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It is extremely important to diagnose beams in accelerators to improve accelerator operation. In the low velocity section of a proton or heavy ion linac, the diagnostic method for longitudinal beam properties is less established compared to that for transverse properties. We have developed a new diagnostic method for the longitudinal bunch size by utilizing an RF deflector. We evaluated the uncertainty in bunch size measurement through simulation, and it was obtained as 0.5°. In addition, we measured longitudinal beam emittance through bunch size measurements at several RF amplitudes of an upstream buncher. The measured emittance was 0 . 13 ± 0 . 01 π deg.MeV, which was consistent with the simulation result.

J-PARC linac is operated with design peak current of 50 mA from October 2018. Recently we succeeded in establishing longitudinal measurement at MEBT1, with which the beam matching is being studied in MEBT1. In this poster, recent measurements and beam tuning results in MEBT1 will be presented., Proceedings of the 10th Int. Particle Accelerator Conf., IPAC2019, Melbourne, Australia

The main purpose of this paper was to carry out a source apportionment of suspended particulate matter (SPM) samples using positive matrix factorization procedure. The central and local Government of Japan introduced strict emission regulations in 2002/10 and 2003/10, respectively, in curbing SPM pollution from major metropolitans. This paper also highlighted the impact of the measures taken by the central and local Government of Japan on the reduction of SPM and the contributions of sources. SPM samples were collected for 6 years starting from 1999 to 2005 at two sites, i.e., site A (urban) and site B (suburban) of Yokohama, Japan. Microwave digestion and inductively coupled plasma-mass spectroscopy (ICP-MS) were employed to measure Mg, Al, Ca, V, Cr, Mn, Ni, Cu, Zn, Ga, As, Se, Rb, Sr, Ag, Cd, Cs, Ba, Pb and Bi, while water soluble ions (Na + , NH $_{4}^{\ \,+}$ , K + , Ca2 + , Mg2 + , Cl − , NO $_{3}^{\ \,-}$ and SO $_{4}^{\ \,2-})$ as well as carbonaceous mass (EC and OC) were analyzed using ion chromatograph and CHN analyzer, respectively. The sources identified at two sites were automobile, soil dust, marine aerosol, mixed sources, and secondarily formed aerosol. Also, source quantification was performed. Automobile and soil dust were striking contributors at site A. Automobile and soil dust of SPM aerosol might be produced from local origin at current study areas. Besides, Asian dust had an impact on high concentrations of SPM aerosol in some certain period of the year due to the outflows of East Asian emission. In contrast, secondary aerosol in the form of sulfate and ammonium as well as mixed sources (coal, long-transported Cs, and other unknown sources) were remarkable at site B. Stationary/industrial combustion has apparently more impact on the release of SPM components at site B than A. Automobile regulations in 2002 and 2003, respectively, resulted in reduction of SPM by 28% for site A and 16% for site B. There was also net reduction of automobile contribution at both sites due to the above measures being implemented.

We analyzed metals (Mg, Al, Ca, V, Cr, Mn, Ni, Cu, Zn, Ga, As, Se, Rb, Sr, Ag, Cd, Cs, Ba, Pb and Bi), water-soluble ions (Na+, NH4+, K+, Ca2+, Cl−, NO3− and SO42−) and carbonaceous mass (EC and OC) in SPM aerosol samples using an ICP-MS, ion chromatograph and CHN corder, respectively. The SPM samples were collected from 1999 to 2005 at two locations (urban site A and industrial site B) of Yokohama, Japan with concentrations in mean and ranges of 34.2 and 19.7–50.3 μg m−3 and 22.9 and 12.7–35.1 μg m−3 for the respective location. Source apportionment of SPM aerosol was conducted appropriately for the first time to these locations employing PCA-APCS technique. Major sources of SPM at site A were a) crustal source, b) urban origin, c) undefined, and d) mineral rock. At site B, the sources were predicted as a) urban origin, b) undefined, c) crustal source, and d) secondarily formed aerosol. The tracers and nature of the source related to urban origin at both sites were similar but retaining different source strength. Secondarily formed aerosol was quite unique at site B. However, mineral rock was remarkable at site A.

This study elucidated the characteristics of ambient PM2.5, PM2.5–10 and PM> 10 with water soluble ions, i.e., Cl−, NO3−, SO42−, Na+, NH4+, K+, Mg2+ and Ca2+ and carbonaceous aerosol, i.e., EC and OC in above size fractions from the samples collected for the period of 2007–2008. The total numbers of PM2.5, PM2.5–10 and PM> 10 samples collected with MCI sampler were 91, 87 and 79, respectively. The ambient particulate samples were collected twice in a week for a period of 24 h at the roof of a three-storied building in Yokohama National University. The annual arithmetic mean concentrations of PM2.5, PM2.5–10 and PM> 10 were 20.6, 9.6 and 5.1 µg m− 3, respectively. The results of the daily PM2.5 concentrations indicated that 67% of the daily PM2.5 exceeded USEPA National Ambient Air Quality Standards (NAAQS) (15 µg m− 3) while 95% in respect of WHO ambient air quality guidelines (10 µg m− 3). The concentrations of water soluble ions in PM2.5, PM2.5–10 and PM> 10 accounted for 40%, 31% and 19%, respectively. The estimation of non-sea-salt particles implies that the major sources of water soluble ions in PM2.5 are anthropogenic. On the other hand, a large proportion of sea salt particles contributes to PM2.5–10 and PM> 10. Spearman correlation indicated that the concentrations of OC and EC in PM2.5 can originate from similar type of sources. However, the concentration of OC and EC in PM2.5–10 and PM> 10 can have multiple sources. In addition, some atmospheric reactions were also characterized in this study.

