TIRILAZAD MESYLATE - EFFECTS OF THE 21-AMINOSTEROID ON THE LYMPHOID SYSTEM OF LABORATORY-ANIMALS - A COMPARISON WITH THE GLUCOCORTICOID METHYLPREDNISOLONE

Four-week toxicity studies with the 21-aminosteroid tirilazad mesylate were conducted in Sprague-Dawley rats, beagle dogs, and cynomolgus mo nkeys to support development of the drug for use in various clinical s yndromes of injury to the central nervous system of humans. As the imm une system is involved in many of the obvious side effects of glucocor ticoids used currently for this indication, particular attention was d irected to the lymphoid system; results were contrasted with similar d ata from studies with methylprednisolone, a classical glucocorticoid. Administration of tirilazad mesylate to rats, dogs and monkeys for 4 w eeks had no effects at the highest doses tasted on parameters assessed , including absolute peripheral blood lymphocyte counts, thymus or adr enal weights, circulating levels of cortisol, or lymphocyte proliferat ion response to phytohemagglutinin-P. Germinal centers in lymphoid tis sues from dogs given high doses of tirilazad contained small numbers o f macrophages with vacuolated cytoplasm but no other changes; lymphoid tissues in rats and monkeys given tirilazad were morphologically norm al, Administration of methylprednisolone for a similar duration in rat s and dogs at high dose levels was associated with increased death rat es due to bacterial infections, markedly decreased peripheral blood ly mphocyte counts and weights of thymus and adrenal glands, and prominen t lymphoid atrophy as well as decreased circulating levels of cortisol . Female dogs infused for 10 days with a high dose of methylprednisolo ne had depression of the in vitro proliferation response of peripheral blood lymphocytes to phytohemagglutinin-P. (C) 1995 Society of Toxico logy.