Masahiro Tsuchimoto

Hypouricemic effect of the novel xanthine oxidase inhibitor, TEI-6720, in rodents.

We investigated the xanthine oxidase/xanthine dehydrogenase inhibitory activity and hypouricemic effect of a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, TEI-6720, 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazole-carboxylic acid, and compared its effects with those of allopurinol in rodents. TEI-6720 was found to inhibit bovine milk xanthine oxidase, and mouse liver and rat liver xanthine oxidase/xanthine dehydrogenase with IC50 values of 1.4, 1.8 and 2.2 nM, respectively. On bovine milk xanthine oxidase, TEI-6720 exhibited mixed-type inhibition and the Ki value was 0.7 nM. TEI-6720 displayed prolonged urate-lowering activity in normal mice and rats. We evaluated the hypouricemic effect of TEI-6720 on hyperuricemia induced by the uricase inhibitor, potassium oxonate (250 mg/kg s.c., 1 h before the test drugs), and measured the total molarity of both serum allantoin and urate in rats. Oral TEI-6720 and allopurinol had a hypouricemic effect 2 h after their administration to oxonate-pretreated rats with ED50 values of 1.5 and 5.0 mg/kg, respectively. Both compounds also reduced the combined molarity of uric acid and allantoin in rats. The ED50 values of TEI-6720 and allopurinol were 2.1 and 6.9 mg/kg p.o., respectively. These results suggest that TEI-6720 may be useful for the treatment of hyperuricemia.

Tacalcitol (1,24(OH)2D3, TV-02) inhibits phorbol ester-induced epidermal proliferation and cutaneous inflammation, and induces epidermal differentiation in mice

In this study, we examined the cutaneous effects of tacalcitol [1, 24(R)(OH)2D3] on epidermal proliferation, differentiation, and skin inflammation in vivo using hairless mice. Tacalcitol was shown to inhibit epidermal proliferation using TPA-induced ornithine decarboxylase activity and DNA synthesis as indices, and the induction of epidermal differentiation using type I transglutaminase activity as an index. Tacalcitol also displayed an antiinflammatory effect on TPA-induced inflammatory changes histopathologically. These results confirm the clinical efficacy of tacalcitol in psoriasis, and suggest that it may be efficacious in the treatment of other inflammatory skin diseases.

IMMUNOPHAFMACOLOGICAL PROFILE OF TEI-3096: A NEW IMMUNOMODULATOR

TEI-3096 [6-p-chlorobenzyl-5H-2,3,6,7-terahydro-5,7-dioxothiazolo (3,2-a) pyrimidine], a novel thiazolopyrimidine compound has been shown to suppress adjuvant arthritis in rats without any effect on conventional inflammation. We examined the immuno-pharmacological profile of TEI-3096 in murine lymphocytes. The blastformation induced by Con A or LPS was inhibited by addition of 50-500 microM concentrations of TEI-3096. This compound suppressed elevated plaque-forming cell (PFC) response against T cell-dependent antigen. However, TEI-3096 had no effect either on normal PFC response or on antibody formation against T cell independent antigen. Although orally administered TEI-3096 had no obvious effect on anti-SRBC PFC response in normal mice, it normalized the colchicine-induced enhancement of antibody formation against TNP-HGG. TEI-3096 also enhanced the delayed type hypersensitivity in mice and rats. These results suggests that TEI-3096 restores the abnormal immune response. Therefore, it may be useful for the treatment of auto-immune disease such as rheumatoid arthritis.