Oral absorption improvement of poorly soluble drug using solid dispersion technique

A new triazol antifungal agent, (+)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1, 2,4-triazol-1-yl)-3-[6-(1H-1,2,4-triazol-1-yl)pyridazin++ +-3-ylthio]butan-2-ol (MFB-1041), shows poor oral absorption and is practically insoluble in water (1.2 micrograms/ml). Solid dispersion systems with an enteric polymer such as hydroxypropylmethylcellulose phthalate (HP-55) and carboxymethylethylcellulose (CMEC), and a nonenteric polymer, hydroxypropylmethylcellulose (Metolose) were evaluated to improve drug absorption and solubility. The oral bioavailabilities of these solid dispersions in beagle dogs were over 6 times higher than that of a suspension system with increasing drug solubility in an alkaline medium. X-Ray powder diffraction measurement of the solid dispersion showed a complete drug phase change from a crystal to an amorphous state. Further, from the results of a stability test, the preparations were stable in a desiccated condition and the absorption profiles also showed no change. From the results, it was suggested that the oral administrative preparation of MFB-1041 having a superior absorption profile and a high stability could be obtained by a drug phase change from a crystal to an amorphous state, especially in the spray-drying method using enteric polymers.     

An empirical approach for structure-based prediction of carbohydrate-binding sites on proteins

A computer program system was developed to predict carbohydrate-bindingsites on three-dimensional (3D) protein structures. The programssearch for binding sites by referring to the empirical rulesderived from the known 3D structures of carbohydrate–proteincomplexes. A total of 80 non-redundant carbohydrate–proteincomplex structures were selected from the Protein Data Bankfor the empirical rule construction. The performance of theprediction system was tested on 50 known complex structuresto determine whether the system could detect the known bindingsites. The known monosaccharide-binding sites were detectedamong the best three predictions in 59% of the cases, whichcovered 69% of the polysaccharide-binding sites in the targetproteins, when the performance was evaluated by the overlapbetween residue patches of predicted and known binding sites. Received April 24, 2003; revised June 2, 2003; accepted June 10, 2003.     

Hybrid Link/Path-Based Design for Translucent Photonic Network Dimensioning

The advancement of ultralong-haul transmission technology has dramatically enhanced the all-optical reaches. However, the actual situations of installed fiber and sites for terrestrial network often prevent implementing a purely transparent network, and thus, opaque reshaping retiming regenerating (3R) regeneration is required to guarantee optical signal reachability. Since 3R regenerators based on optical/electrical/optical conversion tend to dominate the total network costs, an efficient network design method that allocates a minimum number of 3R regenerators to optimum locations is essential to build a cost-effective photonic network. In this paper, we propose such a network-dimensioning method by combining the advantages of link-based and path-based design approaches. It first guarantees optical signal reachability for any possible traffic demand in each segmented linear link. After combining all the links, excessive regenerators are eliminated based on the optical signal quality check with -factor calculation for each wavelength path. A trial design of a large-scale mesh network demonstrated a significant cost savings of more than 30% in comparison with a conventional link-based design. In the trial, the impact of fiber loss coefficient over the total network cost was investigated quantitatively, addressing the importance of such quantitative modeling and analysis.     

Novel B-ring modified combretastatin analogues: syntheses and antineoplastic activity

A series of B-ring modified combretastatin analogues were synthesized and their inhibitory activity against microtubule assembly, cytotoxic activity against Colon 26 adenocarcinoma cancer cell line were evaluated. Among these, pyridone derivative (19) showed strong antimitotic activity and cytotoxicity, along with excellent water-solubility.     

Physicochemical properties of rare earth perovskite oxides used as gas sensor material

The change of the conductivity in the rare earth perovskite oxide took place after the chemisorption of flammable gases. The sensitivity for methanol was highest. From the conductivity change of these perovskite oxides after the injection of methanol, the energy needed to promote an electron from a conducting to a nonconducting state, E=E _c-E _t, could be derived from the equation=A ₀ exp (–E/kT). LnCoO₃ had the smallest E and H (metal-O), which is the binding energy of oxygen coordinating to the metal ions, but exhibited the highest activity for gas sensing. The gas sensing mechanism was also considered.     

