CHARACTERIZATION OF A HISTAMINERGIC RESPONSE TO INTRAVENOUS CI-1010, A NITROIMIDAZOLE RADIOSENSITIZER, IN BEAGLE DOGS USING A CROSSOVER STUDY DESIGN

CI-1010, (R)-alpha-\[\[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol monohydrobromide, a radiosensitizing anticancer agent, has both an affinity for hypoxic cells and an alkylating functionality. Intravenous CI-1010 causes transient clinical signs in dogs consistent with systemic histamine release (erythema, urticaria, pruritus, hypotension, emesis). To characterize the response, six male and six female beagle dogs were given 10 mg / kg CI-1010 iv with or without antihistamine (AH) prophylaxis (diphenhydramine, 2.2 mg / kg im, bid; and cimetidine, 5 mg / kg im, tid) in a randomized crossover design. Plasma histamine levels were determined before and after dosing using a radioimmunoassay, and clinical signs were observed and / or scored. Analysis of the data established an absence of carryover effect between treatments. Plasma histamine levels increased 95- to 339-fold following CI-1010 dosing, regardless of antihistamine pretreatment. Pretreatment with AH significantly reduced erythema in males (p=0.0001) , with the difference approaching statistical significance in females (p=0.08) . AH also moderated the degree of urticaria and the incidence of head rubbing or shaking, facial skin swelling, and vocalization. Using the crossover design, the number of animals required to meet the study's objectives was reduced.