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Table of Contents   
ORIGINAL RESEARCH  
Year : 2013  |  Volume : 24  |  Issue : 5  |  Page : 593-598
A clinical evaluation of 5% amlexanox oral paste in the treatment of minor recurrent aphthous ulcers and comparison with the placebo paste: A randomized, vehicle controlled, parallel, single center clinical trial


1 Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Centre, Whitefield, India
2 Department of Oral Medicine and Radiology, The Oxford Dental College and Hospital, Bommanahalli, Bengaluru, Karnataka, India

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Date of Submission09-May-2012
Date of Decision12-Jun-2013
Date of Acceptance12-Jul-2013
Date of Web Publication21-Dec-2013
 

   Abstract 

Objectives: The primary objective of the following study is to determine and secondary objective is to compare the efficacy and safety of 5% amlexanox oral paste in the treatment of recurrent minor aphthous ulcers and also to evaluate the recurrence rate of aphthous ulcers over a period of 1 year.
Materials and Methods: The present study was conducted on 100 patients diagnosed to have recurrent minor aphthous ulcers of which, 50 patients were advised to apply 5% amlexanox oral paste directly on the ulcer 4 times a day for 6 days and the other 50 patients were given placebo paste for the same duration. The baseline parameters were recorded on the first visit which includes ulcer size, pain, erythema and exudation. Efficacy and safety evaluations were made on the 4 th day and 6 th day. In total 30 patients with increased frequency of ulcers were advised to use 5% amlexanox paste for one whole year and the number of ulcers per month was recorded to evaluate any decrease in the recurrence rate.
Results: Male patients dominated the study with 73 males and 27 females. The mean age of the total sample was 26.6 years. The amlexanox group showed marked reduction in ulcer size (P < 0.001), significant reduction in the visual analog scale scores of pain (P < 0.001), significant lower scores of erythema and exudation (P < 0.001) when compared to the placebo group on the 6 th day of follow-up. The incidence of recurrence of ulcers was significantly reduced up to the 6 th month, but thereafter recurrence rate slowly increased.
Conclusions: Almost 5% of Amlexanox oral paste is clinically beneficial in reducing the pain, erythema, exudation and size of the ulcer over a period of 6 days. There was no definite conclusion drawn with respect to its effect on the recurrence rate of aphthous ulcers over a period of 1 year.

Keywords: Amlexanox oral paste, recurrent aphthous ulcers, visual analogue scale

How to cite this article:
Bhat S, Sujatha D. A clinical evaluation of 5% amlexanox oral paste in the treatment of minor recurrent aphthous ulcers and comparison with the placebo paste: A randomized, vehicle controlled, parallel, single center clinical trial. Indian J Dent Res 2013;24:593-8

How to cite this URL:
Bhat S, Sujatha D. A clinical evaluation of 5% amlexanox oral paste in the treatment of minor recurrent aphthous ulcers and comparison with the placebo paste: A randomized, vehicle controlled, parallel, single center clinical trial. Indian J Dent Res [serial online] 2013 [cited 2019 Nov 14];24:593-8. Available from: http://www.ijdr.in/text.asp?2013/24/5/593/123382
Recurrent aphthous ulceration (RAU) is the most common ulcerative disease of the oral mucosa making the diagnosis and management of these recurring oral lesions common problems in general and speciality dental practice. As high as 15-25% of the population are thought to have these ulcerations and yet these lesions are still poorly understood. Although many exacerbating factors have been identified, the cause as yet remains unknown. [1] Etiologic factors such as local trauma, immunodeficiency, genetic background, allergic agents, nutrition deficiency, hormonal changes in women, physical or psychic stress, chemical irritants and infective agents have been proposed. [1],[2],[3],[4]

