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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 5  |  Issue : 2  |  Page : 159-165

Preclinical pharmacological profile of Eberconazole: A review and update


1 Dr. Reddy's Laboratories Ltd., Hyderabad, Andhra Pradesh, India
2 Director of Research and Study Director, Indian Institute of Toxicology, Pune, Maharashtra, India
3 Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Hyderabad, Andhra Pradesh, India
4 Department of Pharmacology, Azeezia Medical College, Kollam, Kerala, India

Date of Web Publication1-Jul-2014

Correspondence Address:
Latha Subramanya Moodahadu
G5, Mount Meru Apt, Road 5, Avenue 7, Banjara Hills, Hyderabad - 500 034, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: Dr M S Latha, Dr Ashis Patnaik, Dr VV Arvind and Dr Shantala B, are the employees of Dr Reddy’s Laboratories Ltd., which is marketing Eberconazole in India. These authors are stakeholders having fi nancial stakes in Dr. Reddy’s Laboratories Ltd. by means of salary, company stocks or both. Dr Binny Krishnankutty & Dr Katta Kavitha are former employees of Dr Reddy’s Laboratories Ltd and presently not having any stakes in Dr. Reddy’s Laboratories Ltd. Dr RM Bhide is not having any confl ict of interest.

DOI: 10.4103/0975-9727.135757

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  Abstract 

Eberconazole is a broad-spectrum imidazole antifungal agent used as a topical preparation in the management of cutaneous mycoses. In vitro studies have shown that eberconazole is effective against dermatophytes, candidiasis, yeasts (including those which are triazole resistant) and Pityriasis versicolor. It inhibits fungal lanosterol 14α-demethylase, thereby inhibiting ergosterol synthesis leading to inhibition of fungal growth. In addition to its antifungal activity, it is also effective against Gram-positive bacteria, a property that is useful clinically. It also possesses anti-inflammatory property thus making it a suitable agent in the clinical management of inflamed cutaneous mycoses. Topical application of eberconazole was well tolerated in preclinical studies without any report of delayed hypersensitivity or photosensitivity reactions. There were no phototoxic effects. There was no significant systemic absorption. Animal toxicity studies have shown that it is safe, and the No Observed Effect Level was 2 ml/kg body weight in tested animals. It was not mutagenic and shared similar cytotoxicity profile with other imidazole antifungal products studied. Penetration studies using synthetic membranes revealed that eberconazole intrasets showed less variation as compared to clotrimazole and terbinafine intrasets. Overall amount of eberconazole released was more compared to comparators. In vitro and preclinical studies have demonstrated better therapeutic efficacy with eberconazole than clotrimazole and ketoconazole.

Keywords: Animal toxicity, dermatophytoses, eberconazole, inflamed cutaneous mycoses, no observed effect level, penetration study


How to cite this article:
Moodahadu LS, Patnaik A, Arvind VV, Bhide RM, Katta K, Krishnankutty B, Bellary S. Preclinical pharmacological profile of Eberconazole: A review and update. Muller J Med Sci Res 2014;5:159-65

How to cite this URL:
Moodahadu LS, Patnaik A, Arvind VV, Bhide RM, Katta K, Krishnankutty B, Bellary S. Preclinical pharmacological profile of Eberconazole: A review and update. Muller J Med Sci Res [serial online] 2014 [cited 2019 Oct 16];5:159-65. Available from: http://www.mjmsr.net/text.asp?2014/5/2/159/135757


  Introduction Top


Medical fraternity has witnessed an increase in the incidence [1] and change in the spectrum of superficial fungal incidence worldwide in the recent past due to changes in the lifestyle, increased migration, increase in clinical conditions such as diabetes mellitus and other immunocompromised states. [1],[2]

Topical agents are preferred in the management of fungal infections of the skin due to the advantages they offer i.e., ease of application, better local bioavailability, less systemic toxicity, shorter treatment period and reduced rate of recurrence. Among various available topical antifungal agents, azoles are the primary local antifungal agents due to their well-established efficacy and safety. Eberconazole, an imidazole derivative and effective topical antifungal agent, initially designed and investigated in Spain by Centro de Investigacion Wassermann, marketed by Salvat, was launched in 2005 and since then is available in the market. It is relatively new in Indian pharmaceutical market, available since 2007. In this paper, we have reviewed its preclinical pharmacology and toxicology.