This article analyses elemental composition of suspended particulate matter (SPM) samples collected monthly from 1999 to 2005 at two locations in Yokohama, Japan. Microwave digestion and inductively coupled plasma mass spectroscopy was employed to measure Mg, Al, Ca, V, Cr, Mn, Ni, Cu, Zn, Ga, As, Se, Rb, Sr, Ag, Cd, Cs, Ba, Pb, and Bi. Water-soluble ions (Na + , NH4 + , K + , Ca2 + , Cl − , NO3 − , and SO4 2 − ) and carbonaceous mass (elemental and organic carbon) were detected using ion chromatograph and CHN analyzer, respectively. The results indicate that the composition of SPM on one of the sites is determined by automobile emissions and on the other by industrial combustions. The impact of the emission regulations for automobiles in large Japanese cities, which were enacted during 2002 and 2003, on the SPM composition of the samples is also studied.

A laser-driven RF gun with a Cs 2 Te photocathode, a device modeled after the BNL-IV RF gun, has been in development at KEK since 2002. This gun has been operated as an electron source for the Accelerator Test Facility (ATF) and generates a beam with an operational intensity of up to 3.2 nC per bunch. Based on successful results at the ATF, this gun has been applied several times for new research at universities. From 2002 onwards, successive improvements have been incorporated into newer models of the RF gun. Most recently, in 2008, a new gun incorporating all of the earlier modifications was produced for the ATF. Tests have confirmed a significant improvement of the Q-value of the latest model. A typical transverse emittance of 1.3 π mm mrad has been obtained under the following conditions: solenoid field of 0.18 T, beam intensity of 1.6 nC per bunch, and RF power of 9 MW. This RF gun equipped with the Cs 2 Te photocathode is being used for the advanced research programs at the ATF. A survey of its performance has recently been completed.

The laser undulator compact X-ray source (LUCX) is a test bench used with the compact, high-brightness X-ray generator at KEK (High Energy Accelerator Research Organization). Our group is conducting experiments with LUCX to demonstrate the possibility of K-edge digital subtraction angiography, based on Compton scattering. One of the challenging problems is to generate high-brightness multi-bunch electron beams to compensate for the energy difference arising from the beam loading effect. In this paper we calculate the transient beam loading voltage and energy gain from the RF field in the gun and accelerating tube for a multi-bunch train. To do so we consider the process by which the RF field builds up in the gun and accelerating tube, and the special shape of the RF pulse. We generate and accelerate 100 bunches with a 50 nC electron bunch train, effectively compensating for the beam loading effect by adjusting the injection timing. Using a beam position monitor (BPM) and optical transition radiation (OTR) system, we measure the electron beam energy bunch by bunch. The average energy of a 100-bunch train is 40.5 MeV and the maximum energy difference from bunch to bunch is 0.26 MeV.

Kazuo HASEGAWA*, Hidetomo OGURI, Takashi ITO, Etsuji CHISHIRO, Koichiro HIRANO, Takatoshi MORISHITA, Shinichi SHINOZAKI, Hiroyuki AO, Kiyonori OHKOSHI, Yasuhiro KONDO, Jun TAMURA, Saishun YAMAZAKI, Toshihiko HORI, Fumiaki SATO, Yasuo NEMOTO, Isao KOIZUMI, Nobuo OUCHI, Nobuhiro KIKUZAWA, Akira UENO, Akihiko MIURA, Shinpei FUKUTA, Akinobu YOSHII, Koichi SATO, Akira OZONE, Yuki SAWABE, Yusuke KAWANE, Hiroshi IKEDA, Yuichi ITO, Yuko KATO, Kazuo KIKUCHI, Fumio HIROKI, Toshio TAKAYASU, Tsutomu USAMI, Munetoshi YANAI, Kazuhiko TADOKORO, Kenji OHSAWA, Fujio NAITO, Yong LIU, Zhigao FANG, Takashi SUGIMURA, Kenta FUTATSUKAWA, Kiyoshi IKEGAMI, Masato KAWAMURA, Kesao NANMO, Yuji FUKUI, Tomoaki MIYAO, Tomofumi MARUTA and Akira TAKAGI

A multi-bunch photo-cathode RF gun system has been developed as an electron source for the production of intense quasi-monochromatic X-rays based on inverse Compton scattering. The desired multi-bunch beam is 100 bunches/pulse with a total charge of 500 nC and a bunch spacing of 2.8 ns. We modified the gun cavity of a ‘BNL-type IV’ RF gun to allow a CsTe cathode plug in the end plate. The system uses a four-dipole chicane beam line to allow the injection of laser light normal to the cathode surface. We compensate the gun cavity beam loading caused by the high-intensity multi-bunch electron beam by injecting the laser pulse before RF power has filled the cavity. We have achieved a total intensity of 220 nC in 100 bunches with a bunch-to-bunch energy spread under 1.3% (peak-to-peak). This paper concentrates on experiments to generate the high-intensity multi-bunch beam with compensation of the bunch-to-bunch energy spread due to heavy beam loading.

