Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates.
Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Several DP have also been shown to exert significant antiarthritic effects in the rat adjuvant-induced polyarthritis model; however, there is no direct evidence for the anti-inflammatory effects of these compounds. We therefore tested the effects of dichloromethylene diphosphonate on delayed-type hypersensitivity granuloma elicited by s.c. implantation of antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dichloromethylene diphosphonate induced a dose-related inhibition of the delayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/kg/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 were also effective in the same dose range. In contrast, all DP failed to suppress 24-hr delayed-type hypersensitivity paw edema in mice. In addition to rat adjuvant-induced polyarthritis, mouse antigen-induced erosive arthritis was also significantly suppressed by s.c. administration 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-inflammatory agents with excellent therapeutic potential for chronic inflammatory diseases including rheumatoid arthritis.
Dunn
C J
CJ
Department of Hypersensitivity Diseases Research, Upjohn Laboratories, Kalamazoo, Michigan.
Galinet
L A
LA
Wu
H
H
Nugent
R A
RA
Schlachter
S T
ST
Staite
N D
ND
Aspar
D G
DG
Elliott
G A
GA
Essani
N A
NA
Rohloff
N A
NA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D005260:Female; D015745:Granuloma, Foreign-Body / Q000188:drug therapy; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004164:Diphosphonates