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Delamanid has been studied extensively and approved for the treatment of pulmonary multidrug-resistant tuberculosis; however, its potential in the treatment of extrapulmonary tuberculosis remains unknown. We previously reported that, in rats, delamanid was broadly distributed to various tissues in addition to the lungs. In this study, we simulated human plasma concentration-time courses (pharmacokinetic profile) of delamanid, which has a unique property of metabolism by albumin, using two different approaches (steady-state concentration of plasma-mean residence time [C(ss)-MRT] and physiologically based pharmacokinetic [PBPK] modeling). In C(ss)-MRT, allometric scaling predicted the distribution volume at steady state based on data from mice, rats, and dogs. Total clearance was predicted by in vitro-in vivo extrapolation using a scaled albumin amount. A simulated human pharmacokinetic profile using a combination of human-predicted C(ss) and MRT was almost identical to the observed profile after single oral administration, which suggests that the pharmacokinetic profile of delamanid could be predicted by allometric scaling from these animals and metabolic capacity in vitro. The PBPK model was constructed on the assumption that delamanid was metabolized by albumin in circulating plasma and tissues, to which the simulated pharmacokinetic profile was consistent. Moreover, the PBPK modeling approach demonstrated that the simulated concentrations of delamanid at steady state in the lung, brain, liver, and heart were higher than the in vivo effective concentration for Mycobacterium tuberculosis. These results indicate that delamanid may achieve similar concentrations in various organs to that of the lung and may have the potential to treat extrapulmonary tuberculosis.

The pharmacokinetics of brexpiprazole were investigated in the in vitro and in vivo.The total body clearance of brexpiprazole in rat and monkey was 2.32 and 0.326 L/h/kg, respectively, after intrav...

Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug–drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in vitro investigation.Brexpiprazole exhibited weak inhibitory effects (IC50 >13 μmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 μmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes.Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 μmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low.Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 μmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates.These in vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs. Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug–drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in vitro investigation. Brexpiprazole exhibited weak inhibitory effects (IC50 >13 μmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 μmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes. Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 μmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low. Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 μmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates. These in vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs.

We constructed machine learning-based pharmacokinetic prediction models with very high performance. The models were trained on 26138 and 16613 compounds involved in metabolic stability and cytochrome P450 inhibition, respectively. Because the compound features largely differed between the publicly available and in-house compounds, the models learned on the public data could not predict the in-house compounds, suggesting that outside of a certain applicability domain (AD), the prediction results are unreliable and can mislead the design of novel compounds. To exclude the uncertain prediction results, we constructed another machine learning model that determines whether the newly designed compound is inside or outside the AD. The AD was evaluated multi-dimensionally with some explanatory variables: The structural similarities and the probability obtained from the pharmacokinetic prediction model. The accuracy of predicting metabolic stability was 79.9% on the test set, increasing significantly to 93.6% after excluding the low-reliability compounds. The model properly classified the reliability of the compounds. After learning on the in-house compounds, the reliability model classified almost all (90%) of the public compounds as low reliability, indicating that the AD was properly determined by the model.

The objective of this study was to obtain the indicators of physicochemical parameters and structurally active sites to design new chemical entities with desirable pharmacokinetic profiles by investigating the process by which machine learning prediction models arrive at their decisions, which are called explainable artificial intelligence. First, we developed the prediction models for metabolic stability, CYP inhibition, and P-gp and BCRP substrate recognition using 265 physicochemical parameters for designing the molecular structures. Four important parameters, including the well-known indicator h_logD, are common in some in vitro studies; as such, these can be used to optimize compounds simultaneously to address multiple pharmacokinetic concerns. Next, we developed machine learning models that had been programmed to show structurally active sites. Many types of machine learning models were developed using the results of in vitro metabolic stability study of around 30000 in-house compounds. The metabolic sites of in-house compounds predicted using some prediction models matched experimentally identified metabolically active sites, with a ratio of number of metabolic sites (predicted/actual) of over 90%. These models can be applied to several screening projects. These two approaches can be employed for obtaining lead compounds with desirable pharmacokinetic profiles efficiently.

Delamanid (OPC-67683, Deltyba™, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of 14 C-delamanid at 3 mg/kg to rats. In both male and female rats, radioactivity in blood and all tissues reached peak levels by 8 or 24 h post-dose, and thereafter decreased slowly. Radioactivity levels were 3- to 5-fold higher in lung tissue at time to maximum concentration compared with plasma. In addition, radioactivity was broadly distributed in various tissues, including the central nervous system, eyeball, placenta and fetus, indicating that 14 C-delamanid permeated the brain, retinal and placental blood barriers. By 168 h post-dose, radioactivity in almost all the tissues was higher than that in the plasma. Radioactivity was also transferred into the milk of lactating rats. Approximately 6% and 92% of radioactivity was excreted in the urine and feces, respectively, indicating that the absorbed radioactivity was primarily excreted via the biliary route. No significant differences in the absorption, distribution and excretion of 14 C-delamanid were observed between male and female rats. The pharmacokinetic results suggested that delamanid was broadly distributed to the lungs and various tissues for a prolonged duration of time at concentrations expected to effectively target tuberculosis bacteria. These data indicate that delamanid, in addition to its previously demonstrated efficacy in pulmonary tuberculosis, might be an effective therapeutic approach to treating extrapulmonary tuberculosis. Copyright © 2017 John Wiley & Sons, Ltd.

