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Significance Glucagon-like peptide-1 receptor agonists have become established as a leading class of diabetes medications. However, these peptide-based drugs are administered by subcutaneous injection or, in one case, by a complex oral dosing regimen. We now report the discovery of LY3502970, a potent and selective small-molecule GLP-1R agonist. LY3502970 exhibits preclinical pharmacology equivalent to a marketed injectable GLP-1R agonist and possesses pharmacokinetic properties compatible with oral dosing in humans. Cryoelectron microscopy (cryo-EM) studies reveal an ECD-driven receptor binding mode for LY3502970 that provides a favorable pharmacological profile., Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein–coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.

Several kinds of hydroxyapatites (HAp) prepared by modification of Ca2+-HAp with transition metal (Fe2+, Fe3+, Co2+, Ni2+, Cu2+ and Zn2+) or aluminum (Al3+) ions were evaluated via a gas bag-detection tube method whether they could be used as novel deodorant materials. The samples treated with divalent cation (Fe2+, Co2+, Ni2+, Cu2+ and Zn2+) retained hydroxyapatite structure as well as Ca2+-HAp, whereas those treated with trivalent cation (Al3+ and Fe3+) showed lower crystallinity than Ca2+-HAp. 5–8 wt% cation of the samples was introduced by modification with divalent metal cations, whereas about 40 wt% cation of the samples was introduced with relatively larger surface area and higher content of adsorbed water for trivalent cations. For NH3 gas, modification of Ca2+-HAp with a divalent metal cation enhanced its adsorption ability, and that with a trivalent metal cation resulted in considerable improvement of the ability. On the other hand, modification of Ca2+-HAp with Cu2+ ion gave it remarkable H2S gas adsorption ability in comparison to that with other metal cations. However, adsorption ability for H2S of some polycrystalline powders including Cu2+ was not higher than that of Cu2+-modified HAp. The effect of the incorporated cation on adsorption ability for NH3 molecules may be based not only on a simple Lewis acid-base reaction but also on specific surface area and adsorbed water content, and the effect for H2S molecules based on the specific local electron density around the cation present on/in the material.

Adding fatty acids to an oil-in-water (O/W) emulsion changes the stability of the emulsion. In this study, we prepared a series of O/W emulsions consisting of oil (triolein/fatty acid mixture), water and a range of surfactants (sucrose fatty acid esters) with varying hydrophilic-lipophilic balance (HLB) in order to determine the effects of alkyl chain length and the degree of unsaturation of the fatty acid molecules on the stability of the emulsions. As a result, sucrose fatty acid esters with HLB = 5-7 were suitable for obtaining O/W emulsions. In addition, the creaming phenomenon was inhibited for 30 days or more when fatty acids having a linear saturated alkyl chain with 14 or more carbon atoms were added. These findings are useful for designing stable O/W emulsions for food and cosmetic products.

Effects of particle size distribution on physical properties such as viscosity, heat and mechanical properties of injection-molded hydroxyapatite (HA)/poly lactic acid (PLA) were investigated. The melting temperature of PLA was shifted to a lower temperature because of the dispersion of HA particles. However, the cold crystallization temperature shifted to a lower temperature at high HA composition, suggesting that HA particles acted as a nuclear agent. x c,PLA of the composites with bimodal particle size distribution showed the lowest of all three composites, suggesting that mobility of PLA polymer chain was reduced by bimodal particle size distribution, which means the increase of restriction at interface between polymer matrix and particle. Melt flow rate (MFR) increased because of dispersed HA particle. The reason was thought that hydrolysis degradation of PLA occurred during melt-mixing process is accelerated by HAp particle dispersion. The MFR of composites increased concomitantly with increased par...

