Rebamipide: A Novel Agent in the Treatment of Recurrent Aphthous Ulcer and Behcet's Syndrome.

Rebamipide is an amino acid analog of 2 (1H)-quinolinone. It is being introduced and used since 1980 for the treatment of peptic ulcer. Its therapeutic use in recurrent aphthous ulcer was not known. It acts by the decrease in oxygen radicals, increase in blood flow and production of protective prostaglandins in ulcer mucosa, which accelerates the process of healing. In this article, we focus on the pharmacodynamics, pharmacokinetics, side-effects and other therapeutic uses of Rebamipide. It will be a new and effective drug in the dermatologists' drug armamentarium for the treatment of aphthous ulcers and related diseases.

What was known?

Rebamipide is an amino acide analogue used in the treatment of gastroduodenal ulcers.

Introduction

Recurrent aphthous Ulcers (RAU) or stomatitis or mucositis are always problematic to the patient and the dermatologist. The exact cause of recurrent aphthae is unknown and many etiologies like herpes virus, autoimmunity, deficiency of vitamins like B1, B2, B12, zinc, and folic acid, drugs like captopril, gold salts, nicorandil, phenobarbitol, piroxicam, and stress have been indicated. The treatment modalities tried for recurrent aphthae are vitamins, antivirals, thalidomide, colchicine, topical and oral steroids, etc., Treatment of RAU has always been elusive and for years doctors have yearned for a ‘magic bullet’ that is suitable for all patients. Many treatment options have been tried which includes antibiotics (tetracycline, minocycline),[1] anti-inflammatory agents (topical and systemic corticosteroids),[23] immune modulators (thalidomide), pain relieving agents (lidocaine, benzocaine), zinc, vitamin B complex,[4] vitamin C, but none of them gives complete cure. Rebamipide 2-(4-chlorobenzoylamine)-3-[2-(1H)-quinolinon-4-yl] is a new mucoprotective agent which enhances preservation of existing epithelial cells and replacement of lost tissue through a multifactorial mode of action.[5]

Mechanism of action

The mechanism of action of rebamipide in RAU is by preservation of existing cells and replacement of lost tissue. Action of preservation of existing cells occurs through increase in the content of soluble mucus,[67] increase in the gastric concentrations of PGE2 and PGI2, down regulation of 15-hydroxyprostaglandin dehydrogenase,[8] increase in the mucosal blood flow through enhanced nitric oxide synthase activity, decrease in the expression of neutrophil adhesion molecules (CD11b/CD18), inhibition of the secretion of TNF-α by inhibiting the synthesis of inflammatory E-selectin and has a free radical scavenging effect on reactive oxygen species.[9]

Rebamipide helps in replacement of lost tissue by increasing the expression of epidermal growth factor (EGF) and EGF receptors.[10] These EGF causes angiogenesis, increased production of granulation tissue and epithelization of ulcer healing.

Dosage

The adult dosage of rebamipide is 100 mg orally three times daily.

RAU: 3 tablets/day for 7-14 days.

Behcet's disease: 3 tablets/day for 2 months.

Pharmacokinetics

The effective concentration of rebamipide is in the range of 1-1000 μm. Following table[11] briefly explains the pharmacokinetic parameter of ribamipide.

Up to 98.4% of ingested repbamipide is bound to plasma proteins. It is metabolized in the liver by human cytochrome P450 enzyme. The cytochrome P450 enzyme acts on rebamipide through hydroxylation and glucoronidation, resulting in the formation of 6-hydroxy and 8-hydroxyrebamipide.[12] The role of glucoronidation in the metabolism of rebamipide is very low and nonsignificant. Drug interactions of rebmipide with other drugs is very low and safely used concomitantly with other drugs.[9]

Indications of ribamipide in dermatology

Ribamipide has been used for the following indications,[13]

Stomatitis

Recurrent oral aphthae

Behcet's disease

Matsuda et al.,[14] in their multi-centric, double blind, placebo-controlled study, compared Ribamide 300 mg/day with placebo in 35 patients of Behcet's disease for 12-24 weeks. They found, rebamipide to be very effective in controlling the oral apthae and reducing the pain score when compared to placebo and ‘P’ value was significant (<0.01 between groups). They concluded that, rebamipide is an effective and safe drug in the treatment of recurrent oral ulcers.

Till now, there are no randomized, placebo-controlled studies of rebamipide in the treatment of recurrent oral aphthae.[15]

Contraindication

Rebamipide is contraindicated in patients with known history of drug hypersensitivity.

Pregnancy and lactation

It is a category C drug.[16] It should used with caution only when therapeutic benefits outweighs any potential risk. Lactation should be avoided when rebamipide is administered.

Use of rebamipide in children

Clinical evidence to support the use of rebamipide in children is insufficient.

Side-effects of rebamipide

Adverse drug reactions to rebamipide is not common, side effects seen are mild and can be corrected with dose adjustment. The common side-effects noticed after rebamipide use is gastrointestinal like constipation,[17] bloating, diarrhea, nausea and vomiting. Hypersensitivity and rash was seen in less than 1% of patients.

Mouth ulcers and quality of life

The pain of recurrent mouth ulcers is excruciating and increases after eating, drinking and talking. This affects the quality of life of an individual. The patients of severe RAU avoid eating, drinking, kissing and talking. Speech is painful and all these put-together cause depression in the individual.

Rebamipide is chemically an amino acide analog of quinolinone 9[18]

Conclusion

The exact etiology of RAU is not-known and it can be multifactorial. The new drug, rebamipide addresses the problem in many angles and it has ulcer healing and ulcer protective functions. Rebamipide is safe, well tolerated and effective drug in the treatment of RAU and Behcet's disease. The administration of rebamipide is not cumbersome and does not have any specific adverse drug reaction. Therefore, rebamipide is an addition in the armamentarium of management of RAU and Behcets's disease.[18]

What is new?

Rebamipide is an effective and safe drug in the treatment of recurrent aphthous ulcers and Behcet's syndrome.