280 research outputs found
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
Immuno-surgical management of pancreatic cancer with analysis of cancer exosomes
Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine
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
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.Comment: 11 pages, 4 figure
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
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