Recent studies have shown that rebamipide, which suppresses reactive oxygen species, prevents chemoradiotherapy-induced oral mucositis in patients with head and neck cancers. However, anticancer action of radiotherapy and chemotherapy is believed to be partially associated with generation of reactive oxygen species. The aim of this study was to determine whether rebamipide interferes with the antitumor action of radiotherapy and chemotherapy. The effect of rebamipide on tumor cell growth was investigated using a human oral squamous carcinoma cell line, HSC-2, in vitro and in vivo. Rebamipide showed no significant effect on cell or tumor growth in HSC-2 tumor-bearing nude mice. Influences of rebamipide on the antitumor action of radiotherapy and of chemotherapy with cisplatin or docetaxel were investigated using the same animal model. In radiotherapy, the tumor was treated with 2.5 Gy of X-rays for 5 days, and rebamipide (300 mg/kg p.o.) was administered during irradiation periods. In chemotherapy, tumor-bearing mice were treated once with cisplatin (8 mg/kg, i.v.) or docetaxel (15 mg/kg i.v.) and rebamipide (300 mg/kg p.o.) was administered for 5 days following the antitumor drug treatment. Rebamipide did not interfere with the antitumor action of radiotherapy and chemotherapy.

Delamanid (OPC-67683, Deltyba™, nitro-dihydro-imidazooxazoles derivative) is approved for the treatment of adult pulmonary multidrug-resistant tuberculosis. The absorption, distribution and excretion of delamanid-derived radioactivity were investigated after a single oral administration of

Delamanid (Deltyba, OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution, and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as the substrates and inhibitors of various transporters were evaluated in vitro . Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion-transporting polypeptides, or organic cation transporter 1. Similarly, metabolite 1 (M1) was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP, and bile salt export pump (BSEP; ABCB11), SLC transporters, or organic anion transporters. M1 and M2 inhibited P-gp- and BCRP-mediated transport but did so only at the 50% inhibitory concentrations (M1, 4.65 and 5.71 μmol/liter, respectively; M2, 7.80 and 6.02 μmol/liter, respectively), well above the corresponding maximum concentration in plasma values observed following the administration of multiple doses in clinical trials. M3 and M4 did not affect the activities of any of the transporters tested. These in vitro data suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.

We developed new composite polymer system with monolithic azo dye substances (NACzE and NACzH) and high optical quality polymer hosts (PMMA and PEMA), and obtained quite high photorefractive performances of two beam coupling (2BC) gain 451 cm-1 (PMMA/NACzE) and 340 cm-1 (PEMA/NACzH), respectively, without applying external electric field.

Photodynamic diagnosis and therapy (PDD & PDT) of cancer use generally photosensitizers for the discrimination of normal and cancer cells. In contrast we have studied the autofluorescence spectra of normal and cancer cells of rat using a tunable optical parametric oscillator (OPO) laser system as a light excitation source. WKA rat fibroblast (normal cell) and H-ras oncogene-transfected rat fibroblast (cancer cell) were used in this study. The samples were mounted in a quartz cuvette. The absorption peaks were observed at about 205 nm for both normal and cancer cells. On the other hand, the specific emission peaks were observed at 450 nm and 455 nm for normal and cancer cells, respectively, whereas the autofluorescence intensity of cancer cells was 2.5 times larger than that of normal cells. These changes are attributed to changes in proteins in the cancer cell and to the increase of nuclei. This suggests the possibility that the autofluorescence of cancer cell can be used to diagnose a human malignant tum...

We prepared maltose-polyrotaxane (Mal-PRX)-immobilized beads by 4 steps: (1) making polypseudorotaxane using amine-terminated poly(ethylene glycol)-immobilized polystyrene (PEG-PS) beads and α-cyclodextrins, (2) capping the amine terminal of PEG in the polypseudorotaxane beads, (3) succination and (4) conjugating with maltose. The Mal-PRX-immobilized beads were mixed with biotinylated concanavalin A (Con A) to check the multivalent interaction with lectin. Quantum dot-streptavidin conjugate (QD-SV) was further introduced to enhance the fluorescence for the fluorescence microscope observation. The surface of Mal-PRX-immobilized beads became bright red by the emission 655 nm of QD-SV.

We prepared photorefractive composites using poly(methyl methacrylate) (PMMA) as a host material doped with 3-[(4-Nitrophenyl)azo]-9H-carbazole-9-ethanol (NACzE) as an NLO chromophore. Photorefractive properties were characterized by means of a two beam coupling (2BC) and a degenerated four wave mixing (DFWM) methods performed at 632.8 nm and room temperature. We successfully observed asymmetric 2BC under non-electric field: photorefractive characteristics obtained are a net 2BC gain of 426 cm−1 and a diffraction efficiency of 35%. We could also demonstrate its high performance by DFWM image processing experiment. In order to reduce the glass transition temperature Tg of photorefractive composites we selected poly(ethyl methacrylate) (PEMA) as a host material. Photorefractive properties obtained are a net 2BC gain of 398 cm−1 and a diffraction efficiency of 40%.

