Virtual bioequivalence for achlorhydric subjects: The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations

Observation of the east-west anisotropy of the atmospheric neutrino flux

The east-west anisotropy, caused by the deflection of primary cosmic rays in the Earth's magnetic field, is observed for the first time in the flux of atmospheric neutrinos. Using a 45 kt-year exposure of the Super-Kamiokande detector, 552 e-like and 633 mu-like horizontally-going events are selected in the momentum range between 400 and 3000 MeV/c. The azimuthal distribution of e-like and mu-like events agrees with the expectation from atmospheric neutrino flux calculations that account for the geomagnetic field, verifying that the geomagnetic field effects in the production of atmospheric neutrinos in the GeV energy range are well understood.Comment: 8 pages,3 figures revtex, submitted to PR

Measurement of the flux and zenith-angle distribution of upward through-going muons by Super-Kamiokande

A total of 614 upward through-going muons of minimum energy 1.6 GeV are observed by Super-Kamiokande during 537 detector live days. The measured muon flux is 1.74+/-0.07(stat.)+/-0.02(sys.)x10^{-13}cm^{-2}s^{-1}sr^{-1} compared to an expected flux of 1.97+/-0.44(theo.)x10^{-13}cm^{-2}s^{-1}sr^{-1}. The absolute measured flux is in agreement with the prediction within the errors. However, the zenith angle dependence of the observed upward through-going muon flux does not agree with no-oscillation predictions. The observed distortion in shape is consistent with the \nu_\mu \nu_\tau oscillation hypothesis with \sin^22\theta > 0.4 and 1x10^{-3} < \Delta m^2 < 1x10^{-1} eV^{2} at 90% confidence level.Comment: 8 pages w/ 3 figures new version contains minor fixes, as it appears in PR

Calibration of Super-Kamiokande Using an Electron Linac

In order to calibrate the Super-Kamiokande experiment for solar neutrino measurements, a linear accelerator (LINAC) for electrons was installed at the detector. LINAC data were taken at various positions in the detector volume, tracking the detector response in the variables relevant to solar neutrino analysis. In particular, the absolute energy scale is now known with less than 1 percent uncertainty.Comment: 24 pages, 16 figures, Submitted to NIM

Constraints on neutrino oscillation parameters from the measurement of day-night solar neutrino fluxes at Super-Kamiokande

A search for day-night variations in the solar neutrino flux resulting from neutrino oscillations has been carried out using the 504 day sample of solar neutrino data obtained at Super-Kamiokande. The absence of a significant day-night variation has set an absolute flux independent exclusion region in the two neutrino oscillation parameter space.Comment: 11 pages, 3 figures, submitted to PRL, single-spacin

Evidence for oscillation of atmospheric neutrinos

We present an analysis of atmospheric neutrino data from a 33.0 kiloton-year (535-day) exposure of the Super-Kamiokande detector. The data exhibit a zenith angle dependent deficit of muon neutrinos which is inconsistent with expectations based on calculations of the atmospheric neutrino flux. Experimental biases and uncertainties in the prediction of neutrino fluxes and cross sections are unable to explain our observation. The data are consistent, however, with two-flavor nu_mu nu_tau oscillations with sin^2(2theta)>0.82 and 5x10^-4 < delta m^2 < 6x10^-3 eV^2 at 90% confidence level.Comment: 9 pages (two-column) with 4 figures. Small corrections to Eqn.4 and Fig.3. Final version to appear in PR

Measurement of radon concentrations at Super-Kamiokande

Radioactivity from radon is a major background for observing solar neutrinos at Super-Kamiokande. In this paper, we describe the measurement of radon concentrations at Super-Kamiokande, the method of radon reduction, and the radon monitoring system. The measurement shows that the current low-energy event rate between 5.0 MeV and 6.5 MeV implies a radon concentration in the Super-Kamiokande water of less than 1.4 mBq/m$^3$.Comment: 11 pages, 4 figure

Measurement of a small atmospheric νμ/νe\nu_\mu/\nu_e ratio

From an exposure of 25.5~kiloton-years of the Super-Kamiokande detector, 900 muon-like and 983 electron-like single-ring atmospheric neutrino interactions were detected with momentum $p_e > 100$ MeV/$c$, $p_\mu > 200$ MeV/$c$, and with visible energy less than 1.33 GeV. Using a detailed Monte Carlo simulation, the ratio $(\mu/e)_{DATA}/(\mu/e)_{MC}$ was measured to be $0.61 \pm 0.03(stat.) \pm 0.05(sys.)$, consistent with previous results from the Kamiokande, IMB and Soudan-2 experiments, and smaller than expected from theoretical models of atmospheric neutrino production.Comment: 14 pages with 5 figure