In this work, the availability of calcium phosphates for the light emitting layer of a thin-film electroluminescent (TFEL) device was investigated. The goal of this work was to develop an electronic device with ordinary materials such as a calcium phosphate, the principal ingredient of the skeleton of the vertebrate. Compositions of 2CaO·P 2 O 5 (Ca 2 P 2 O 7 ), 3CaO·P 2 O 5 (Ca 3 (PO 4 ) 2 ) and 4CaO·P 2 O 5 (Ca 4 O(PO 4 ) 2 ) were examined as the candidates for the light emitting layer. Before composing the TFEL device, the photoluminescence (PL) properties of the three compositions were investigated in the powder form to evaluate the performance as the light emitting layer. Among the examined calcium phosphates, Eu-doped β-Ca 3 (PO 4 ) 2 showed the best PL properties. It showed typical red-emission from Eu 3+ . The PL intensity was enhanced with the heat-treatment temperature and the optimal temperature was 1250 °C. Then, a TFEL device was prepared by a spray pyrolysis method with the β-Ca 3 (PO 4 ) 2 :Eu 3+ phosphor layer on a BaTiO 3 disk. The TFEL device exhibited the red emission originating in Eu 3+ at 610 nm under applying alternating voltage. Different from the power sample, the intensity of EL decreased with the heat-treatment temperature from 1000 to 1250 °C. The deterioration of EL at the higher temperatures was attributed to chemical interaction between the phosphor layer and the BaTiO 3 disk.

BaCO3 and anatase-type TiO2 were adopted as initial materials to prepare BaTiO3 powder by the solid-state reaction method at a heating rate of 350°C/h. The electron paramagnetic resonance (EPR) technique was employed to monitor the formation of BaTiO3. TiO2 showed a series of complicated EPR signals associated primarily with Fe impurities. The formation of BaTiO3 can be monitored in terms of the evolution of EPR signals associated with Fe impurities with calcination and measurement temperatures. The activation of the g = 2.004 signal above the Curie point of BaTiO3 and the disappearance of the other EPR signals in the BaCO3/TiO2 mixture at room temperature are characteristic of the formation of BaTiO3.

Some enzymes catalyze the formation of precipitants of metal ions, and some others directly interact with metal-containing precursors. Such enzymes allow the synthesis of inorganic solids under mild conditions. Due to the nature of enzymatic reactions, enzyme-mediated ceramic synthesis techniques can facilitate (1) site-selective ceramic deposition, (2) low temperature ceramic synthesis, (3) intact combination of ceramics with heat-sensitive materials, and sometimes (4) synthesis of metastable phases. The morphology of the resultant ceramics can be tailored in many ways by immobilizing enzymes onto various templates. So far, successful cases have been reported in preparing thin film coatings, hollow micro- or nanospheres, multi-layer stacking, nanotubes, 2D patterns, honeycombs, 3D replicas of biominerals, and so on. Enzyme-mediated ceramic synthesis provoked the emergence of a new type of processing technique which employs proteins or peptides as the mediators. Practical applications of enzyme- or peptide-mediated ceramics are on the horizon in many fields, such as biomaterials, enzyme immobilization supports, and enzyme sensors. This article presents a comprehensive survey of the recent advances of enzyme-mediated ceramic synthesis and related techniques as well as future outlook.

In this work, two approaches were developed to extend the coating area of diamond by continuous deposition in a plasma-assisted chemical vapor deposition (CVD) method above the liquid. The techniques were based on the methods previously developed by our research group and the characteristic was to use dc (direct current) plasma generated between the liquid surface and the metal electrode. In the first approach, a tungsten rod was rotated in a chamber at reduced pressure so that a diamond film was formed as a ‘belt’ in 6 mm width around the side of the rod. The deposited diamond was polycrystalline with a grain size of 1–3 μm. The film thickness increased almost linearly with deposition time, whereas the grain size was almost constant against the deposition time. The second approach was for a plate substrate. A tungsten plate was hung with an iron wire and the plasma was horizontally generated between the liquid and plate surfaces. When the W plate was vertically slid down slowly, a diamond film was continuously deposited on the surface. The deposited film was covered with a soot-like carbon layer on the top and the post-treatment with H2O/N2 gas at 600 °C was effective in removing it. The continuous deposition successfully demonstrated the expansion of the deposition area with the novel plasma CVD method above the liquid.