The purpose of the present study was to examine whether the intestinal absorption of low-permeability drugs could be improved by utilization of the intestinal influx transporter PEPT1. We investigated whether peptide derivatives of poorly absorbable nonamino acid-like drugs might be substrates of PEPT1, using rebamipide (Reb) as a model drug. We synthesized several peptide derivatives of rebamipide and examined their inhibitory effect on the uptake of [3H]Gly-Sar by PEPT1-expressing HeLa cells. Some of the peptide derivatives inhibited PEPT1-mediated uptake of [3H]Gly-Sar. Next, uptake of the inhibitory peptide derivatives was evaluated in PEPT1-expressing Xenopus oocytes and HeLa cells. Ser(Reb)-Gly exhibited significantly increased uptake by PEPT1-expressing cells in comparison with that by mock cells. The permeability of Ser(Reb)-Gly across a Caco-2 cell monolayer was significantly higher than that of rebamipide itself, and the transport was decreased in the presence of PEPT1 substrates. Further, a rat intestinal perfusion study revealed increased absorption of Ser(Reb)-Gly compared with rebamipide. These results demonstrate that the addition of a dipeptide moiety to a poorly absorbable nonpeptide/nonamino acid-like drug can result in absorption via the intestinal transporter PEPT1, though there is some selectivity as regards the structure of the added peptide moiety.

We prepared photorefractive composites using poly(3,4-ethylenedioxythiophene)-block-polyethylene glycol (PEDOT-block-PEG) as a key material doped with nonlinear optical chromophore ((S)-(-)-l-(4-Nitrophenyl)-2-pyrrolidinemethanol (NPP). To adjust the optical absorbancc PMMA was used as a matrix. Photorefractive properties were characterized by means of a two beam coupling (2BC) method and a degenerated four wave mixing (DFWM) method. We successfully observed asymmetric 2BC under non-electric field: Photorefractive characteristics obtained are a net 2BC gain of 175 cm−1, a diffraction efficiency of 49%, and a phase shift of 90°. Furthermore, we could demonstrate its high performance by DFWM image processing experiment.

Low-molar-mass organic compounds can form oriented crystal fibers on various substrates by a simple casting technique. A dilute solution of an aromatic organic compound, such as a tetrathiofulvalene derivative, an annulated aromatic such as tetracene, or a perylene diimid, is cast on a substrate, and the solvent is allowed to evaporate while rolling a glass bar over the substrate. Because the crystal formation takes place at the solution edge, crystals grow in the roller direction. Optical microscopy, fluorescence microspectrometry, and scanning nearfield optical microscopy were used to characterize the resulting fibers and crystals. Casting on interdigitated electrodes enabled us to measure conductivity and field effect transistors in these oriented crystals.

We measured the reliability of two different organic light-emitting diodes (OLEDs) composed of indium tin oxide (ITO)/4,4'-bis[N-(1-naphthyl)-N-phenyl-amino]biphenyl (α-NPD)/tris(8-hydroxyquinoline)aluminum (Alq3)/MgAg (two layer) or ITO/α-NPD/α-NPD:Alq3 (mixed layer)/Alq3/MgAg. Changes in the carrier trap distribution were estimated by thermally stimulated current (TSC) measurements. Improved device reliability was observed in the mixed-layer device. In the case of the two-layer device, the TSC peaks gradually changed depending on the duration of continuous operation, while the mixed device showed no change in its TSC spectra. These spectral differences indicate that the mixing of α-NPD and Alq3 occurs during the continuous operation in the two-layer device.

We demonstrated that oligo(9,9-diarylfluorene) derivatives have high potential for optoelectronic applications such as organic lasers and light-emitting organic field-effect transistors (LE-OFETs). The oligo(9,9-diarylfluorene) derivatives have high photoluminescence quantum efficiencies up to ΦPL ≈ 70−75% and very low amplified spontaneous emission thresholds (Eth) down to 0.5 μJ/cm2 in their vacuum-deposited neat films. In particular, the trimer derivatives (B3 and T3) show higher ΦPL and lower Eth than those of the dimers (B2 and T2). Efficient deep-blue LE-OFETs with the electroluminescence (EL) peaking at λpeak = 429 nm were demonstrated using the ter(9,9-diarylfluorene) as the active layer. Rather high luminance up to L ≈ 150 cd/m2 and EL quantum efficiency up to ηext ≈ 0.60% were achieved with the optimum source-drain channel length, indicating bipolar carrier injection in the terfluorene layer under the FET operation.

Electroabsorption (EA) studies at room temperature on organic thin films based on a dicyanovinyl-quaterthiophene 4T-V(CN) 2 are reported. An electric field modulation is applied to the samples for two different electrode geometries, i.e. sandwich and coplanar versus the organic layer. Changes in optical absorption coefficient of 4T-V(CN) 2 based thin films are measured and analyzed to determine the character of the optical transition in the visible range (400–800 nm). Depending on the experimental electrode configuration, magnitude of electroabsorption responses are different, possibly due to different distribution of the externally applied electric field. The results indicate a higher resolution of EA response for the sandwich electrode configuration and confirm the charge transfer exciton character of 4T-V(CN) 2 in contrast to the unsubstituted quaterthiophene 4T. Finally, a third-order nonlinear susceptibility χ (3) (− ω ; ω , 0, 0) of 16 × 10 −12 e.s.u. is obtained.

