DEMONSTRATION OF NOVEL ANTIARTHRITIC AND ANTIINFLAMMATORY EFFECTS OF DIPHOSPHONATES

Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Severa l DP have also been shown to exert significant antiarthritic effects i n the rat adjuvant-induced polyarthritis model; however, there is no d irect evidence for the anti-inflammatory effects of these compounds. W e therefore tested the effects of dichloromethylene diphosphonate on d elayed-type hypersensitivity granuloma elicited by s.c. implantation o f antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dich loromethylene diphosphonate induced a dose-related inhibition of the d elayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/k g/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 we re also effective in the same dose range. In contrast, all DP failed t o suppress 24-hr delayed-type hypersensitivity paw edema in mice. In a ddition to rat adjuvant-induced polyarthritis, mouse antigen-induced e rosive arthritis was also significantly suppressed by s.c. administrat ion of all four DP. Toxicity was minimal for each DP (>600 mg/kg p.o. or s.c.). We conclude that DP represent a novel class of anti-inflamma tory agents with excellent therapeutic potential for chronic inflammat ory diseases including rheumatoid arthritis.