It was early shown that Ti metal spontaneously bonds to living bone through an apatite layer formed on its surface in the living body, when it was subjected to NaOH and heat treatment to form a sodium titanate on its surface. This kind of bioactive Ti metal was applied to artificial hip joint and already clinically used in Japan. During the study of fabrication process of the hip joint, it was found that sodium content of the surface layer of the Ti metal is largely varied with washing condition after the NaOH treatment, and that apatite-forming ability of the NaOH- and heat-treated Ti metal is liable to decrease in humid environment for a long period. In the present study, the sodium content of the surface layer of the Ti metal was systematically changed by water or HCl treatment after NaOH treatment. Effect of the sodium content of the surface layer on apatite-forming ability in a simulated body fluid and its stability in humid environment of the NaOH- and heat-treated Ti metal were investigated. As a result, it was found that the NaOH- and heat-treated Ti metal gives high and stable apatite-forming ability, when the Ti metal was treated with water after the NaOH treatment to remove partially sodium ions in the surface layer, and subjected to heat treatment.

Titanium (Ti) metal was treated with water or HCl solutions after 5 M NaOH solution treatment and then subjected to heat treatment at 600 degrees C. The apatite-forming abilities of the treated Ti metals were examined in simulated body fluid. The apatite-forming ability of the Ti metal subjected to NaOH, water and heat treatment was lower than that of just NaOH and heat treatments. Ti metals subjected to NaOH, HCl and heat treatment showed apatite-forming abilities, which increased with increasing HCl concentrations up to the same level as that of NaOH- and heat-treated Ti metal. The former did not show a decrease in its apatite-forming ability, even in a humid environment for a long period, whereas the latter decreased its ability. The increase in the apatite-forming ability with increasing HCl concentrations suggests a different mechanism of apatite formation from that previously proposed.

Hollow hydroxyapatite (HAp) microspheres a few tens micrometers in diameter were fabricated by precipitating HAp preferentially on the surface of an organic polymer template using enzymatically supplied precipitant. The template, polydivinylbenzene (PDVB) microsphere encapsulating urease, was synthesized in W/O/W emulsion. HAp was precipitated on the surface of the template as ammonia was enzymatically supplied from inside of the template in a solution containing calcium ion, phosphate ion and urea. Within 21.6 ks, the surface of the template was covered with HAp. After the template was removed by calcination at 873 K, the HAp hollow microspheres were obtained. The size of the HAp microspheres reflected that of the template and the latter was easily controlled in a range from 10 to 200 μm by the preparation condition of the W/O/W emulsion. The shell thickness of the HAp sphere was also regulated by the duration of the enzymatic reaction. This material can be a promising candidate for the carrier of the drug delivery system.

In order to study method for preparing bioactive titanium metal, calcium ions were attempted to be incorporated into the surface of the titanium metal by ion exchange method. Titanium metal was soaked in 5M NaOH solution and 100mMCaCl2 solution and subjected to heat treatment. About 5 atom% of Na was incorporated into the surface of the titanium metal by the NaOH treatment This Na was completely replaced with calcium ion by the CaCl2 treatment and maintained even after the heat treatment. Critical detaching strength of the surface layer to the substrate of NaOH-treated titanium metal was a little increased by the CaCl2 treatment and remarkably increased by the heat treatment. Apatite-forming ability of the NaOH-treated titanium metal in SBF was increased by the CaCl2 treatment, but decreased by the subsequent heat treatment.