They appear as small, round to ovoid, recurrent, moderately painful ulcers that affect non-keratinized oral mucosa such as buccal mucosa, lateral and ventral aspects of the tongue, floor of the mouth, soft palate and oropharyngeal mucosa with a crateriform base covered by a greyish white pseudomembrane and surrounded by a distinct erythematous halo. [2],[3] They may severely interfere with eating, speaking and swallowing. [2]

Due to uncertain etiology and unpredictable course of the disease, the primary goals of therapy are to control the pain of ulcer, promote ulcer healing and prevent recurrence. [3] There is no curative therapy to prevent the recurrence of ulcers and all available treatment modalities can only reduce the frequency or severity of the lesions. [5] Although topical agents do not prevent ulcer recurrence they are arguably the most commonly used treatment. Topical agents available for symptomatic relief includes antibiotics, local anesthetics, antihistamines, non-steroidal anti-inflammatory drugs, gamma globulins and immunosuppressants. [6]

Amlexanox (C 16 H 14 N 2 O 4 ) is one of the most extensively studied topical agents available for treatment of RAU. It is an anti-inflammatory, anti-allergic drug, can inhibit the formation and release of histamine and leukotrienes from mast cells, neutrophils and mononuclear cells. [2],[6] Various studies have demonstrated that 5% amlexanox paste accelerates ulcer healing and resolution of erythema, pain and lesion size of RAU. It was noted that 5% amlexanox paste might be beneficial if commenced during the prodromal stage of ulceration. [6] Amlexanox oral paste has been specifically formulated to adhere to the oral mucosa, thus limiting the likelihood that the drug will be rubbed away or rinsed away with saliva flow (as per the manufacturer's instructions) (Macleods Pharmaceuticals® ).

The aim of the present study was twofold. Firstly, the efficacy and safety of topical 5% amlexanox oral paste at the onset of prodromal symptoms or at the onset of RAU were evaluated and compared with those receiving no treatment. Secondly, the recurrence rate of aphthous ulcers over a period of 1 year among these patients was determined.


   Materials and Methods Top


Study design

The study was a single center, open, parallel comparison study with subjects allocated to one of two treatment groups. Ethical approval for the study was obtained from the Research Ethics Committee, The Oxford Dental College and Research Center, Rajiv Gandhi University of Health Sciences. A total of 100 patients diagnosed to have recurrent minor aphthous ulcers were selected from among the out-patients attending the Department of Oral Medicine and Radiology and all subjects gave their written informed consent [Table 1].
Table 1: Selection criteria


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Materials

Amlexanox is 2-amino-7-isopropyl-5-oxo-5H-(1) benzopyrano-(2, 3-b) pyridine-3-carboxylic acid. The study drug Lexanox was supplied by Macleod's pharmaceuticals, India, in plastic tubes containing 5 g of oral paste. It contains 5% amlexanox with mineral oil, gelatin, pectin, carboxymethlycellulose sodium, methylcellulose sodium, glycerol and white petroleum. Placebo paste contained the above mentioned excipients except the active ingredient (amlexanox). This agent was produced and packaged by Shristi Pharmaceuticals, Bangalore.

Subjects

Patients reporting with single or multiple minor aphthous ulcers less than 72 h old visiting the out-patient of Oral Medicine clinic were recruited. Out of the 100 patients, 50 patients were advised to apply 5% Lexanox oral paste and the other 50 patients were given placebo paste.

Patients with multiple ulcers, only one ulcer that occurred most recently and/or in an area easily accessible was chosen for evaluation. Detailed case history comprising the baseline parameters (number of ulcers, ulcer size, pain, erythema and exudation) were recorded on the first visit before the drug application. Investigator supervised the first application of the drug and provided the subject with written instructions on how to apply the drug.

The patients were advised to apply the drug as soon as possible after noticing the symptoms of an aphthous ulcer, 4 times a day, preferably following oral hygiene, after breakfast, lunch, dinner and at bedtime. They were asked to squeeze out approximately ¼ inch (0.5 cm) of the paste from the tube on a clean fingertip and apply to the site of the ulcer. They were told to apply the paste after drying the ulcer by gently patting it with a soft piece of clean cotton.

