Solid Nanocrystals of Rebamipide Promote Recovery from Indomethacin-Induced Gastrointestinal Bleeding

Abstract

Indomethacin (IMC)-induced gastrointestinal (GI) injuries are more common in rheumatoid arthritis (RA) patients than in other IMC users, and the overexpression of nitric oxide (NO) via inducible NO synthase (iNOS) is related to the seriousness of IMC-induced GI injuries. However, sufficient strategies to prevent IMC-induced GI injuries have not yet been established. In this study, we designed dispersions of rebamipide (RBM) solid nanocrystals (particle size: 30–190 nm) by a bead mill method (RBM-NDs), and investigated whether the oral administration of RBM-NDs is useful to prevent IMC-induced GI injuries. The RBM nanocrystals were spherical and had a solubility 4.71-fold greater than dispersions of traditional RBM powder (RBM-TDs). In addition, the RBM-NDs were stable for 1 month after preparation. The RBM contents in the stomach, jejunum, and ileum of rats orally administered RBM-NDs were significantly higher than in rats administered RBM-TDs. Moreover, the oral administration of RBM-NDs decreased the NO levels via iNOS and area of the GI lesions in IMC-stimulated RA (adjuvant-induced arthritis rat) rats in comparison with the oral administration of RBM-TDs. Thus, we show that the oral administration of RBM-NDs provides a high drug supply to the GI mucosa, resulting in a therapeutic effect on IMC-induced GI injuries. Solid nanocrystalline RBM preparations may offer effective therapy for RA patients.

Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates Risk of Gastrointestinal Side Effects

“…On the other hand, no intestinal lesions were detected in the rats treated with MLX-NPs, and there were fewer gastric lesions in rats treated with MLX-NPs than in rats administered MLX-TDs (P < 0.05). Previous studies have reported that NSAIDs inhibit cyclooxygenase and cause the depletion of endogenous prostaglandins (PG), resulting in the formation of gastric lesions [39][40][41]. In addition, the direct stimulation by NSAIDs in the stomach and small intestine induces the overexpression of neutrophils, the formation of nitric oxide (NO) via inducible NO synthase, and these changes in the levels of neutrophils, NO and prostaglandins cause the pathogenesis of intestinal ulceration [39][40][41].…”

“…Previous studies have reported that NSAIDs inhibit cyclooxygenase and cause the depletion of endogenous prostaglandins (PG), resulting in the formation of gastric lesions [39][40][41]. In addition, the direct stimulation by NSAIDs in the stomach and small intestine induces the overexpression of neutrophils, the formation of nitric oxide (NO) via inducible NO synthase, and these changes in the levels of neutrophils, NO and prostaglandins cause the pathogenesis of intestinal ulceration [39][40][41]. Taken together, the data suggest decreasing the MLX dosage (the amount administered orally) by improving BA attenuates the direct stimulation by MLX in the stomach and small intestine, resulting in a decrease in the onset of gastrointestinal lesions.…”

Recovery from indomethacin-induced gastrointestinal bleeding by treatment with teprenone

“…3 ). Our previous study showed that gastrointestinal injuries caused by IMC were similar in normal and sham-operated rats [ 9 ]. Analysis of the lesion area showed a significant decrease in the disability rate in the TEP-treated AA rats compared to that in the control group.…”

“…In general, if side effects occur, NSAIDs can be discontinued, or the patient can be treated with a proton pump inhibitor (PPI) or PG preparation [ 8 ]. However, we previously reported that the oral administration of rebamipide (RBM) enhanced the repair of indomethacin (IMC)-induced gastrointestinal injuries in adjuvant-induced arthritis (AA) rats, an animal model of RA [ 9 ]. Therefore, gastrointestinal injuries caused by NSAIDs may be treated with mucosal protective drugs such as RBM and teprenone (TEP) [ 10 – 12 ].…”

Nanomedicine for Drug Delivery throughout the Alimentary Canal

“…Labeled bacteriophages were embedded in cell membranes, and no transcytosis was seen for encapsulated phages, whereas unencapsulated phages crossed the cell membranes, indicating that liposomes increase the time that the phages are in the stomach. Lastly, a solid nanocrystal formulation of rebamipide has been developed for gastrointestinal bleeding . Solid nanocrystals were created with the bead mill method and were 30–190 nm.…”