Total suspended particulate (TSP) samples were collected from three areas (commercial, residential and agricultural) in and near Akita City in northern Japan, October 1996 (rice straw burning period), over three days with a one-hour sampling interval for each area. The elemental composition and particle shape of TSP samples were determined and/or observed by PIXE and a Scanning Electron Microscope (SEM) combined with Energy Dispersive X-ray (EDX) analysis. In the hourly TSP samples collected during the rice straw burning period, values of 24 elements were determined for each area, and Na , Mg , Al , Si , S , K , Ca and Fe were the major components. Comparing the arithmetic means of elemental concentrations in TSP for the rice straw burning and non-snow-clad period (May – June 1996), in the residential and agricultural areas the Si concentration in the rice straw burning period was approximately two times that in the non-snow-clad period, and K and Ca concentrations in the rice straw burning period were a little higher than those in the non-snow-clad period. In the residential and agricultural areas, change in SPM concentration and change in Si , K and Ca concentrations were in relative agreement during the hours that smoke from rice straw burning was present in the atmospheric space. With the aid of SEM- EDX analysis, many cubic particles were observed for almost all hourly TSP samples. The cubic particles were of the silicon-rich type, and their morphology was rice straw fragments or aggregation of fragments.

We describe in this report an upgraded version of the laser wire beam profile monitor developed at KEK to measure a low-emittance electron beam in the ATF damping ring. This monitor is based on the Compton scattering of electrons with a laser light target. A thin and intense laser beam is produced by exciting a Fabry–Perot optical cavity with a CW laser. Various improvements were made to the original setup. First, the effective laser power inside the cavity was increased by an order of magnitude, leading to a drastic increase in a signal-to-background ratio and a decrease in measurement time. Second, readout circuits were modified to separately measure beam sizes of each bunch in a multi-bunch beam. Third, two cavities were installed to measure both horizontal and vertical beam sizes. With this upgraded setup, measurements of electron beam emittance operated in a multi-bunch mode were carried out successfully.

We have previously found that carboxymethylpullulan (CMPul) conjugated with sialyl Lewis X (Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc-, 2-3SLex) preferentially accumulates in the lymph nodes and spleen. In the present study, we investigated the structural requirements of the 2-3SLex moiety for this accumulation using rats. Radiolabeled CMPul conjugates with various degrees of substitution (d.s.) of the 2-3SLex moiety were intravenously administered to rats, and their tissue distributions were monitored by radioactivity. When the d.s. was more than 0.5, preferential accumulation in the lymph nodes as well as the spleen was observed. However, when the d.s. was 0.025, little effect of the 2-3SLex moiety was noted. Changes in the carbohydrate structure of 2-3SLex, i.e., a change to alpha2-6-linked sialic acid (Neu5Acalpha2-6Galbeta1-4(Fucalpha1-3)GlcNAc-, 2-6SLex) or an elimination of the fucose (Neu5Acalpha2-3Galbeta1-4GlcNAc-, sialyl N-acethyllactosamine (SLN)), also made the 2-3SLex moiety ineffective. Furthermore, Microautoradiography analyses revealed that 2-3SLex-CMPul was incorporated by particular subsets of macrophages in these tissues, and that CMPul and SLN-CMPul were also located in the same cells to a lesser extent. 2-3SLex-CMPul may be able to serve as a novel drug delivery carrier to target drugs to the peripheral lymphoid tissues.

Total suspended particulate (TSP) samples were collected from three areas (commercial, residential and agricultural) in and near Akita City in northern Japan, from May – June 1996 (non-snow-clad period) and January – February 1997 (snow-clad period), over three days with a one-hour sampling interval for each area. The elemental composition and particle shape of TSP samples were determined and/or observed by Particle Induced X-ray Emission (PIXE) and a Scanning Electron Microscope (SEM) combined with Energy Dispersive X-ray (EDX) analysis. In the hourly TSP samples collected during the non-snow-clad period, 23 elements were determined for each area, and Na , Mg , Al , Si , S , Cl , K , Ca and Fe were the major components. On the other hand, 25 elements, excluding As and Rb , were found in the snow-clad period samples, and P , Ga , Nb and Mo were only found in the snow-clad-period samples. Dominant elements, i.e., major components, of the snow-clad period were the same as the non-snow-clad period. Comparing the arithmetic means of elemental concentrations in TSP for the non-snow-clad and snow-clad periods, in the commercial area the elemental concentrations in the snow-clad period were the same or lower than those in the non-snow-clad period, with the concentrations of Na , Mg , Al , Si , S , K , Ca , Ti and Fe in particular being markedly lower. In the residential area the concentrations of Na , Mg and Cl were markedly higher in the snow-clad period than in the non-snow-clad period, while the concentrations of the other elements were the same or only slightly lower. In the agricultural area, the concentrations of Na and Cl were markedly higher in the snow-clad period relative to the non-snow-clad period, and the concentrations of the other elements, except for P , were low. The concentrations of the major elements and Pb were particularly low. Thus, in the residential and agricultural areas the effect of northwesterly winter wind on TSP can be observed by Cl , and it is conjectured that soil particles rising up into the air is inhibited by snow accumulation. Soil particles rising up into the air seems to be inhibited by snow accumulation in the commercial area as well. With the aid of SEM and EDX analysis, aggregates of diesel exhaust particles (DEP), soil particles and small silicon-rich spherical particles were observed in the non-snow-clad and snow-clad period samples for each area. In addition, small aluminum-rich and iron-rich spheres were observed during the non-snow-clad period in the commercial area. Zinc-rich fiber was observed during the non-snow-clad period in the residential area.