Fatty liver is strongly associated with the metabolic syndrome characterized by obesity, insulin resistance, and type 2 diabetes, but the genetic basis and functional mechanisms linking fatty liver with the metabolic syndrome are largely unknown. The SMXA-5 mouse is one of the SMXA recombinant inbred substrains established from SM/J and A/J strains and is a model for polygenic type 2 diabetes, characterized by moderately impaired glucose tolerance, hyperinsulinemia, and mild obesity. SMXA-5 mice also developed fatty liver, and a high-fat diet markedly worsened this trait, although SM/J and A/J mice are resistant to fatty liver development under a high-fat diet. To dissect loci for fatty liver in the A/J regions of the SMXA-5 genome, we attempted quantitative trait loci (QTLs) analysis in (SM/JxSMXA-5)F2 intercross mice fed a high-fat diet. We mapped a major QTL for relative liver weight and liver lipid content near D12Mit270 on chromosome 12 and designated this QTL Fl1sa. The A/J allele at this locus contributes to the increase in these traits. We confirmed the effect of Fl1sa on lipid accumulation in liver using the A/J-Chr12(SM) consomic strain, which showed significantly less accumulation than A/J mice. This suggests that the SM/J and A/J strains, neither of which develops fatty liver, possess loci causing fatty liver and that the coexistence of these loci causes fatty liver in SMXA-5 mice.

Modification of organic polymer with silanol groups in combination with calcium salts enables the polymer to show bioactivity, that is, the polymer forms apatite on its surface after exposure to body environment. However, how modification with silanol groups influences ability of apatite formation on the polymer substrate and adhesive strength between polymer and apatite is not yet known. In the present study, polyamide containing carboxyl groups was modified with different amounts of silanol groups, and its apatite-forming ability in 1.5SBF, which contained ion concentrations 1.5 times those of simulated body fluid (SBF), was examined. The rate of apatite formation increased with increasing content of silanol groups in the polyamide films. This may be attributed to enhancement of dipole interactions. A tendency for the adhesive strength of the apatite layer on the polyamide film to be decreased with increasing content of silanol groups was observed. This may be attributed to swelling in 1.5SBF and having a high degree of shrinkage after drying. These findings clearly show that modification of organic polymers with the functional groups induces apatite deposition, and also determines the adhesive strength of the apatite layer to the organic substrates.

In some countries, non-point source pollution derived from a city's economic activities tends to be a barrier to the improvement of water quality. Roadway runoff is known to contain toxic micro-pollutants such as polycyclic aromatic hydrocarbons (PAHs). Conversely, red soil is known to adsorb some organic matter. In this study, artificial roadway runoff water containing toxic micro-pollutants was made using roadway dust collected from a highway, and used for both batch-type tests and soil column tests with red soil in order to understand adsorption ability of the red soil on such toxic micro-pollutants, especially PAHs. In the batch-type tests, PAHs could be removed by approximately 40% when the contact time was 90 minutes. In the soil column tests, PAHs were removed by more than 80% while suspended solids were removed by more than 90%. Notably, PAHs with a high molecular weight were removed more readily in the tests than PAHs with a low molecular weight.

The aim of this study is evaluate to the cellular viability of elution from the newly developed resin and Osteobond® in vitro. The basis of the newly developed resin are methacryloyloxyethyl methyl succinate and 1,6-Hexanediol dimethacrylate. The basis of Osteobond is methyl methacrylate. The concentrations of basis in each elution were determined by high-performance liquid chromatography (HPLC). Cellular viabilities of L-929 mouse fibroblasts were evaluated by direct cells counting, and then, each IC50 value was calculated. Moreover, patterns of cell death were analyzed using annexin V/propidium iodide staining with the phase-contrast microscope and flow cytometry. The concentration of Osteobond elution was 2.16 mM of MMA, and the newly developed resin elution was 1.02 mM of TA and 1.87 x 10-2 mM of HX. Until 72 hours of incubation, treatment with each elution impaired the viability of L-929 cells in a dose-dependent manner. IC50 value of Osteobond was 6.48 x 10-4 mM of MMA. However, IC50 of the newly developed resin was not calculated. Treatment with Osteobond elution showed more necrotic cells than with the newly developed resin elution. In conclusion, the results demonstrated much more excellent cellular viability of the newly developed resin than that of MMA resin. Thus, it is suggested that the newly developed resin will be more useful as an implantation material for dentistry and orthopaedics.

Apatite formation on polyamide films containing either carboxyl or sulfonic groups was compared in 1.5SBF, whose ion concentrations are 1.5 times those of a simulated body fluid (SBF). The sulfonic groups induced the apatite nucleation earlier than the carboxyl groups. In contrast, the rate of crystal growth depended not on the kind of functional group, but on the degree of supersaturation of the surrounding solution. The more ready association of sulfonic groups with calcium ions may lead to earlier apatite nucleation than that of carboxyl groups. Adhesive strength of the apatite layer to polyamide film containing sulfonic groups was significantly lower than that with carboxyl groups depending on the chemical interactions as well as on the mechanical properties of the polyamide film.

The association constant between guanine and a series of cytosine derivatives in dichloromethane was determined by fluorescence quenching experiment of pyrene connected to guanine with methylene spacer. The association constant for guanine with 5-methylcytosine is found to be higher than that with cytosine. This enables us to distinguish target cytosine from its derivatives.

It is well known that bone morphogenetic protein (BMP) induces bone formation and requires for carriers. Poly-lactic acid / poly-glycolic acid (PLGA) is frequently used as the carriers of BMP. We developed a biodegradable composite PLGA membrane, which was containing oriented needle-like apatite with BMP. The composite membranes were implanted into the thigh muscle pouch of 3-week-old-mice. At 3 weeks after implantation, the implanted area was observed by optical microscopy. The composite membrane containing oriented needle-like apatite with BMP induced new bone formation. It seems that this composite membrane might be a scaffold of BMP and promoting the healing of bone defects.

Organic polymer coated with hydroxyapatite (so-called apatite) on its surface is a candidate of new hybrid materials for medical applications since it is expected to show bone-bonding ability and achieve mechanical properties derived from organic substrate. We have shown that some kinds of polyamide films containing carboxyl group or sulfonic group form hydroxyapatite in the simulated body environment, when they are incorporated with calcium chloride. In the present study, the polyamide containing carboxyl groups were modified with silanol groups and its apatite-forming ability was investigated in 1.5SBF, which has ion concentrations 1.5 times those of a simulated body fluid (SBF). It was found that polyamide films modified with silanol groups showed higher ability to induce apatite on its surface in 1.5SBF than the films without the modification, when they were incorporated with calcium chloride.

The purpose of this study was to evaluate the physical properties of the composite membrane before and after soaking in simulated body fluid (SBF) and discuss both degradation and maintenance of their properties. Before and after soaking in SBF, some deposits were found on the preexisted apatite crystals, and Ca and P were mainly detected by energy dispersive X-ray analyzer (EDX). Our results suggest that the composite membrane consisting of apatite and the biodegradable PLGA copolymer would have excellent biocompatibility and maintain adequate physical properties for in vivo use.

Coating organic polymers with hydroxyapatite is an attractive method for the development of materials for medical applications, as it allows hydroxyapatite to show its unique biological properties such as its ability for bone bonding and protein adsorption. The biomimetic process focuses attention on fabricating such hydroxyapatite-polymer hybrids, where bone-like apatite is deposited on an organic polymer surface in solutions mimicking physiological conditions. In this process, a bone-like apatite layer can be coated onto organic substrates either by using a simulated body fluid (SBF), which has ion concentrations nearly equal to those of human extracellular fluid, or by using fluids that are supersaturated with respect to apatite at ambient conditions. We previously reported that apatite was deposited on polyamide films containing carboxyl groups in a solution mimicking body fluid, when they were incorporated with calcium salts. In the present study, to find an alternative functional group effective in apatite formation, we examined the apatite-forming ability of polyamide films containing sulfonic groups in the same solution. It was found that the polyamide film containing sulfonic groups could deposit apatite on its surface in the solution when the film was incorporated with calcium salts. These results show that the sulfonic group also acts as a functional group, and is as effective for apatite deposition in the body environment as the carboxyl group.

