***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 
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    ***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 AIM The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics ( PK ) , tolerability and safety of selexipag , an orally active prostacyclin receptor agonist . METHODS Two prospect i ve , open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679  in healthy subjects and in subjects with mild , moderate and severe hepatic impairment or severe renal function impairment ( SRFI ) . A single dose of 200 μg or 400 μg was administered . The PK parameters were derived from plasma concentration-time profiles . RESULTS Exposure increased with the severity of hepatic impairment . Geometric mean ratios and 90 % confidence intervals of the area under the concentration-time curve from time zero to infinity ( AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold ( 1.7 - 2.6 ) and 1.2-fold ( 0.9 - 1.6 ) in subjects with mild hepatic impairment , and 4.5-fold ( 3.4 - 5.8 ) and 2.2-fold ( 1.7 - 2.8 ) in subjects with moderate hepatic impairment when compared with healthy subjects . The two subjects with severe hepatic impairment showed similar dose-normalized exposure to that of subjects with moderate hepatic impairment . A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects . Although exposure to selexipag and /or ACT-333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects , no safety concerns were raised in these groups . CONCLUSIONS Based on these observations , the PK data suggest that the clinical ly used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI . However , doses should be up-titrated with caution in these patients . The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag , an orally available , selective prostacyclin receptor ( IP receptor ) agonist , as a treatment for pulmonary arterial hypertension ( PAH ) . 43 adult patients with symptomatic PAH ( receiving stable endothelin receptor antagonist and /or a phosphodiesterase type-5 inhibitor therapy ) were r and omised three to one to receive either selexipag or placebo . Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 ( maximum allowed dose of 800 μg twice daily ) . Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point , and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results . A statistically significant 30.3 % reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks ' treatment with selexipag compared with placebo ( 95 % confidence limits -44.7– -12.2 ; p=0.0045 , Wilcoxon rank sum test ) . This was supported by a similar result from the all-treated set . Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect . Our results encourage the further investigation of selexipag for the treatment of PAH The effects of selexipag and its active metabolite ACT-333679 on cardiac repolarization were assessed in a thorough QT study as per International Conference on Harmonisation E14 guidance . In this r and omized , double-blind , placebo/positive-controlled , parallel-group study , healthy male and female subjects were r and omized to receive escalating doses of selexipag ( n=91 ) or placebo/moxifloxacin ( n=68 ) . Ascending multiple doses of selexipag in the range of 400–1,600 μg or placebo were administered twice daily for 21 days . Following a nested crossover design , subjects in the moxifloxacin/placebo treatment group received a single oral 400 mg dose of moxifloxacin on day 2 or 24 . The primary endpoint ( QT interval correction using individualized formula [ QTcI ] ) was chosen based on a prospect ively defined test applied to on-treatment data . The mean baseline-adjusted placebo-corrected ΔQTcI ( ΔΔQTcI ) for selexipag was small at all time points and never exceeded 1.4 msec ( upper bound of 90 % confidence interval [ CI ] , 3.9 msec ) on 800 μg or –0.7 msec ( upper bound of 90 % CI , 2.1 msec ) on 1,600 μg . The mean ΔΔQTcI peak effect for moxifloxacin was 7.5 msec ( lower bound of 90 % CI , 4.8 msec ) . The exposure-response analysis did not demonstrate a relevant relationship between plasma concentrations of selexipag or ACT-333679 and ΔΔQTcI but , in contrast , a positive slope within the expected range for moxifloxacin . In conclusion , selexipag does not have an effect on cardiac repolarization Purpose The aim of this single-center , open-label study was to assess the absolute bioavailability of an oral ( tablet ) versus intravenous ( i.v . ) formulation of selexipag in healthy subjects . Methods A pilot phase in three healthy male subjects , which preceded the main study , consisted of a single 20-minute i.v . infusion of 50 μg selexipag . Its objectives were to ensure the safety of the i.v . formulation and to select the i.v . dose for the main study . The main study had a r