AMELIORATION OF RAT EXPERIMENTAL ARTHRITIDES BY TREATMENT WITH THE ALKALOID SINOMENINE

The effects of treatment with sinomenine, a pure alkaloid extracted fr om the chinese medical plant Sinomenium acutum, were investigated in r at adjuvant arthritis (AA) and antigen-induced arthritis (AIA). In AA, long-term, intraperitoneal (i.p.) treatment induced significant impro vement of arthritic score, hind paw swelling, body weight and erythroc yte sedimentation rate (ESR) beginning past the clinical peak of the d isease. In acute AIA, short and middle-term treatment with sinomenine around and following induction of arthritis induced a dose-dependent d ecrease of both joint swelling and ESR, starting after the peak of art hritis, and a significant reduction of joint destruction on day 3. The re was no rebound of the arthritic signs following suspension of treat ment. Long-term treatment of chronic AIA partially ameliorated clinica l parameters and significantly counteracted joint destruction. Maximal plasma concentrations of 22.5 mu g/ml, fast wash out (half-life 4.24/-0.99 h; mean +/-S.E.M.) and no evidence of accumulation of sinomenin e were observed following single or repeated i.p. injection of 150 mg/ kg. In vitro, sinomenine markedly inhibited proliferation of synovial fibroblasts from AIA or normal rats, both at rest and following activa tion with either transforming growth factor beta 2 (TGF-beta 2) or int erleukin-1 beta (IL-1 beta). The effect was dose-dependent and half-ma ximal inhibition of proliferation occurred at 20.6 mu g/ml, that is, w ithin the in vivo therapeutic range of the drug. Late therapeutic effe cts of sinomenine in rat arthritic models despite early start of treat ment may be related to its antiproliferative effects on synovial fibro blasts in addition to its previously reported anti-inflammatory proper ties. (C) 1997 International Society for Immunopharmacology.