Protective effects of D-penicillamine and a thiazole derivative, SM-8849, on pristane-induced arthritis in mice.
To evaluate the antiarthritic properties of a novel thiazole derivative, the drugs SM-8849, D-penicillamine and indomethacin were administered to pristane-injected DBA/1 mice. The mice were treated daily with the agents for 32 weeks, starting from the day of the pristane injection. Treatment with SM-8849 (50 mg/kg) resulted in an amelioration of arthritic disease, as assessed by clinical, radiographic, and histologic examinations. Similar results were obtained in mice treated with 50 mg/kg D-penicillamine, although this disease modifying antirheumatic drug was slightly less effective than the same dose of SM-8849. In contrast, indomethacin at the maximum tolerated dose of 2 mg/kg did not alter the course of the disease. SM-8849 and D-penicillamine were also shown to reduce serum levels of rheumatoid factors and the acute-phase reactant, serum amyloid P component. Indomethacin failed to affect either parameter. Flow cytometric analysis revealed an elevation in the T-cell population that expressed CD44, a marker of murine memory T-cells, in spleens from pristane-injected mice. SM-8849, but not D-penicillamine, prevented the increase in this cell population. These results led us to conclude that pristine-induced arthritis was a useful model for the evaluation of antirheumatic agents, in that using this model, we were able to distinguish disease modifying antirheumatic drugs from nonsteroidal anti-inflammatory drugs. Our findings also indicate that SM-8849 shows antiarthritic activity, with a unique mechanism of action, differing from that of D-penicillamine.
Nishikaku
F
F
Research Laboratories, Sumitimo Pharmaceuticals Co., Ltd, Osaka, Japan.
Aono
S
S
Koga
Y
Y
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000032:analysis; D018960:Hyaluronan Receptors; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010396:Penicillamine / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000032:analysis; D016201:Receptors, Lymphocyte Homing / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D013729:Terpenes; D013844:Thiazoles / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D001713:Biphenyl Compounds; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D011956:Receptors, Cell Surface; D016201:Receptors, Lymphocyte Homing; D013729:Terpenes; D013844:Thiazoles; C072865:4-(1-(2-fluoro-4-biphenyl)ethyl)-2-methylaminothiazole; C009042:pristane; D010396:Penicillamine