Skip to main content
SpringerLink
Log in

Efficacy of Rebamipide as Adjunctive Therapy in the Treatment of Recurrent Oral Aphthous Ulcers in Patients with Behçet’s Disease

A Randomised, Double-Blind, Placebo-Controlled Study

  • Original Research Article
  • Published:
Drugs in R & D Aims and scope Submit manuscript

Abstract

Background: Behçet’s disease (BD) is a recurrent inflammatory disease involving chronic recurrent oral aphthous ulcers (aphthae), uveitis, skin lesions and genital ulcers. We prospectively investigated the efficacy of rebamipide, a gastroprotective drug, against oral aphthous ulcers in BD patients.

Methods: In a multicentre, double-blind, placebo-controlled study, 35 patients with BD, having as the main symptom oral aphthosis, were randomised to receive rebamipide 300 mg/day or placebo for 12 to 24 weeks between August 1994 and December 1996. Oral aphthosis must have occurred within 4 weeks prior to enrolment and must have been visible for at least 7 days during that time. Oral aphthae count and pain scores were recorded daily in a diary by the patients themselves. Monthly aphthae count and pain scores were defined as the sum of aphthae count and pain scores for a month, respectively. Investigators rated the global improvement in aphthae count and pain using a 6-point scale. The rate of change in monthly aphthae count and pain scores in the first 3 and last 3 months of treatment were assessed in patients with more severe symptoms whose aphthae count and pain score were >28 at baseline (trial entry).

Results: The rate of moderate or marked improvement in aphthae count and pain was 36% (5 of 14 subjects) in the placebo group and 65% (11 of 17 subjects) in the rebamipide group. During months 2 to 6 of treatment, aphthae count tended to increase and reached a peak at month 4 in the placebo group but decreased in the rebamipide group. Pain score decreased to the same extent in both groups for the first 3 months of treatment; however, in the fourth to sixth months of treatment, the pain score tended to increase in the placebo group but decreased in the rebamipide group. In patients with a monthly aphthae pain score >28 at baseline, pain and count scores decreased throughout the 6 months of rebamipide treatment but increased during the last 3 months of treatment in the placebo group (p < 0.01 for the between-group comparisons).

Conclusions: Rebamipide is well tolerated and improves the aphthae count and pain score in BD patients. It may therefore be useful in the treatment and prevention of frequently recurrent oral aphthous ulcers (not restricted to BD). Administration of rebamipide is not cumbersome, and it does not cause any discomfort, which corticosteroid ointments for example may do; furthermore, there are no specific adverse drug reactions. Rebamipide is therefore recommended as a long-term treatment for recurrent oral aphthous ulcers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II
Table III
Table IV
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Matsuda T, Mizushima Y. Fifteen years of progress in the study of Behçet’s disease: etiology, pathogenesis, therapy. Saishin Igaku 1988; 43: 249–58

    Google Scholar 

  2. Niwa Y, Miyake S. Auto-oxidative damage in Behçet’s disease: endothelial damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol 1982; 4: 247–55

    Google Scholar 

  3. Matsuda T, Yamada H, Hoshi K, et al. The beneficial effect of rebamipide on recurrent oral aphthous ulcers in Behçet’s disease. J Clin Exp Med 1994; 170: 773–4

    Google Scholar 

  4. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behçet’s disease. Semin Arthritis Rheum 1998; 27: 197–217

    Article  PubMed  CAS  Google Scholar 

  5. Matsuda T, Tanaka C, Imamura Y. Behçet’s disease. Medical Postgraduates 2000; 38: 112–21

    Google Scholar 

  6. Uchida M, Tabusa F, Komatsu M, et al. Studies on 2(1H)-quinolinone derivatives as gastric antiulcer active agents. 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid and related compounds. Chem Pharm Bull (Tokyo) 1985; 33: 3775–86

    Article  CAS  Google Scholar 

  7. Shiraki M, Yamasaki K, Ishiyama H, et al. Healing promoting effect of proamipide, a novel drug that increases gastric defense mechanisms, on acetic-induced gastric ulcers in the rat. Folia Pharmacol Japon 1988; 92: 389–95

    Article  CAS  Google Scholar 

  8. Yamasaki K, Kanbe T, Chijiwa T, et al. Gastric mucosal protection by OPC-12759, a novel antiulcer compound, in the rat. Eur J Pharmacol 1987; 142: 23–9

    Article  PubMed  CAS  Google Scholar 

  9. Nakamura H, Arakawa T, Kobayashi K, et al. Mucosal protective action of proamipide (OPC-12759) against gastric mucosal cell damage. J Adult Dis 1989; 19: 1109–14

    Google Scholar 

  10. Kleine A, Kluge S, Peskar BM. Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats. Dig Dis Sci 1993; 38: 1441–9

    Article  PubMed  CAS  Google Scholar 

  11. Suzuki M, Miura S, Mori M, et al. Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut 1994; 35: 1375–8

    Article  PubMed  CAS  Google Scholar 

  12. Yoshikawa T, Naito Y, Nakamura S, et al. Effect of rebamipide on lipid peroxidation and gastric mucosal injury induced by indomethacin in rats. Arzneimittel Forschung 1993; 43 (II) 12: 1327–30

    PubMed  CAS  Google Scholar 

  13. Yoshikawa T, Naito Y, Tanigawa T, et al. Free radical scavenging activity of the novel anti-ulcer agent rebamipide studied by electron spin resonance. Arzneimittel Forschung 1993; 43 (I) 3: 363–6

