Preclinical Pharmacodynamic and Pharmacokinetic Studies of Investigational New Drugs

The occurrence of clinical signs of toxicity and observable effects on and around the injection site following iv injection for 7 days of a single, daily dose of an artelinic acidlysine ALlysine formulation, equal to or greater than the anticipated clinical dose, was investigated in Beagle dogs. Groups consisting of one or two male and one or two female dogs were given an iv dose of 2 or 4 mL of an ALlysine formulation containing 0, 10, or 30 mgmL of artelinic acid daily for 7 days. All doses were delivered into a peripheral leg vein over an approximate 10-minute interval, using an infusion pump. On Days 1-14, each dog was observed at least twice daily for signs of clinical toxicity and the site of injection was closely examined for irritationswelling or other adverse reactions. No clinical signs of toxicity or adverse reactions at the injection site were observed for any dogs given the vehicle control formulation either 2 mL or 4 mL, or for dogs given 2 mL of either the 10 or 30 mgmL ALlysine formulation, or for the male dogs given 4 mL of the 30 mgmL ALlysine formulation. The two female dogs given 4 mL of 30 mgmL ALlysine displayed transient swelling in the leg, near the injection site, beginning on Day 5 or 6 of dosing and continuing through Day 10 or 11 no necrosis, discoloration, or other adverse signs were evident in these two animals. The results of this study indicated that an injectable formulation of artelinic acidlysine was well tolerated by dogs given a single iv dose for 7 consecutive days. In future work, the pharmacodynamic effects of iv administered antelinic acid and artesunic acid, as assessed by signs of clinical and pathological toxicity, will be investigated in rats.