Original Research. Received: 15thOctober 2013 Accepted: 16th December 2013 Conflict of Interest: None. Contributors:

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1 Journal of International Oral Health 4; 6():- Received: thoctober Accepted: 6th December Conflict of Interest: None Original Research Clinical to know the efficacy of Amlexanox % with other topical Antiseptic, Analgesic and Anesthetic agents in treating minor RA D D Darshan, C N Vijay Kumar, A D Manoj Kumar, N Manikantan, Dhanya Balakrishnan, M P Uthkal 4 Contributors: Introduction Recurrent aphthous ulceration or recurrent aphthous stomatitis is the most common oral mucosal disease known to human beings and has ever since been the subject of considerable clinical and research attention, because of its multiple etiologies and various treatment modalities with no much of cure. The term aphthae refers to presence of an otherwise undefined ulcer. Hippocrates (46-7BC) was the first to use the term aphthai, he used this term to describe all disorders affecting the mouth. However, the first valid clinical description of RA is credited to Von Mikulicz and Kummel (888). The prevalence of RA in general population is of the order of to %, effecting men and women of all ages, races, and geographic regions. The disease is characterized by recurrent, painful ulcers that are small, round to ovoid, affecting non-keratinized oral mucosa such as buccal mucosa, lateral and ventral aspects of the tongue, floor of the mouth and soft palatal and oropharyngeal mucosa with a crateriform based covered by a grey white pseudomembrane and surrounded by a distinct erythematous halo. Many investigators have classified RA into three subtypes: minor aphthous ulcers, major aphthous ulcers and herpetiform ulcer.4-9 Minor RAU is the most common manifestation of the disorder, occurring in 7-8% of patient with RAU. This is characterized by shallow round or oval lesions of < mm in diameter.4-9 Major RAU is a more severe from, affecting approximately % of patients with RAU. Lesions are generally deeper than those observed in minor RAU, often exceed mm in diameter and generally take several weeks to heal with scar.4-9 Herpetiform ulcers are multiple clusters of ulcers and are between - mm in diameter, approximately % of patients presenting with RAU have the herpetiform manifestation.4-9 RAU can also be classified as simple aphthosis or complex aphthosis. The imple manifestation is characterized by Assistant Professor, Department of Oral Medicine & Radiology, K V G Dental College & Hospital, ullia, Karnataka, India; Reader, Department of Conservative Dentistry & Endodontics, K V G Dental College & Hospital, ullia, Karnataka, India; Reader, Department of Prosthodontics, K V G Dental College & Hospital, ullia, Karnataka, India; 4Assistant Professor, Department of Oral Medicine & Radiology, Malabar Dental College and Hospital, Mallappuram, Kerala, India. Correspondence: Dr. Darshan DD. Department of Oral Medicine and Radiology, K V G Dental College & Hospital, ullia, Karnataka, India. Phone: darshandevang@gmail.com How to cite the article: Darshan DD, Kumar CN, Kumar AD, Manikantan N, Balakrishnan D, Uthkal MP. Clinical to know the efficacy of Amlexanox % with other topical Antiseptic, Analgesic and Anesthetic agents in treating minor RA. J Int Oral Health 4;6();-. Abstract: Background: To evaluate the efficacy of topical antiinflammatory agent (amlexanox %), along with topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride %), in promoting ulcer healing, decreasing ulcer size, erythema, pain and recurrence in minor RA. Materials & Methods: A randomized control trial was conducted on patients of RA who fulfilled the inclusion criteria. The number, size, erythema and pain with the ulcer were recorded. Visual analogue scale (VA) and erythema scale were used to record pain and erythema. patients comprising the group received anti inflammatory paste (amlexanox %) applied four times daily and the control group of patients received topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride %) paste, patients were evaluated after rd, 6th, 9th and on th, 6th day for recurrence. Results: The group had reduction in ulcer number, size; erythema, pain and frequency of ulcers during follow up. The healing period and recurrence of ulceration reduced in both the groups but the group had significant reduction in th and 6th day follow up for recurrence of ulcers. Conclusion: Amlexanox % can reduce the frequency, duration and symptoms associated with the aphthous ulcers with no sideeffects attributed to the drug. Key Words: Amlexanox, recurrent aphthous stomatitis (RA), visual analogue scale (VA)

