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Review Article

Knowledge on Rebamipide a novel agent used for the treatment of recurrent aphthous - 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 (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 that mainly affect non-keratinized . 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 .[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 , 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 “” has been used interchangeably Hematinic deficiency with “aphthous ulcers” and may be more accurate Deficiencies of , , 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 , the buccal Gluten sensitive enteropathy mucosa, the floor of the mouth, the soft , 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 , and the of gluten, a wheat protein in susceptible individuals. dorsal surface of the tongue, are uncommon locations. It is characterized by severe malnutrition, , abdominal pain, diarrhea, aphthous oral ulcers, Predisposing Factors , 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 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 An increased frequency in the occurrence of RAS has Trauma been reported on using SLS-containing toothpaste Trauma to the oral mucosa due to 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. 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. is considered to be the protective factor as it stimulates the production of adrenal by its Stress action on the hypothalamic adrenal axis and reduces Stress has been emphasized as a causative factor in production of tumor 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 or cheek biting and this trauma may predispose

Drug Invention Today | Vol 11 • Issue 3 • 2019 625 Sanjay Madhavan and Mebin George Mathew to ulceration. A more recent study shows lack of direct consultation without an understanding of the nature of correlation between levels of stress and severity of the condition and that it represents a specific disease RAS episodes and suggests that psychological stress like any other disease will not regard the condition may act as a triggering or modifying factor rather than as anything other than a mouth ulcer. This is a self- etiological factor in susceptible RAS patients.[18] defeating position. The diagnosis and management of RAU require consultation time and review time Pathophysiology and preferably not slotted against “more important” The pathophysiology of aphthous ulcers is poorly issues such as a dental restoration. A sequence for the understood. Histologically, aphthae contain a diagnostic process used by the authors is as follows. mononuclear infiltrate with a fibrin coating.[19] Patients with recurrent aphthae may have an alteration General medical history of local cell-mediated immunity. Systemic T and Written pro forma, include medications history, review B cell responses have also been reported as altered with the patient, signed by both patient, and clinician. in patients with recurrent aphthae.[20] The complex interactions of various etiological factors together History of the ulcerative disease can trigger ulcer formation. Etiological factors Age at onset, duration of condition, frequency of can be classified into predisposing factors and recurrence, remission periods, exacerbating factors/ precipitating/triggering factors. The factors such as events/medications, (dairy, wheat, HLA associations, immune dis-regulation, nutritional nuts, tomatoes, and chocolate), role of trauma, deficiency, and personality type A are the predisposing association with stress/anxiety, and familial history. factors. Microtrauma, infections, and stress could be the initiating or triggering factor for ulcer formation. Clinical features of lesions Those individuals who are susceptible when exposed Single or multiple average size, margins - irregular to the triggering factors for certain duration tend to (traumatic), linear (Crohn’s disease), vesicular develop ulcers. Based on the intensity and duration or non-vesicular, duration of individual lesions, of the triggering factors, ulcer starts growing until tissue morbidity, level of functional morbidity and the factors are removed. The pain suffered by the restriction, and rate of onset ( multiforme). patients is directly proportional to the size of the ulcer and severity of the triggering factors. For example, Extra oral features the serum cortisol level-which is a biomarker of the stress was increased in the subjects with RAS, and the Ocular or genital lesions (Behcet’s Disease and Reiter’s increase was directly proportional to the ulcer size.[21] Syndrome), skin lesions (), GIT symptoms (inflammatory bowel disease), Classification hematological abnormality/deficiency pyrexia, and RAU is classified as minor, major, and herpetiform.[7,8] alternative blood screens. Hematological screen is 70–87% of all RAU cases are minor. Minor RAU covering full blood examination (FBE), iron studies, involves the presence of 1 to 5 ulcers at a time, with , and Vitamin B12 for all patients presenting each ulcer <1 cm in diameter. These ulcers are self- with RAU. Only a small number of patients show a limiting and resolve in 7–10 days without scarring. specific anemia or other hematological deficiency, but Major RAU occurs in 7–20% of affected patients. their exclusion is an important part of the complete There are 1–10 ulcers at a time, the ulcers exceed 1 cm patient work-up. They have also noted that 10–20% in diameter, and they persist for up to 6 weeks. Major of patients with RAU show a tendency toward a aphthae are a cause of significant dysphagia and often sideropenia and this requires attention. The eyes, result in extensive scarring. Herpetiform aphthae skin, and other mucosal surfaces are also examined account for 7–10% of RAU cases. In herpetiform RAU, either directly or by questioning as a routine. This is there are 10–100 ulcers at a time, ulcer size is usually a required part of the work-up of all mucosal disease 1–3 cm, and the ulcers form clusters that coalesce patients and in many conditions can be surprisingly into widespread areas of ulceration lasting 7–10 days. informative. Similarly, folate levels are an indicator These ulcers are only herpes-like in appearance; of intestinal absorption function, but patients are also has not been cultured from them. questioned concerning any abdominal symptoms and particularly those without an identified cause.[22] Guidelines for Management of Patients The successful management of RAU depends on Management and Treatment a careful patient work-up and correct diagnosis The primary goals of therapy of RAS are relief of including any features peculiar to a patient’s pain, reduction of ulcer duration, and the restoration presentation. It also requires a patient understanding of normal oral function. Secondary goals include a of the nature of the disease. A patient who leaves the reduction in the frequency and severity of recurrence

