Short Communication A comparative study to evaluate efficacy, safety and cost- effectiveness between Whitfield’s ointment + oral fluconazole versus topical 1% butenafine in tinea infections of skin Saket J. Thaker, Dimple S. Mehta, Hiral A. Shah1, Jayendra N. Dave1, Kunjan M. Kikani2 ABSTRACT Aims and Objectives: The aim of this study is to compare the efficacy, safety and cost-effectiveness of topical Whitfield’s ointment plus oral fluconazole with topical 1% Departments of Pharmacology, butenafine in tinea infections of the skin. 1Dermatology Venereology and Materials and Methods: Patients were randomly allocated to the two treatment groups Leprology, and 2Microbiology, and advised to apply either agent topically twice-a-day for 4 weeks on the lesions and C.U. Shah Medical College, fluconazole (150 mg) was administered once a week for 4 weeks in the study group Surendranagar, Gujarat, India applying Whitfield’s ointment. Patients were followed-up at an interval of 10 days for clinical score and global evaluation response was assessed at baseline and during each Received: 29-08-2012 follow-up. Revised: 09-04-2013 Results: Out of 120 patients enrolled in the study 103 completed the study. Patients Accepted: 03-07-2013 treated with Whitfield’s ointment and oral fluconazole reduced mean sign and symptom Correspondence to: score from 8.81 ± 0.82 to 0.18 ± 0.59 while butenafine treated patients reduced it from Dr. Saket J. Thaker, 8.88 ± 0.53 to 0.31 ± 0.67 at the end of the treatment. Nearly, 98% patients were completely rd E-mail: [email protected] cleared of the lesion on the 3 follow-up with both treatments. Conclusion: Whitfield’s ointment with oral fluconazole is as efficacious, safe and cost- effective as compared with 1% butenafine in tinea infections of the skin. KEY WORDS: Butenafine, fluconazole, tinea infections, Whitfield’s ointment Introduction in tinea infections of the skin. The primary objective was to assess the cure rate, relapse, safety and cost-effectiveness of Dermatophytoses are fungal infections of keratinized tissue both treatments while secondary objective was to assess the (hair, skin, and nails).[1] Whitfield’s ointment is one of the oldest Clinicomycological correlation and to study the distribution of and cheapest antifungal agent containing 3% of salicylic acid different species of tinea. and 6% of benzoic acid.[2,3] Fluconazole is a fungistatic that impairs fungal cell wall synthesis by inhibiting the enzyme Materials and Methods 14-α lanosterol demethylase.[4] Their combination enhances The study was registered with Clinical Trial Registry of India the efficacy and minimizes the chances of relapse. Butenafine is a benzylamine group of fungicidal drug, which impairs (CTRI/2012/08/002914 and was approved by ethics committee fungal cell wall synthesis by inhibiting the enzyme squalene of the teaching hospital. It was a prospective, randomized, epoxidase.[4] The present study was under taken to compare open-label, controlled, comparative clinical study, conducted in the efficacy, safety and cost-effectiveness of topical Whitfield’s patients attending the skin out-patient Department of C U Shah ointment plus oral fluconazole with topical 1% butenafine Medical College and Hospital, Surendranagar from May 2009 to November 2009. Diagnosis of tinea infections was performed Access this article online by the Dermatologist. Patients newly diagnosed with tinea Quick Response Code: infections of skin were included in the study while follow-up Website: www.ijp-online.com cases, pregnant or lactating women, patients having an allergy DOI: 10.4103/0253-7613.121378 to imidazoles or allylamines were excluded. All patients were explained about the study and written informed consent was obtained. Patients were randomly allocated in two groups. Group A received topical Whitfield’s ointment to be applied twice-a-day for 4 weeks plus oral fluconazole (150 mg once a 622 Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 week for 4 weeks) while Group B received topical 1% butenafine Graph Pad Instat 3.0 was used for the statistical analysis. cream twice-a-day for 4 weeks. All patients were administered Normality of the data was checked by Kolmogorov Smirnov oral chlorpheniramine maleate (4 mg) twice-a-day for a month test. Mann Whitney test was used to compare the groups to relieve pruritus. Whitfield’ ointment, fluconazole (150 mg) with respect to age. Fisher’s exact test was used to find the and 1% butenafine were purchased from the pharmacy store difference in both groups in terms of gender distribution. of the hospital. Baseline comparison of sign and symptom score between the Skin scraping was collected on the slides having 1-2 drops of groups was performed by Mann Whitney test. Total score of 20% KOH and observed under ×10 and ×45 of the microscope erythema, pruritus and scaling before and after treatment at each follow-up [Figure 1].