Purpose. To evaluate the ability of a water-in-oil (W/O) emulsion containing ovalbumin (OVA), a model antigen, to induce oral tolerance and to elucidate the mechanism for the induction of oral tolerance by the emulsion system. Methods. A W/O emulsion containing OVA was prepared and evaluated its ability to induce oral tolerance in mice. Also, the Th1/Th2 balance in the mice tolerized was investigated in terms of the ratios of anti-OVA IgG2a titer to anti-OVA IgG1 titer (IgG2a/IgG1 ratios) and cytokine profiles. Results. Anti-OVA total IgG antibody titer of mice administered OVA in saline was approximately 3.5-fold higher than that of the mice administered OVA in W/O emulsion at a dose of 0.1 mg/mouse/day. Similar total IgG responses were observed between the above two at a dose of 1 mg/mouse/day. The IgG2a/IgG1 ratios decreased as the dose of OVA in W/O emulsion, but not in saline, increased at doses of 0, 0.1, and 1 mg/mouse/day. Interferon-γ secretion of PLN cells from the mice administered OVA in W/O emulsion decreased, whereas their interleukin-4 secretion remained high. Although interferon-γ secretion for the mice administered OVA in saline decreased, interleukin-4 secretion did not change. Conclusions. The present study suggests that oral delivery of OVA via the W/O emulsion system may more efficiently enhance the induction of Th2-dominated imbalance than that of OVA in saline.

Recombinant interleukin-2 (IL-2) was strongly and almost completely adsorbed onto small hydrophobic liposomes under optimal conditions (liposome: DSPC-DSPG; molar ratio, 10:1; 30-50 nm in size, ratio of IL-2 to liposome: 4.0 JRU/nmol lipid). This liposomal IL-2 improved the distribution of IL-2 after intravenous administration as reported, previously. Liposomal IL-2 (300-10000 JRU/mouse per day) was significantly more effective than free IL-2 alone for inhibiting against the experimental metastases of M5076 in mice. The inhibitory effect of liposomal IL-2 was greatest in the liver. The ED(50) of liposomal IL-2 and that of free IL-2 in the liver were 1640 and 12500 JRU/mouse per day, respectively. This simple preparation (mixture) using IL-2 and liposome suspension is expected to have potential for increasing therapeutic efficacy against hepatic metastases.

Several liposomes containing ovalbumin (OVA), a model antigen, with different lipid compositions were prepared in order to evaluate their ability to induce oral tolerance. Oral administration of these liposomal OVAs induced suppression of the proliferative responses of popliteal lymph node cells from the treated mice to OVA, suggesting that these treated mice were tolerized. The efficiency of the induction of oral tolerance was affected by the liposome composition. OVA entrapment in these liposomes could modulate the tolerizing dose of OVA itself. These results suggest that some liposomes can be suitable antigen-delivery systems for modulated and/or effective induction of oral tolerance.

Continuous measurement of PM 10 , PM 2.5 and carbon (organic, elemental composition) concentrations, and samples of PM 10 and PM 2.5 collected on a polycarbonate membrane filter (Nuclepore ® , pore size: 0.8 μm), were carried out during a period from December 1998 to January 1999 at Shinjuku in Tokyo in order to investigate the chemical characterization of particles in winter-night smog within a large area of the Japan Kanto Plain including the Tokyo Metropolitan area. These were measured using an ambient particulate monitor (tapered element oscillating microbalance—TEOM) and a carbon particulate monitor. Elemental compositions in the filter samples of PM 10 and PM 2.5 were determined by means of particle-induced X-ray emission (PIXE) analysis. Ionic species (anion: F − , Cl − , NO 3 − , SO 4 2− and C 2 O 4 2− ; cation: Na + , NH 4 + , K + , Ca 2+ and Mg 2+ ) in the filter samples were analyzed by ion chromatography. The temporal variation patterns of PM 2.5 were similar to those of PM 10 and carbon. PM 2.5 made up 90% of the PM 10 at a high concentration, and 70% at a low concentration. Concentrations of 22 elements in both the PM 10 and PM 2.5 samples were consistently determined by PIXE, and Na, Mg, Al, Si, S, Cl, K, Ca, Fe, Zn and Pb were found to be the major components. Among these S and Cl were the most dominant elements of the PM 2.5 and PM 10 at high concentrations. Ionic species were mainly composed of Cl − , NO 3 − , SO 4 2− and NH 4 + . The component proportion of carbon, the other elements (total amount of measured elements other than S and Cl) and secondary-formed particles of PM 2.5 was similar to that of PM 10 . The major component was carbon particles at a low concentration and secondary-formed particles at a high concentration. The proportion of NH 4 NO 3 and NH 4 Cl plus HCl in secondary-formed particles at a high concentration, in particular, was as high as 90%.

We present experimental results for a traveling wave resonant ring in a low-duty beam test and a high-duty RF test. In the low-duty beam test, we studied the RF characteristics of the traveling wave resonant ring and measured the multiplication factor, M, and conversion efficiency, η. We obtained multiplication factors of 3.2 under no beam loading and 2.2 under a beam loading of 100 mA and these were in good agreement with calculations. A high conversion efficiency of 0.74 was achieved by using the traveling wave resonant ring. In the high-duty RF test, we measured the multiplication factor as a function of phase shifter position and temperature of the traveling wave resonant ring. From the experimental results, we calculated the variation of the phase shifter position to a temperature rise. Understanding this variation is necessary to keep the multiplication factor at the maximum for the design point 20% duty operation.

Total suspended particulate (TSP) samples were collected at the west-facing slope (altitude 700 m) of Mt. Moriyoshi in northern Japan, from 24 – 27 June (non-snow-clad period) and 11 – 14 December (snow-clad period) in 1996, with a one-hour sampling interval. The elemental composition and particle shape of TSP samples were determined and/or observed by Particle Induced X-ray Emission (PIXE), a Scanning Electron Microscope (SEM) combined with Energy Dispersive X-ray (EDX) analysis. In the hourly TSP samples collected during the non-snow-clad period, 27 elements were determined. Na, Mg, Al, Si, S, K, Ca and Fe were found to be the major elemental components. On the other hand, 25 elements, excluding Nd and Mo, were found in the snow-clad period samples, and Cl is a dominant element, i.e., a major element, of the snow-clad period samples, unlike the non-snow-clad period. Comparing the arithmetic means of concentrations of major elements in TSP for non-snow-clad and snow-clad periods, Mg, Al, Si, K, Ca and Fe levels in the snow-clad period are 2 – 4 times as much as those in the non-snow-clad period, and 30 times for Na. S is similar. For temporal variation patterns of element concentrations, the non-snow-clad period is different from the snow-clad period. Al, S, Ca, Ti, Fe, Zn and Pb are similar throughout the non-snow-clad period, and Al, Si, Ca and Fe are similar throughout the snow-clad period. With the aid of SEM and EDX analysis, aggregates of car exhaust particles, soil particles and plant spores were observed in the non-snow-clad period samples. In the snow-clad period samples, small silicon-rich spherical particles, aggregates of car exhaust particles and soil particles were observed.

Purpose. To demonstrate the potential of carboxymethylpullulan (CMPul) as a carrier for targeting immune tissues, and to find whether immune tissues could be set as the target of an immunosuppressant to treat autoimmune diseases. Methods. The biodistribution of CMPul was investigated to evaluate its potency as a carrier for targeting immune tissues. Furthermore, an immunosuppressant-CMPul conjugate was prepared and its suppressive effect on rat adjuvant arthritis was examined. Results. The disappearance rate of 3H-labeled CMPul from the blood circulation was much slower than that of 3H-labeled pullulan (Pul) after intravenous injection to normal rats. The concentration of 3H-labeled CMPul in the spleen and lymph nodes was much higher than that of 3H-labeled Pul at 24 hours after the injection, whereas the concentration of 3H-labeled CMPul in the liver was significantly lower than that of 3H-labeled Pul. A similar targeting property of 3H-labeled CMPul for these immune tissues was observed in arthritic rats. A conjugate composed of a novel immunosuppressant PA-48153C and CMPul showed a suppressive effect on rat adjuvant arthritis judging from a reduction of the arthritic index and spleen weight and an increase of body weight. Conclusions. CMPul is expected to be a promising carrier for targeting immune tissues with an immunosuppressant to enable treatment of autoimmune diseases.

In vitro studies have shown that conjugation of a model compound [p-di(hydroxyethyl)-amino-D-phenylalanine (D-MOD)] with L-Glu can improve D-MOD permeation through the bovine brain microvessel endothelial cell monolayers (Sakaeda et al., 2000). The transport of this D-MOD-L-Glu conjugate is facilitated by the L-Glu transport system. In this paper, we evaluate the in vivo brain delivery of model compounds (i.e. D-MOD, p-nitro-D-phenylalanine (p-nitro-D-Phe), 5,7-dichlorokynurenic acid (DCKA) and D-kyotorphin) and their L-Glu conjugates. DCKA was also conjugated with L-Asp and L-Gln amino acids. The analgesic activities of D-kyotorphin and its L-Glu conjugate were also evaluated. The results showed that the brain-to-plasma concentration ratio of D-MOD-L-Glu was higher than the D-MOD alone; however, the plasma concentration of both compounds were the same. The plasma concentration of p-nitro-D-Phe-L-Glu conjugate was higher than the parent p-nitro-D-Phe; however, the brain-to-plasma concentration ratio of p-nitro-D-Phe was higher than its conjugate. On the other hand, both DCKA and DCKA conjugates have a low brain-to-plasma concentration ratio due to their inability to cross the blood-brain barrier (BBB). The L-Asp and L-Glu conjugates of DCKA have elevated plasma concentrations relative to DCKA; however, the DCKA-L-Gln conjugate has the same plasma concentration as DCKA. For D-kyotorphin, both the parent and the L-Glu conjugate showed similar analgesic activity. In conclusion, conjugation of a non-permeable drug with L-Glu may improve the drug's brain delivery; however, this improvement may depend on the physicochemical and receptor binding properties of the conjugate.

Total suspended particulate (TSP) samples were collected along a highway (Barajima air pollution monitoring station) in the center of Akita City in northern Japan, from 9 – 11 May, 1996 (non-snow-clad period) and 7 – 9 February, 1997 (snow-clad period), with a one-hour sampling interval, The elemental composition and particle shape of TSP samples were determined and / or observed by Particle Induced X-ray Emission (PIXE) and a Scanning Electron Microscope (SEM) combined with Energy Dispersive X-ray (EDX) analysis. In the hourly TSP samples collected during the non-snow-clad period, 26 elements were determined. Na, Mg, Al, Si, S, Cl, K, Ca and Fe are the major components. On the other hand, 24 elements, excluding As, Rb and Nb, are found in the snow-clad period samples, and Gallium is only found in the snow-clad period samples. Dominant elements, i.e., major components, of the snow-clad period were the same as the non-snow-clad period. Comparing the arithmetic means of major elemental concentrations in TSP for the non-snow-clad and snow-clad periods, Na, Mg, Al, Si and Fe are similar. However, S and Ca levels in the non-snow-clad period samples were 4 and 6 times higher than those in the snow-clad period samples, respectively, while Cl and K levels in the snow-clad period samples were 1.5 and 2 times higher than those in the non-snow-clad period, respectively. In the non-snow-clad period, the temporal variation pattern of total elemental amount was consistent with the variation pattern of NO and CO, which are pollutants used to observe the effects of automobile exhaust gas, and it was comparatively consistent with the variation pattern of SPM. On the other hand, in the snow-clad period, the temporal variation pattern of total elemental amount was not consistent with the variation pattern of NO and CO when the wind was blowing from the southeast, so the TSP may be strongly influenced by wind direction and wind velocity in addition to automobile traffic. Factor analysis allowed us to identify four major sources, with automobile emission, industry and soil being the major contributors. With the aid of SEM and EDX analysis, aggregates of diesel exhaust particles (DEP), soil particles and small silicon-rich spherical particles were observed in the non-snow-clad and snow-clad period samples.

Aerosolized IFN-gamma is very unstable. We have improved the stability of IFN-gamma in the jet nebulizer by adding small liposomes. Aerosolized IFN-gamma was recovered in PBS solution by bubbling and its concentration was determined. After nebulization for 30 min, aerosolized IFN-gamma was detected only 0.4+/-0.2% of the initial amount in the PBS solution and 3.1+/-0.7% in the reservoir. On the other hand, the addition of small liposomes (HSPC/DSPG=10/1 (molar ratio), 45+/-24 nm) in the nebulizer increased the stability of IFN-gamma, 27.2+/-4.7% of the initial amount in the PBS solution and 25.7+/-12.6% in the reservoir. The present study also examined the effects of composition and concentration of liposomes on the stabilization of aerosolized IFN-gamma. Liposome prepared from distearoyl phosphatidylcholine (DSPC) or hydrogenated soy phosphatidylcholine (HSPC) was very effective for stabilization of aerosolized IFN-gamma (DSPC/DPPG=10/1, HSPC/DSPG=10/1). HSPC/DSPG liposome was efficient at the concentration higher than 12.5 micromols/ml for the stabilization of 5x10(5) JRU/ml of IFN-gamma. In considering the mechanism of this stabilization, the results of gel filtration chromatography suggest that IFN-gamma is inactivated by polymerization or aggregation in nebulization, while the inactivation is suppressed by liposomes due to their adsorption to IFN-gamma.

The destruction of liposomes and their transition into multiple emulsions induced by the addition of α-tocopheryl acetate (Toc) were investigated. With the increase of incorporated Toc in lipid bilayers composed of hydrogenated soybean lecithin (HSL), the polarity in the hydrophobic region of the bilayers decreased. When the added Toc exceeded its capacity to be incorporated, the excess formed multiple emulsions. There were two characteristic Toc/HSL molar ratios defined as R1 and R2. R1 is the molar ratio at which the alteration in the physical properties of membranes becomes significant. R2 is the molar ratio at which emulsions begin to be formed, that is, the capacity of Toc in HSL membranes. In our system, these ratios were ca. 0.03 and 0.6, respectively. The proportion of the emulsions can be successively predicted by the mean field approach. The physical effect of Toc on phospholipid membranes and the transition mechanism from liposomes to multiple emulsions are discussed.

Two different chemical approaches for brain drug delivery and targeting are proposed in the present review. One is a chemical drug delivery using a ring-closure reaction to the hydrophilic quaternary thiazolium compound in the brain. The other is a chemical drug targeting utilizing the nutrient receptor (transporter) system on the blood–brain barrier. The brain delivery system has been optimized and it was demonstrated that the brain delivery of three drugs, a drug for Parkinson's disease, an excitatory amino acid antagonist and a free radical scavenger, were improved by the conjugation with cis-2-formylaminoethenylthio derivatives in vivo. As for the brain targeting system, it was demonstrated that the conjugation with l -Glu improved the drug's brain distribution via the l -Glu excitatory and/or transport receptors in vitro and in vivo. These findings suggest that the concepts of two chemical approaches will contribute to the development of new central nervous system drugs.

Purpose. Stachyflin and its derivatives which are active against the influenza virus in vitro, were studied to improve their reduced in vivo activity after oral administration by chemical modification and some vehicles.

Fresh surface snow samples were collected at the summit or near the summit (700 - 1500 m altitude) of five mountains in Akita Pref., Japan. The elemental composition and particle shape of insoluble material in these snow samples was determined and/or observed by Particle Induced X-ray Emission (PIXE), a Scanning Electron Microscope (SEM) combined with Energy Dispersive X-ray (EDX) analysis. 21 kinds of elements for each mountain snow sample were determined by PIXE. Na , Mg , Al , Si , P , S , Cl , K , Ca , Ti and Fe were the major components in each of the mountain snow samples, and those in relative abundance were almost the same in each case. With the aid of SEM and EDX analysis, silicon-rich small sphere (spherule) particles and aggregates of car exhaust particles were observed in every mountain snow sample. These results are represented as insoluble components of clouds and provide important knowledge for the source and mechanism of snowfall and rainfall at the ground level.

The blood flow rates of 14 tissues in the body were determined by microsphere method using normal and tumor-bearing rats kept conscious or under urethane anesthesia. The effects on the blood flow rate in the tissues were assessed for multimodal therapy, systemic hypothermia for ischemic brain injury, and local hyperthermia and angiotensin II-induced hypertensive chemotherapy for cancer. Urethane anesthesia showed no effect on cardiac output, while there was a tendency of decrease of blood flow rate and % of cardiac output in each tissue other than muscle tissue, in which they increased as a counterbalance, in normal and tumor-bearing rats. Systemic hypothermia gave results similar to those of urethane anesthesia in normal rats, but for tumor-bearing rats, it decreased cardiac output, and consequently the blood flow rate in most tissues. Brain blood flow rate was about half of that in the conscious rats. Local hyperthermia also decreased the cardiac output and blood flow rate in each tissue, including the tumor tissue. Angiotensin II-induced hypertension showed no effect on cardiac output, had various effects on blood flow rate in each tissue, and led to no increase in the tumor blood flow rate. Simulations based on the physiological pharmacokinetic modeling suggested that intramuscular injection of a lung-specific derivative of ceftazidime would provide the ideal biodistribution to ensure its optimal therapeutic efficacy during systemic hypothermia. This methodology, namely the pharmacokinetic simulation based on the physiological values of the body, will provide a useful piece of information on drug delivery systems under various conditions.

The pharmacokinetics and pharmacodynamics of antihemorrhagic vitamin, menatetrenone after intravenous injection as the lipid emulsion, were compared to those as the micellar solutions. Menatetrenone was selectively delivered to the liver, lungs and spleen and retained in them. Hepatic and splenetic concentration at 6 h (C6h) increased 21.6- and 27.1-fold, respectively, and the area under the tissue concentration-time curve up to 6 h (AUC(0-6h)) were 2.3- and 11.4-fold, respectively, when compared with its micellar solution. Antihemorrhagic effect of menatetrenone was assessed using warfarin-induced hypoprothrombinemic rats. The lipid emulsion of menatetrenone decreased the prothrombin time at 6h after intravenous injection more effectively than micellar solution. The dose response curves indicated that the efficacy of the lipid emulsion was 2.4-2.9 times that of a micellar solution, and this was correlated with AUC(0-6h) rather than C6h. The plasma level of clotting factor VII and the hepatic level of descarboxyprothrombin were also recovered more effectively, while no significant differences were noted between the two formulations for the plasma level of factor II or descarboxyprothrombin at the dose levels examined. Although selective delivery of menatetrenone in the liver by the lipid emulsion was due to phagocytosis by non-parenchymal cells, menatetrenone in the whole liver appeared to contribute to recovery from hypoprothrombinemia.

Plasma concentrations of oil particles after intravenous injection of oil-in-water (O/W) lipid emulsions were monitored based on the plasma concentration of phospholipids (PL) and triglycerides (TG), and the light scattering intensity (LSI) of plasma. Previously, we found that their time profiles after injection of the standard O/W lipid emulsion composed of soybean oil (SO) and egg yolk phosphatides (EYP) were similar and suggested that the oil particles with diameter of about 200 nm were entrapped by reticuloendothelial system (RES). Herein, in order to develop a delivery system to avoid the RES uptake by using the lipid emulsions, biological fate of lipid emulsions with oil particles of various sizes or those emulsified by surfactants with polyoxyethylene segments were subjected to the investigations. Lipid emulsions with oil particles of various sizes (about 150-550 nm) were prepared by altering EYP content. The oil particles were stable in plasma in vitro, but oil particle size decreased time-dependently after intravenous injection. Plasma clearance of oil particles depended on their initial size and was decreased by pretreatment with dextran sulfate 500 (DS500), a known RES suppressor. These results suggested that oil particles are still entrapped by RES, even for small-sized oil particles (about 150 nm). Lipid emulsion with small-sized oil particles was also prepared using medium chain triglycerides. The oil particles were stable in vitro, but the time profiles of plasma concentrations of PL and TG, and LSI of plasma were different, and oil particle size decreased time-dependently after intravenous injection. Plasma clearance of the oil particles also depended on their initial size and was decreased by DS500, suggesting that in vivo instability could be due to RES-mediated processes. Artificial surfactants with polyoxyethylene segments, HCO-60 (HCO60) and polysorbate 80 (PS80), were used for RES avoidance. HCO60 resulted in drastic reduction of the plasma clearance of the oil particles for both lipid emulsions composed of soybean oil and medium chain triglycerides. The time-dependent decrease of oil particle size after intravenous injection was marginal. In contrast, PS80 could not prolong the circulation time of the oil particles, and their size decreased time-dependently after intravenous injection.

Purpose. Elucidating the transport characteristics of S-1090, a new orally active cephalosporin in rat small intestinal brush-border membranes.

Two thioether-linked conjugates composed of monoclonal antibody (MoAb) to alpha-fetoprotein (AFP), 80G or its F(ab')2 fragment, and a type 1 ribosome-inactivating protein (RIP), gelonin, were prepared as potent immunotoxins [80G-CS-GL(IT) and F(ab')2-CS-GL(IT)]. Each conjugate contained one gelonin per 80G or its F(ab')2 fragment. The binding activity of these conjugates was as high as that of intact 80G or F(ab')2. The in vitro cytotoxic effect of F(ab')2-CS-GL(IT) on AFP-producing HuH-7 cells was approximately 100-fold more potent than that of 80G-CS-GL(IT). Also, F(ab')2-CS-GL(IT) showed slight cytotoxicity against non-AFP-producing HuH-13 cells, while 80G-CS-GL(IT) did not. On the other hand, both conjugates had similar selective antitumor activity against HuH-7N cells in nude mice, possibly due to their similar distribution in the tumor. The results suggest that our MoAb 80G is a suitable carrier for delivering type 1 RIP such as gelonin into AFP-producing hepatoma cells and that its F(ab')2 fragmentation does not enhance targeting efficiency.