We found that 1,3,6,8-tetraphenylpyrene (TPPy) demonstrates unusual photoluminescence (PL) characteristics in the solid-state morphologies. We investigated the PL characteristics of TPPy in various morphologies including powder, deposited film, and solutions. The TPPy powder (A), which was prepared through column chromatography, recrystallization, and train sublimation, showed blue fluorescence with a peak of maximum wavelength of λ max = 451 nm. The TPPy powder (B), which was obtained by thermal annealing of TPPy powder (A) in a quartz tube in nitrogen, showed green fluorescence with λ max = 510 nm. Furthermore, the TPPy powder (B) was reversibly converted into TPPy powder (A) by recrystallization. We conclude that TPPy dimers form locally in the TPPy monomer aggregates during thermal annealing and redissociate into the monomer states during recrystallization.

We demonstrate a low-damage technique for forming an indium tin oxide (ITO) layer on an organic layer by using a unique cylindrical sputtering module and the fabrication of high-performance transparent organic light-emitting diodes (TOLEDs). The ITO target has an off-axis alignment to the substrate, and it confines plasma to the inside of the module, thereby forming ITO with little damage to the underlying organic layers. We found that the composition ratio of In2O3 (90%) and SnO2 (10%) in the deposited film is the same as the target composition ratio, and that the composition ratio distribution was spatially uniform, showing no angular dependence. We fabricated an ITO [110 nm]/4,4'-bis[N(1-naphthyl)-N-phenyl-amino]biphenyl (α-NPD) [50 nm]/tris-(8-hydroxy-quinoline)aluminum (Alq3) [30 nm]/Cs:phenyldipyrenylphosphine oxide (POPy2) [20 nm]/ITO [100 nm] device, using a cylindrical target for the top ITO cathode fabrication. The device showed excellent J–V characteristics, with a current density of J=883 mA/cm2 at an applied voltage of 10 V and a maximum external quantum efficiency of ηext=0.76%.

A series of thiophene-based oligomers are investigated by electroabsorption spectroscopy in terms of influence of chain length and peripheral substitution for the first time. Polycrystalline thin films of nonsubstituted oligomers, 8T, 6T and 4T, and of oligothiophenes with electron-withdrawing cyano substituents, 4T-V(CN) 2 and CN-TET-CN, are measured and analyzed to determine the character of optical transitions. The results of the nonsubstituted oligomers suggest that the transitions at 500–600 nm present a neutral (Frenkel exciton) character, while those of oligothiophenes with electron-withdrawing substituents suggest that the transitions present a polar (charge-transfer exciton) one, indicating significant contribution of noncentrosymmetric substitution. Third-order nonlinear susceptibilitiy χ (3) (− ω ; ω , 0, 0) is also evaluated, and it is shown that the longest unsubstituted oligomer 8T presents a high value of χ (3) ∼ 45 × 10 −12 esu, and substituted one CN-TET-CN presents further higher value of χ (3) ∼ 250 × 10 −12 esu. These investigations indicate multiple significance of electron-withdrawal substitution in molecular design of an oligothiophene-based nonlinear optical material.

筆者らは, 青色リン光材料をゲスト分子として用いた有機EL素子において, 高効率青色発光を得るためにπ共役系の短いシロキサン化合物であるHexaphenylcyclotri siloxane (DPSiO3) をホスト材料として試みた. この材料をEPA溶液に溶解し, T=77Kにおいてリン光スペクトルを測定したところ, DPSiO3のリン光スペクトルはベンゼンのリン光スペクトルとほぼ同じ波長領域 (λonset～350nm) に観測され, これらの化合物は本質的にベンゼン環にπ電子系が局在していることが示唆された. Iridium (III) bis (4,6-di-fluorophenyl) -pyridinato-N, C2) picolinate (FIrpic) をゲスト分子としたEL素子において, DPSiO3をホストとした素子では最大ηext=11.1%の外部EL量子効率を得ることができた.

We fabricated an organic light-emitting field effect transistors (OLEFET) using a co-deposited layer of TPTPT and NTCDA which has p-type and n-type semiconducting behaviors, respectively. The organic layer was formed on a comb type electrode (source-drain electrodes) with a channel length of 25μm on a p-Si/SiO2 substrate. Bipolar and EL characteristics were investigated by changing co-deposition ratio of TPTPT and NTCDA. In the optimum deposition ratio, we observed typical ambipolar characteristics, demonstrating saturation current characteristics at low Vd (source-drain voltage), followed by divergent current characteristics at high Vd.

The phosphorescence intensities of the green phosphor, fac tris(2-phenylpyridine) iridium [Ir(ppy)3], in a polymethylmethacrylate [PMMA] host matrix are independent of temperature, while the phosphorescence lifetimes increase significantly at temperatures below T ∼ 50 K. In this paper, to rationalize the characteristic temperature dependence of the transient phosphorescence of Ir(ppy33, we propose a model where the triplet excited states split by spin-orbital interaction, forming three levels in which mutual energy transfer between the sub-levels of triplet states occurs. We discuss the validity of this numerical model by comparing with the experimental result of the transient phosphorescence in a PMMA host matrix and demonstrate that the model well explains the characteristic temperature dependence.