[1,5] The scraping were cultured was compared by Wilcoxon matched pair test. Chi-square on the plates of Sabouraud’s agar supplemented with 1% test was used to compare global evaluation score between chloramphenicol in the incubator at 32-35°C for 7-10 days. The both groups at each follow-up. P < 0.05 was considered to species were identified by lactophenol cotton blue preparation. be statistically significant. Cost-effectiveness was calculated Photographs of both gross cultures and microscopic appearance on the basis of total expenditure incurred on medicines, cost of lactophenol cotton blue preparation were taken. Patients were of conveyance at the end of treatment in ` Indian rupee and followed-up at the interval of 10 days for 4 weeks to assess the cure rate in percentage. Incremental cost (ΔC) and incremental [9] relapse. Outcome of the treatment was assessed by the clinical effectiveness (ΔE) were calculated. [6,7] and mycological care. Results Clinical cure was assessed by scoring of three parameters Out of 120 patients enrolled in the study, 8 patients from that is erythema; pruritus and scaling, Each parameter was group A and 9 patients from group B were lost to follow-up and categorized into - mild - 1, moderate - 2, severe - 3. Global 103 patients completed the study. Evaluation Response was assessed at each follow-up.[7] Mycological cure was assessed by examining skin scraping Demographic Characteristics microscopically and culture. Both KOH and culture negative Median age in both groups was 35 years. Both groups were specimens were considered mycologically cured. also similar in terms of gender distribution (P = 0.1209). Tinea corporis was the most common diagnosis (37.84%) followed Statistical Analysis by tinea corporis and cruris mixed infection (30%). Most of the Sample size calculation patients (96.12%) were suffering from severe tinea infections Sample size was calculated by nMaster 1.0. As no previous at the first visit. Trichophyton mentagrophytes (60.94%) was studies have been conducted between combination of Whitfield’s the most common species followed by Trichophyton rubrum ointment and oral fluconazole, a pilot study on 10 patients was (28.12%). carried out to assess the cure rate. As per the result of the pilot Efficacy study, cure rate with Whitfield’s ointment + oral fluconazole was Combination of Whitfield’s ointment and oral fluconazole [8] taken as 90% and as per study by Tschen et al. cure rate with treatment and butenafine significantly reduced mean sign and butenafine was taken as 88%. Assuming population difference symptom score (P < 0.0001). Global Evaluation Response revealed of proportions as 0.085, setting alpha error at 5% and power that skin lesions were completely cleared with Whitfield’s ointment of study at 80% and using two sided test, 104 patients were + oral fluconazole and butenafine creamin majority of the patients needed. Assuming a dropout rate of approximately 15 20%, a (98%) [Table 1]. At the end of treatment, 97% of the patients in both total 120 patients were enrolled for the study. groups were mycologically cured and no relapse was observed in both treatment groups at the end of 4 weeks. Figure 1: Butenafine is less cost-effective as compared to the Safety combination treatment of Whitfield’s ointment and oral fluconazole. Both drug treatments were well-tolerated. However, two ∆C-Incremental cost, ∆E-Incremental effectiveness, L-line – Line patients complained of burning and one patient complained of passing from 0–, Red Dot-Showing cost-effectiveness redness with Whitfield’s ointment. Gastritis was reported in one patient with fluconazole. No adverse event was reported with 1% butenafine. Cost-Effectiveness Cost per patient for complete treatment for Whitfield’s ointment plus fluconazole was ` 293.49, while that for butenafine was ` 707.60. ΔC was ` 414.11 and ΔE was 0.08 (ΔE). The line passing from 0 is called L-line. The zone below the line is acceptable zone. In the present study, the difference lies above L-line shown by the red dot. This represents that butenafine was less cost-effective as compared to Whitfield’s ointment + oral fluconazole. Discussion This study combined Whitfield’s ointment and oral fluconazole to minimize the chances of relapse as both are Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 623 Table 1: Global evaluation response of patient treated with Wf+flu and topical butenafine at different time interval Response Follow-up 1 Follow-up 2 Follow-up 3 Wf+flun (%) Butenafine n (%) Wf+flu (%) Butenafine (%) Wf+flu n (%) Butenafine (%) Cleared 00 (0) 00 (0) 40 (76.92) 32 (62.74) 51 (98.08) 50 (98) Excellent 49 (94.23) 41(80.39) 11 (21.15) 18 (35.29) 01 (1.92) 01 (2) Good 02 (3.85) 08 (15.69) 01 (1.92) 01 (1.96) 0 (0) 0 (0) Fair 01 (1.92) 02 (3.92) 0 (0) 0 (0) 0 (0) 0 (0) Values are in absolute numbers.