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Kenjiro Koga,1 Mayuri Kawamura,1 Hiroshi Iwase,2 Nobuji Yoshikawa31Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, 2Research Division, 3Research and Development Division, Cokey Systems Co, Ltd, Matsusaka, JapanBackground: The purpose of this study was to evaluate absorption and elimination from the gastrointestinal tract of glycyrrhizic acid diethyl ester (GZ-DE) which was prepared as a prodrug of glycyrrhizic acid (a poorly absorbed compound) in rats.Methods: After the GZ-DE solution was administered via the intravenous, intraduodenal, intraileal, and stomach routes, GZ-DE and GZ concentrations in bile were determined by high-performance liquid chromatography. The stability of GZ-DE was estimated from residual GZ-DE and GZ produced in GZ-DE solutions prepared with distilled water, a pH 1.2 solution, 0.9% NaCl solution, and phosphate-buffered solution (pH 7.4) at 37°C.Results: GZ-DE was eliminated into bile by the pharmacokinetic parameters of apparent distribution rate constant (4.56 ± 0.36 per hour) and apparent elimination rate constant (0.245 ± 0.042 per hour). After intravenous and intraduodenal administration of GZ-DE, the concentration ratio of GZ-DE to GZ in bile was approximately 4:1, and the bioavailability of GZ containing GZ-DE was three-fold higher compared with the bioavailability of GZ after intraduodenal administration. GZ-DE was immediately precipitated in pH 1.2 solution and was converted to GZ by hydrolysis in pH 7.4 solution.Conclusion: Improvement of intestinal absorption of GZ was made possible by administration of GZ-DE into the intestine where absorption of GZ is lower than in the strong acidic environment of the stomach. However, because the elimination rate in bile simulated from kinetic parameters of GZ-DE was higher than the conversion rate from GZ-DE to GZ by hydrolysis, it is thought that the availability of GZ as a revolutionary prodrug was not high from the viewpoint of bioavailability of GZ in the liver by intestinal administration of GZ-DE.Keywords: glycyrrhizic acid, prodrug, intestinal absorption, bile elimination, pharmacokinetics, rat

Radiation monitoring at high energy proton accelerators poses a considerable challenge due to the complexity of the encountered stray radiation fields. These environments comprise a wide variety of different particle types and span from fractions of electron-volts up to several terra electron-volts. As a consequence the use of Monte Carlo simulation programs like FLUKA is indispensable to obtain appropriate field-specific calibration factors. At many locations of the LHC a large contribution to the particle fluence is expected to originate from high-energy neutrons and thus, benchmark experiments with mono-energetic neutron beams are of high importance to verify the aforementioned detector response calculations. This paper summarizes the results of a series of benchmark experiments with quasi mono-energetic neutrons of 100, 140, 200, 250 and 392 MeV that have been carried out at RCNP - Osaka University, during several campaigns between 2006 and 2014.

Secondary neutron-production cross-sections have been measured from interactions of 230 MeV/nucleon He, 400 MeV/nucleon N, 400 MeV/nucleon Kr, 400 MeV/nucleon Xe, 500 MeV/nucleon Fe, and 600 MeV/nucleon Ne interacting in a variety of elemental and composite targets. We report the double-differential production cross sections, angular distributions, energy spectra, and total cross sections from all systems. Neutron energies were measured using the time-of-flight technique, and were measured at laboratory angles between 5 deg and 80 deg. The spectra exhibit behavior previously reported in other heavy-ion-induced neutron production experiments; namely, a peak at forward angles near the energy corresponding to the beam velocity, with the remaining spectra generated by preequilibrium and equilibrium processes. The double-differential spectra are fitted with a moving-source parameterization. Observations on the dependence of the total cross sections on target and projectile mass are discussed.

Secondary neutron-production cross-sections have been measured from interactions of 290 MeV/nucleon C and 600 MeV/nucleon Ne in a target composed of simulated Martian regolith and polyethylene, and from 400 MeV/nucleon Ne interactions in wall material from the International Space Station. The data were measured between 5 and 80 deg in the laboratory. We report the double-differential cross sections, angular distributions, and total neutron-production cross sections from all three systems. The spectra from all three systems exhibit behavior previously reported in other heavy-ion, neutron production experiments; namely, a peak at forward angles near the energy corresponding to the beam velocity, with the remaining spectra generated by pre-equilibrium and equilibrium processes. The double differential cross sections are fitted with a moving-source parameterization. Also reported are the data without corrections for neutron flux attenuation in the target and other intervening materials, and for neutron production in non-target materials near the target position. These uncorrected spectra are compared with SHIELD-HIT and PHITS transport model calculations. The transport model calculations reproduce the spectral shapes well, but, on average, underestimate the magnitudes of the cross sections.

An overview of experimental secondary neutron measurements relevant to space-related activities is presented. Stopping target yields and cross section measurements conducted at particle accelerators using heavy ions with energies >100 MeV per nucleon are discussed.

A method for reducing excessive constant-fraction-discriminator walk that utilizes experimental data in the off-line analysis stage is introduced. Excessive walk is defined here as any walk that leads to an overall timing resolution that is much greater than the intrinsic timing resolution of the detection system. The method is able to reduce the contribution to the overall timing resolution from the walk that is equal to or less than the intrinsic timing resolution of the detectors. Although the method is explained in the context of a neutron time-of-flight experiment, it is applicable to any data set that satisfies two conditions. (1) A measure of the signal amplitude for each event must be recorded on an event-by-event basis; and (2) There must be a distinguishable class of events present where the timing information is known a priori.