RAPAMYCIN, A POTENTIAL DISEASE-MODIFYING ANTIARTHRITIC DRUG

Rapamycin (RAPA), a potent immunosuppressive agent that prevents organ graft rejection in animal models of transplantation, possesses a mech anism of action different than that of cyclosporin A and FK-506. In th is study, the pharmacological activity of RAPA in a variety of immune and inflammatory models was assessed in order to define better its pot ential utility as an antiarthritic agent. RAPA inhibited T cell-mediat ed inflammation in mouse methylated bovine serum albumin-induced delay ed-type hypersensitivity (ED40 = 4.7 mg/kg p.o.) and produced oral ED5 0 of 2.0 mg/kg against developing adjuvant arthritis in rats (3-day do sing schedule) and 9.5 mg/kg in established adjuvant arthritis in rats (daily dosing schedule). In both models of adjuvant arthritis, effect s of RAPA were maintained even after cessation of drug dosing. In cont rast, after discontinuation of cyclosporin A (5- and 1 0-mg/kg doses), disease activity returned. RAPA was also effective in another T cell- mediated model, experimental allergic encephalomyelitis (ED50 approxim ately 5 mg/kg p.o.). At higher doses, RAPA significantly inhibited car rageenan paw edema in rats, a model of acute inflammation (ED40, 56 mg /kg p.o.), without increasing serum corticosterone levels. In this mod el, doses approximately 1 0 to 20 times greater than active doses in T cell-mediated models were required. RAPA at 1 to 50 muM did not inhib it in vitro human synovial phospholipase A2 or 5-lipoxygenase and cycl o-oxygenase activity in the human blood leukocyte assay. The total pro file of RAPA suggests that it may be effective in the treatment of rhe umatoid arthritis, multiple sclerosis and other autoimmune diseases.