Abstract. Drug concentrations that would prolong repolarization parameters by 10%, including action potential duration (APD 90 , APD 30 -90 ), in in vitro assays using guinea-pig papillary muscle and QTc intervals in in vivo assays using conscious dogs, conscious monkeys, and anesthetized dogs were compared. Although, both the in vitro and in vivo assays showed concentrationdependent responses for compounds that have been classified as torsadogenic in humans, only a weak correlation in EC 10 values was observed between the in vitro and in vivo assays. Among the in vivo QT assays, the EC 10 values obtained from conscious dogs, conscious monkeys, and anesthetized dogs correlated well with each other, but the EC 10 values in monkeys were somewhat lower in comparison to those in dogs. When in vivo QT assay EC 10 values were compared to the respective human effective therapeutic plasma concentration (ETPC), the ratios of EC 10 values to ETPCs were less than 20 for most torsadogenic compounds. In conclusion, the relationships between the extent of QTc interval prolongation and the concentration of drugs was highly consistent among the three in vivo models, suggesting that the ratios of EC 10 values in in vivo QT assays are useful for estimating the safety margin of drugs that prolong the QTc interval.

The effects of chondroitin sulfate-C (CAS 25322-46-7, Chondroitin ZS Tab) on type II collagen (CII)-induced arthritis (CIA) in mice were evaluated. DBA/1J mice were immunized with bovine CII emulsified in Freund's complete adjuvant, followed by a booster injection 21 days later. Chondroitin sulfate-C at doses of 100, 300 and 1000 mg/kg was administered orally once daily beginning 14 days before initial immunization. An arthritis index and hind paw edema were examined from day 0 to day 49, when the mice were killed by ether anesthesia for histopathological examination. The delayed-type hypersensitivity (DTH) reaction, serum anti-CII antibody titer, and histopathologic characteristics of both synovitis and destruction of articular cartilage were analyzed. Both the arthritis index and the serum anti-CII antibody titer were reduced by treatment with chondroitin sulfate-C in a dose-dependent manner. Chondroitin sulfate-C (1000 mg/kg) significantly inhibited hind paw edema, synovitis and destruction of the articular cartilage, but not DTH reaction.

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