence interval , 65 to 139 m ; P<0.001 ) . Exercise training was well tolerated and improved scores of quality of life , WHO functional class , peak oxygen consumption , oxygen consumption at the anaerobic threshold , and achieved workload . Systolic pulmonary artery pressure values at rest did not change significantly after 15 weeks of exercise and respiratory training ( from 61±18 to 54±18 mm Hg ) within the training group . Conclusions — This study indicates that respiratory and physical training could be a promising adjunct to medical treatment in severe PH . The effects add to the beneficial results of modern medical treatment RATIONALE A previous trial of bosentan in idiopathic pulmonary fibrosis ( IPF ) showed a trend to delayed IPF worsening or death . Also , improvements in some measures of dyspnea and health-related quality of life were observed . OBJECTIVES To demonstrate that bosentan delays IPF worsening or death . METHODS Prospect i ve , r and omized ( 2:1 ) , double-blind ,  placebo-controlled , event-driven , parallel-group , morbidity-mortality trial of bosentan in adults with IPF of less than 3 years ' duration , confirmed by surgical lung biopsy , and without extensive honeycombing on high-resolution computed tomography . The primary endpoint was time to IPF worsening ( a confirmed decrease from baseline in FVC ≥ 10 % and diffusing capacity of the lung for carbon monoxide ≥ 15 % , or acute exacerbation of IPF ) or death up to End of Study . Effects of bosentan on health-related quality of life , dyspnea , and the safety and tolerability of bosentan were investigated . MEASUREMENTS AND MAIN RESULTS Six hundred sixteen patients were r and omized to bosentan ( n=407 ) or placebo ( = 209 ) . No significant difference between treatment groups was observed in the primary endpoint analysis ( hazard ratio , 0.85 ; 95 % confidence interval , 0.66 - 1.10 ; P=0.2110 ) . No treatment effects were observed on health-related quality of life or dyspnea . Some effects of bosentan treatment were observed in changes from baseline to 1 year in FVC and diffusing capacity of the lung for carbon monoxide . The safety profile for bosentan was similar to that observed in other trials . CONCLUSIONS The primary objective in the Bosentan Use in Interstitial Lung Disease-3 trial was not met . Bosentan was well tolerated . Clinical trial registered with www . clinical trials.gov ( NCT 00391443 ) OBJECTIVE Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis ( SSc ; scleroderma ) and lead to pain , impaired function , and tissue loss . We investigated whether treatment with the endothelin receptor antagonist , bosentan , decreased the development of new digital ulcers in patients with SSc . METHODS This was a r and omized , prospect i ve , placebo-controlled , double-blind study of 122 patients at 17 centers in Europe and North America , evaluating the effect of treatment on prevention of digital ulcers .  The primary outcome variable was the number of new digital ulcers developing during the 16-week study period . Secondary assessment s included healing of existing digital ulcers and evaluation of h and function using the Scleroderma Health Assessment Question naire . RESULTS Patients receiving bosentan  had a 48 % reduction in the mean number of new ulcers during the treatment period ( 1.4 versus 2.7 new ulcers ; P = 0.0083 ) . Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers ; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 ( P = 0.0075 ) . In patients receiving bosentan , a statistically significant improvement in h and function was observed . There was no difference between treatment groups in the healing of existing ulcers . Serum transaminase levels were elevated to > 3-fold the upper limit of normal in bosentan-treated patients ; this elevation is comparable with that observed in previous studies of this agent . Other side effects were similar in the 2 treatment groups . CONCLUSION Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc . Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving h and function in patients with SSc Background — The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1 . The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension , renal water , and sodium balance under acute and prolonged exposure to high-altitude – associated hypoxia . Methods and Results — In a double-blind fashion , healthy volunteers were r and omly assigned to receive bosentan ( 62.5 mg for 1 day and 125 mg for the following 2 days ; n=10 ) or placebo ( n=10 ) at sea level and after rapid ascent to high altitude ( 4559 m ) . At sea level , bosentan did not induce any significant changes in hemodynamic or renal parameters . At altitude , bosentan induced a significant reduction of systolic pulmonary artery pressure ( 21±7 versus 31±7 mm Hg , P<0.03 ) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment . However , both urinary volume and free water clearance ( H2OCl/glomerular filtration rate ) were significantly reduced versus placebo after 2 days of ET-1 antagonism ( 1100±200 versus 1610±590 mL ; −6.7±3.5 versus −1.8±4.8 mL/min , P<0.05 versus placebo for both ) . Sodium clearance and segmental tubular function were not significantly affected by bosentan administration . Conclusions — The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation . These findings must be considered for the prevention and treatment of acute mountain sickness BACKGROUND Patients with precapillary pulmonary hypertension ( PH ) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries . By causing the pulmonary artery to dilate , inhaled nitric oxide ( NO ) may allow an increase in exercise capacity in patients with PH . METHODS AND RESULTS On 2 separate days , 3 days apart , 14 patients with precapillary PH ( 10 primary PH , 4 residual PH after correction of an intracardiac shunt ; age , 40+/-12 years ; mean pulmonary artery pressure , 60+/-23 mm Hg ) performed exercise , with and without inhalation of 20 ppm NO , on a cycle ergometer . The work rate was increased 15 W/min until their symptom-limited maximum , with breath-by-breath gas analysis . Patients were r and omly and blindly selected to inhale NO on either their first or second test . Peak exercise load and anaerobic threshold tended to increase , but not significantly . Peak oxygen consumption ( f1.gif " BORDER="0" > O(2 ) ) and Deltaf1.gif " BORDER="0" > O(2)/DeltaW ratio increased significantly , by 18 % and 22 % , respectively ( peak f1.gif " BORDER="0" > O(2 ) , 13.6+/-3.6 to 16.0+/-4 . 1 mL. kg(-1 ) . min(-1 ) ; Deltaf1.gif " BORDER="0" > O(2)/DeltaW ratio , 5 . 8+/-2.4 to 7.1+/-2.3 mL. kg(-1 ) . min(-1 ) . W(-1 ) ; both P 
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There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists ( OR 0.57 ; 95 % CI 0.26 to 1.24 ) , and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients .
Hepatic toxicity was not common , and endothelin receptor antagonists were well tolerated in this population .
Endothelin receptor antagonists can increase exercise capacity , improve WHO/NYHA functional class , prevent WHO/NYHA functional class deterioration , reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III .
However , there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension .
Efficacy data are strongest in those with idiopathic pulmonary hypertension .
The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists