Validation of the Absorption-Enhancing Ability of Oligoarginines Grafted onto a Backbone of Hyaluronic Acid through Animal Studies from Rodents to Primates.

The purpose of our research is to develop functional additives that enhance mucosal absorption of biologics, such as peptide/protein and antibody drugs, to provide their non-to-poor invasive dosage forms self-managed by patients. Our previous in vivo and in vitro studies demonstrated that the intranasal absorption of biologics in mice was significantly improved when coadministered with oligoarginines anchored chemically to hyaluronic acid via a glycine spacer, presumably through syndecan-4-mediated macropinocytosis under activation by oligoarginines. The present mouse experiments first revealed that diglycine-L-tetraarginine-linked hyaluronic acid significantly enhanced the intranasal absorption of sulpiride, which is a poor-absorptive organic compound with a low molecular weight. However, similar enhancement was not observed for levofloxacin, which has a similarly low molecular weight but is a well-absorptive organic compound, probably because its absorption was mostly dominated by passive diffusion. The subsequent monkey experiments revealed that there was no species difference in the absorption-enhancing ability of diglycine-L-tetraarginine-linked hyaluronic acid for not only organic compounds but also biologics. This was presumably because the expression levels of endocytosis-associated membrane proteins on the nasal mucosa in monkeys were almost equivalent to those in mice, and poorly membrane-permeable/membrane-impermeable drugs were mainly absorbed via syndecan-4-mediated macropinocytosis, regardless of animal species. Drug concentrations in the brain assessed in mice and monkeys and those in the cerebral spinal fluids (CSFs) assessed in monkeys indicated that drugs would be delivered from the systemic circulation to the central nervous system by crossing the blood-brain and the blood-CSF barriers under coadministration with the hyaluronic acid derivative. In line with our original hypothesis, this new set of data supported that our oligoarginine-linked hyaluronic acid would locally perform on the mucosal surface and enhance the membrane permeation of drugs under its colocalization.

Position detection of a beta particle emitter by utilizing self-absorption in a scintillation fiber.

Self-absorption in a plastic scintillation fiber can be utilized to determine the incident position of single beta particles. A dichroic mirror directs scintillation photons with shorter wavelengths to one Si photomultiplier and those with longer wavelengths to another. An index calculated from the two signals is a monotonic function of the distance between the tip of the fiber and the incident point. Once this relation is known, one can determine the distance from the two measurables. In an experiment, such a calibration curve was acquired to detect the position of a 90Sr source up to a distance of 240 cm. The average total number of photoelectrons for a single beta particle was about 15-17. Depending on the propagation distance in the scintillation fiber, they were unevenly divided by the two photodetectors.

Spectral study on utilizing ambient light with luminescent materials for display applications.

A luminous reflective display can be constructed by placing an electro-optic shutter on the stack of a luminescent layer, a color filter, and a reflector in this order. The luminescent materials convert a part of the incident light to photoluminescence photons. The reflector redirects the downward photon flux toward an observer. The color filters prevent the photons with unwanted wavelengths from being reflected. The upward spectral flux from this multi-layer structure is formulated. Experiments with off-the-shelf components revealed more than three-fold increase in spectral flux and up to 55% color gamut extension, compared with a control device without luminescent materials.

Concentric re-emission pattern from a planar waveguide with a thin uniform luminescent layer.

When a beam of light excites a single spot on a thin luminescent layer embedded in a planar waveguide, a concentric re-emission pattern is observed. An analytical expression is formulated by following the series of events in the waveguide: generation of angle-dependent photoluminescence spectra, reflection at the waveguide-air boundary, absorption by the luminescent layer, and generation of next-generation photoluminescence. The formula reproduces the peak radii observed in the experiments with some organic dyes. It provides insights for the re-emission events in a luminescent solar concentrator and the cross talk in an energy-harvesting display based on photoluminescence.

Cross talk and optical efficiency of an energy-harvesting color projector utilizing ceramic phosphors.

A color projector screen was fabricated by filling three kinds of ceramic phosphor powders in the periodic hollow columns formed in a ${50}\;{{\rm mm}}\; \times \;{50}\;{{\rm mm}}\; \times \;{10}\;{{\rm mm}}$50mm×50mm×10mm acrylic waveguide. When a blue laser beam excited a single spot on the screen, a disk-shaped cross-talk pattern appeared. Its intensity was 5 orders of magnitude lower than that of the excited spot. The solar cells attached to the waveguide edge harvested less than 0.8% of the incident optical power. The photons scattered by the phosphors are responsible for these characteristics, and the use of non-scattering luminescent materials is desired for improving them.

Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of bucolome to restore diuretic response in nephrotic syndrome.

To determine whether bucolome (5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine), a nonsteroidal anti-inflammatory agent, can reverse diuretic resistance of furosemide in patients with nephrotic syndrome, we examined the inhibitory effect of bucolome on the protein binding of furosemide in serum and urine. Bucolome significantly inhibited the protein binding of furosemide not only in serum but also in urine of preparation albumin (UPA), which mimics urinary albumin concentration in patients with nephrotic syndrome by ultrafiltration method. The binding percentage of furosemide to albumin was approximately 70% in UPA. With coadministration of bucolome to healthy volunteers, renal clearance of furosemide was increased, reflecting the increase of the free fraction of furosemide in serum. Furthermore, coadministration of bucolome caused a significant increase of urine volume and sodium concentration in urine. Even at higher urine levels of furosemide, the inhibitory effect of bucolome on the protein binding of furosemide in UPA remains constant, and changes in pH at weakly acidic pH levels (pH 5.5-6.5) did not alter the inhibitory effect of bucolome. Interestingly, coadministration of bucolome with furosemide in doxorubicin (Adriamycin)-induced nephrotic syndrome model rats alleviated the diuretic resistance. These results suggest that bucolome has a potent inhibitory effect on the protein binding of furosemide in the urine and can partially restore the diuretic response of furosemide in patients with nephrotic syndrome by increasing the free fraction of furosemide at the site of action.

Pharmacokinetics and tissue distribution of uraemic indoxyl sulphate in rats.

The purpose of the present study was to examine the pharmacokinetic properties of indoxyl sulphate, a harmful uraemic toxin that accumulates during chronic renal failure. The pharmacokinetics and tissue distribution of indoxyl sulphate were examined in normal and 5/6 nephrectomized (CRF) rats. The uptake process of indoxyl sulphate by rat renal cortical slices in vitro was also investigated. Endogenous indoxyl sulphate was found to be mainly distributed in the kidney. The rate of elimination of indoxyl sulphate from plasma was lower in CRF rats compared with sham-operated rats. The majority of intact indoxyl sulphate was excreted in the urine. In renal cortical slice experiments, uptake of indoxyl sulphate was a saturable process with a K(m) of 43.0 microm. Furthermore, sulphate conjugates, such as oestrone sulphate and dehydroepiandrosterone sulphate, inhibited the uptake of indoxyl sulphate to a greater extent than PAH. Thus, indoxyl sulphate is primarily eliminated from the plasma via the kidney by active tubular secretion, and renal uptake of indoxyl sulphate appears to be mediated by an organic anion transport system with a high affinity for oestrone sulphate and dehydroepiandrosterone sulphate.

Renal disposition of a furan dicarboxylic acid and other uremic toxins in the rat.

The aim of this study was to understand the mechanisms that underlie the renal elimination of albumin-bound uremic toxins, particularly the highly bound furan acid 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), that accumulate in chronic renal failure. These toxins inhibit the binding of acidic drugs and have various other untoward effects. The pharmacokinetics and tissue distribution of CMPF plus three other such toxins, indoxyl sulfate, indole acetic acid, and hippuric acid, have been examined in the anesthetized rat. The effects of p-aminohippuric (PAH) acid and tetraethylammonium on the uptake of CMPF by rat renal cortical slices in vitro were also investigated to characterize its mechanism of uptake. Plasma and tissue concentrations of the uremic toxins were determined by high-performance liquid chromatography. The rate of elimination of the toxins from plasma was indoxyl sulfate > hippuric acid > indole acetic acid > CMPF. Although the renal clearance of CMPF was low, its main elimination pathway was via urinary excretion with active tubular secretion. In renal cortical slice experiments, mutual inhibition between CMPF and PAH was observed. In addition, alpha-ketoglutarate stimulated the uptake of CMPF by renal cortical slices. The base tetraethylammonium did not inhibit slice uptake of CMPF. The pharmacokinetics of CMPF was characterized by slow plasma clearance and localization in the kidney. Furthermore, the evidence from experiments with renal cortical slices indicates that the uptake of CMPF is mediated by an anion/dicarboxylate exchanger, similar to that for PAH.