Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects

BACKGROUND\ud \ud Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).\ud \ud METHODS\ud \ud Study 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective).\ud \ud RESULTS\ud \ud Study 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h x μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower.\ud \ud CONCLUSIONS\ud \ud Considering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria

Impact of cross-section uncertainties on supernova neutrino spectral parameter fitting in the Deep Underground Neutrino Experiment

A primary goal of the upcoming Deep Underground Neutrino Experiment (DUNE) is to measure the $\mathcal{O}(10)$ MeV neutrinos produced by a Galactic core-collapse supernova if one should occur during the lifetime of the experiment. The liquid-argon-based detectors planned for DUNE are expected to be uniquely sensitive to the $\nu_e$ component of the supernova flux, enabling a wide variety of physics and astrophysics measurements. A key requirement for a correct interpretation of these measurements is a good understanding of the energy-dependent total cross section $\sigma(E_\nu)$ for charged-current $\nu_e$ absorption on argon. In the context of a simulated extraction of supernova $\nu_e$ spectral parameters from a toy analysis, we investigate the impact of $\sigma(E_\nu)$ modeling uncertainties on DUNE's supernova neutrino physics sensitivity for the first time. We find that the currently large theoretical uncertainties on $\sigma(E_\nu)$ must be substantially reduced before the $\nu_e$ flux parameters can be extracted reliably: in the absence of external constraints, a measurement of the integrated neutrino luminosity with less than 10\% bias with DUNE requires $\sigma(E_\nu)$ to be known to about 5%. The neutrino spectral shape parameters can be known to better than 10% for a 20% uncertainty on the cross-section scale, although they will be sensitive to uncertainties on the shape of $\sigma(E_\nu)$. A direct measurement of low-energy $\nu_e$-argon scattering would be invaluable for improving the theoretical precision to the needed level.Comment: 25 pages, 21 figure

2,2-difluorovinyl benzoates for diverse synthesis of gem-difluoroenol ethers by Ni-catalyzed cross-coupling reactions

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A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child–Pugh Classification

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