Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.

Effect of helium-oxygen (heliox) gas mixtures on the function of four pediatric ventilators.

OBJECTIVE: To evaluate the effects of helium on the function of four ventilators commonly used in pediatrics: the Bird VIP, Bird VIP Gold, Servo 300, and Servo 900C. DESIGN: Prospective setting. SETTING: Research laboratory at a university hospital. SUBJECTS: Helium was administered as an 80:20 mixture of helium-oxygen through the air inlet of the ventilator. Delivered fraction of inspired oxygen (Fio(2)) was compared with the Fio(2) set on the blender dial. Inspiratory displayed tidal volume was recorded as an indicator of what the ventilator "believed" it had delivered and was compared with the V(T) displayed during ventilation with 100% oxygen (control). Actual delivered V(T) was measured by a Neonatal Bicore connected to the side port of a "bag-in-box" spirometer, making measurements independent of inspired gas properties, and was compared with V(T) delivered during ventilation with 100% oxygen. INTERVENTIONS: Five gas mixtures were evaluated: Fio(2) = 0.2, 0.4, 0.6, 0.8, and 1.0 (balance helium). MEASUREMENTS AND MAIN RESULTS: Delivered Fio(2) was less than set Fio(2) on the Servo 900C and VIP ventilators. V(T) displayed was minimally altered by helium during volume-controlled ventilation but substantially decreased during pressure-controlled ventilation, particularly with the Bird ventilators. During volume-controlled ventilation, V(T) delivered was substantially increased by helium with the Bird and, to a lesser degree, the Servo 900C ventilators. In contrast, V(T) delivered decreased slightly in helium with the Servo 300. The same pattern, but with a decreased magnitude, was observed for V(T) delivered during pressure-controlled ventilation. CONCLUSIONS: The addition of helium has a significant effect on Fio(2) delivery, displayed inspiratory V(T), and actual delivered V(T) during both volume- and pressure-controlled ventilation in four ventilators commonly used in pediatric critical care. These effects are both ventilator specific and ventilation mode specific, mandating vigilance during helium ventilation in clinical practice.