    PubMed  CAS  Google Scholar 

  14. Inaba G. Diagnostic criteria of Behçet’s disease. Clin Immunol 1983; 15: 370–81

    Google Scholar 

  15. Arakawa T, Kobayashi K, Yoshikawa T, et al. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci 1998; 43 (9): 5S–13S

    PubMed  CAS  Google Scholar 

  16. Sun WH, Tsuji S, Tsujii M, et al. Induction of cyclooxygenase-2 in rat gastric mucosa by rebamipide, a mucoprotective agent. J Pharmacol Exp Ther 2000; 295 (2): 447–52

    PubMed  CAS  Google Scholar 

  17. Tarnawski A, Arakawa T, Kobayashi K. Rebamipide treatment activates epidermal growth factor and its receptor expression in normal and ulcerated gastric mucosa in rats: one mechanism for its ulcer healing action? Dig Dis Sci 1998; 43 (9): 90S–8S

    PubMed  CAS  Google Scholar 

  18. Wu-Wang CY, Patel M, Feng J, et al. Decreased levels of salivary prostaglandin E2 and epidermal growth factor in recurrent aphthous stomatitis. Arch Oral Biol 1995; 40 (12): 1093–8

    Article  PubMed  CAS  Google Scholar 

  19. Ishihara K, Komoru Y, Nishiyama N, et al. Effect of rebamipide on mucus secretion by endogenous prostaglandin-independent mechanism. Arzneimittel Forschung 1992; 42: 1462–6

    PubMed  CAS  Google Scholar 

  20. Suetsugu H, Ishihara S, Moriyama N, et al. Effect of rebamipide on prostaglandin EP4 receptor gene expression in rat gastric mucosa. J Lab Clin Med 2000; 136 (1): 50–7

    Article  PubMed  CAS  Google Scholar 

  21. Ogino K, Hobara T, Ishiyama H, et al. Antiulcer mechanism of action of rebamipide, a novel antiulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers in rats. Eur J Pharmacol 1992; 212: 9–13

    Article  PubMed  CAS  Google Scholar 

  22. Naito Y, Yoshikawa T, Tanigawa T, et al. Hydroxyl radical scavenging by rebamipide and related compounds: electron paramagnetic resonance study. Free Radic Biol Med 1995; 18: 117–23

    Article  PubMed  CAS  Google Scholar 

  23. Watanabe S, Wang X-E, Hirose M, et al. Effects of rebamipide on bile acid-induced inhibition of gastric epithelial repair in a rabbit cell culture model. Aliment Pharmacol Ther 1996; 10: 927–32

    Article  PubMed  CAS  Google Scholar 

  24. Naito Y, Yoshikawa T, Iinuma S, et al. Local gastric and serum concentrations of rebamipide following oral administration to patients with chronic gastritis. Arzneim-Forsch 1996; 46: 698–700

    CAS  Google Scholar 

  25. Akamatsu T, Nakamura N, Furuya N, et al. Local gastric and serum concentrations of rebampidie following oral ingestion in healthy volunteers. Dig Dis Sci 2002: 47: 1399–1404 1988; 92: 389–95

    Article  PubMed  CAS  Google Scholar 

  26. Ishiyama H, Kawai K, Azuma A, et al. Therapeutic effect of rebamipide in a modified acetic acid-induced buccal mucosal ulcer model. Inflammopharmacology. In press

  27. Hong KW, Kim KE, Rhim BY, et al. Effect of rebamipide on liver damage and increased tumor necrosis factor in a rat model of endotoxin shock. Dig Dis Sci 1998; 43: 154S–9S

    PubMed  CAS  Google Scholar 

  28. Murakami N, Hara H, Hashimoto M, et al. Effect of oral administration of rebamipide on laryngeal granuloma. Larynx Jpn 2002; 14: 53

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank Prof. Shinichi Kawai of the Institute of Medical Science, St Marianna University School of Medicine, for performing the duties of controller (assignment of the investigational drug, preservation of blindness, methods for processing the data, etc.) in this study. In honour of the memory of Prof. Tsuyoshi Sakane (deceased) of St Marianna University School of Medicine, the authors would like to acknowledge his extensive contribution to the performance of the study.

This study was funded by Otsuka Pharmaceutical Co. Ltd, Osaka, Japan.

Author information

Authors and Affiliations

  1. Institute of Medical Science, St Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan

    Takahide Matsuda & Yutaka Mizushima

  2. Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Japan

    Shigeaki Ohno & Satoshi Nakamura

  3. Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan

    Shunsei Hirohata

  4. Department of Ophthalmology, Tokyo Women’s Medical University Daini Hospital, Tokyo, Japan

    Yoshitaka Miyanaga, Hiroshi Ujihara & Goro Inaba

  5. Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan

    Shun-ichi Tanaka

  6. Department of Ophthalmology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan

    Mitsuko Kogure

Authors
  1. Takahide Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigeaki Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shunsei Hirohata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshitaka Miyanaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroshi Ujihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Goro Inaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoshi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shun-ichi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mitsuko Kogure
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yutaka Mizushima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takahide Matsuda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matsuda, T., Ohno, S., Hirohata, S. et al. Efficacy of Rebamipide as Adjunctive Therapy in the Treatment of Recurrent Oral Aphthous Ulcers in Patients with Behçet’s Disease. Drugs in R&D 4, 19–28 (2003). https://doi.org/10.2165/00126839-200304010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00126839-200304010-00002

Keywords

Search

Navigation