Once-Daily, Oral Tetomilast (OPC-6535) in a Rat Model of Colitis: Comparative Study on Prevention and Treatment Versus 5-ASA

Purpose: Activated leukocytes play crucial roles in the pathophysiology of inflammatory bowel disease (IBD). Tetomilast (TML), a novel thiazole derivative, has demonstrated multiple inhibitory effects on leukocyte activation, including inhibition of O2− production, cytokine release, and endothelial cell adhesion. The compound has also exhibited significant effects on colonic damage in rat models of colitis. Clinical efficacy was recently demonstrated in a phase II trial in patients with active UC. The purpose of this study was to compare the effects of TML and 5-aminosalicylic acid (5-ASA) on the outcomes in a rat model of chemically induced colitis. The effects of TML and salazosulfapyridine (SASP), a 5-ASA agent, on colitis, as assessed by ulceration area (UA), were examined both prior to (prevention study) and after (treatment study) induction of colitis with trinitrobenzene sulfonate (TNBS). Methods: In the prevention studies, the compounds were administered orally at 1 hour prior to rectal injection of TNBS, and the treatment was continued until Day 6 (total dosing period, 7 days). In the treatment study, rats were treated orally with these agents for 7 consecutive days beginning from 1 day after TNBS injection (total dosing period, 7 days). On Day 7 (prevention study) or Day 8 (treatment study), the UA in the excised colon was evaluated as a measure of colonic damage. Results: Among the TML-treated groups (0.1, 0.3, 1 mg/kg/day, OD) in the prevention study, the 0.3- and 1-mg/kg/day groups exhibited significant reduction in UA (p < 0.01). All the dosage groups in the treatment study also showed a significant reduction in UA (p < 0.01). Among animals in the SASP-treated groups (50, 100 mg/kg/day, BID) in the prevention study, the 100-mg/kg/day group exhibited a significant reduction in UA (p < 0.05). However, this dose regimen of SASP was without effect in the treatment study. Conclusions: The present study demonstrated that TML produced significant improvement in colitis, as measured by UA, in both treatment and prevention models. However, there were differences between the effectiveness of TML and 5-ASA in reducing UA. It has been suggested that the potent inhibitory effect of TML on leukocyte activation plays a critical role in mediating its beneficial effects in reducing colonic damage. Based on the results from the present study, it is expected that TML may be clinically beneficial in IBD patients resistant to 5-ASA therapies.