Effects of triclabendazole and its metabolite exposure on the heart-rate-corrected QT intervals: A randomized, placebo- and positive-controlled thorough QT study in healthy individuals.

Triclabendazole is an effective and well-tolerated treatment for human fascioliasis. A placebo- and positive-controlled, four-sequence by four-period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo-corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two-sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3-, 4-, and 6-h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment-emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized, Open-label Study in Healthy Subjects.

PURPOSE: The goal of this study was to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) siponimod in healthy subjects. METHODS: This randomized, open-label study was conducted in 2 parts. In Part 1, a total of 16 eligible subjects received either a single oral dose of siponimod (0.25 mg) followed by a single IV infusion (0.25 mg/3 h) in Sequence 1, or vice versa in Sequence 2. In Part 2, a total of 17 eligible subjects received single IV infusions of siponimod (1 mg/24 h). FINDINGS: No clinically relevant effect on mean 5-minute or hourly average heart rate was observed following the siponimod IV dosing regimens and both remained above 50 beats/min. Observed atrioventricular blocks and sinus pauses were asymptomatic. The mean change in absolute lymphocyte count from baseline was comparable for the siponimod 0.25 mg oral regimen and the two IV siponimod regimens. Oral siponimod displayed a good absolute bioavailability of 84%. The mean peak exposure of oral siponimod was approximately 48% lower than that of IV siponimod. The M17 metabolite was found to be the most prominent systemic metabolite of siponimod in humans. IMPLICATIONS: Siponimod IV infusions were well tolerated, with safety and PD (absolute lymphocyte count) profiles similar to those of oral siponimod. The PD/PK findings supported the development of an innovative rapid IV titration regimen for patients with intracerebral hemorrhage.

CYP3A but not P-gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta-specific phosphoinositide-3 kinase inhibitor leniolisib.

This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P-gp, the potential interaction with quinidine, a strong inhibitor of P-gp but not CYP3A, was studied as well. Using a fixed-sequence, 3-way crossover design, 20 healthy male subjects received single oral doses of 10 mg leniolisib during three phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 h before and 3 h after leniolisib. Itraconazole increased the leniolisib oral drug exposure (AUCinf ) by on average 2.1-fold, whereas the peak drug concentration (Cmax ) was less impacted (1.25-fold). The terminal elimination half-life (T1/2 ) of leniolisib was also increased by ~2-fold. Neither oral AUCinf nor Cmax or T1/2 was found to be altered by quinidine. These findings suggest that the interaction with itraconazole occurred mainly systemically through inhibition of CYP3A, and corroborate our in vitro findings that leniolisib is neither a sensitive CYP3A substrate nor a relevant in vivo substrate for intestinal or hepatic P-gp. Assuming itraconazole levels achieved complete inhibition of CYP3A, the fractional contribution of CYP3A to the overall disposition of leniolisib is estimated to be about 50%. The concomitant use of leniolisib with strong inhibitors of CYP3A as well as strong and moderate inducers of CYP3A is best avoided.

Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects.

PURPOSE: To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects. METHODS: This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18-45 years). In Period 1 (Days 1-12), siponimod was up-titrated from 0.25 to 2 mg over 5 days (Days 1-6) followed by 2 mg once daily on days 7-12. In Period 2, siponimod 2 mg qd was co-administered with rifampin 600 mg qd (Days 13-24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC). RESULTS: Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3 years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6 ng/mL) was achieved in 4 h (median Tmax,ss; range, 1.58-8.00) and the geometric mean AUCtau,ss was 546 h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h × ng/mL, respectively; median Tmax remained unchanged (4 h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L. CONCLUSIONS: The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.

An ex-vivo model for hypothermic pulsatile perfusion of porcine pancreata: hemodynamic and morphologic characteristics.