Microstructure and superconducting properties of rapidly-quenched copper-based alloys containing immiscible lead and bismuth elements

Copper-based superconducting alloys including finely dispersed f c c lead or h c p (Pb- Bi) particles in f c c copper matrix have been obtained by rapid quenching (Cu-M)_100-x Pb_x and (Cu-M)_100-x (Pb_0.6Bi_{0.4 x} (M = aluminium, silicon or tin;x < 10 at%) alloys containing immiscible elements such as lead and bismuth. The particle size and interparticle distance were about 30 to 130 nm and 20 to 200 nm for had particles and about 30 to 60 nm and 30 to 150 nm for (Pb- Bi) particles. The transition temperature,T _c, was in the range of 3.2 to 5.5 K for the Cu-M-Pb alloys and 6.2 to 6.3 K for the Cu-M-Pb-Bi alloys. Critical magnetic field,H _c2, and critical current density,J _c, for the later alloys were 0.47 to 0.93T at 4.2 K and 1.1 × 10⁵ to 2.7 × 10⁵ Am^–2 at zero applied field and 4.21 K. The mechanism of the appearance of such a soft-type superconductivity for the rapidly quenched copper-based alloys was discussed, and inferred to be due to the formation of a percolation path of a superconducting lead or Pb-Bi phase along the grain boundaries, sub-boundaries and/or tangled dislocations where the lead or Pb-Bi phase precipitated preferentially, rather than the proximity effect based on lead or Pb-Bi particles.     

Screening of Inhibitors Targeting Heat Shock Protein 47 Involved in the Development of Idiopathic Pulmonary Fibrosis

Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of Compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic Compound library established at Nagasaki University. Among 1023 Compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three Compounds, is a typical polyphenol Compound derived from tea leaves. Structurally related Compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis.     

Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.     

Identification of SYS1 as a Host Factor Required for Shiga Toxin-Mediated Cytotoxicity in Vero Cells

Shiga toxin (STx) or Vero toxin is a virulence factor produced by enterohemorrhagic Escherichia coli. The toxin binds to the glycosphingolipid globotriaosylceramide (Gb3) for its entry, and causes cell death by inhibiting ribosome function. Previously, we performed a loss-of-function screen in HeLa cells using a human CRISPR knockout (KO) library and identified various host genes required for STx-induced cell death. To determine whether this library targeted to the human genome is applicable to non-human primate cells and to identify previously unrecognized factors crucial for STx-induced cell death, we herein performed a similar screen in the African green monkey kidney-derived Vero C1008 subline. Many genes relevant to metabolic enzymes and membrane trafficking were enriched, although the number of enriched genes was less than that obtained in the screening for HeLa cells. Of note, several genes that had not been enriched in the previous screening were enriched: one of these genes was SYS1, which encodes a multi-spanning membrane protein in the Golgi apparatus. In SYS1 KO Vero cells, expression of Gb3 and sphingomyelin was decreased, while that of glucosylceramide and lactosylceramide was increased. In addition, loss of SYS1 inhibited the biosynthesis of protein glycans, deformed the Golgi apparatus, and perturbed the localization of trans-Golgi network protein (TGN) 46. These results indicate that the human CRISPR KO library is applicable to Vero cell lines, and SYS1 has a widespread effect on glycan biosynthesis via regulation of intra-Golgi and endosome–TGN retrograde transports.     

Characterization of blasted austenitic stainless steel and its corrosion resistance

It is known that the corrosion resistance of stainless steel is deteriorated by blasting, but the reason for this deterioration is not clear. A blasted austenitic stainless steel plate (JIS-SUS304) has been characterized with comparison to the scraped and non-blasted specimens. The surface roughness of the blasted specimen is larger than that of materials finished with #180 paper. A martensite phase is formed in the surface layer of both blasted and scraped specimens. Compressive residual stress is generated in the blasted specimen and the maximum residual stress is formed at 50–100 μm from the surface. The corrosion potentials of the blasted specimen and subsequently solution treated specimen are lower than that of the non-blasted specimen. The passivation current densities of the blasted specimens are higher those of the non-blasted specimen. The blasted specimen and the subsequently solution treated specimen exhibit rust in 5% sodium chloride (NaCl) solution, while the non-blasted specimen and ground specimen do not rust in the solution. It is concluded that the deterioration of corrosion resistance of austenitic stainless steel through blasting is caused by the roughed morphology of the surface.