To make an efficient electron injection electrode by photolithography, we studied MgAu alloy electrodes, which have a low work function and high resistance to humidity and oxygen. The measured work function of MgAu alloy thin film was 3.7 eV, which is comparable with that of a pure Mg layer and ∼0.8 eV lower than that of a pure Au layer. This low work function was maintained even after photolithography, suggesting excellent stability for solvent treatment. Investigating organic field-effect transistor (OFET) characteristics when MgAu alloy comb type source and drain electrodes were used, we successfully obtained n-type FET operation. Furthermore, organic light-emitting diodes (OLEDs) demonstrated the efficient electron injection characteristics of the MgAu alloy cathode, which were similar to those of the conventional MgAg cathode. © 2005 Wiley Periodicals, Inc. Electr Eng Jpn, 152(1): 37–42, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ eej.20153

Summary: Grepafloxacin (GPFX) is a new quinolone antibiotic (NQ) which is highly distributed to the lung and other tissues. In the present study, to characterize the distribution mechanism of GPFX to the lung, the uptake of GPFX by isolated rat lung cells was examined in vitro. GPFX was rapidly taken up by the cells, and the uptake reached a steady-state within 5 min. The cell-to-medium concentration ratio at equilibrium was 56.8 ± 1.9 μ L/mg protein, which was much higher than the cellular volume. GPFX uptake consisted of a saturable component (K m : 264 ± 181 μ M, V max : 2.94 ± 2.33 nmol/min/mg protein) and a nonsaturable component (P dif : 7.04±2.17 μ L/min/mg protein). The uptake of GPFX was reduced in the presence of ATP-depletors (FCCP and Rotenone) and by the replacement of sodium with choline in the medium, suggesting that GPFX uptake is at least partially mediated by an Na + - and energy-dependent process. GPFX uptake tended to be reduced in the presence of other NQs such as levofloxacin, lomefloxacin and sparfloxacin, but was only minimally affected by the substrates of several uptake mechanisms already identified in the liver and kidney such as taurocholate, p-aminohippurate, L-carni- tine and tetraethylammonium. These results suggested that GPFX is taken up by the lung partially via carrier-mediated transport system(s), distinct from the identified transporters, and such active transport systems may at least partially account for the efficient distribution of GPFX to the lung.

To understand confinement of the triplet exciton of Ir(ppy)3 by hole-transport layers, we compared energy-dissipative processes of the triplet exciton of Ir(ppy)3 which is doped into 4,4′-bis[N-(1-naphthyl)-N-phenyl-amino]biphenyl (α-NPD), 4,4′-bis [N-(p-tolyl)-N- phenyl-amino]biphenyl (TPD), 1,1-bis[(di-4-tolylamino)phenyl]cyclohexane (TAPC), and 4,4′-N,N′-dicarbazole-biphenyl hosts. Significant energy transfer from Ir(ppy)3 into the triplet levels of α-NPD was observed. In the case of the TPD host, however, partial confinement of the Ir(ppy)3 triplet exciton was observed. This result suggests both forward and backward energy transfer from Ir(ppy)3 to the TPD triplet levels. Furthermore, employing TAPC as a hole-transport layer achieved strong confinement of the Ir(ppy)3 triplet exciton. One conclusion from these results is that electrophosphorescence efficiency is well correlated with the triplet energy level of the hole-transport layer host materials.

Rebamipide, an antiulcer agent, is known as a potent hydroxyl radical (*OH) scavenger. In the present study, we further characterized the scavenging effect of rebamipide against *OH generated by ultraviolet (UV) irradiation of hydrogen peroxide (H2O2), and identified the reaction products to elucidate the mechanism of the reaction. Scavenging effect of rebamipide was accessed by ESR using DMPO as a *OH-trapping agent after UVB exposure (305 nm) to H2O2 for 1 min in the presence of rebamipide. The signal intensity of *OH adduct of DMPO (DMPO-OH) was markedly reduced by rebamipide in a concentration-dependent fashion as well as by dimethyl sulfoxide and glutathione as reference radical scavengers. Their second order rate constant values were 5.62 x 10(10), 8.16 x 10(9) and 1.65 x 10(10) M(-1) s(-1), respectively. As the rebamipide absorption spectrum disappeared during the reaction, a new spectrum grew due to generation of rather specific reaction product. The reaction product was characterized by LC-MS/MS and NMR measurements. Finally, a hydroxylated rebamipide at the 3-position of the 2(1H)-quinolinone nucleus was newly identified as the major product exclusively formed in the reaction between rebamipide and the *OH generated by UVB/H2O2. Specific formation of this product explained the molecular characteristics of rebamipide as a potential *OH scavenger.

This paper reports on novel electron transport materials, 1,3,5-triazine derivatives (TRZ), which have been useful in high-efficiency electrophosphorescent (EP) organic light-emitting diodes (OLEDs). We synthesized four 2,4,6-tris(diarylamino)-1,3,5-triazine derivatives (TRZ1−TRZ4) that had electron-donating substituents and examined their OLED characteristics. Of these, we found that TRZ 2, 3, and 4 function as a host for tris(2-phenylpyridine)iridium (Ir(ppy)3) and, in particular, 2,4,6-tris(carbazolo)-1,3,5-triazine (TRZ2) demonstrated a very high external electroluminescent (EL) quantum efficiency (ηext) of ∼10.2 ± 1.0% and an energy conversion efficiency (ηenergy) of 14.0 ± 2.0 lm/W. Detailed transient photoluminescent (PL) measurement revealed that the triplet energy level of TRZ2 (ET1 = 2.81 eV) is higher than that of conventional 4,4‘-N,N‘-dicarbazol-biphenyl (CBP) (ET1 = 2.56 eV), suggesting that TRZ2 has excellent capabilities in confining Ir(ppy)3 triplet excitons.

