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

The antipyretic activity of AD-1590 (2-[8-methyl-10,11-0xodibenz[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 mgg kg-1). Its potency was 10-12, 20-35, 100-170, 400-540, greater than 1500 and greater than 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 (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.