The (R)-enantiomer of the NSAID ketoprofen was administered orally at 20 mg/kg to a series of 8 animal species. In all species, a highly significant degree of inversion occurred after 1 h which varied from 27% (gerbil) to 73% (dog) and persisted or increased in plasma samples obtained 3 h after drug administration. Although the (R)-enantiomer was inactive as an inhibitor of cyclooxygenase, the analgesic effects of that isomer was almost the same as the (S)-isomer in animal analgesic assays, following oral administration of the drugs to mice and rats. Taken together, the present results suggest that (R)-ketoprofen administered alone functioned primarily as a prodrug for (S)-ketoprofen under the experimental conditions of this study.

Preclinical Research The mechanisms mediating canine pruritus are poorly understood with few models due to limited methods for inducing pruritus in dogs. Chloroquine (CQ) is a widely used antimalarial drug that causes pruritus in humans and mice. We have developed a canine model of pruritus where CQ reliably induced pruritus in all dogs tested following intravenous administration. This model is presently being used to test antipruritic activity of drug candidate molecules. This publication has been validated in a blinded cross-over study in eight beagle dogs using the reference standards, oclacitinib and prednisolone, and has been used to test a new compound, norketotifen. All compounds reduced CQ-induced pruritus in the dog. The sensitivity of the model was demonstrated using norketotifen, which at three dose levels, dose-dependently, inhibited scratching events compared with placebo.

Four benzodiazepines (diazepam, chlordiazepoxide, halazepam, lorazepam) were tested for their effects on the acquisition of a passive-avoidance task in mice. This was done to determine whether amnesic effects, as reported in humans after diazepam and lorazepam, could be demonstrated by blockade of passive-avoidance responding in mice and, if so, to investigate the possible causes of the blockade by studying the relationships between the blockade and times of drug administration. Each of these benzodiazepines, at doses that did not alter overt behavior, blocked acquisition of the passive-avoidance response when they were administered to mice prior to the training session, but not when they were administered after the training session or prior to testing 24 h later. The block of avoidance responding was reversed, however, when the drugs were administered prior to both training and test sessions. These results suggest that state-dependent learning occurred; i.e., apparent amnesia occurred in the test session with untreated mice that had undergone passive-avoidance learning 24 h earlier under the influence of drug.

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