Impact of Low Temperatures on the Lithiation and Delithiation Properties of Si-Based Electrodes in Ionic Liquid Electrolytes.

Lithium-ion batteries are used in various extreme environments, such as cold regions and outer space; thus, improvements in energy density, safety, and cycle life in these environments are urgently required. We investigated changes in the charge and discharge properties of Si-based electrodes in ionic liquid electrolytes with decreasing temperature and the cycle life at low temperature. The reversible capacity at low temperature was determined by the properties of the surface film on the electrodes and/or the ionic conductivity of the electrolytes. The electrode coated with a surface film formed at a low temperature exhibited insufficient capacity. In contrast, a Si-only electrode precoated with the surface film at room temperature exhibited a cycle life at low temperatures in ionic liquid electrolytes longer than that in conventional organic liquid electrolytes. Doping phosphorus into Si led to improved cycling performance, and its impact was more noticeable at lower temperatures.

Thinking Outside the Tooth: Diagnosis and Management of Patients with Neuropathic Orofacial Pain.

Nonodontogenic orofacial pain exists, and diagnosis and management of those conditions can be challenging. This article highlights and discusses how to take a complete and systematic pain history and the important red flags to recognize in patients presenting with perplexing nonodontogenic orofacial pain. Cause and epidemiology, clinical presentation, clinical evaluation and diagnosis, and management options for common neuropathic pain conditions are included. Neuralgia and neuropathic pain conditions and red flags as secondary cause of orofacial pain are more common in older-aged patients.

Clinical Profiles of Nalfurafine Hydrochloride for the Treatment of Pruritus Patients.

Nalfurafine hydrochloride is a selective kappa-opioid agonist that has antipruritic effects. Here we describe the clinical trials for treatment of uremic pruritus in dialysis patients and on hepatic pruritus in patients with chronic liver disease. Among cytochrome P-450 (CYP) isoforms in humans, CYP3A4 is the major isoform involved in metabolic decyclopropylmethylation of nalfurafine hydrochloride. Nalfurafine hydrochloride was found to be a substrate for P-glycoprotein (P-gp), but had no inhibitory effects on P-gp-mediated transport. The efficacy of oral nalfurafine hydrochloride at 2.5 and 5 µg for refractory pruritus in hemodialysis patients was observed within the first 7 days of treatment, and the effects persisted for the 52-week treatment period. Nalfurafine hydrochloride is also effective in the treatment of conventional refractory pruritus in peritoneal dialysis patients. Moreover, nalfurafine hydrochloride at 2.5 and 5 µg is effective for the treatment of refractory pruritus in chronic liver disease patients within the first 7 days of drug administration. In all the clinical trials, most adverse drug reactions (ADRs) were mild and resolved quickly and there was no clinical safety problem. Following 52 weeks of treatment, hemodialysis patients did not develop physical or psychological dependence, indicating no addiction risks. In summary, nalfurafine hydrochloride administered orally at doses of 2.5 and 5 µg was safe and effective for treatment of refractory pruritus in patients undergoing hemodialysis or peritoneal dialysis and in chronic liver disease patients.

Bioresorbable porous ß-tricalcium phosphate chelate-setting cements with poly(lactic-co-glycolic acid) particles as pore-forming agent: fabrication, material properties, cytotoxicity, and in vivo evaluation.

Calcium-phosphate cements (CPCs) have been used as bone filling materials in orthopaedic surgery. However, CPCs are set using an acid-base reaction, and then change into stable hydroxyapatite (HAp) in a living body. Therefore, we developed bioresorbable chelate-setting ß-tricalcium phosphate (ß-TCP) cements based on surface modifications of inositol phosphate (IP6). In order to improve the bioresorbability, we fabricated IP6/ß-TCP cements hybridized with poly(lactic-co-glycolic acid) (PLGA) particles as a pore-forming agent. The compressive strengths of the cements with the amounts of 5 and 10 mass% PLGA particles were 23.2 and 22.8 MPa, respectively. There was no significant difference from cements without PLGA (23.4 MPa). The setting times of the cement specimens with PLGA particles (30 min) were a little longer than those without PLGA particles (26.3 min). The lack of cytotoxicity of the cement specimens was confirmed using osteoblast-like cells (MC3T3-E1). Cylindrical defects were made by drilling into the tibia of mini-pigs and injecting the prepared cement pastes into the defects. Twelve weeks after implantation the specimens were stained with toluidine blue and histologically evaluated. Histological evaluation of cement specimens with PLGA particles showed enhanced bioresorbability. Newly-formed bone was also observed inside cement specimens with PLGA particles. The IP6/ß-TCP cement specimens with PLGA particles had excellent material properties, such as injectability, compressive strength, high porosity, no cytotoxicity in vitro, bioresorption and bone formation abilities in vivo. Organic-inorganic hybridized CPCs are expected to be valuable as novel biodegradable paste-like artificial bone fillers.

