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BackgroundPrimary 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.MethodsThis open-label study evaluated the safety and tolerability of maralixibat ≤10mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.ResultsOf 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% (-14.84µmol/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% (-22.3µmol/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.ConclusionsMaralixibat 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.

We aimed to elucidate the relationships between pleural (Ppl), esophageal (Pes), and superimposed gravitational pressures in acute lung injury, and to understand the mechanisms of recruitment and derecruitment. In six dogs with oleic acid respiratory failure, we measured Pes and Ppl in the uppermost, middle, and most dependent lung regions. Each dog was studied at positive end-expiratory pressure (PEEP) of 5 and 15 cm H2O and three levels of tidal volume (VT; low, medium, and high). For each PEEP-VT combination, we obtained a computed tomographic (CT) scan at end-inspiration and end-expiration. The variations of Ppl and Pes pressures were correlated (r = 0.86 +/- 0.07, p0.0001), as was the vertical gradient of transpulmonary (PL) and superimposed pressure (r = 0.92, p0.0001). Recruitment proceeded continuously along the entire volume-pressure curve. Estimated threshold opening pressures were normally distributed (mode = 20 to 25 cm H2O). The amount of end-expiratory collapse at the same PEEP and PL was significantly lower when ventilation was performed at high VT. End-inspiratory and end-expiratory collapse were highly correlated (r = 0.86, p0.0001), suggesting that as more tissue is recruited at end-inspiration, more remains recruited at end-expiration. When superimposed pressure exceeded applied airway pressure (Paw), collapse significantly increased.

Sympathetic and parasympathetic activity was evaluated in ten healthy controls, nine asymptomatic, untreated asthmatic subjects and ten asthmatic patients during treatment for acute asthma, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by ECG and respiratory rate by impedance plethysmography. Spectral density of the beat-to-beat heart rate was measured within the low frequency band 0.04 to 0.10 Hz (low frequency power) modulated by sympathetic and parasympathetic activity, and within a 0.12 Hz band width at the respiratory frequency mode (respiratory frequency power) modulated by parasympathetic activity. Acute asthmatics had higher heart rates than either of the other two groups; this was probably related to the effects of beta-adrenoceptor agonist medication. Sympathetically mediated heart rate variability (normalized low frequency power) was significantly lower in both asymptomatic (p less than 0.002) and acute (p less than 0.02) asthma subjects compared to controls. This is consistent with altered sympathetic/parasympathetic regulation of heart rate in subjects with bronchial asthma.