The biocompatibility and osteoconductive potential of Bonelikeand Bonelike � /PLGA hybrid materials were evaluated through subcutaneous and tibiae implantations for a 4 week period. Qualitative histology was performed to evaluate new bone formation and characterise bone-implant interface and results showed that Bonelike � /PLGA hybrid materials promote extensive bone growth. After the 4 week implantation period, Bonelikeresorption was recognized, which may be due to the presence of resorbableand �-tricalcium phosphate phases.

Hollow magnetite (Fe3O4) microspheres a few tens micrometers in diameter were fabricated by calcining iron hydroxide precipitated on spherical polydivinylbenzene (PDVB) template with enzymatically supplied ammonia. Monophasic Fe3O4 hollow spheres were obtained by calcining the precursor at 1073 K for 3.6 ks in an equimolar mixed gas of CO2 and H2. The prepared Fe3O4 hollow spheres had smooth surfaces. The particle size and monodispersity of Fe3O4 spheres reflected those of the PDVB template, and the latter was controllable 10-30 μm in diameter during the process of the polymerization. The Fe3O4 spheres showed ferrimagnetic behavior. The use of urease to precipitate the precursor was found to be effective for preparing template-directed microspheres, and the Fe3O4 microspheres synthesized are considered to be promising thermoseeds for hyperthermic treatment.

6-Hydroxynicotinate 3-monooxygenase, a membrane-bound, 42-kDa monomeric enzyme from Pseudomonas fluorescens TN5 was purified and characterized. The enzyme catalyzes the oxidative decarboxylation of 6-hydroxynicotinate and depends on O2, NADH and FAD with the holoenzyme containing 1 M of FAD per 1 M of enzyme. The isolated enzyme was used for the synthesis of 2,5-dihydroxypyridine, a precursor for the chemical synthesis of 5-aminolevulinic acid, which is applied as a plant growth hormone, a herbicide and in cancer therapy. A 1.8-kbp DNA fragment, which contains the ORF encoding 6-hydroxynicotinic acid 3-monooxygenase, was cloned, sequenced and expressed in Escherichia coli. The deduced 385 amino acid sequence of the cloned ORF is in agreement with the enzyme molecular mass, amino acid sequence of an internal peptide, contains a putative FAD-binding site and is homologous to similar flavoproteins such as salicylate 1-monoxygenase.

Highly transparent ZnO thin films were prepared by calcining ZnO2 precursor films deposited from aqueous solutions. The transparency of the resultant ZnO thin films, which was directly associated with that of the precursor films, depended on the kind of zinc source, the composition of the starting solution, and the deposition temperature of the ZnO2 precursor. The most highly transparent ZnO thin film was obtained by calcining a ZnO2 precursor film which was deposited from a solution containing 0.01 mol/dm3 of ZnSO4, 1.8 mol/dm3 of H2O2, and 2.1 mol/dm3 of NH3 at 303 K. Doping of a ZnO thin film with indium was attempted by an immersion of the thin film in an In(NO3)3 solution and a subsequent heat-treatment at 773 K in a N2 atmosphere, which resulted in an electrical conductivity of 535 S/m.

We prepared an apatite/polymer composite material with a fractal surface by transferring the hierarchical rough surface of a plaster replica onto calcium phosphate paste and immersing the paste in ...

There are several types of mineral resources under or on the deep-sea bed. Manganese Nodules, Cobalt-rich Manganese Crusts, and Sea-floor Massive Sulfides (SMS) are well known future metal resources in the deep-sea. Although, there have been a lot of activities to study those resources as scientific interests as well as a business point of view, any deep-sea mineral resources has not been developed yet.

5-Methyl-5-phenylpyrroline N-oxide was proved to be a useful 1,3-dipole for determining the absolute configuration of chiral allenes by means of NMR spectroscopy.

