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    Original Paper

    Dermatology 2013;226:4751 DOI: 10.1159/000346641

    Topical Treatment of Tinea Pedis Using 6%Coriander Oil in Unguentum Leniens: A Randomized,Controlled, Comparative Pilot Study

    F.C. Beikert a Z. Anastasiadou a B. Fritzen b U. Frank c M. Augustin a

    a Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg, Hamburg , b Department of Dermatology, Venerology and Allergology, HELIOS Hospital Krefeld, Krefeld , and c Department ofHospital Hygiene and Environmental Health, University Medical Center Heidelberg, Heidelberg , Germany

    Introduction

    Almost one fourth of the entire population is affected by fungal diseases of the skin, hair or nails [1] , with tinea pedis showing the highest prevalence of >5% [2] . By enter-ing through minimal cutaneous fissures, dermatophytes can penetrate through keratinized squamous epithelium of the human skin and thereby cause a symptomatic infec-tion [3] . The spectrum of the pathogenic agents varies widely between different regions [4] . In industrialized countries, tinea pedis is most frequently caused by Tricho-phyton rubrum, Trichophyton interdigitale and Epider-mophyton floccosum [3, 5, 6] . Potential risk factors include familial predisposition, male gender, diabetes mellitus, peripheral neuropathy, peripheral arterial occlusive dis-ease and the use of community swimming pools [7] . In the treatment of tinea pedis, topical agents are mostly used whereas systemic antimycotics such as azoles, hydroxypyr-idone or allylamine are restricted to severe cases. With a remarkably high rate of recurrences and patients being refractory to treatment, the management of tinea pedis represents a great challenge and might often be frustrating for both patients and therapists. Phytotherapeutics are widely used in medicine, e.g. for skin infections and chronic inflammatory skin diseases, and could serve as an

    Key Words Coriander oil Tinea pedis Fungal foot infection Trichophyton rubrum Trichophyton mentagrophytes Coriandrum sativum L.

    Abstract Background: The antifungal activity of coriander oil has al-ready been demonstrated in vitro. Objective: Evaluation of the efficacy and tolerability of 6% coriander oil in unguen-tum leniens in the treatment of interdigital tinea pedis. Methods: Half-side comparative pilot study on subjects with symmetric, bilateral interdigital tinea pedis. Active drug and placebo control were applied twice daily on the affected ar-eas, and follow-up visits were performed on days 14 and 28. Results: 40 participants (mean age 52.5 years, 60% male) were included in the study. For 6% coriander oil in unguen-tum leniens, a highly significant improvement of the clinical signs (p < 0.0001) was observed during the entire observa-tion period; the number of positive fungal cultures also tend-ed to decrease (p = 0.0654). The tolerability of the tested sub-stances was good. Conclusion: Coriander oil is effective and well tolerated in the treatment of interdigital tinea pedis.

    Copyright 2013 S. Karger AG, Basel

    Received: August 23, 2012 Accepted after revision: December 18, 2012 Published online: March 1, 2013

    Dr. med. Florian C. Beikert Institute for Health Services Research in Dermatology and Nursing University Medical Center Hamburg Martinistrasse 52, DE20246 Hamburg (Germany) E-Mail f.beikert @ uke.de

    2013 S. Karger AG, Basel10188665/13/22610047$38.00/0

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    alternative to established treatment regimens for tinea pe-dis. While various studies have proven the antimicrobial activity of coriander oil ( Coriandrum sativum L.) against Staphylococcus aureus and other Gram-positive and Gram-negative bacteria [813] , the antimycotic activity of coriander oil resulting in a growth inhibition of e.g. Mi-crosporum canis , Candida species, Aspergillus niger , and Penicillium species has only been demonstrated in vitro [1417] . The purpose of this study was to gain the first in vivo data on the antimycotic efficacy of coriander oil by using 6% coriander oil in unguentum leniens in the treat-ment of interdigital tinea pedis. Secondly, the skin toler-ability of the coriander oil was addressed.