Evaluation of efficacy

To measure pain, a visual analog scale (VAS) consisting of a 10 cm horizontal line between poles connoting no pain to unbearable pain was used. The subjects were told to mark the line with a vertical line at the point that best represented the present pain level of the ulcer. The maximum diameter of the ulcer was assessed by the investigator with a William's calibrated periodontal probe on day 0 and on treatment days 4 and 6 to evaluate the short-term benefits of the intervention as RAU has a self-limited history. The degree of erythema and exudation was evaluated on a 4-point scale ranging from 0 to 3 based on the methods of Greer et al. with some modifications [4] [Table 2].
Table 2: Erythema and exudation levels


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The efficacy indices (EI) of the ulcer size and pain improvement were calculated with the following formula (V4 and V6 refer to the values measured at day 4 visit and day 6 visit, while V1 refers to the baseline value measured before the study entry):

EI = ([V4 or V6−V1] χ V1) × 100%

The EI were evaluated on a 4-rank scale:

  • Heal: EI = 100%
  • Marked improvement: 100% >EI ≥70%
  • Moderate improvement: 70% >EI ≥30%
  • No improvement: EI <30%


A total of 30 subjects with increased frequency of ulcers from the amlexanox group were followed up for a year from the date of commencement of treatment to determine the recurrence rate of the ulcers.

Safety evaluation

Physical examination was performed at the screening visit and final visit. Subjects were specifically questioned about adverse events at each visit and were recorded in the case report forms.

Statistical methods

All randomized subjects were analyzed in terms of demographic and baseline characteristics. A P < 0.05 was taken to indicate statistical significance. A group difference between the amlexanox group and the placebo group was evaluated for each visit. Student t-test was used to find the significance between amlexanox group and placebo group for parameters on the continuous scale. Mann-Whitney U-test was used to find the significance between two groups for parameter on the non-interval scale. Chi-square test was used to find the significance of the frequency of RAU over a period of 1 year.


   Results Top


A total of 100 patients with minor recurrent aphthous stomatitis were enrolled in this study. They were randomly divided into two groups, placebo group (n = 50) and amlexanox group (n = 50) and patients of both groups were clinically evaluated and later compared the topical efficacy of 5% amlexanox oral paste and placebo in the treatment of recurrent minor aphthous ulcers.

The mean age of the subjects was about 27 years old, which may reflect the subject population mostly affected. The number of male patients dominated in the present study with 68% (37) in the placebo group and 72% (36) in the amlexanox group.

Reduction in ulcer size

The 1 st day, size of the ulcer (mm) was recorded for all the patients. Following application of amlexanox and placebo paste, the patients were recalled on the 4 th and the 6 th day and the ulcer size was again recorded. The amlexanox group had a statistically significant improvement between the 1 st and 4 th day (2.65 ± 1.51-1.93 ± 1.29), when compared with that of the placebo controlled group (2.58 ± 1.03-2.92 ± 0.80). At the day 6 visit, the amlexanox group maintained a significantly greater effectiveness between the 4 th day and the 6 th day (1.93 ± 1.29-0.70 ± 0.79), when compared with that of the placebo group (2.92 ± 0.80-2.42 ± 0.70). At day 6 visit, compared with those of the placebo group, the amlexanox group maintained a significantly greater efficacy index (P < 0.001**), the "improvement" rate (96% vs. 36%), and "marked improvement" rate (56% vs. 2%).