626 Drug Invention Today | Vol 11 • Issue 3 • 2019 Sanjay Madhavan and Mebin George Mathew and maintenance of remission. The best treatment must The anti-inflammatory properties of diclofenac 3% control the ulcers for the longest period with minimal with hyaluronic acid 2.5% have also been effective. side effects. The treatment approach is determined by disease severity (pain), the patient’s medical history, Therapies the frequency of flare-ups, and the patient’s ability to 0.2% rinse to all patients presenting with tolerate the medication. In all patients in RAS, it is RAS to decrease the likelihood of superinfection with important to rule out predisposing factors and treat Gram-positive and Gram-negative and fungi. any such factors, where possible, before introducing In addition, chlorhexidine has been shown to have more specific therapy.[23] The forms of therapy range activity against enveloped (herpes simplex from topical application to systemic administration of virus, cytomegalovirus, influenza, and respiratory drugs, and even the newer technologies of ultrasound syncytial virus). Chlorhexidine is also effective in have been tried. The treatment to be initiated practically eliminating and preventing the formation of biofilms depends on the severity of the ulcers and whether its that are commonly found in dental plaque.[22] associated with any systemic illness.[24] Management of RAS can be very challenging, especially in patients Topical antibiotics with severe disease. When oral aphthosis is secondary Doxycycline or is to an underlying disease, it is advisable to treat the also effective, likely secondary to inhibition of primary disease to hopefully improve the oral aphthae. metalloproteinases. In the case of RAS, and even some cases of secondary oral aphthosis, the following treatment ladder may be Topical corticosteroids utilized. At present, the management of RAS is aimed Betamethasone mouthwash, at supportive care. No pharmacological treatment spray, triamcinolone in an oral preparation are has been curative, although several modalities have commonly successful in the treatment of active ulcers been effective in decreasing pain and erythema and and can be administered with to reduce the increasing the rate of re-epithelialization associated risk of for long-term use.[26] with healing lesions. It is reasonable to begin treatment with topical medication and advance to Systemic therapies systemic medication and laser as necessary with a When a patient reports little to no improvement in goal of decreasing recurrence rate and severity of the frequency or severity of outbreaks with topical therapy outbreaks. alone, systemic medications have been reported as effective for treating RAS. There is evidence to Topical therapy suggest that oral antimicrobials, such as penicillin G Topical agents are the first choice of management (50 mg QIDx 4 days), decrease ulcer size and pain. for RAU. They are cheap, effective, safe, and Clofazimine, an antimicrobial, in combination with available usually. Several topical medications with rifampin and dapsone, has been shown to prevent distinct mechanisms are effective in managing RAS the formation of new lesions. Zinc at 50 mg/day lesions. Topical treatment is aimed at prevention of has also produced beneficial effects on wound re- superinfection, protection of existing ulcers, analgesia, epithelialization and healing. Pentoxifylline has shown decreasing inflammation, and treating active ulcers. promising results in reducing the severity of outbreaks but has little effect in preventing new outbreaks and has Local Anesthetics and numerous GI side effects. Low-dose oral tetracyclines About 2% lidocaine is proven to be effective in may also be helpful due to their anti-inflammatory relieving pain associated with RAU (RAS), but the properties. Oral (initial dose of 25 mg/ combination of adrenaline (1:8000) further increases day with taper) is the first-line systemic therapy and the period of pain relief which allows the patient is typically reserved for the acute treatment of severe enough time to take the meals. The patient is instructed RAS outbreaks. Systemic corticosteroids are relatively to apply 2–3 drops of it directly onto the ulcer surface or absolutely contraindicated in certain patients; for and ask to keep the mouth open.[23] these cases, leukotriene-receptor antagonists are a safer alternative. Montelukast 10 mg daily was Lidocaine as a 2% containing gel (Gelicaine 2% gel found to be equally effective in pain reduction and and Xylocaine 2% gel), or as a spray (Xylocaine pump accelerating healing of lesions when compared to spray), polidocanol as a paste (Solcoseryl adhesive oral systemic corticosteroids. When the disease is dental paste), and in the form of lozenges not adequately controlled with oral corticosteroids, (Anesthesia lozenges) can be used.[25] The protective immunomodulators have shown promise in reducing coating of existing ulcers can be achieved with the severity of the outbreak and preventing further bioadhesive pastes formulated with benzocaine 20% outbreaks. -sparing agents, such as colchicine for pain relief. Lidocaine 5% ointment and lidocaine at starting at 0.5 mg/day and gradually increasing 10% spray are also effective for temporary analgesia. to 1.5 mg/day or dapsone 25 mg/day and gradually

