Systemic toxicity of polyinosinic acid: Polycytidylic acid in rodents and dogs

Abstract The double-stranded polymer of polyinosinic acid:polycytidylic acid (poly I:C), an interferon inducer, was well tolerated by mice, rats, and guinea pigs following the acute iv or ip administration of 20 mg/kg doses. The acute LD50 of Poly I:C was calculated to be 75 and 150 mg/kg in the mouse and 185 and 365 mg/kg in the rat following iv and ip administration, respectively. Poly I:C was lethal to mongrel dogs following acute iv doses as low as 2.5 mg/kg; toxicity was characterized by depression of spontaneous motor activity, incoordination, vomiting, and flaccid prostration. Subchronic (42 days) administration of poly I:C at daily doses of 2.0 mg/kg ip to rats or 0.2 mg/kg iv to beagle dogs was not accompanied by signs of toxicity. However, severe toxic manifestations were elicited in dogs upon the subchronic administration of poly I:C at a dose of 2.0 mg/kg daily iv, and 3 of 6 dogs died during the course of the experiment. Toxicity was characterized by decreased spontaneous activity, incoordination, vomiting, anorexia, weight loss, hematologic changes reflecting decreased hematopoiesis, increased alkaline phosphatase and transaminase activities, thymus degeneration, destruction of bone marrow, dilatation of hepatic sinusoidal capillaries in the centrolobular areas, necrosis of liver cells, collapse of hepatic structures, and a generalized arteritis. It was concluded that useful systemic therapeutic application of poly I:C will require that the effective doses be quite small, but that, since daily doses of 2.0 mg/kg in the rat and 0.2 mg/kg in the dog were well tolerated in subchronic experiments, cautious exploration of low systemic doses in man may be justified.