OBJECTIVES: Hypothermic machine perfusion is a well-established preservation method for kidneys that allows for better preservation over longer periods and pretransplant assessment of graft viability. This technique has only sporadically been used for pancreatic grafts. The aim of this study was to establish a hypothermic machine perfusion model for porcine pancreas perfusion. MATERIALS AND METHODS: Fifteen porcine pancreata were subjected to 25 minutes of warm ischemia and 149 minutes of cold ischemia before undergoing meticulous bench work preparation and perfusion, via an aortic segment, on the RM3 perfusion machine with University of Wisconsin (Barr Laboratories Inc., Pomona, NY, USA) solution. Perfusion variables (degrees C, temperature; mm Hg, systolic perfusion pressure; mL/min, flow volume; mm Hg/mL/min, resistance) were recorded every 30 minutes. Tissue samples were assessed for each pancreas preperfusion and postperfusion using a semiquantitative scoring scale to grade histopathologic changes: acinar cell damage (0-4), islet cell damage (0-3), inflammation (0-3), and edema (0-3). RESULTS: Hypothermic machine perfusion time was set at 315 minutes, and all grafts were maintained between 4-10 degrees C. The results were as follows (range, mean -/+ SD): systolic perfusion pressures were 5-13 mm Hg (9.61 -/+ 3.25 mm Hg) during the first 60 minutes (priming), and 15-23 mm Hg (21.07 -/+ 4.26 mm Hg) during the maintenance period. Target flow volumes reached 141-152 mL/min (147.6 -/+ 8.969 mL/min) at 60 pulses per minute. Intrapancreatic resistance decreased throughout priming to 0.03-0.09 mm Hg/mL/min (0.083 -/+ 0.042 mm Hg/mL/min), and remained unchanged until completion of perfusion. Pancreatic weight increase varied from 3.2% to 18.3% (13.36% -/+ 4.961%). There was significant postperfusion reduction in islet and acinar cell damage (P = .001 and P = .01 respectively). CONCLUSIONS: We have developed a model of machine perfusion for porcine pancreata which is simple, reliable, and protects graft histopathologic integrity. The model can be used in further studies to improve the quality of pancreas preservation, and assess and improve the viability of the condition of borderline pancreatic grafts.

The school community council: creating an environment for student success.

A model of community-school partnerships is developing within a school district in Evansville, Indiana. Based on a full-service community school philosophy, the model started in one elementary school in the Evansville-Vanderburgh School Corporation and has expanded into a districtwide initiative called the School Community Council. The council is made up of over seventy community organizations and social service agencies working together to establish full-service schools as places of community and to enhance youth and family development.

Which nurseries currently care for ventilated neonates in Illinois and Wisconsin? Implications for the next generation of perinatal regionalization.

We were interested in the extent to which advances in the availability of neonatalogy expertise have provided a centrifugal impetus to perinatal care. Specifically, we wondered where infants who were sick enough to require mechanical ventilation were currently being managed. We surveyed 116 of 140 hospitals in Illinois and Wisconsin that offered obstetric/newborn services in 1998-1999. The 23 Level I nurseries were consistently small, and offered virtually no "advanced" neonatal intensive care unit (NICU) technology. The 16 Level III NICUs were consistently large, offered advanced technology and personnel, and received sick infants from many hospitals in their regional network. The 77 Level II nurseries (two thirds of all hospitals with newborn services) were less consistently characterized. In general, Level II nurseries were a "spoke" (not a hub), and did not offer extracorporeal-membrane oxygenation (ECMO), nitric oxide (NO), or cardiovascular (CV) surgery. However, 19 (25%) of 77 Level II centers self-designated as "Level II+". These were significantly more likely to offer ventilators, percutaneous central venous catheters (PCVCs), total parenteral nutrition (TPN), and surgery. Fifty-three percent (18/34) of all nurseries offering mechanical ventilation self-designated as a Level II or II+, as opposed to Level III. Facile inferences about the appropriate role of Level II centers derived from decades-old data are probably unsupportable. It is time to acknowledge the distinction between the Level II nursery of the past and the newly evolving Level II+ NICUs.