Drug Invention Today | Vol 11 • Issue 3 • 2019 627 Sanjay Madhavan and Mebin George Mathew increasing to 100 mg/day, may also be effective. Pharmacokinetics Thalidomide at a dose of 50–100 mg/day is considered The effective concentration of rebamipide is in the range the most effective immunomodulator for RAS but is of 1–1000 μm. Up to 98.4% of ingested rebamipide is obviously limited by its side-effect profile. In addition, bound to plasma proteins. It is metabolized in the liver a recent study explored the effects of daily ascorbic by human cytochrome P450 enzyme. The cytochrome acid 2000 mg/m2/day for managing minor RAS. A 50% P450 enzyme acts on rebamipide through hydroxylation reduction in oral ulcer outbreaks and a significant and glucuronidation, resulting in the formation of reduction in pain level was noted in these patients. 6-hydroxy and 8-hydroxyrebamipide.[32] The role There is strong evidence to suggest that ascorbate of glucuronidation in the metabolism of rebamipide decreases neutrophil-mediated inflammation through is very low and nonsignificant. Drug interactions of modulation of reactive oxygen species (ROS).[27] rebamipide with other drugs are very low and safely Ascorbic acid as adjunctive therapy to topicals should used concomitantly with other drugs.[33] be considered as well due to its relatively benign side effect profile. Contraindication Rebamipide is contraindicated in patients with known Light therapy history of drug hypersensitivity. Low-level laser therapy at a wavelength of 658 nm may also be beneficial in RAS patients as an Side effects adjunctive. It was shown to be equal or even superior Side effects seen are mild and can be corrected with to pharmacological treatment in managing pain and dose adjustment. The common side effects noticed inflammation and increasing re-epitheliazation of after rebamipide use are gastrointestinal such as aphthous ulcers. constipation,[34] bloating, diarrhea, nausea, and vomiting. Hypersensitivity and rash were seen in <1% Rebamipide of patients. Rebamipide is an amino acid analog of 2(1H)- quinolinone. Rebamipide 2-(4-chlorobenzoylamine)- CONCLUSION 3-[2-(1H)-quinolinon-4-yl] is a new mucoprotective agent which enhances the preservation of existing The pain of recurrent mouth ulcers is excruciating epithelial cells and replacement of lost tissue through and increases after eating, drinking, and talking. This a multifactorial mode of action.[28] affects the quality of life of an individual. The patients of severe RAU avoid eating, drinking, kissing, and Mechanism of action talking. Speech is painful and all these put-together The mechanism of the action of rebamipide in cause depression in the individual. RAU is by the preservation of existing cells and replacement of lost tissue. Action of preservation The exact etiology of RAU is not-known, and it can of existing cells occurs through increase in the be multifactorial. The new drug, rebamipide addresses content of soluble mucus,[29] increase in the gastric the problem in many angles, and it has ulcer healing concentrations of PGE2 and PGI2, downregulation of and ulcer protective functions. Rebamipide is safe, 15-hydroxyprostaglandin dehydrogenase,[30] increase well tolerated and effective drug in the treatment of in the mucosal blood flow through enhanced nitric RAU and Behcet’s disease. The administration of oxide synthase activity, decrease in the expression of rebamipide is not cumbersome and does not have any neutrophil adhesion molecules (CD11b/CD18), and specific adverse drug reaction. Therefore, rebamipide inhibition of the secretion of TNF-α by inhibiting the is an addition in the armamentarium of management synthesis of inflammatory E-selectin and has a free of RAU and Behcets’s disease. radical scavenging effect on ROS.[31] Rebamipide helps in replacement of lost tissue by increasing the REFERENCES expression of epidermal growth factor (EGF) and 1. Ship JA. Recurrent aphthous stomatitis. An update. Oral Surg EGF receptors.[32] These EGF causes angiogenesis, Oral Med Oral Pathol Oral Radiol Endod 1996;81:141-7. increased production of granulation tissue and 2. Zakrzewska JM, Robinson P, Williams IG. Severe oral epithelization of ulcer healing. ulceration in patients with HIV infection: A case series. Oral Dis 1997;3 Suppl 1:S194-6. 3. MacPhail LA, Greenspan JS. Oral ulceration in HIV infection: Dosage Investigation and pathogenesis. Oral Dis 1997;3 Suppl 1:S190-3. The adult dosage of rebamipide is 100 mg orally 4. Femiano F, Lanza A, Buonaiuto C, Gombos F, Nunziata M, 3 times daily. Piccolo S, et al. Guidelines for diagnosis and management of aphthous stomatitis. Pediatr Infect Dis J 2007;26:728-32. • RAU: 3 tablets/day for 7–14 days. 5. Compilato D, Carroccio A, Calvino F, Di Fede G, Campisi G. • Behcet’s disease: 3 tablets/day for 2 months. Haematological deficiencies in patients with recurrent aphthosis.

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