2 short lived episodes involving a few lesions that heal quickly with minimal pain. Conver-sely, complex aphthosis is a more disabling state, char-acterized by numerous and large lesions, continued ulceration and marked pain. Furthermore, lesions may occur in the genital or perianal regions., Despite extensive investigations, studies have failed to find the exact etiology and pathogenesis of this condition. Hereditary, hematinic deficiencies, immune dysregulation, some food, drugs, psychic stress, local trauma, hormonal disturbances, infections, cessation of smoking, poor oral hygiene are proposed factors., ince the etiology is unknown, the diagnosis is entirely based on history and clinical criteria and no laboratory procedures exist to confirm the diagnosis. Although a variety of treatment modalities have been suggested to eliminate or reduce the duration of recurrences, their clinical value remains unproven and can be controversial, most common treatment involves the use of topical agents to provide symptomatic relief, and these include antibiotics, analgesics, non-steroidal antiinflammatory drugs, corticosteroids and, immunomodulators. The purpose of this is to evaluate the efficacy of amlexanox % in promoting ulcer healing, decreasing ulcer number, size, erythema, resolving pain and recurrence associated with RA when applied topically. Compared with topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride % Materials and Methods A total of patients with minor RA were volunteered in the. These patients were randomly selected from different private dental clinic of different parts of Karnataka. syndrome, hematological diseases, nutritional deficiencies and allergic conditions. Patients who are receiving or have received chemotherapeutic drugs. immunomodulators or systemic corticosteroids in the recent year.. Patient having other mucosal lesions, with recurrent minor aphthous ulcers 4. Pregnant and lactating mothers. All patients underwent a routine hematological investigation to rule out any hematological abnormalities. An informed consent was obtained and randomized controlled was performed. Patient details were recorded on pro-forma designed for this. A Clinical examination was performed to assess the number, site, size with caliberated periodontal probe, erythema with (erythema scale,,, ) and Pain using Visual Analogue cale (VA) from to (with being the most severe). patients were randomly selected to receive amlexanox % oral paste at the first visit presenting with minor aphthous ulcers with instructions to apply four times daily, preferably following oral hygiene procedures, till the ulcer heals they formed the group. The control group also comprised of patients and received topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride % paste. The patients were then recalled at rd, 6th, 9th, th and 6th day, following the onset of treatment. The effectiveness of the treatment in both the groups were assessed on the basis of reduction in number, size, maximum VA scores, maximum erythema score and the recurrence at th and 6th day. tatistical test like student s t-test for comparison of the and the control group, and paired t-test for comparison of parameters obtained at different time periods with the baseline values within the group itself was used. A p-value of. was taken as statistically significant. Results In the group, out of patients, 4 were male and 9 were females (male: female ratio of 4.:) their age range from 4 years -6 years (mean years). Of the patient in comparison group, were males and 8 were females (male: female ratio of.7:) their age range from 8 years 6 years (mean 7 years). The following criteria were utilized to select patient:.. Patients giving history of recurrence ulcers in the oral cavity with at least episodes per year and with no signs of any systemic disease. Patients above years with apparently normal immune system. Exclusion criteria comprised:. Journal of International Oral Health 4; 6():- Patient with any systemic disease causing oral ulcerations like- gastrointestinal disorders (ulcerative colitis, Cohns disease), Bechets disease, Reiter 6

