Review Article Knowledge on Rebamipide a novel agent used for the treatment of recurrent aphthous ulcer - A Review Sanjay Madhavan1, Mebin George Mathew2* ABSTRACT Aim: The aim of this review paper is to assess the efficacy of rebamipide in the treatment of recurrent aphthous ulcer (RAU). Objective: The purpose of this review is to evaluate the use, mechanism of action, dosage, and adverse effects of rebamipide. Background: Recurrent aphthous stomatitis (RAS) or RAU, frequently referred to as “canker” sores, is among the most common oral condition. The classic presentation of RAS is recurrent, self-limiting ulcers that mainly affect non-keratinized oral mucosa. The etiology appears to be multifactorial with numerous causative and precipitating factors. The primary goals of therapy of RAS are relief of pain, reduction of ulcer duration, and the restoration of normal oral function. 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 stimulation of PGs release and inhibition of free radicals and might also be useful in preventing and treating frequently recurrent oral aphthous ulcers. Clinical and experimental data indicate that rebamipide accelerates ulcer healing, improves scar quality and prevents ulcer recurrence. Several electronic databases were searched and potentially relevant articles were taken for literature review about rebamipide. Conclusion: RAS is one of the common clinical oral diseases that produce painful ulcerations in the oral cavity. The available treatments still remain unsatisfactory with the ability to reduce the severity, healing time, and the frequency of recurrence of ulceration with no permanent and definitive treatment. This review is done to provide a review on the recent treatment modality which may give the clinician broad and detailed picture to deal with RAS in an appropriate way. KEY WORDS: Aphthous, Rebamipide, Stomatitis, Treatment INTRODUCTION Rebamipide is an amino acid analog of 2 (1H)- quinolinone. It is being introduced and used since Aphthous ulcers are among the most common oral 1980 for the treatment of peptic ulcer. Its therapeutic lesions in the general population, with a frequency use in RAU was not known. It acts by the decrease of 5–25% and 3 months recurrence rates as high as in oxygen radicals, increase in blood flow and 50%.[1] Aphthous ulcers have been reported in 2–4% production of protective prostaglandins in ulcer of HIV-seropositive patients, these patients suffer from mucosa, which accelerates the process of healing. larger and more frequent aphthae in advanced stages In this article, we focus on the pharmacodynamics, of their disease.[2] Aphthous ulcers are often quite pharmacokinetics, side effects, and other therapeutic painful, may lead to difficulty in speaking, eating, and uses of rebamipide. It will be a new and effective drug swallowing, and may negatively affect patients quality of in the dermatologists’ drug armamentarium for the life.[2,3] In patients with advanced HIV disease, aphthous treatment of aphthous ulcers and related diseases. ulcers may exacerbate weight loss. While most aphthae are small and heal within 7–10 days, larger ulcers can Oral aphthous ulcer - commonly referred to as aphthae, persist for weeks or months. Consequently, therapy for or canker sores have been routinely appreciated by the disease of recurrent aphthous ulcers (RAU) should medical and dental professionals in otherwise healthy address both healing and the prevention of new ulcers. patients for thousands of years. They are the most common lesion of the oral mucosa in the general Access this article online population.[4] The term aphthae are derived from the Greek word aphthae, which means “to set on fire” or Website: jprsolutions.info ISSN: 0975-7619 “to inflame,” and is thought to have been first used 1Department of Pedodontics and Preventive Dentistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India, 2 Department of Pediatric and Preventive Dentistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai,Tamil Nadu, India *Corresponding author: Dr. Mebin George Mathew, Department of Pediatric and Preventive Dentistry, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India. E-mail: [email protected] Received on: 18-11-2018; Revised on: 22-12-2018; Accepted on: 14-01-2019 624 Drug Invention Today | Vol 11 • Issue 3 • 2019 Sanjay Madhavan and Mebin George Mathew by the philosopher Hippocrates to describe the pain for patients who develop RAU on cessation of associated with a common disorder of the mouth smoking.[14] during his time.