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 monkeys to support development of the drug for use in various clinical syndromes of injury to the central nervous system of humans. As the immune system is involved in many of the obvious side effects of glucocorticoids used currently for this indication, particular attention was directed to the lymphoid system; results were contrasted with similar data from studies with methylprednisolone, a classical glucocorticoid. Administration of tirilazad mesylate to rats, dogs and monkeys for 4 weeks had no effects at the highest doses tested on parameters assessed, including absolute peripheral blood lymphocyte counts, thymus or adrenal weights, circulating levels of cortisol, or lymphocyte proliferation response to phytohemagglutinin-P. Germinal centers in lymphoid tissues from dogs given high doses of tirilazad contained small numbers of macrophages with vacuolated cytoplasm but no other changes; lymphoid tissues in rats and monkeys given tirilazad were morphologically normal. Administration of methylprednisolone for a similar duration in rats and dogs at high dose levels was associated with increased death rates due to bacterial infections, markedly decreased peripheral blood lymphocyte counts and weights of thymus and adrenal glands, and prominent lymphoid atrophy as well as decreased circulating levels of cortisol. Female dogs infused for 10 days with a high dose of methylprednisolone had depression of the in vitro proliferation response of peripheral blood lymphocytes to phytohemagglutinin-P.
Jackson
T A
TA
Upjohn Company, Kalamazoo, Michigan 49001, USA.
Ochoa
R
R
Kakuk
T J
TJ
D000818:Animals; D002490:Central Nervous System / Q000293:injuries; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D008208:Lymphatic System / Q000187:drug effects* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use / Q000633:toxicity*; D011281:Pregnatrienes / Q000627:therapeutic use / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011281:Pregnatrienes; D008775:Methylprednisolone; C053355:tirilazad