The purpose of this study is to characterize the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of sodium–glucose cotransporter (SGLT) inhibitors. PK–PD studies of SGLT inhibitors (CH4941527 and T-1095), which have different half-life and selectivity to SGLT2, were performed using db/db mice. The time courses of compound concentration in plasma, blood glucose (BG), and renal glucose excretion were measured after a single oral administration of each SGLT inhibitor. An indirect-response PK–PD model was developed, in which it was assumed that an SGLT inhibitor enhances renal glucose excretion and the enhanced glucose excretion reduces BG. In the PK–PD study, both SGLT inhibitors increased renal glucose excretion and reduced BG in a dose-dependent manner. The present PK–PD model could suitably capture the effect of SGLT inhibitors and the effect shown suggested that the BG reduction could be explained by the enhanced renal glucose excretion. There were no great differences in the estimated PD parameters between the two inhibitors and they were comparable to the data from previously reported pharmacological studies. The present PK–PD model is helpful for understanding the plasma concentration-dependent effect of SGLT inhibitors on renal glucose excretion and BG. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4347–4356, 2012

Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.

Needle-like hydroxyapatites obtained through a hydration reaction process between anhydrous dicalcium phosphate (ADCP) and tetracalcium phosphate (TTCP) were reinforced with wheat starch to form co...

Hybrids consisting of bone-like apatite and biodegradable polymers are attractive materials for bone repair. We have shown that an alginate gel crosslinked covalently with ethylenediamine (EDA) enhances the repair of skin and nerves. In this study, we report a novel method for fabrication of an apatite-alginate nanohybrid using a simulated body fluid (SBF). Alginate was reacted with 3-aminopropyltriethoxysilane (APES), which gives silanol groups after hydrolysis, and/or EDA, by dehydration condensation using water-soluble carbodiimide to form gels. Modification of alginate with APES alone also gave a gel, because the alginate could be crosslinked by dehydration of silanol groups derived from APES. The gels obtained were soaked in a 1 mol/L CaCl2 solution and subsequently soaked in SBF. Apatite was formed on and inside the alginate gels modified with APES, whereas it was not formed on the gels without APES. Modification of alginate with silanol groups induced not only gel formation but also the apatite-forming ability on and inside the alginate gel in SBF. Consequently, a hydroxyapatite-alginate hybrid can be produced by modification of alginate with silanol groups and subsequent soaking in CaCl2 solution and SBF. Such a material is expected to be useful in bone repair.

Oxidation products of cyclopropanoid terpenes, (-)-carane (4), (+)-cyclosativene (5), laurinterol methyl ether (6), and thujopsane (7), with ruthenium tetraoxide were investigated.

It was possible to trace real-time change of redox balance in a plant in vivo by a spin probe-ESR method, after exposing it to various physical and chemical stresses. Consequently, a strong light, ...

Guanine derivatives connected to pyrene with methylene spacers exhibited exciplex emission in highly polar solvents such as N,N-dimethylformamide, acetonitrile, and water. The result will open up a novel approach to synthesis of fluorescent nucleic bases.

Reflection high-energy electron diffraction (specular beam intensity) in migration-enhanced epitaxy of AlAs and GaAs has been investigated. The step flow growth mode was realized in the migration-enhanced epitaxy of AlAs by using a 0.5° misoriented GaAs(111)B substrate. In AlAs growth, excess As adsorption occurred easily in comparison with that in GaAs MEE growth. The control of the number of As4 molecules per cycle was found to be important in obtaining a flat surface.

胆石症症例に対し定圧流量を施行した47例, 定流内圧測定を施行した44例について, 乳頭機能および乳頭形成術適応について検討した.定圧流量10ml/min未満を乳頭形成術適応とし, 胆嚢結石群は平均49.1ml/min, 胆管結石群100.2ml/min, 乳頭形成群6.4ml/minを示した.乳頭形成群が定流内圧測定において明らかに異常値を示したのは, 灌流圧と回復時間でそれぞれ平均59.5cmH2O, 45.2秒であった, さらに, 薬物負荷による流量・圧変化をみる事により, 器質的のみならず機能的な病変の把握も可能で, 従来の乳頭形成術適応の判定基準より的確であることが示唆された, 特に, 定圧流量, 灌流圧および回復時間が重要な因子であると思われる.