3 At the time of presentation, the number of the ulcers in each patient (Table ) and the sites of the ulcers were Journal of International Oral Health 4; 6():- % in control group, the patients were recalled at intervals of rd, 6th, 9th day and th and 6th day to check recurrence Table : at the time of presentation in both the groups. tudy group Control group Prodromal phase ulcer ulcer 6 or more ulcer 4 Table : ite distribution of the ulcers in the tudy and Control group. ite of ulcers tudy group Labial mucosa and lip 4 Buccal mucosa Lateral border and dorsum of tongue Floor of mouth and ventral aspect of tongue oft palate recorded (Table ) in both the groups. The first day values (baseline value) of all patients were collected i.e. the number of ulcers, size of ulcers, erythema Control group 9 of new ulcers. The comparison of the number, size, erythema, maximum pain, during different stages with the first day values were Table : Pair wise comparison of the st day with rd, 6 th, 9 th days of treatment with amlexanox % in group w.r.t the number of ulcers, size of ulcers, erythema of ulcers, maximum pain in (VA) of the ulcers. ( and (D) standard deviation of group with amlexanox %). st Day D ize of ulcers D D Pain in VA D ize of ulcers Pain in VA Table 4: tudy group t-value for rd, 6 th, 9 th day compared with st day...7 N in ulcers (erythema scale,,, ), and maximum pain recorded on (VA). Following administration of amlexanox % in the group and topical analgesic, anesthetic and antiseptic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride 9th Day made. tudy group showed significant results, but values were not significant on st day and rd day in the number. imilarly comparing the control groups also yielded significant difference in number, size, erythema, pain. Except, for the 7

4 number and size of the ulcers on st day and rd day (Table, 4,, 6). On comparing the number of ulcers between two groups, there was no significant difference between st, rd, 6th day. Results were significant on 9th day only indicating considerable reduction in number in Journal of International Oral Health 4; 6():- between two groups, there was significant difference on rd, 6th and 9th day. Indicating considerable reduction in size of ulcers in group compared to control group (Table 4 and 6) (Graph ). There was also significant reduction in the erythema of Table : Pair wise comparison of the st day with rd, 6th, 9th, days of treatment with topical analgesic, anesthetic and antiseptic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride% control group w.r.t the number of ulcers, size of ulcers, erythema of ulcers, maximum pain in (VA) of the ulcers. ( and (D) standard deviation of control group with dentogel). st Day ize of ulcers Pain in VA ize of ulcers Pain in VA D D D D Table 6: Control group t-value for rd, 6 th,9 th day compared with st day...9 N N.6.9 N comp. st day st day rd day 6th day 9th day rd day 6th day 9th day Graph : comparison of the tudy and Control group w.r.t mean size of ulcers. Graph : comparison of the tudy and Control group w.r.t mean number of ulcers. ulcer in both the groups when rd, 6th, 9th day values when compared with the first day values of respective group. On comparing between the groups significant difference was noted on 6th and 9th day showing good results in the group than control group (Table 4 and 6) (Graph ). Comparing the means of the VA scores, showed significant difference in both the groups and between two group then control group. Though the number also reduced in group it was not statistically significant (Table 7) (Graph ). There was significant reduction in the size of ulcer in both the groups when rd, 6th, 9th, day values were compared with the first day values of respective group. On comparing 8

5 Journal of International Oral Health 4; 6():- 6% recurrence in th day and 8% recurrence in 6th day (Table 8) (Graph ). groups. However when overall comparison of the score was made, the group had lower pain scores then the Table 7: t-value between tudy group and Control group. st Day N N N ize of ulcers N N N Pain in VA N- No significance for p>. -ignificance for p<. Calculated for table value (.96), < (.96) no signifince > (.96) signifince Recurrence tudy group Control group Table 8: % of recurrence between tudy group and Control group on th and 6th day follow-up th Day % % 9 patients 8% 7 patients 4% patients 6% 4 patients 8%.... comp com st day rd day 6th day 9th day th day 6th day Graph : comparison of the tudy and Control group w.r.t mean erythema of ulcers. Graph : comparison of the tudy and Control group w.r.t mean recurrence of ulcers. howing a tremendous reduction in the recurrence of ulcers in the group when compared to control group. 8 Discussion Recurrent aphthous stomatitis is one of the most common oral ailments. The patient of RA presents with painful, recurring ulcers of the oral cavity. Diagnosis of RA rests on features like: a history of recurrent ulcers since childhood or adolescence and presence of typical multiple round or ovoid ulcers on examination. Although most cases of RA are idiopathic, a careful history taking and physical examination is essential to rule out any secondary cause. A number of systemic conditions can give rise to oral ulcerations resembling RA. They are Crohns disease, Ulcerative Colitis, Gluten-ensitive Enteropathy, Behcets syndrome, Reiters syndrome, weets 6 comp 4 st day rd day 6th day 9th day Graph 4: comparison of the tudy and Control group w.r.t maximum VA scores to measure pain. control group (Table 4 and 6) (Graph 4). Recurrence was calculated between two groups on th and 6th day, group showed 8% recurrence in th day and 4% recurrence in 6th day and control group showed 9