To realize an efficient electron injection electrode into organic layers by photolithography, we form a MgAu alloy electrode which has capability of low work function and high durability for humidity and organic solvents during photolithography process. The MgAu alloy thin film shows a work function of 3.7eV which is comparable with that of a neat Mg layer and 0.8eV lower than that of a neat Au layer. The low work function of 3.7eV was maintained even after the photolithography process, suggesting excellent stability for the solvent treatments. We examine a MgAu alloy comb bottom electrode for organic field-effect transistor (OFET) and successfully obtain FET operation of n-type driving. We also demonstrate efficient electron injection characteristics of a MgAu alloy cathode in organic light-emitting diodes (OLEDs). The MgAu alloy cathode can inject electrons efficiently similar to the conventional MgAg cathode.

High efficiency white organic light emitting diodes (WOLED) have been expected for applications of lighting, illumination and back-light sources for LCD. Recently, since organic phosphors demonstrated very high electroluminescence (EL) quantum efficiency of ˜100%, high efficiency WOLED with the organic phosphors has been anticipated. In this study, we employed an emitter layer which is doped with blue and red phosphorescence molecules. In our optimized device structure, we obtained maximum EL quantum efficiency of 4%. However, the shapes of the EL spectrum were strongly dependent on current density. With analysis of exciton decay process under optical and electrical excitations, we conclude that triplet-triplet annihilation occurs in blue and red phosphors independently, resulted in a significant change of the EL spectrum. Thus, the coincidence of the lifetimes of the blue and red phosphors is indispensable to escape change of EL spectrum with current density.

We demonstrate high-efficiency white electrophosphorescence in organic light emitting diodes (OLED) employing blue and red phosphorescent molecules. As an emitting layer, bis[2-(4,6-difluorophenyl)pyridinato- N,C2’] iridium picolinate (FIrpic) as blue and bis[2-(2’-benzo[4,5-a]thienyl)pyridinato-N,C3’]iridium (acetylacetonate) [Btp2Ir(acac)] as red phosphors were doped into a 4,4’-bis(9-carbazolyl)-2,2’-biphenyl (CBP) host. The OLED characteristics using multi-phosphors doped layers were studied. We focused on suppression of the color change with an increase of a current density while keeping high-efficiency. With an insertion of a 3 nm-thick 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (BCP) layer, high ηext of 4.9±0.5% and pure white emission of CIE (0.32, 0.33) at 10 mA/cm2 were achieved. Moreover, the color change with an increase of a current density was suppressed to a certain extent with in an insertion of other buffer layers, CBP and bis[N-(1-naphthyl)-N-phenyl]benzidine (α-NPD).

To achieve efficient electron injection in organic light-emitting diodes, we examine ultra thin layers (0.50 nm) of the low-work-function metals, Cs (1.9eV), Rb (2.2eV), K (2.3eV), Na (2.4eV), Li (2.9eV), and Ca (2.9eV) capped with aluminum (Al) as a cathode layer. While all the alkali metals show a decrease of driving voltage compared with a single Al cathode, the Cs layer especially shows a significant decrease, and we obtain a high current density of 1.9 A/cm2 at an applied voltage of only 10V by using this layer. We demonstrate that efficient electron injection is achieved when we use a Cs layer with a thickness of less than 3 nm, although electron injection efficiency abruptly decreases when using a Cs layer thicker than 3 nm. From the Cs thickness dependence of current-voltage characteristics, we conclude that Cs atoms form an alloy layer with aluminum atoms at the organic/Al cathode interface, organic layer/Cs:Al/Al, that significantly enhances electron injection compared with that obtained from bulk Cs layers.

Novel soluble binuclear vanadylphthalocyanines linked by terminal diacetylene bridges, such as 1,4-bis{2′-[23″-(1″,2″,3″,4″,8″,9″,10″,11″,15″,16″,17″,18″-dodecakis-(2,2,2-trifluoroethoxy)phthalocyaninyl)]ethynyl}benzene divanadyl complex, 4,4′-bis{2″-[23-(1,2,3,4,8,9,10,11,15,16,17,18-dodecakis(2,2,2-trifluoroethoxy)phthalocyaninyl)]ethynyl}- benzophenone divanadyl complex and 3,6-bis{2′-[23″-(1″,2″,3″,4″,8″,9″,10″,11″,15″,16″,17″,18″-dodecakis(2,2,2-trifluoroethoxy)phthalocyaninyl)]ethynyl}-9-tetradecylcarbazole divanadyl complex, were synthesized using a palladium-catalyzed, cross-coupling reaction between the corresponding terminal diacetylenes and an excess of 23-iodo-1,2,3,4,8,9,10,11,15,16,17,18-dodecakis(2,2,2-trifluoroethoxy)phthalocyaninato vanadyl complex. A mononuclear vanadylphthalocyanine with a conjugated carbazole moiety namely, vanadyl 23-(2′-(6″-nitro-9″-tetradecyl-3″-carbazolyl)ethynyl)-1,2,3,4,8,9,10,11,15,16,17,18-dodecakis(2,2,2-trifluoroethoxy)phthalocyaninate, was also prepared for comparison. All target phthalocyanines were separated by common column chromatography and characterized by elemental analysis, IR and 1 H-NMR, UV–visible and fast-atom-bombardment mass spectroscopies. Their UV–visible absorption spectra in solution showed that the target phthalocyanine dimers were non-aggregated compounds.