and omized , two-way crossover design in 16 healthy male subjects . Subjects received a single oral dose of 400 μg selexipag and a single 80-minute i.v . infusion of 200 μg selexipag . Results Three subjects in the pilot and 15 in the main phase completed the study as planned , whereas one subject of the main study withdrew the consent . A geometric mean total body clearance ( 95 % confidence interval ( CI ) ) of 17.9 L/h ( 15.0–21.5 ) and a volume of distribution of 11.7 L ( 10.6–13.0 ) were determined . The absolute oral bioavailability  of selexipag ( 90 % CI ) was 49.4 % ( 42.6–57.2 ) . Selexipag was well-tolerated ; no adverse event ( AE ) occurred during the pilot phase , and the main observed AEs were headache , nausea , and vomiting . Conclusion A single i.v . administration of selexipag in healthy subjects was safe and well-tolerated . The bioavailability of selexipag after oral administration is approximately 50 % Purpose Targeting the prostacyclin pathway is an effective treatment option for pulmonary arterial hypertension ( PAH ) . Patients with PAH have a deficiency of prostacyclin and prostacyclin synthase . Selexipag is an orally available and selective prostacyclin receptor ( IP receptor ) agonist . Selexipag is hydrolyzed to its active metabolite ACT-333679 , also a selective and potent agonist at the IP receptor . Methods In this phase I study the pharmacokinetics ( PK ) and tolerability of single and multiple ascending doses of selexipag were investigated in a double-blind , placebo-controlled manner in 64 healthy male subjects . An additional group of 12 subjects received an open-label dose of selexipag 400 μg in the fasted condition and after a meal . Results Maximum plasma concentrations of selexipag and ACT-333679 were reached within 2.5 and 4 h , respectively , with mean half-lives of 0.7–2.3 and 9.4–14.22 h. In the presence of food , exposure to ACT-333679 was decreased by 27 % . The most frequent adverse event was headache . Selexipag was well tolerated up to a single dose of 400 μg and multiple doses of 600 μg following an up-titration step . No relevant treatment-related effects on vital signs , clinical laboratory , and electrocardiogram ( ECG ) parameters were detected . ConclusionS elexipag exhibits a good tolerability profile and PK properties that warrant further investigation Objective : The objective of this study was to assess the safety , tolerability , pharmacokinetics , and pharmacodynamics of selexipag , an orally available selective prostacyclin receptor agonist , in development for pulmonary arterial hypertension in healthy subjects . Methods : This was a double-blind , placebo-controlled , r and omised , multiple-ascending-dose , up-titration study . Male subjects received increasing oral doses of selexipag ( 400 - 1,800 µg ; n = 12 )  or placebo  ( n = 4 ) twice daily for 3 days each , using incremental steps of 200 µg between each dose level . St and ard safety and tolerability data were collected . Blood sample s were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation . Results : Dose levels of selexipag up to 1,600 μg were well tolerated and this dose was identified as the maximum tolerated dose . Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag . Steady-state conditions for both compounds were reached on day 3 of each dose level , and no accumulation of selexipag or ACT-333679 was observed . Based on the area under the curve and the maximum plasma concentration , the pharmacokinetics of selexipag and ACT-333679 were dose proportional . At the highest dose level , the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h , respectively . The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern . Conclusions : Oral administration of increasing doses of selexipag was well tolerated . The present results support the conduct of future clinical trials RATIONALE Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension ( PAH ) , the minimal important difference ( MID ) of the 6-minute walk test ( 6MWT ) has not been well defined for this population of patients . OBJECTIVES To estimate the MID in the 6MWT in patients with PAH . METHODS Study subjects from the clinical trial of tadalafil in PAH , a 16-week , parallel-group , r and omized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist , were eligible . 6MWT was performed using a st and ardized protocol . Distributional and anchor-based methods were used to estimate the M 
    Output:
    
Selexipag also improved 6-minute walk distance and lowered hospitalization risk .
Common adverse events included headache , diarrhea , nausea , and jaw pain .
Conclusions : The specific role of selexipag for managing PAH patients is unclear because of its modest efficacy , lack of mortality reduction , and cost similar to intravenous prostacyclins .