Synthesis and Synthetic Application of Chloro- and Bromofuroxans.

Furoxans are potentially useful heteroaromatic units in pharmaceuticals and agrichemicals. However, the applications for furoxan-based compounds have been hampered due to the underdevelopment of their synthetic methods. Herein, we report a new synthetic approach for the synthesis of chloro- and bromofuroxans. The starting materials were dichloro- and dibromofuroxans, and the substituents were directly introduced to the furoxan ring in a modular fashion. The synthesized monohalofuroxans served as substrates for the installation of a second substituent to prepare further functionalized furoxans.

Modular Synthesis of Carbon-Substituted Furoxans via Radical Addition Pathway. Useful Tool for Transformation of Aliphatic Carboxylic Acids Based on "Build-and-Scrap" Strategy.

Utilizing radical chemistry, a new general C-C bond formation on the furoxan ring was developed. By taking advantage of the lability of furoxans, a wide variety of transformation of the synthesized furoxans have been demonstrated. Thus, this developed methodology enabled not only the modular synthesis of furoxans but also short-step transformations of carboxylic acids to a broad range of functional groups.

Near infrared two-photon-excited and -emissive dyes based on a strapped excited-state intramolecular proton-transfer (ESIPT) scaffold.

Fluorophores that can undergo excited-state intramolecular proton transfer (ESIPT) represent promising scaffolds for the design of compounds that show red-shifted fluorescence. Herein, we disclose new near infrared-emissive materials based on a dialkylamine-strapped 2,5-dithienylpyrrole as an ESIPT scaffold. The introduction of electron-accepting units to the terminal positions of this scaffold generates acceptor-π-donor-π-acceptor (A-π-D-π-A) type π-conjugated compounds. Following the ESIPT, the electron-donating ability of the core scaffold increases, which results in a substantially red-shifted emission in the NIR region, while increasing the oscillator strength. The electron-accepting units play a vital role to achieve intense and red-shifted emission from the ESIPT state. The strapped dialkylamine chain that forms an intramolecular hydrogen bond is also essential to induce the ESIPT. Moreover, an extended A-π-D-π-A skeleton enables two-photon excitation with the NIR light. One of the derivatives that satisfy these features, i.e., borylethenyl-substituted 5, exhibited an intense NIR emission in polar solvents such as acetone (λem = 708 nm, ΦF = 0.55) with a strong two-photon-absorption band in the NIR region.

Fracture strength testing of crowns made of CAD/CAM composite resins.

PURPOSE: The purpose of this study was to ascertain whether computer aided design/computer aided manufacturing (CAD/CAM) composite resin crowns have sufficient strength to withstand the bite force of the molar teeth. The null hypothesis was that the fracture strength of CAD/CAM composite resin crowns is lower than the average maximum bite force of the molar tooth. METHODS: The crowns, which shape is the right maxillary first molar, were fabricated using four CAD/CAM blanks made of composite resins (Block HC: HC, KZR-CAD HR: HR, KZR-CAD HR2: HR2, Avencia Block: AVE) and one CAD/CAM blank made of lithium disilicate glass-ceramic (IPS e.max CAD: IPS), which was used as a control. Fracture strength of fabricated crowns bonded to metal abutment and biaxial flexural strength of the materials were evaluated. RESULTS: The results of fracture strength test and biaxial flexural strength test showed different tendencies. The fracture strength of CAD/CAM composite resin crowns except HC ranged from 3.3kN to 3.9kN, and was similar to that of IPS (3.3kN). In contrast, biaxial flexural strength of CAD/CAM composite resins ranged from 175MPa to 247MPa, and was significantly lower than that of IPS (360MPa). CONCLUSIONS: All CAD/CAM composite resin crowns studied presented about 3-4 times higher fracture strength than the average maximum bite force of the molar tooth (700-900N), which result leads to the conclusion that CAD/CAM composite resin crowns would have sufficient strength to withstand the bite force of the molar teeth.

Synthesis of alkynyl furoxans. Rare carbon-carbon bond-forming reaction on a furoxan ring.

A rare carbon-carbon-bond forming reaction on a furoxan ring has been developed. The nucleophilic aromatic substitution (SNAr) reaction of 4-nitrofuroxans with alkynyl lithium proceeded with high yields, which enabled the first practical synthesis of both alkynyl furoxan regioisomers. Due to the versatility of the alkyne functional group, various derivatizations of the carbon-carbon triple bond in the afforded products were possible. Thus, this developed method is a convergent approach to a wide spectrum of carbon-substituted furoxans.

Identification of Transporters Involved in Beraprost Sodium Transport In Vitro.

