Hideakira Yokoyama

Reduction of Gastric Ulcerogenicity During Multiple Administration of Diclofenac Sodium by a Novel Solid-in-Oil Suspension

This article reports a significant reduction of gastric ulcerogenicity by complex formation of a nonsteroidal anti-inflammatory drug with surfactants. Diclofenac sodium (DFNa) was suspended in medium chain triglyceride (MCT) by forming a complex with an edible lipophilic surfactant. Two types of suspensions, prepared through a membrane emulsification with different pore sizes, were evaluated according to the degree of gastric damage following multiple oral administration in rats. It was shown that gastric ulcerogenicity of DFNa was reduced by the surfactant–drug complexes, at doses up to 12 mg/kg, whereas severe gastric damage was observed upon oral administration of the aqueous solution at doses of 6 mg/kg. Comparable blood levels of DFNa were observed after administration of solution and suspension formulations.

Design and synthesis of new mitochondrial cytotoxin N-thiadiazolylanilines that inhibit tumor cell growth.

New N-thiadiazolylanilines were designed and synthesized to develop mitochondrial cytotoxins superior to SF 6847. The mitochondrial cytotoxin N-thiadiazolylanilines, TX-108 and TX-109, inhibited EMT6/KU mammary sarcoma cell growth at a low micromolar concentration. Their inhibitory activities were parallel to their mitochondrial cytotoxicity, such as uncoupling oxidative phosphorylation and inhibiting ATP synthesis. This report also supports the notion that the inhibition of tumor cell growth of inhibitor of protein tyrosine kinase AG17, which is identical to SF 6847, may be due to its mitochondrial cytotoxicity.

Respiratory activities of liver mitochondria, isolated from freshwater turtle Chinemys revesii as an experimental anoxia-tolerant model system, determined by mitochondrial modifiers

Abstract We isolated liver mitochondria from the anoxia-tolerant, Chinese three keeled pond freshwater turtle ( Chinemys revesii ). We found that the turtle liver mitochondria (TLM) had slow respiratory activities, which were dependent upon the amounts of complexes in respiratory chain, and H + /O and VH + /V H + leak ratios, induced by proton leakage. All of these values were lower than those of rat liver mitochondria (RLM). When mitochondrial modifiers, such as oligomycin and the uncoupler TX-109, were added to TLM, respiratory substrates such as isocitrate, 2-oxoglutarate, and malate were not significantly different between TLM and RLM. Respiration inhibition experiments showed that the enhanced rate of glutamate-dependent state 4 respiration in RLM was sixteen times faster than that in TLM, and other substrate-dependent state 4 respiration in RLM was eight times faster than that of TLM. We originally identified ubiquinone-10 (UQ-10) in TLM. In UQ-depleted TLM, the synthetic UQ analog idebenone at 0.1 mM restored the respiratory activity to a maximum of 12.8 natom O/min per mg protein, while in native TLM, idebenone at 0.4 mM restored the respiratory activity to a maximum of 26.2 natom O/min per mg protein. These results indicated that the low respiratory activities of TLM are attributed to their low substrate oxidation rate.