Although the mean ulcer size of the amlexanox group and placebo group matched well at the study entry, significant group differences appeared at the later visits. Ulcer size between the amlexanox and placebo controlled groups was significantly different at the day 4 and day 6 visit (P < 0.001**) [Table 3], [Table 4] and [Figure 1].
Figure 1: Comparison of size of recurrent aphthous ulceration ulcers between both groups

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Table 3: Comparison of ulcer size and pain score between two groups


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Table 4: Efficacy of ulcer size reduction on 6th day of visit


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Moderation of pain

At the study entry, the mean ulcer pain of the two groups matched well (P = 0.315), but it was later significantly relieved in the amlexanox group. At the day 4 visit, the effectiveness index of the amlexanox group was much greater than that of the placebo controlled group (P < 0.001). The amlexanox group had a statistically significant marked improvement between the 1 st and 4 th day (7.74 ± 1.01-3.04 ± 1.46), when compared with that of the placebo controlled group (7.52 ± 1.17-6.82 ± 1.21). At the day 6 visit, the amlexanox group maintained a significantly greater effectiveness between the 4 th day and the 6 th day (3.04 ± 1.46-0.80 ± 0.83), when compared with that of the placebo group (6.82 ± 1.21-5.86 ± 1.44) [Table 3], [Figure 2]. At day 6 visit, compared to those of the placebo group, the amlexanox group maintained a significantly greater efficacy index (P < 0.001**) and "marked improvement" rate (98% vs. 4%) [Table 5].
Figure 2: Comparison of pain score (visual analog scale) between both groups

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Table 5: Efficacy of ulcer pain moderation on 6th day of visit

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Reduction in erythema

Out of 50 patients in the amlexanox group, the ulcers in 10 patients were "red but not dark in color" and in 40 patients they were "very red, dark in color" on the 1 st day. At the day 4 visit, ulcers in 24 patients were "light red/pink", in 22 patients they were "red but not dark in color" and in 4 patients they were "very red, dark in color" At the day 6 visit, ulcers in 23 patients had no erythema, in 25 patients it was "light red/pink" and in 2 patients it was "red but not dark in color".

Out of 50 patients in the placebo group, the ulcers in 7 patients were "red but not dark in color" and in 43 patients they were "very red, dark in color" on the 1 st day. At the day 4 visit, ulcers in 21 patients they were "red but not dark in color" and in 29 patients they were "very red, dark in color" At the day 6 visits, ulcers in 7 patients were "light red/pink" and in 43 patients it was "red but not dark in color" [Table 6].
Table 6: Comparison of the erythema and exudation levels between the two groups


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Reduction in exudation

In the amlexanox group, the ulcers in 2 patients had "light exudation", 24 patients had "moderate exudation" and 24 patients had "heavy exudation with pseudomembrane" on the 1 st day. At the day 4 visit, ulcers in 10 patients had "no exudation", 23 patients had "light exudation", in 16 patients it was "moderate exudation" and in 1 patient the ulcer had "heavy exudation with pseudomembrane". At the day 6 visit, ulcers in 37 patients had "no exudation" and in 13 patients it was "light exudation".

Out of 50 patients in the placebo group, the ulcers in 26 patients had "moderate exudation" and 26 patients had "heavy exudation with pseudomembrane" on the 1 st day. At the day 4 visit, ulcers in 1 patient had "light exudation", in 43 patients it was "moderate exudation" and in 6 patient the ulcer had "heavy exudation with pseudomembrane". At the day 6 visit, ulcers in 25 patients had "light exudation" and in 25 patients it was "moderate exudation" [Table 6].

Recurrence rate of RAU ulcers in amlexanox group

Totally 30 patients from the amlexanox group were followed up for a period of 1 year and checked for the recurrence of ulcers. The number of ulcers during every episode was recorded every month. Recurrence of ulcers is significantly reduced up to visit 6 but after visit 7 recurrence rates slowly started increasing as shown in the trend line [Figure 3].
Figure 3: Depicting smile line trend of initial decrease and later increase in recurrence of recurrent aphthous ulceration ulcers

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Safety evaluation

There were a total of 8 patients belonging to the amlexanox group who complained of adverse events during the study. 3 patients complained of a transient "stinging" at the application site, which was considered to be mild in severity and probably related to the studied medications. 2 patients complained of a metallic taste in the oral cavity soon after application of the paste. 3 other patients complained of a "cooling" sensation at the application site following which they felt slight discomfort for a few minutes. None of these 8 cases discontinued the trial due to the adverse events.