    Patients and Methods

    The randomized, prospective, placebo-controlled, intraindi-vidual comparison pilot study was performed at the Department of Dermatology, Allergology and Venerology of the University Medical Center Freiburg, Germany. An approval of the local ethics committee was obtained prior to the initiation of the study. After granting written informed consent, adults of both genders with the clinical signs of a symmetric bilateral interdigital mycosis were in-cluded in the study. Exclusion criteria were lack of mental, physical or linguistic capacity for participation, treatment with systemic an-timycotics in the previous 4 weeks or the use of topically applied antimycotic agents in the week before the inclusion. The study medication consisted of an ointment of 6% coriander oil in un-guentum leniens (Oleum Coriandri e Semine; Caesar & Loretz GmbH, Hilden, Germany), which was prepared at the Pharmaceu-tical Department of the University Medical Center Freiburg, Ger-many. The concentration of 6% coriander oil was chosen due to the results of Reichling et al. [18] who found a significant fungal growth inhibition using this concentration of coriander oil. Un-guentum leniens served as placebo control. Study visits were per-formed at inclusion (t0), and after day 14 (t1) and day 28 (t2). At the inclusion visit (t0), data on demographics (age, gender, profes-sion) and preexisting diseases of the participants were recorded, and both study medication and placebo control handed out to the participants. Due to the inherent smell of the study medication, a blinded study design was not feasible. Randomization of the allo-cation of the study medication (active drug and placebo) to the two sides was conducted by coin flipping. In order to realize a com-parative half-side study, participants were instructed and trained to apply the active study drug and placebo as indicated twice daily directly on the affected areas. At each visit, clinical signs of the tinea pedis were scored using a 5-step scale (0 = none, 1 = minor, 2 = moderate, 3 = marked, 4 = severe) which was developed for this study and mycologic swabs of both feet were obtained. Mycologic examination included microscopy using 15% potassium hydrox-ide solution and fungal cultures on a Sabouraud agar (Merck, Darmstadt, Germany) for 5 weeks. If growth of Candida species was suspected, specimens were also cultured on rice extract agar (heipha Dr. Mller GmbH, Eppelheim, Germany) in order to dif-ferentiate Candida species. For data evaluation, positive fungal cultures (Candida species, T. rubrum, Trichophyton mentagro-

    phytes) were coded as 1 and negative cultures as 0. At both follow-up visits, participants and physicians rated the efficacy of the cori-ander oil using a visual analogue scale (0 = not effective, 1 = very good efficacy), and participants evaluated the tolerability of the tested substances on a visual analogue scale (0 = poor tolerability, 1 = very good tolerability). For statistical analyses, SAS for Win-dows (version 9.3) was used. Further analyses were performed us-ing nonparametric tests such as the sign test and Wilcoxon signed-rank test since the data were ordinally scaled and not normally distributed; 95% confidence intervals (CI) and quantiles were cal-culated. Significance was set at 5% (p 0.05). All analyses were performed using an intention-to-treat mode as soon as follow-up data were available.

    Results

    In total, 40 participants with clinical signs of interdig-ital tinea pedis were included in the study. Five partici-pants were lost to follow-up without known reasons be-fore any data documentation, leaving 35 subjects for data evaluation. The mean age of the participants was 52.5 years (range 1983), and 60% were male. In this study, 3 pathogenic agents were isolated ( T. rubrum, T. mentagro-phytes and Candida species). The latter was included in the analysis, although by definition it is not a typical caus-ative agent of tinea pedis.

    Efficacy For the entire observation period of 28 days, the num-

    ber of participants with clinical signs of mycosis was high-ly significantly lower on the side where 6% coriander oil in unguentum leniens was applied compared to the ve-hicle side (p < 0.0001; fig.1 ).

    In addition, a tendency towards less positive fungal cultures on the side where the active drug had been ap-plied compared to the control side was observed through-out the treatment period (p = 0.0654; fig.2 ). However, these results were not statistically significant.

    After 14 days, the participants rated the efficacy of the coriander oil as 0.71 (95% CI = 0.640.78) and the physi-cians as 0.67 (95% CI = 0.590.75). After 28 days, both participants and physicians perceived the efficacy of the coriander oil as rather good [0.8, 95% CI (participants) = 0.740.86; 95% CI (physicians) = 0.750.86].