BACKGROUND AND OBJECTIVE: Beraprost sodium (BPS) is a chemically stable and orally active prostacyclin analog that is used in the treatment of chronic arterial occlusive disease since 1992 and primary pulmonary hypertension since 1999 in Japan. Multiple-drug therapy is common in clinical practice, and BPS is co-administered with other drugs. Membrane transporters are known to markedly affect pharmacokinetics, safety and efficacy, and many transporter-based drug-drug interactions have been recently reported. However, information on the transporters involved in the pharmacokinetics of BPS is limited. METHODS: First of all, we have examined 11 transporters, ABCB1 (P-glycoprotein: P-gp), ABCG2 (breast cancer resistance protein: BCRP), SLC22A6 (organic anion transporter 1: OAT1), SLC22A8 (organic anion transporter 3: OAT3), SLCO1B1 (organic anion transporting polypeptide 1B1: OATP1B1), SLCO1B3 (organic anion transporting polypeptide 1B3: OATP1B3), SLCO2B1 (organic anion transporting polypeptide 2B1: OATP2B1), SLC22A1 (organic cation transporter 1: OCT1), SLC22A2 (organic cation transporter 2: OCT2), ABCB11 (bile-salt export pump: BSEP), and ABCC2 (multidrug resistance associated protein 2: MRP2) to clarify which of them would be candidates that might recognize BPS as their substrate in transporter-expressing LLC-PK1, S2, and HEK293 cells as well as in membrane vesicles. Furthermore, we determined whether the transport of BPS was inhibited by the typical inhibitors of each transporter, i.e., verapamil for P-gp, Ko143 for BCRP, probenecid for OAT3, rifampicin for OATP1B1 and OATP1B3, cyclosporine for BSEP, and sulfobromophthalein (BSP) for MRP2. RESULTS: The results obtained showed that P-gp, BCRP, OAT3, OATP1B1, OATP1B3, BSEP and MRP2 might be candidates for BPS transporters. From the further evaluation with the typical inhibitors of each transporter, it was confirmed that BPS is a substrate for P-gp, BCRP, OAT3, OATP1B1, OATP1B3 and MRP2, because the typical inhibitor, cyclosporine, had no effects on BPS transport by BSEP. CONCLUSIONS: BPS is a substrate of 6 transporters: P-gp, BCRP, OAT3, OATP1B1, OATP1B3, and MRP2, because their expressing cells and vesicles transported BPS more than in the controls, and BPS transport activities were reduced by the typical inhibitors of tested transporters. Although there are no reports regarding drug-drug interactions between BPS and possible combination drugs expected due to transporters, it may be necessary to notice that that substrates or inhibitors for the 6 mentioned transporters may have effects on pharmacokinetics of BPS when co-administered.

Drug-Drug Interactions of a Novel κ-Opioid Receptor Agonist, Nalfurafine Hydrochloride, Involving the P-Glycoprotein.

BACKGROUND AND OBJECTIVE: Nalfurafine hydrochloride (TRK-820), which exhibits strong κ-opioid agonistic activity, has an antipruritic effect on uremic pruritus. The permeability of nalfurafine across human P-glycoprotein (P-gp)-expressing LLC-PK1 cells was investigated to evaluate drug-drug interactions (DDI) involving the P-gp efflux transporter of nalfurafine. Furthermore, we assessed the ratio of brain/plasma concentrations (K p) as an indicator to investigate the changes in the blood-brain barrier (BBB) transport through P-gp when digoxin or verapamil was concomitantly administered with nalfurafine in mice. METHODS: All samples were analyzed by liquid chromatography-tandem mass spectrometry or a liquid scintillation counter. RESULTS: The cleared volume ratio (cleared volume from basal to apical/cleared volume from apical to basal) of nalfurafine in P-gp-expressing cells was higher than that in the control cells; however, no concentration-dependent decrease in the cleared volume ratio of digoxin was observed in the presence of nalfurafine. The K p value in mice showed similar profiles to those observed with nalfurafine alone and when co-administered with digoxin or verapamil. CONCLUSIONS: From these results, nalfurafine was found to be a substrate for P-gp, but had no inhibitory effect on P-gp-mediated transport. Furthermore, it is unlikely that nalfurafine transport via the BBB is affected by P-gp substrates in humans.

Hepatic microsomal UDP-glucuronosyltransferase (UGT) activities in the microminipig.