6 syndrome, cyclic neutropenia, nutritional deficiencies, and drugs like Nicorandril.4 If the history and clinical examination are characteristic of RA, routine laboratory testing is not necessary in most individuals. A complete blood count and measurements of levels of red-cell, folate, serum vitamin B and serum ferritin is suggested by few authors.,6 These investigations are useful only if there are other clinical findings suggestive of nutritional or haematological abnormalities. Immune dysregulation in a genitically susceptible individual is also accepted and reasonably documented cause of RA. Immunopathogenesis of RA probably involves a cell mediated immune response. Few studies have shown an alteration in the T-cell fractions in individuals of RA.7,8 Role of humoral immunity in RA too has been suggested by some authors. In a on panish patient the IgG subclass was lowered.9 Hence treatments such as corticosteroids and Immunosuppressive agents like cyclosporine, azathioprine, thalidomide are also used but can produce a number of serious side effects. Amlexanox % (Lexanox), a topical anti-inflammatory agent has recently been found to have significant role in management of minor aphthous ulcers. Amlexanox (C6H4NO4) is a topical anti-inflammatory, anti-allergic drug. Amlexanox potentialy inhibit the formation and release of histamine and luekotrines from mast cells, neutrophils, and mononuclear cells. Histamine and leukotrines are vasoactive inflammatory mediators which can only increase the permeability of vessels and therefore cause swelling of the involved tissues, but also contribute to inflammation by affecting the functions of other leukocytes in the involved area., In present patient on amlexanox % reported reduced number of ulcers on comparison to pre treatment period and in control group, though the number reduced was not of that significance indicating greater ulcer free days in group. ize and erythema also reduce in both the groups. On comparision between the groups the size and erythema was lower in the group than the control group. This reduction was not significant on the day of ulcer size and st, rd day of erythema which showed near approximation with previous studies done by Jie Liu et al and Greer et al., Journal of International Oral Health 4; 6():- igns and symptoms in both the groups had reduced which was noted by reduction in the VA scores throughout treatment and post-treatment period. This indicates that both drugs could bring about reduction in the pain. However, on comparing between two groups, the patients on amlexanox % had a significant lower VA values than the control group. Which showed approximation with previous studies done by Atul Khandwala et al., Calculating recurrence, group showed 8% recurrence in th day and 4% recurrence in 6th day follow-up and control group showed 6% recurrence in th day and 8% recurrence in 6th day follow-up showing tremendous reduction in recurrence of ulcers in the group then control group. No adverse effects were reported in the present. Corroborating with the of Atul Khandwala wher in no adverse reactions were reported. Conclusion Anti-inflammatory oral paste (Amlexanox %) when used topically can bring considerable improvement in signs and symptoms associated with RA. This has shown reduction in number, size, erythema, pain associated with ulcers and also the reduction in recurrence of ulceration with no side-effects attributed to the drug. When compared with topical antiseptic, analgesic, and anesthetic agent (benzalkonium chloride.%, choline salicylate 8.7% and lidocaine hydrochloride % paste. Hence topical amlexanox could be a treating modality for minor RA and has tremendous scope for further research in management this intractable condition. References. hip JA, Arbor A. Recurrent Aphthous tomatitis. Oral urg Oral Med Oral Pathol Oral Radiol Endod 996;8:4-7.. Mason J. Concepts in dental public health. Philadelphia: Lippincott Williams & Wilkins;.. cully C. Clinical practice. Aphthous ulcerations. N Engl J Med 6;: hip II. Epidemiologic aspects of recurrent aphthous ulcerations. Oral urg Oral Med Oral Pathol 97;():4-6.. Cooke BE. Recurrent oral ulceration. Br J Dermatol 969;8() Lehner T. Autoimmunity in oral diseases, with special reference to Recurrent oral ulceration. Proc R oc Med 968;6():-4.

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