  Eberconazole Top


Eberconazole ((1-(2,4-dichloro-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1H-imidazole) [Figure 1] is an imidazole antifungal with a broad spectrum of activity, effective against a wide range of yeast and fungi such as dermatophytes, candidiasis, yeasts (Malassezzia furfur) and Pityriasis versicolor in in vitro and animal studies. [3],[4],[5],[6] Its antifungal activity has been demonstrated in Candida albicans serotype B membrane protoplasts. This study also showed that minimal inhibitory concentration (MIC) of eberconazole increased 14-fold in the presence of isolated membrane phospholipids. [7] In vitro studies have demonstrated its efficacy against eight species of clinically relevant disease causing organisms such as Candida including Candida parapsilosis. In vitro studies have also demonstrated its efficacy against many triazole-resistant yeasts (Candida krusei and Candida glabrata) [8] and also fluconazole-resistant C. albicans. [4],[5] Studies have shown its efficacy against Gram-positive bacteria. [5] However, its broad spectrum action is limited compared to other agents such as echinocandins and the next generation triazoles. [5]
Figure 1: Stuctural formula of eberconazole

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Eberconazole is either fungicidal or fungistatic based on its concentration, having fungicidal activity at higher concentrations. It inhibits the ergosterol synthesis (inhibition of fungal lanosterol 14α-demethylase), an essential component of the cytoplasmic membrane thus leading to structural and functional changes, thereby inhibiting fungal growth. At high concentrations, it promotes leakage of smaller molecules from the cell membrane. It has also shown to possess anti-inflammatory activity in vivo, which is attributed to the inhibition of 5-lipoxygenase; it is also known to inhibit cyclooxygenase-2, though to a lesser extent, whereas it has not proved to inhibit cyclooxygenase-1. This property is useful in conditions such as inflamed cutaneous mycoses, thus favoring the reduction of inflammatory symptoms and enhancing treatment compliance. [9]

Eberconazole 1% cream is available in the market as an antifungal agent having characteristic molecular structure, which is both lipophilic-hydrophilic. This helps in better penetration of cell membrane by the drug and prolongs its duration of action. [10]


  Preclinical Pharmacology Top


Studies with the strain, Candida vaginalis serogroup B have shown that eberconazole binds to the lipid fraction of fungal membrane. The phospholipids sub-fraction of the membrane is responsible for binding and sterol synthesis is the intracellular target. [9] A comparative study with clotrimazole has shown that eberconazole showed more inhibitory activity against the phospholipid fraction of membrane protoplasts of C. albicans than clotrimazole. This study also showed that eberconazole was active against a wide range of yeast and fungi. [7]

It has shown to have anti-inflammatory activity in a dose-dependent manner, with an SD 50 of 65.5 mg/mL, which was comparable to that with acetyl salicylic acid (70.1 mg/mL) and ketoprofen (41.7 mg/ml). [9]

In vitro studies have shown that eberconazole is effective against disease causing Candida including C. parapsilosis (minimum inhibitory concentration 90, MIC 90 = 0.125 μg/ml). In this study, effects of eberconazole on clinical isolates of yeast including C. krusei, C. glabrata, C. albicans, and C. parapsilosis was studied. Eberconazole showed lower MIC values and excellent activity against triazole-resistant Candida species such as C. krusei and C. glabrata compared to ketoconazole and clotrimazole, with a statistically significant difference between eberconazole and ketoconazole. Majority of triazole-resistant yeasts (C. krusei and C. glabrata) and fluconazole-resistant C. albicans showed sensitivity to eberconazole. This study demonstrated excellent activity of eberconazole against C. krusei and T. glabrata; comparable efficacy to that of comparators was noted against C. albicans and C. parapsilosis.[4],[11] Although Cryptococcus neoformans isolates were less sensitive to eberconazole than to ketoconazole and clotrimazole, lower MIC values (0.162 μg/ml) were observed. [5] The antifungal activity of eberconazole against 124 clinical isolates of Candida, which included eight different species and 34 isolates of Cryptococcus neoformans was determined and was compared to that of clotrimazole and ketoconazole.[4],[11] In vitro activity of eberconazole was compared with clotrimazole, ketoconazole and miconaozole against 200 strains of dermatophytes. Eberconazole was more active (P < 0.05) than the other agents, against the majority of the species tested. [12]