The microminipig, a small minipig, was bred as a novel experimental animal for nonclinical pharmacology/toxicology studies by Fuji Micra Inc. (Shizuoka, Japan). Species differences in drug metabolism between humans and the microminipig need to be elucidated in more detail in order to discuss the results of nonclinical studies. Glucuronidation catalysed by UDP-glucuronosyltransferase (UGT) is an important pathway in the metabolism of a wide variety of compounds. The aim of the present study was to identify the characteristics of hepatic UGT activity in the microminipig and compare them with those in humans and other experimental animals. This study examined in vitro UGT activities using liver microsomes from microminipigs (8 months old and 1 day old), humans, mice, rats, dogs, monkeys and minipigs. The glucuronides of estradiol, imipramine, serotonin, propofol, 3'-azido-3'-deoxythymidine (AZT) and morphine, selective substrates of human UGT1A1, 1A4, 1A6, 1A9 and 2B7 (AZT and morphine), respectively, were measured using LC-MS/MS. Estradiol-3-glucuronidation activity was higher in the microminipig than in humans and the other animals. High levels of estradiol-3-glucuronidation were observed in the microsomes of 1-day-old microminipigs. Imipramine-N-glucuronidation, a distinctive conjugation by human UGT1A4, was catalysed by microminipig liver microsomes, but not by dog liver microsomes. Although AZT-glucuronidation activity was low in the microminipig compared with humans, morphine-3-glucuronidation activity in the microminipig was higher than that in humans. The UGT activities in the microminipig were similar to those in the minipig. The results of the present study have provided useful information for selecting an appropriate animal model for nonclinical studies.

A computational drug metabolite detection using the stable isotopic mass-shift filtering with high resolution mass spectrometry in pioglitazone and flurbiprofen.

The identification of metabolites in drug discovery is important. At present, radioisotopes and mass spectrometry are both widely used. However, rapid and comprehensive identification is still laborious and difficult. In this study, we developed new analytical software and employed a stable isotope as a tool to identify drug metabolites using mass spectrometry. A deuterium-labeled compound and non-labeled compound were both metabolized in human liver microsomes and analyzed by liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS). We computationally aligned two different MS data sets and filtered ions having a specific mass-shift equal to masses of labeled isotopes between those data using our own software. For pioglitazone and flurbiprofen, eight and four metabolites, respectively, were identified with calculations of mass and formulas and chemical structural fragmentation analysis. With high resolution MS, the approach became more accurate. The approach detected two unexpected metabolites in pioglitazone, i.e., the hydroxypropanamide form and the aldehyde hydrolysis form, which other approaches such as metabolite-biotransformation list matching and mass defect filtering could not detect. We demonstrated that the approach using computational alignment and stable isotopic mass-shift filtering has the ability to identify drug metabolites and is useful in drug discovery.

Focused DNA microarray analysis for sex-dependent gene expression of drug metabolizing enzymes, transporters and nuclear receptors in rat livers and kidneys.

Cytochrome P450(CYP)s are known to show a sexual dimorphic expression in rat livers. However, the comprehensive analysis for the sex-dependent gene expressions of drug metabolizing enzymes except for CYPs, transporters and nuclear receptors in rat livers and kidneys has not been investigated yet. The purpose of the present study was to identify the novel drug metabolizing and pharmacokinetics (DMPK)-related gene(s) which show the sex difference in the mRNA expressions in rat livers and kidneys. Total RNAs were prepared from livers and kidneys in both male and female rats (Crl:CD(SD) and Crlj:WI). A DNA microarray analysis using a "GeneSQUARE Multiple Assay DNA Microarray Drug Metabolism Gene Expression for Rat" was performed. DMPK-related genes which showed sex differences in the mRNA expression were identified in rat livers or kidneys. Especially, the female dominant expressions of UDP glucuronosyltransferase (UGT) s were seen in rat livers and kidneys. The sex difference of UGT expressions in rats might be one of the causal factors of the sex difference of the biological response to UGT substrates.

Identification of human cytochrome P450 enzymes involved in the metabolism of a novel к-opioid receptor agonist, nalfurafine hydrochloride.

Nalfurafine hydrochloride (TRK-820) exhibits strong к-opioid agonistic activity and is a new antipruritic agent for uremic pruritus. This study was performed to identify the human hepatic cytochrome P450 isoforms involved in the metabolic conversion of nalfurafine to the decyclopropylmethylated form, de-CPM, using human liver microsomes and E. coli membrane fractions expressing human P450 isoforms. Samples were analysed by liquid chromatography with a radioactivity detector and liquid chromatography-tandem mass spectrometry. The metabolism of nalfurafine by human liver microsomes exhibited a biphasic kinetic profile. Experiments examining the metabolism by E. coli membrane fractions expressing human P450 isoforms indicated that CYP1A1, 2C8, 2C19 and 3A4 had the ability to produce de-CPM. In experiments with human liver microsomes that examined the inhibition of nalfurafine metabolism by anti-human P450 antibodies, anti-CYP3A4 antibody predominantly, and anti-CYP2C8 and 2C19 antibodies moderately, inhibited de-CPM formation. From these results, CYP3A4 appeared to be the major isoform involved in the metabolic decyclopropylmethylation of nalfurafine, while CYP2C8 and 2C19 most likely play a minor role in the formation of de-CPM.