[5] Local trauma, genetic factors, nutritional deficiencies, viral and bacterial infections, Drugs and immune or endocrine disturbances have all been Certain drugs have been associated with the implicated as etiological factors of frequent oral development of RAU; these include angiotensin- ulcerations. In a subset of patients, no etiology can converting enzyme inhibitor captopril, gold salts, be identified and a diagnosis of exclusion must be nicorandil, phenindione, phenobarbital, and sodium made; such cases are referred to as recurrent aphthous hypochlorite. Nonsteroidal anti-inflammatory drugs stomatitis (RAS) such as propionic acid, diclofenac, and piroxicam may also cause oral ulceration similar to RAS.[15] Clinical Features “Aphthous stomatitis” has been used interchangeably Hematinic deficiency with “aphthous ulcers” and may be more accurate Deficiencies of iron, Vitamin B12, and folic acid terminology.[6,7] Aphthous ulcers are round or oval, predispose the development of RAS. Contrary with a grayish yellow, crateriform base surrounded findings in various studies relating to the association by an erythematous halo of inflamed mucosa.[8] For of hematinic deficiency and RAS have been explained 24–48 h preceding the appearance of an ulcer, most as due to varying genetic backgrounds and dietary patients have a pricking or burning sensation in the habits of the population.[9] affected area. The ulcer usually occurs on the non- keratinized oral mucosa, including the lips, the buccal Gluten sensitive enteropathy mucosa, the floor of the mouth, the soft palate, and the It is an autoimmune inflammatory disease of the ventral surface of the tongue. Regions of keratinized small intestine that is precipitated by the ingestion oral mucosa, such as the hard palate, the gums, and the of gluten, a wheat protein in susceptible individuals. dorsal surface of the tongue, are uncommon locations. It is characterized by severe malnutrition, anemia, abdominal pain, diarrhea, aphthous oral ulcers, Predisposing Factors glossitis, and stomatitis. RAS may be the sole Genetics manifestation of the disease. The use of a gluten- A genetic predisposition for the development of free diet in the improvement of RAS is considered aphthous ulcer is strongly suggested as about 40% of uncertain. It has been suggested that evaluation for patients have a family history and these individuals celiac disease may be appropriate for RAS patients.[16] develop ulcers earlier and are of more severe nature.[9] Inflammatory bowel diseases such as Crohn’s disease Various associations with human leukocyte antigen and ulcerative colitis may present with aphthous-like (HLA) antigens and RAS have been reported. These ulceration. associations vary with specific racial and ethnic origins. Sodium lauryl sulfate (SLS)-containing toothpaste An increased frequency in the occurrence of RAS has Trauma been reported on using SLS-containing toothpaste Trauma to the oral mucosa due to local anesthetic with some reduction in ulceration on use of SLS-free injections, sharp tooth, dental treatments, and toothpaste. However, due to the widespread use of toothbrush injury may predispose to the development SLS-containing dentifrice, it has been proposed that of RAU.[10] Wray et al., in 1981, proposed that this may not truly predispose to RAS.[10] mechanical injury may aid in identifying and studying patients prone to aphthous stomatitis.[11] Hormonal changes Conflicting reports exist regarding the association of Tobacco hormonal changes in women and RAU. The studies Several studies reveal a negative association between state association of oral ulceration with the onset of cigarette smoking, smokeless tobacco, and RAS. menstruation or in the luteal phase of the menstrual Possible explanations given include increased cycle. McCartan and Sullivan,[17] in 1992, established mucosal keratinization; which serves as a mechanical no association between aphthous stomatitis and and protective barrier against trauma and microbes.[12] premenstrual period, pregnancy, or menopause. Nicotine is considered to be the protective factor as it stimulates the production of adrenal steroids by its Stress action on the hypothalamic adrenal axis and reduces Stress has been emphasized as a causative factor in production of tumor necrosis factor-alpha (TNF-α) RAU. It has been proposed that stress may induce and interleukins 1 and 6 (IL-1 and IL-6).[13] Nicotine trauma to oral soft tissues by parafunctional habits such replacement therapy has been suggested as a treatment as lip or cheek biting and this trauma may predispose Drug Invention Today | Vol 11 • Issue 3 • 2019 625 Sanjay Madhavan and