Similar MICs were observed with eberconazole and clotrimazole in 116 strains of yeast and 45 dermatophytes, whereas bifonazoles produced different results with higher MICs and resistant strains, i.e., growth at concentrations above 40 μg/mlin C. tropicalis and C. albicans. Eberconazole produced the lowest MICs with Torulopsis. glabrata although they are only fungicidal in slightly >50% of the cases. It also demonstrated lowest MICs for T. mentagrophytes and fungicidal activity was not seen in the majority of strains. In M. canis and T. rubrum, it also appeared to be the antifungal with the greatest MIC in relation to other comparator imidazoles. [9]


  Efficacy Top


There has been encouraging results of anti-dermatophytic efficacy of various antifungal agents in optimized guinea pig models, which, were found to be highly reproducible and therefore, a useful tool in the primary screening of a compound. [13] The therapeutic efficacy of eberconazole 1% was similar with an excellent tolerance when compared to clotrimazole 1% in an experimental model of cutaneous candidiasis in guinea pigs, suggesting feasibility of the use of eberconazole in the management of skin infections in humans caused by C. albicans. [4],[9] Efficacy of eberconazole 1% cream was compared with clotrimazole 1% cream in experimentally produced candidiasis through a double blind comparative study in 22 male guinea pigs. Ten animals were in each study group and two animals did not receive treatment for the lesions caused. Eberconazole or comparator cream was applied at a dose of 1-1.3 g by means of finger massage. Treatment was suspended on 6 th day to collect samples on the following day. Treatment was reinitiated for 5 days. Samples were collected once again after a 2-day rest period. This study has shown that there was clinical recovery (disappearance of lesions and negative culture) in 9/10 animals in the group treated with eberconazole, whereas, clotrimazole produced lower cure rate (3/10). No clinical improvement of the lesion was observed in two cases in the clotrimazole group. In eberconazole group, mycological cultures were negative in all except one animal, which showed a lesser number of colonies of C. albicans. Eberconazole's antimicrobial activity was greater than clotrimazole against yeast, mould, and bacteria. It was more effective than clotrimazole in eliminating exogenous contamination on carriers in yeast, mould and bacteria. The antimicrobial activity of eberconazole was greater in yeasts and moulds than in bacteria. In a similar study in guinea pigs, eberconazole 1% cream showed a better clinical response as early as one week that became obvious from 14 days, and reduction of dermatophyte colonies isolated per culture compared to bifonazole 1%. [9]

Eberconazole 1% was similar in efficacy when compared to ketoconazole 1% cream in experimentally produced pityriasis in guinea pigs. The animals in both groups showed significant improvement and in many cases the lesions disappeared totally. Eberconazole also showed good local anti-inflammatory activity on application on the external ear [rats], which was comparable to that of acetyl salicylic acid and ketoprofen. [9]


  Animal Pharmacokinetics Top


Pharmacokinetic (PK) tests and bioavailability (BA) assay of eberconazole lotion was carried out on four minipigs in France, procured from Charles River. Two male and two female miniature pigs of the YUCATAN breed aged approximately 8-10 months were used. PK and BA were tested following topical application, using radiolabelled eberconazole (with C14) and intravenous administration. For topical application 10 g of cream was applied on about 100 cm 2 of the skin surface in the interscapular region and spread by gentle massage to favor the absorption. Its effect on applied on scarified skin (lanced used for finger pricking) was also studied. Blood and urine samples were collected at baseline and at subsequent intervals. Blood samples were taken after 30, 60, 90, 120, 240 and 480 minutes and 24, 32, 48, and 72 h post-administration. Urine and fecal samples were collected at 0-4 h, 4-8 h, 8-24 h and 48-72 h. The results of animal pharmacokinetic parameters studied are tabulated in [Table 1]. [9]
Table 1: Animal pharmacokinetic parameters of eberconazole

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In urine, 17.2% of the injected product was obtained whereas, 29.4% was obtained in feces. After 72 hrs of assessment (AUC 72 = 28.03), 46.6% of the injected product was recovered in urine and feces. On parenteral administration, 46.6% of the injected eberconazole was recovered in feces and urine. [9]