This study was carried out to investigate the most important factor(s) governing the tissue distribution of grepafloxacin (GPFX), a fluoroquinolone antibiotic, in rats. The tissue-to-blood concentration ratio (K(p)) of GPFX at steady state during constant infusion was highest in the lung, followed by the pancreas, kidney, and spleen. After bolus injection, GPFX was efficiently taken up by most of the organs examined, the uptake clearance other than the lung being almost blood flow-limited. Approximately 10% of the intravenously injected dose was rapidly trapped by the lung, but GPFX distribution rapidly decreased within 30 s due to the washout by the plasma flow. Thus, the higher distribution of GPFX to the lung compared with the other organs cannot be accounted for by a difference in its uptake or efflux. Subcellular fractionation after the infusion indicated that GPFX is primarily distributed to the organelle fractions in most organs, 60% of lung-associated GPFX being recovered in the nucleus and plasma membrane fraction. Such subcellular distribution in the lung was proportional to the phosphatidylserine (PhS) content of each fraction. The steady-state K(p) value in each tissue in vivo also correlated with the tissue content of PhS. GPFX preferentially binds to PhS, compared with other phospholipids, and this binding was inhibited by weakly basic drugs, such as quinidine, imipramine, and propranolol, that have also been reported to bind to PhS. The association of GPFX with PhS synthase transformants of Chinese hamster ovary (CHO-K1) cells depends on the PhS content of each cell line, this association being also inhibited by basic drugs. These results suggest that binding of GPFX to PhS is the major determinant of the high distribution of GPFX to the lung.

Association and dissociation reactions of cytochrome b562 on solid surfaces were investigated by means of surface plasmon resonance spectroscopy. Propionates of side chains in the heme molecule were modified with sulfur moiety as an anchor part to be adsorbed on the gold substrate. This modified heme was firstly reconstituted with apo-protein in solution. This reconstituted holo-protein was then adsorbed on either bare gold substrate or pre-modified gold substrate. Native cytochrome b562 was also adsorbed to the same substrates for the control experiment. The reconstituted cytochrome b562 was successfully adsorbed on the pre-treated gold substrate without denaturation in structure, probably with homogeneous anisotropic orientation. Guanidine hydrochloride in the buffer of pH 5.0 was applied to remove the apo-protein from the surface, with the thiolated heme derivative remaining on the surfaces. Apo-protein was again introduced to the same surface for the reconstitution of holo-cyt.b562. The success of the...

Femtosecond time-resolved fluorescence spectroscopy has been used to study the excited-state dynamics of pharaonis phoborhodopsin (ppR) from Natronobacterium pharaonis. Upon excitation of ppR with ...

1. The metabolism of rebamipide, a gastroprotective agent, was investigated using human liver microsomes and cDNA-expressed human cytochrome P450 systems. 2. 6-Hydroxy and 8-hydroxyrebamipide were produced by human cytochrome P450 enzyme(s), and 8-hydroxylation was the major metabolic pathway. K(m) and V(max) for 8-hydroxylation were 1.35 +/- 0.20 mM and 0.32 +/- 0.34 nmol min(-1) mg protein(-1), respectively (mean SD, n = 6). Kinetic analysis showed that the 8-hydroxylation reaction consisted of a single component. 3. 8-Hydroxylation was inhibited by the addition of CYP3A4 antibodies as well as troleandomycin, a specific inhibitor of CYP3A4. Furthermore, the metabolism of rebamipide in human liver microsomes was compatible with that in a human cDNA-expressed CYP3A4 system, but not for other human P450 expression systems. It is therefore suggested that the hydroxylation of rebamipide only involves CYP3A4. 4. Rebampide showed no inhibitory effect on CYP1A2-, 2C9-, 2C19-, 2D6-, 2E1- and 3A4-catalysed metabolism. In addition, the metabolic contribution by CYP3A4 was considered to be slight for the overall elimination of rebamipide in man. It is therefore considered that drug interactions with cytochrome P450 enzymes are not involved in either the metabolism of rebamipide or the metabolism of other drugs concomitantly administered with rebamipide.

