Effect of long-term proton pump inhibitor therapy and healing effect of irsogladine on nonsteroidal anti-inflammatory drug-induced small-intestinal lesions in healthy volunteers

Abstract

This study assessed time-course changes of the small intestinal lesions during long-term treatment with diclofenac sodium plus omeprazole and the effects of irsogladine on such lesions. Thirty two healthy volunteers were treated with diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day) for 6 weeks, with irsogladine (4 mg/day) added from weeks 6 to 10 (Group A) or with diclofenac sodium plus irsogladine for 6 weeks (Group B). Five volunteers received diclofenac sodium plus omeprazole for 10 weeks (Group C). Subjects underwent capsule endoscopy at each time. In Group A, the number of lesions remarkably increased at week 2, but the worse was not found at week 6 compared with week 2, whereas no exacerbation of lesions was observed in Group B. Additional treatment with irsogladine from weeks 6 to 10 in Group A significantly decreased the number of lesions at weeks 10 compared with Group C. In Group C, no significant change in lesions was observed since weeks 2. In conclusions, a PPI did not prevent the occurrence of small intestinal damage. However such lesions were not aggravated since weeks 2. These suggested mucosal adaptation may occur in the small intestine. Irsogladine was effective in both preventing and healing such lesions.

Keywords: NSAIDs; PPI; capsule endoscopy; irsogladine; small bowel.

Fig. 1

Study design. Study 1: Thirty-two healthy volunteers were randomized into two groups to receive the following treatments: diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day) for 6 weeks with irsogladine (4 mg/day) added from weeks 6 to 10 (Group A, n = 16) or diclofenac sodium (75 mg/day) plus irsogladine (4 mg/day) for 6 weeks (Group B, n = 16). Subjects underwent capsule endoscopy at baseline and at weeks 2, 6, and 10 in Group A and at baseline and at weeks 2 and 6 in Group B. The capsule endoscope did not reach into cecum in one patient each in Groups A and B; thus, 15 subjects were analyzed in each group. Study 2: Five healthy volunteers were enrolled as a control group to receive diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day) for 10 weeks (Group C, n = 5). Subjects underwent capsule endoscopy at baseline and weeks 2, 6, and 10. CE, capsule endoscopy.

Fig. 2

Representative images of capsule endoscopy. Typical examples of the bleeding, mucosal breaks, and reddened lesions found in this study are shown. Reddened folds, denuded areas, and petechiae were grouped in a single classification termed ”reddened lesions.”

Fig. 3

Number of mucosal breaks in the small intestine in Study 1. In Group A, the number of small intestinal mucosal breaks detected by capsule endoscopy was significantly higher at week 2 (*p<0.05, Wilcoxon’s signed-rank test) than at baseline, but the change for the worse of lesions was not found at week 6 compared with at week 2. Subjects in Group A had significantly more mucosal breaks at weeks 2 and 6 than those in Group B (^#p<0.05, Wilcoxon’s rank-sum test). Mucosal breaks decreased further during add-on treatment with irsogladine from weeks 6 to 10.

Fig. 4

Number of mucosal breaks in the small intestine in Study 2. The number of mucosal breaks detected in the small intestine by capsule endoscopy increased at week 2, but no further change in the number of mucosal breaks was observed from weeks 2 to 10 in Group C (week 2 vs baseline, p = 0.0625, Wilcoxon’s signed-rank test).

Fig. 5

Changes in the number of lesions in each segment of the small intestine. In patients in Groups A and C who received diclofenac sodium plus omeprazole (n = 16 + 5 at baseline and weeks 2 and 6, n = 5 at week 10). The number of lesions decreased in the first segment and increased in the second and third segments after weeks 6 and 10.

Fig. 6

Number of mucosal breaks in the small intestine in Study 1 and Study 2. In subjects who received diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day for 6 weeks), the number of small intestinal mucosal breaks remarkably increased by week 2 (^#p<0.05, Wilcoxon’s signed-rank test), but the change for the worse of lesions was not found at week 6 compared with at week 2. Subjects who received diclofenac sodium (75 mg/day) plus omeprazole (10 mg/day for 6 weeks) as well as irsogladine (4 mg/day) from weeks 6 to 10 had significantly fewer erosions and ulcers than those for whom irsogladine was not added (*p<0.05, Wilcoxon’s rank-sum test).