After topical administration on normal skin, area under curve (AUC) was 15.09 mm 2 in the 0-72 h period, which was remarkably low compared to that of intravenous administration. The elimination or recovery of the product in urine was 0.44% and 0.31% in feces in 0-72-h period; urinary elimination was significant in males in first few hours and fecal route of elimination was more significant in females. These results imply that topical administration of eberconazole does not reach the central compartment in quantifiable values. [9]

After topical administration to scarified skin, the AUC in the plasma according to time was 2.77 mm 2 compared with the 856.99 mm 2 of the AUC of intravenous administration, and bioavailability was 0.32%. Elimination of eberconazole in urine was 0.31% of the total administered. Its elimination in feces of female mini pigs was notable. Following the 72-h period, 0.42% of the product administered was recovered in feces. Total recovery was 0.72%. [9]

In albino rabbits, in therapeutic doses, eberconazole 1% cream, when applied on healthy skin was not absorbed. [9]


  Animal Toxicity of Eberconazole Top


The LD 50 (median lethal dose) of eberconazole was 1424.6 mg/kg with limits of 1127.3 and 1800.3 mg/kg per oral (p.o.) in Swiss albino male mice and 685.7 mg/kg p.o. with limits of 517.2 and 909.1 mg/kg p.o. in female mice. Testicular atrophy was noted in autopsy in male mice with relative reduction in testicular weight, which was 3.15 in control group and 1.93, 2.01, and 2.03 in the dose 1125, 1343, and 1651 mg/kg p.o. No notable effects were observed in females except for a greater toxicity of the product. [9]

In subchronic dermal toxicity tests at different doses, no toxic effects were seen when eberconazole lotion was applied to rats, rabbits and dogs in 28-day dermal toxicity study indicating a good safety profile. Histopathological toxicity tests did not show any significant lesions of nosological importance. No lesions or alterations attributable to the application of the eberconazole were observed. No neoplastic or degenerative necrotic lesions were noted in the animals studied. No systemic toxicity was seen with eberconazole 1% lotion via the dermal route for a period of 28 days in rats and rabbits treated up to 1000 mg/kg body weight. [14] Salmonella typhimurium reverse mutation assay of eberconazole lotion was negative. No mutations were noted in the mouse lymphoma thymidine kinase locus assay. [5] Eberconazole 1% w/w lotion was found to be safe in rabbits and rats when applied over a period of 28 days and the no observed effect level (NOEL) was 2 ml/kg in male and female animals. [14]

Eberconazole cream did not present allergic effects of skin sensitization (Buchler test) in guinea pigs under experimental conditions. No significant cytotoxic effects were seen in the BALB/3T3 cell lines and there was no significant difference between the cytotoxicity of eberconazole and other imidazole antifungal agents tested (miconazole, econazole, and clotrimazole). [9]


  Local Toxicity of Eberconazole Top


It was non-irritant in the primary ocular tolerance test with index of acute ocular irritation of 1.33. Local toxicity of eberconazole cream was compared to bifonazole in albino rats. Both produced similar degree of irritation, but eberconazole found to be slightly lesser irritant compared to bifonazole. It was non-irritant to vaginal mucosa of New Zealand rabbits. No allergy or hypersensitivity was observed as Buehler test was negative in guinea pigs. It shared similar cytotoxicity profile with other imidazole antifungal products studied i.e., miconazole, econazole, and clotrimazole when studied using BALB/3T3 cell line. Skin reaction score was measured using eberconazole 1% w/w lotion in Sprague Dawley rats (method of Draize). [9]

In Vitro [TAG:2] Penetration Studies[/TAG:2]

In vitro penetration studies were conducted for eberconazole cream 1% w/w and the data was compared with that of clotrimazole 1% w/w [Table 2] and terbinafine HCl 1% w/w [Table 3]. The studies were done using synthetic membranes through Franz diffusion cell. Two sets of three cells were tested with eberconazole against clotrimazole and terbinafine, separately and subjected to permeation. Solubility and sink conditions were tested using different media and back diffusion studies were also conducted.
Table 2: Comparison of penetration of eberconazole 1% cream and clotrimazole 1% cream

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Table 3: Comparison of penetration of eberconazole 1% cream and terbinafi ne1% cream

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These studies revealed that the release of the drug from eberconazole intra sets (set 1 and 2) showed less variation as compared to clotrimazole and terbinafine intrasets. Overall amount of eberconazole released was more compared to the other two drugs.