This paper describes a method suitable for purifying immunotoxin containing type 1 ribosome-inactivating protein, gelonin. The separation of free (unreacted) 80G, a monoclonal antibody against alpha-fetoprotein (AFP), from semipurified 80G-gelonin conjugate was unsuccessful by conventional CM-Sepharose ion-exchange chromatography because the isoelectric point of the conjugate did not increase enough to reach that of gelonin alone. In contrast, Blue Sepharose affinity chromatography could efficiently separate free 80G from the semipurified conjugate because the conjugate was bound to the column by its gelonin moiety while free 80G was not in buffer containing NaCl of a particular concentration range. However, a small amount of conjugate containing gelonin modified with N-succinimidyl 3-(2-pyridyldithio)propionate, but not with 2-iminothiolane, could not bind to the column. The conjugate purified by the use of Blue Sepharose showed selective cytotoxicity against AFP-producing human hepatoma cells.

Common problems in developing renin inhibitors are low solubility, insufficient oral absorption, and fast hepatic clearance. We focused on the molecular structure of renin inhibitors to overcome these problems. Cyclodextrins (CD) improved the low solubility of renin inhibitors, with β-CD showing the best ability to dissolve renin inhibitors. The intestinal absorption of renin inhibitors varied with both their solubility and molecular structure. Coadministration of β-CD improved the intestinal absorption of some renin inhibitors with low solubility as measured by transport into the mesenteric vein in the absorption experiment using the rat intestinal loop. Substitutions at both the N and C terminals was essential for absorption from the small intestine. A naphthyl group at the N-terminal further improved intestinal absorption. A carrier system appeared to be involved in the intestinal absorption of some renin inhibitors. N-methylation at the amide bond of thiazolylalanine suppressed the high hepatic clearance of one of the test compounds 18 which was well absorbed from the small intestine and it improved its oral bioavailability.

The characteristics of ceftibuten uptake into Caco-2 cells grown in a collagen-coated dish were examined. Ceftibuten showed stereoselective and pH-dependent uptake. The pH-dependency of ceftibuten was more marked than that of cefaclor or cephalexin, but all three antibiotics showed maximal uptake at pH 5.5. Ceftibuten uptake was linear for the initial 1 hr and then reached a plateau. The initial uptake (15 min) was markedly reduced by the addition of 2,4-dinitrophenol or FCCP (a protonophore), or by lowering the incubation temperature. The uptake of ceftibuten into the brush-border membrane vesicles prepared from cultured Caco-2 cells showed an overshoot in the presence of an H+-gradient. These findings indicated that the uptake of ceftibuten was energy-dependent, especially H+-gradient-dependent. Uptake inhibition by various compounds was compared using Caco-2 cells. Amino acids and a tetrapeptide did not inhibit uptake, whereas di- or tri-peptides were effective inhibitors. These observations suggest that ceftibuten is taken up by a carrier-mediated transport system(s) for dipeptides. Various antibiotics differed in their ability to inhibit uptake, with cyclacillin showing maximum inhibition. Differences in the inhibitory effect may be accounted for by the heterogeneity (multiplicity) of the transport systems.

The potential usefulness of oil in water (O/W) lipid emulsions as parenteral drug delivery system for lipophilic drugs was examined in tumor-bearing rats. A model lipophilic drug, sudan II (PCoct = 226000), was formulated in five lipid emulsions consisting of soybean oil and various surfactants. Compared with HCO-60 micellar and plasma solutions of sudan II, the blood concentration of sudan II was markedly elevated by administration as a lipid emulsion. However, the distribution of sudan II to the liver, lungs, spleen, and adipose tissue was not altered, and that to the brain, heart, kidneys, muscle, and tumor was slightly decreased. To understand these results, pharmacokinetic analysis was performed using a newly derived compartmental model, and moreover, the organ distribution clearance was analyzed. It was suggested that the oil particles deliver the incorporated drug selectively to the liver, lungs, and spleen, and the speed of delivery could be surpressed by using HCO-60. However, in the case of sudan II, its rapid release from the oil particles after i.v. injection prevented a drastic alteration in the distribution of sudan II. The simulation studies suggested that a considerable decrease in the release rate or an increase in partition coefficient (experimentally more than 10(8) would be required for delivery.

The sustained release mechanism of gentamicin (GM) from lactic acid/glycolic acid copolymer (PLGA) microspheres was investigated. The terminal free carboxyl group of polymer was proved to be necessary for GM to be highly incorporated into microspheres by comparing interactions with GM and two types of polymers; free (ionized and non ionized) and the terminal esterified carboxyl group of polymer. The weight-average molecular weights (Mws) of component PLGAs of microspheres with an ionizable carboxyl group used here were approximately 4900 and 10000. The release pattern of GM was tested in phosphate buffered saline. The release rate of GM was dependent on the initial Mw and surface form. The GM release continued for 20 and 30 d from PLGA 4900- and PLGA10000-microspheres, respectively. The changes of total weight of microspheres tended to decrease with time, and the molecular weight distribution of PLGA gradually shifted to lower distribution, indicating a decrease in Mw. The changes and the shifts were dependent on the initial Mws of PLGAs but independent of their surface form. The half-times of wight loss of PLGA 4900- and PLGA10000-microspheres were about 10 and 20 d, respectively. From these results, the release profile of GM from PLGA microspheres was explained by the following three steps, i.e., 1) the release from the surface, 2) the relatively slow release caused by the obstruction of channels followed by the degradation of PLGA, 3) the release accompanied by the erosion of microspheres.