   Discussion Top


The success in the treatment of RAU is fraught with difficulty owing to the large number of etiological factors. There is no definite curative treatment for the same. Hence, any treatment modality for RAU is aimed at decreasing the symptoms, reducing recurrences of ulcers and increasing disease-free intervals.

Not all treatment modalities are successful at achieving all these goals. Reduction in symptoms seems to be all that most modalities are able to offer. Therefore, it is important to critically evaluate any clinical trial to determine if a medication should be recommended for widespread use.

For treatment of RAU, topical medications has played a crucial role in reducing ulcer pain and accelerating ulcer healing. [2] Amlexanox has recently been found to have a significant role in management of minor aphthous ulcers. The present study aimed at evaluating the potential of this drug in reducing the size of the ulcer, pain, erythema and exudation. In this study, the number of male patients dominated with 68% in the placebo group and 72% in the amlexanox group. Labial mucosa, buccal mucosa and tip of the tongue were the most common sites of lesions observed during the study. On the 6 th day of treatment, the ulcer size in the amlexanox group showed statistically significant (P < 0.001) reduction when compared to placebo group. This finding was matching the results of the studies by Liu et al., Greer et al., Khandwala et al. and Meng et al. [2],[3],[4],[7]

Both groups had a reduction in the VAS scores throughout the treatment period. This indicates that both amlexanox and the placebo could bring about reduction in the pain associated with ulceration. However, on comparing the two groups, the patients on amlexanox had a statistically lower (P < 0.001) VAS values than the placebo group. This indicates that amlexanox has a significant therapeutic effect. This was in accordance with studies conducted previously by Meng et al., Liu et al., Greer et al. and Khandwala et al. [2],[3],[4],[7]

Even though both the groups showed improvement in erythema and exudation associated with RAU, there was significant lower scores (P < 0.001) among amlexanox group when compared to the placebo group. Similar observations were reported by Liu et al., Greer et al., Khandwala et al. and Meng et al. [2],[3],[4],[7]

In a study by Greer et al. proposed that the treatment effect is caused by inhibition of histamines and leukotrienes in the development of an aphthous ulcer in the oral mucosa; although the exact working mechanism is still unclear. [4] Scully were of the opinion that the cyclic nature of RAU makes it difficult to conduct a well-designed prospective double-blind controlled clinical study. Some patients of RAU have mild outbreaks, whereas others have severe and longer episodes. Some patients have fewer ulcers, whereas others present with larger or combination of small and large ulcers. In some, the severity and frequency of outbreaks ease with passing of years; in others, it worsens. All these factors contribute for the inconsistency in the vast literature on the treatment of RAU. [8]

We found that there was some effect for pain relief and healing in the placebo group as well. Three possible reasons have been proposed to explain this phenomenon. First, the cellulose recipients may have formed a protective film to cover the ulcer and therefore, produced some curative effect. Second, minor aphthous ulcers are a self-limiting disease, which can get relief without any treatment. Finally, stress factors have been known as etiologic factors, and subjects of the placebo group might be consoled by the feeling of "being treated" in the trial. [2]

In the present study, 30 patients on 5% Amelaxnox oral paste were followed up for a period of 1 year. It showed some improvement in the recurrence of ulcers up to the 6 th month, but it slowly started increasing thereafter. No such follow up studies on 5% amlexanox oral paste have been reported in the previous literature. Only one article mentions about the role of 5% amlexanox in decreasing the recurrence of ulcers. [6]