Four new unsymmetrical metallophthalocyanines were synthesized. The vanadium trichloride-mediated statistical condensation of 5-nitro-1,3-diiminoisoindoline with 5- tert -butyl-1,3-diiminoisoindoline or with 5-neopentoxy-1,3-diiminoisoindoline in anhydrous 2-( N , N -dimethylamino)ethanol under reflux did not yield the desired 2-nitro-9,16,23-tri( tert -butyl)phthalocyaninato or 2-nitro-9,16,23-tri(neopentoxy)phthalocyaninato vanadyl complexes, but yielded the unexpected 2-amino-9,16,23-tri( tert -butyl)phthalocyaninato or 2-amino-9,16,23-tri(neopentoxy)phthalocyaninato vanadyl complexes. 2-Nitro-9,16,23-tri( tert -butyl)phthalocyaninato vanadyl complex was prepared by a statistical condensation of 4- tert -butylphthalonitrile and 4-nitrophthalonitrile in the presence of vanadium trichloride and dry urea at 175–180 °C, while zinc 2-nitro-9,16,23-tri(neopentoxy)phthalocyaninate was synthesized by the zinc acetate-mediated statistical condensation of the two corresponding 1,3-diiminoisoindolines in 2-( N , N -dimethylamino)ethanol under reflux. All the target unsymmetrical phthalocyanines were separated by common column chromatography and characterized by elemental analysis, IR and 1 H-NMR, UV-visible and fast-atom-bombardment mass spectroscopies.

Crosslinkable polymer with host–guest and side chain system was investigated to increase the content of NLO chromophores in second order nonlinear optics. Though very low poling temperature has been applied, the observed UV absorption difference before and after poling was large due to low glass transition temperature of the polymer and high content of chromophores introduced by side chain and guest molecules. Highly stable NLO properties have been achieved through crosslinked polymer matrices. The crosslink reaction between polymer matrix and chromophore was confirmed by FT-IR and 29 Si solid state NMR. The d 33 values of modified DR1/polymer films are high, around 40 pm/V, and there is a no change during 2 months at ambient temperature though for some samples d 33 values slightly decreased.

Two types of multifunctional thin films based on DNA polyion complex intercalated with photofunctional chromophore were fabricated on the 2D-surface. One is monolayer of DNA polyion complex transferred to a glass substrate at the air/water interface, and is intercalated with acridine orange (AO). Another is DNA containing thiol moiety, and is intercalated with AO and formed polyion complex with lipid, and is fabricated on a gold substrate at the solid/liquid interface. Molecular orientation of AO was investigated by surface plasmon resonance, polarized UV and FT-IR spectroscopy. AO intercalated DNA polyion complex film (a) was aligned perpendicular to the DNA long axis. In the case of DNA polyion complex film (b), orientated DNA could be fabricated on the gold substrate through S-Au interaction, and the orientation of DNA was more stable by mixing with lipid to provide polyion complex. AO in DNA polyion complex film (b) was aligned parallel to the substrate.

The polarization and depolarization behavior of electric field-induced polar alignment in a side- and main-chain photorefractive polymer was measured by thermally stimulated current (TSC) and electro-optic (EO) modulation experiments. A relaxation peak was observed around the glass transition temperature (Tg) for the poled photorefractive polymer in a TSC experiment. The apparent TSC was not observed at room temperature. The polarization calculated from the relaxation peak linearly increased with the strength of the poling electric field. This result was consistent with the EO behavior which showed the linear dependence of the EO coefficients on the poling electric field. The main- and side-chain photorefractive polymer could be aligned by the electric field at an elevated temperature, and the polar alignment was stable at room temperature, which could lead to the long-term stability of the photorefractive responses without an external applied electric field.

The average direction of molecules and the absolute value of an effective second order nonlinear optical constant (∣d eff 7∣) were simultaneously determined using a new second harmonic generation (SHG) phase measurement with theoretical curve fitting. The theoretical curve fitting process was demonstrated using poled poly (methyl methacrylate) films doped with p-nitroaniline (PNA/PMMA), which were used as a reference and a sample. The second harmonic (SH) interference generated between the two poled PNA/PMMA films was modulated by rotating the phase generator inserted between the two. The fitting process derived d eff itself. The average direction of molecules was shown by the sign of d eff . The obtained value of ∣d eff ∣ was verified by that from a Maker fringe measurement. The obtained average direction of molecules coincided with that determined by a poling geometry.

Conductive thin films of a bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) salt have been constructed by a successive dry–wet process, which is a combination of the ultra-high vacuum (UHV) deposition of neutral BEDT-TTF molecules and an electrochemical doping process that utilizes an aqueous solution of LiClO4 as the electrolyte. The optimal temperature of the BEDT-TTF deposition source is 80°C, which gives a uniform coverage of the substrate without any decomposition. The doping starts at the electrode/film interface, proceeds outwards from the interface and is completed after 5–7 h between the electrode gaps. The change in the surface plasmon resonance spectroscopy (SPRS) curve upon doping is best fitted by varying the dielectric constant of the BEDT-TTF film while keeping the thickness of the film constant. The conductivity of the doped BEDT-TTF film along the film plane was in the range 10−3–10−4 S cm−1.

We present a new analytical method of molecular orientation in films using a phase measurement of second harmonic generation (SHG) with a theoretical curve fitting. The new analytical method provides the average direction of molecules and the absolute value of the effective second-order nonlinear optical constant (|d eff|) simultaneously. In conventional methods, the average direction of molecules in a sample has been relatively determined with that in a standard sample having preknown molecular direction. The second harmonic (SH) interference fringe obtained between a reference having preknown molecular direction and the sample has been compared with that between the reference and the standard sample. In the new method, however, the average direction of molecules can be obtained without the standard sample. The value of |d eff| is calculated through the fitting process, the average direction of molecules is determined by the sign or the phase of d eff, which is introduced by a reference. Complete express...