TRK-530 is a novel bisphosphonate derivative. We examined the anti-inflammatory effects of TRK-530 on adjuvant arthritis (AA) rats. When TRK-530 at a dose of 2.5 mg/kg was administered for 2 weeks to AA rats, it inhibited destructive changes in arthritic joints such as paw edema, bone loss and joint degeneration. TRK-530 also inhibited splenomegaly and suppressed the increase in serum sialic acid which is measured as a systemic parameter of inflammation. To clarify the inhibitory mechanism of TRK-530, interleukin-1 (IL-1)-like activities of resident peritoneal macrophages in AA rats given TRK-530 were compared with those of control rats. We found that TRK-530 inhibited IL-1-like activity induced by bacterial lipopolysaccharide 6 weeks after administration when the IL-1-like activities of control rats were still at high levels. These findings suggest that TRK-530 exerts anti-inflammatory activities in AA rats.

TRK-530, a newly synthesized bisphosphonate, was assessed for its effects on the accumulation of superoxide anions derived from human formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes (PMN), and for its effects on bone resorption using a pit formation assay. TRK-530 concentration-dependently inhibited superoxide accumulation derived from PMN and osteoclast pit formation stimulated by 1,25-dihydroxyvitamin D₃. Incadronate and risedronate had a strong inhibitory effect on pit formation, but no antioxidative activity. These data suggest that the anti-bone resorption activities of TRK-530 are possibly unrelated to its antioxidant properties. However, it is difficult to conclude at present which mechanisms play the most important role in the anti-bone resorption activities of TRK-530.

In an allergic inflammation model of air pouch type in rats, histamine level in the pouch fluid and histidine decarboxylase activity of pouch wall tissues in the postanaphylaxis phase were increased. Although treatment with dexamethasone failed to inhibit histamine release from mast cells in the anaphylaxis phase, histamine production in the postanaphylaxis phase was inhibited dose dependently. Histamine production-increasing activity in the pouch fluid collected 8 h after the Ag challenge, which was estimated by an activity to stimulate histamine production by bone marrow cells, was decreased by the administration of dexamethasone at the time of the Ag challenge. The addition of steroidal antiinflammatory drugs, dexamethasone, prednisolone, or hydrocortisone, into the incubation medium inhibited the pouch fluid-induced histamine production by bone marrow cells. Hydrocortisone mesylate antagonized the inhibitory effect of dexamethasone on histamine production by bone marrow cells. However, hydrocortisone mesylate failed to recover the decrease in histamine production-increasing activity of the pouch fluid collected from dexamethasone-treated rats. In addition, the dialyzed sample of pouch fluid obtained from dexamethasone-treated nonsensitized rats did not reduce the stimulated histamine production by the pouch fluid sample obtained from the sensitized rats. However, increase in histamine production of bone marrow cells stimulated by the pouch fluid was not inhibited by cyclosporin A that inhibited histamine production induced by Con A. This observation indicates that the pouch fluid has no effect to induce production of the histamine production-increasing factor by bone marrow cells. Consequently, it is suggested that dexamethasone inhibits not only the production of histamine production-increasing factor but also the response of histamine-producing cells to this factor.

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