Nearly 5% amlexanox oral paste was well tolerated during the study period with negligible adverse effects. Few patients complained of a transient "stinging" sensation that was mild in severity, metallic taste in the oral cavity soon after application of the paste and "cooling" sensation at the application site. It is probable that these transient reactions were caused by benzyl alcohol in the paste or by mechanical irritation of the coarse paste on an open ulcer. [9] Until date, there is lack of complete details into the exact etiology and causative factor of RAU. [10] This probably is one of the reasons why until date there is no cure for this disease. Until a definitive treatment for RAU surfaces, topical analgesic, anesthetic and anti-inflammatory like amlexanox have a definite role to play in controlling disease process of RAU and can be safe alternative for corticosteroids. When administered for a period of 1 year whenever the ulcer developed, is not associated with any adverse effects. This shows a tremendous scope for further research for use of amlexanox in management of an intractable condition like RAU.

Any relief for the vexing problem of RAU would be welcomed by the millions of patients who suffer from this condition and by the clinicians who treat it. The difficulty lies in our ability to distinguish those treatments for this self-limiting problem that are clinically effective from those that have no real value.

In this study, we have demonstrated that amlexanox oral paste reduces aphthous ulcer erythema and exudation, lesion size and pain with a good safety record. Furthermore, because amlexanox oral paste is easy to use without any unfavorable taste and was easy for patients to carry, a large number of patients showed preference for it over other agents. The drug is easily available in local pharmacies with the trade names of "Amlenox" and "Lexanox" with the cost ranging from 60 to 65 rupees/5 g tube. Therefore, in clinical practice, amlexanox oral paste may be a better choice for RAU patients. However, studies on a larger series of patients for a longer duration may be required in order to determine the true therapeutic effects of 5% amlexanox oral paste on the recurrence of minor recurrent aphthous stomatitis.

 
   References Top

1.Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol 1992;74:79-86.  Back to cited text no. 1
[PUBMED]    
2.Liu J, Zeng X, Chen Q, Cai Y, Chen F, Wang Y, et al. An evaluation on the efficacy and safety of amlexanox oral adhesive tablets in the treatment of recurrent minor aphthous ulceration in a Chinese cohort: A randomized, double-blind, vehicle-controlled, unparallel multicenter clinical trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:475-81.  Back to cited text no. 2
[PUBMED]    
3.Khandwala A, Van Inwegen RG, Charney MR, Alfano MC. 5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers: II. Pharmacokinetics and demonstration of clinical safety. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:231-8.  Back to cited text no. 3
[PUBMED]    
4.Greer RO Jr, Lindenmuth JE, Juarez T, Khandwala A. A double-blind study of topically applied 5% amlexanox in the treatment of aphthous ulcers. J Oral Maxillofac Surg 1993;51:243-8.  Back to cited text no. 4
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5.Ship JA. Recurrent aphthous stomatitis. An update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:141-7.  Back to cited text no. 5
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6.Murray B, Biagioni PA, Lamey PJ. The efficacy of amlexanox Ora Disc on the prevention of recurrent minor aphthous ulceration. J Oral Pathol Med 2006;35:117-22.  Back to cited text no. 6
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7.Meng W, Dong Y, Liu J, Wang Z, Zhong X, Chen R, et al. A clinical evaluation of amlexanox oral adhesive pellicles in the treatment of recurrent aphthous stomatitis and comparison with amlexanox oral tablets: A randomized, placebo controlled, blinded, multicenter clinical trial. Trials 2009;10:30.  Back to cited text no. 7
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8.Scully C. Clinical practice. Aphthous ulceration. N Engl J Med 2006;355:165-72.  Back to cited text no. 8
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9.Bell J. Amlexanox for the treatment of recurrent aphthous ulcers. Clin Drug Investig 2005;25:555-66.  Back to cited text no. 9
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10.Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am 2005;49:31-47, vii-viii.  Back to cited text no. 10
[PUBMED]    

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Correspondence Address:
Suraksha Bhat
Department of Oral Medicine and Radiology, Vydehi Institute of Dental Sciences and Research Centre, Whitefield
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.123382

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