154 S.-H. Park et al. NSAIDs for the first time. Patients who had been taking NSAIDs were excluded from the study, since they were vulnerable to dyspepsia, and this could make it difficult to clearly determine the incidence of dyspepsia, the purpose of this study. Several studies have been performed in attempts to identify agents that can be coadministered to prevent NSAID-induced ulcers and ulcer complications. Recently, administration of proton pump inhibitors has been reported to be associated with acceleration of ulcer healing and prevention of ulcer relapse among long-term users of NSAIDs [12, 13]. Repeated use of the synthetic prostaglandin misoprostol as a form of replacement therapy has been shown to prevent NSAID- induced gastroduodenal ulcers and reduce the incidence of life-threatening ulcer complications [3, 10]. Misoprostol features poor compliance and adverse effects such as diarrhea, abdominal pain, and nausea during administration [14]. In our study, the misoprostol group had more adverse events such as diarrhea, abdominal pain, and bloating than did the rebamipide group. These adverse effects of miso- prostol suggest that rebamipide is more useful for prevention of NSAID-induced gastrointestinal complications. These findings suggest that strong suppression of acid secretion and increase in PG production were effective in preventing NSAID-induced gastric ulcers. For these reasons, we performed the present randomized, multicenter, controlled study of rebamipide and misoprostol. Both of these agents stimulate PG biosynthesis. In this study, the incidences of NSAID-induced peptic ulcer in the miso- prostol and rebamipide groups were equivalent (Odds Ratio: 0.98, 95%CI = 0.33-2.81, p = 0.9796). The number of cases of gastric ulcer in the rebamipide group was seven, although this group included two patients with serious mucosal damage before initiation of the trial (grades 3 and 4, as determined using modified Lanza score). In this study, patients were relatively young, with a mean age in the rebamipide group of 48 and in the misoprostol group of 46 years. This was one of the reasons for the relatively low rates of induction of gastric ulcer in this trial. The high-risk group was defined to include patients with age above 65 years, concurrent use of anticoagulation, history of peptic ulcer or bleeding, concurrent use of corticosteroid therapy, and/or high-dose administration of NSAIDs >2 times. The results for this group are shown in Table 4, and were similar to those for the group of all patients. In addition, rebamipide was better tolerated than miso- prostol. The cumulative incidence of dyspeptic symptoms in the rebamipide group was significantly lower than that in the misoprostol group (diarrhea p<0.0001, low abdominal pain p = 0.0228, and bloating p = 0.00229, respectively). Rebamipide stimulates the production of endogenous PGs [6]. This finding demonstrated the importance of PG induction in the prevention of NSAID-induced gastric ulcer. Blood flow is known to be regulated by prostaglandins. In our preliminary study on the prevention of ibuprofen-induced gastrointestinal complications for healthy volunteers, rebamipide did not decrease blood flow in the antrum [15]. In conclusion, in this randomized, multicenter, controlled trial, rebamipide prevented peptic ulcers as effectively as misoprostol in patients on long-term NSAID therapy. In addition, rebamipide decreased low abdominal symptoms more significantly than misoprostol. Rebamipide may thus be a useful therapeutic option for the prevention of NSAID- induced gastrointestinal ulcer because of its therapeutic effect and safety. Acknowledgments This study was supported by a grant from Korea OIAA (Otsuka International Asia Arab) Co., Ltd., Seoul, Korea. Other investigators participating in this study Xin-Guang Liu, De-An Tian, and He-Sheng Luo from China and Varocha Mahachai and Ong-ard Praisontarangkul from Thailand. References [1] Maetzel, A., Ferraz, M.B., and Bombardier, C.: The cost- effectiveness of misoprostol in preventing serious gastro- intestinal events associated with the use of nonsteroidal anti-inflammatory drugs. Arthritis Rheum., 41, 16–25, 1998. [2] Raskin, J.B., White, R.H., Jackson, J.E., Weaver, A.L., Tindall, E.A., Lies, R.B., and Stanton, D.S.: Misoprostol dosage in the prevention of nonsteroidal anti-inflammatory drug-induced gastric and duodenal ulcers: a comparison of three regimens. Ann. Intern. Med., 123, 344–350, 1995. [3] Silverstein, F.E., Graham, D.Y., Senior, J.R., Davies, H.W., Struthers, B.J., Bittman, R.M., and Geis, G.S.: Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti- inflammatory drugs. Ann. Intern. Med., 123, 241–249, 1995. [4] Elliott, S.L., Yeomans, N.D., Buchanan, R.R.C., and Smallwood, R.A.: Efficacy of 12 months’ misoprostol as prophylaxis against NSAID-induced gastric ulcers. Scand. J. Rheumatol., 23, 171–176, 1994. [5] Yamasaki, K., Ishiyama, H., Imaizumi, T., Kanbe, T., and Yabuchi, Y.: Effect of OPC-12759, a novel antiulcer agent, on chronic and acute experimental gastric ulcer, and gastric secretion in rats. Jpn. J. Pharmacol., 49, 441–448, 1989. [6] Arakawa, T.: Rebamipide, a novel prostaglandin-inducer, accelerates healing and reduces relapse of acetic acid- induced rat gastric ulcer: comparison with cimetidine. Dig. Dis. Sci., 40, 2469–2472, 1995. [7] Zea-Iriarte, W.L., Makiyama, K., Goto, S., Murase, K., Urata, Y., Sekine, I., Hara, K., and Kondo, T.: Impairment of anti- oxidants in colonic epithelial cells isolated from trinitrobenzene J. Clin. Biochem. Nutr.