AD-1590, a potent antagonist of lipopolysaccharide-induced fever in rabbits

Abstract

The antipyretic activity of AD-1590 (2-[8-methyl-10,11-oxodibenz[b,f]oxepin-2-yl]propionic acid), a non-steroidal anti-inflammatory drug with a novel chemical structure, was investigated in rabbits with lipopolysaccharide (LPS)-induced fever and monkeys with leucocytic pyrogen-induced fever. AD-1590 produced a dose-related inhibition of the LPS-fever at oral doses of 0·1 mg kg−1 or more (ED50 = 0·089 mg kg−1). Its potency was 10–12, 20–35, 100–170, 400–540, >1500 and >2000 times that of ketoprofen, diclofenac sodium, indomethacin, ibuprofen, mefenamic acid and aspirin, respectively. The fever caused by leucocytic pyrogen was significantly inhibited by intravenous administration of 0·1–0·2 mg kg−1 of AD-1590. AD-1590 (10 mg kg−1 oral or i.v.) did not affect body temperature in afebrile rabbits or monkeys. These results suggest that AD-1590 shows a potent antipyretic activity in the rabbit and monkey and is a potent antagonist of LPS-fever.