    Tolerability At both follow-up visits, patients assessed the tolera-

    bility of coriander oil as very good (0.94, 95% CI = 0.900.98 on day 14 and 0.91, 95% CI = 0.860.95 on day 28). Side effects such as pruritus (n = 4/35) and burning sen-sation (n = 2/35) were rare.

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    Discussion

    The objective of this study was the evaluation of the antimycotic efficacy and tolerability of 6% coriander oil in unguentum leniens in the treatment of interdigital tin-ea pedis in order to gain the first in vivo data on the anti-mycotic activity of coriander oil. For 6% coriander oil in unguentum, a highly significant effect on the clinical symptoms and signs of tinea pedis was shown (p < 0.0001). Moreover, compared to controls, fungal cultures tended to decrease on the active drug side without reaching a level of significance (p = 0.0654), which might be attribut-able to the comparatively short follow-up period. Fur-

    thermore, the participants perceived the efficacy and tol-erability of the study medication as good. In this study, tinea pedis affected predominantly men (60%), which corresponded well to the published literature on this sub-ject [1921] and might be attributable to predisposing oc-cupational activities or less interest in cosmetics. Taking into account that the prevalence of fungal diseases in-creases with patients age [19, 22] , the mean age of the study participants (52.5 years) seems comparatively low.

    To date, the antimycotic efficacy of coriander oil against e.g. M. canis, C. albicans, A. niger, Penicillium spe-cies and Saccharomyces cerevisiae has only been demon-strated in vitro [1417, 23] . The proven antimicrobial ac-

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    Fig. 1. Clinical signs of tinea pedis at study visits (t0 = inclusion visit, t1 = day 14, t2 = day 28). Results of active drug (left col-umns) versus controls (right columns) in percent, n = 35.

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    Fig. 2. Positive mycologic cultures at study visits (t0 = inclusion visit, t1 = day 14, t2 = day 28). Results of active drug (left col-umns) versus controls (right columns) in percent, n = 35.

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    tivity of coriander oil might be attributable to the syner-gistic effect of the terpenes, in which the antimicrobial and antioxidant effect has been demonstrated for every single fraction [2428] . Conceivably, the antimycotic ef-fect of the coriander oil is due to a complex interaction of its single components. In previous studies, the main com-ponent of coriander oil, linalool, and other terpenes were deemed responsible for the growth inhibition of Candida species [29, 30] . The activity against dermatophytes could probably be explained analogously. However, to the best of our knowledge, no data on this subject have been pub-lished so far.

    Many studies have focused on the allergenic potential of coriander oil and linalool. Only a few cases of IgE-me-diated coriander allergies have been reported exclusively in patients that were professionally exposed to coriander [31] . Allergic contact dermatitis may rarely be caused by coriander [32, 33] with its ingredient linalool being iden-tified as a putative type IV allergen [34] . In conclusion, in this study, coriander oil shows an efficacy superior to controls with a subjectively good efficacy and only minor side effects. When interpreting the study results, one has to consider that the number of participants with clinical

    signs of an interdigital mycosis and the number of par-ticipants with positive fungal cultures also decreased in controls, which raises the question whether unguentum leniens itself represents a suitable placebo in studies eval-uating the anti-inflammatory potential of test substances. Besides the comparatively small number of patients, a further limitation of this pilot study was the lack of a blinded study design due to the inherent smell of the test substance. The interpretation of the study results should therefore be performed with precaution and conclusions need to be supported by further clinical trials including a larger patient sample. As a result of the proven antimicro-bial, anti-inflammatory and antimycotic activity, corian-der oil could be considered as a treatment option in vari-ous indications including acute skin infection (e.g. tinea pedis) and chronic inflammatory skin diseases (e.g. atop-ic dermatitis).

    Disclosure Statement

    F.C. Beikert, Z. Anastasiadou and B. Fritzen have no conflict of interests. U. Frank and M. Augustin are German patent holders of some coriander preparations.

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