Viscosity of eberconazole was between 8.7 and 5.8 poise at 60-110 rpm whereas that of clotrimazole was between 6.6 and 4.8 poise at the same rpm. Flux ratio i.e., amount of drug released in μg/cm 2 for eberconazole with respect to clotrimazole ranged from 2.3 to 2.9 and that with respect to Terbinafine ranged from 1.8 to 2.01. Although viscosity of eberconazole was higher than clotrimazole, the penetration of ebrconazole was also significantly higher than clotrimazole.

In vitro penetration studies conducted (on synthetic membranes) have shown that the release of the drug molecule from eberconazole cream was less variable when compared to clotrimazole and Terbinafine. The comparators had high variability in the release. As indicated by the flux ratio, the overall amount of drug released from eberconazole cream was comparatively more than clotrimazole [Figure 2] and [Figure 3] and Terbinafine [Figure 4] and [Figure 5]. It can be concluded that eberconazole cream has comparatively more penetrative ability than clotrimazole or terbinafine cream and may result in improved efficacy outcome. [15]
Figure 2:

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Figure 3:

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Figure 4:

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Figure 5:

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  Discussion Top


Preclinical tests are required to prove the safety of the product prior to its use in humans in Phase I studies. These studies should prove the higher therapeutic effect of a compound on the organism with minimal effect on the host for it to become a novel agent. Understanding the preclinical data helps the physician to select the appropriate agent among many in the market.

In vitro studies demonstrated lower MICs with eberconazole than with comparators against many species of yeast, dermatophytes, T. glabrata, and T. mentagrophytes. It demonstrated higher efficacy against the majority of species against which it was tested. Its effectiveness against Gram-positive bacteria is an added advantage in the management of secondary bacterial infections associated with superficial fungal infections. Its antimicrobial activity along with anti-inflammatory actions is thought to be clinically useful in the treatment of inflamed cutaneous mycoses, thereby minimizing the need of a topical steroid in this condition.

Animal PK studies have shown that topical application of eberconazole 1% is not significantly absorbed as negligible amount of the drug was found in the central compartment; similar observations were made on administration on scarified skin. Animal toxicity studies have shown that it was safe and, NOEL was 2 ml/kg body weight in tested animals. Eberconazole was found be slightly irritant compared to bifonazole in rats; no allergic or hypersensitivity reactions were noted when tested for local toxicity.

In vitro penetration studies conducted on synthetic membranes, showed eberconazole has less variation compared to clotrimazole and terbinafine. Overall release of eberconazole was comparatively more. Viscosity of eberconazole was between 8.7 and 5.8 poise when compared to 6.6 to 4.8 poise (clotrimazole), indicating that the higher viscosity did not show any impact on the in vitro permeation of the drug by the test product. Flux ratio indicated that eberconazole shows faster rate of drug release over other two comparative products.


  Conclusions Top


Preclinical data of eberconazole showed that it is well-tolerated. It is evident from literature that it is not absorbed systemically. In the preclinical trials, eberconazole, has shown high efficacy and antimycotic activity against yeasts and fungi. It was found to be effective in vitro against a wide range of dermatophyte species than the other topical agents thus offering a therapeutic advantage for the treatment of dermatophytosis where topical therapy is indicated. Animal toxicity studies have proved its safety.


  Acknowledgments Top


Authors acknowledge Dr. Lalitha Ramani for assisting in editing of this manuscript. Authors acknowledge the support of their colleagues Mr. Prabhakar Rao, Asst Manager, Global Medical Affairs, Dr. Madhusudan Bommanagi, former Associate Director, Project Management and Dr. Satish Chava, Asst Manager, Global Medical Affairs, Dr. Reddy's Laboratories Ltd., Hyderabad, India, and Dr. R. Arunkumar, Associate Professor, Dept. of Pharmacology, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnad, India. We thank Dr. Akhilesh D Sharma, Senior Vice President, Global Medical Affairs, Dr. Reddy's Laboratories Ltd., Hyderabad, India for his valuable guidance and support.

 
  References Top

1.Southwest Human Fungal Infections Spike over the Past Decade. Cochrane & Associates. Press Release PRLOG dated 29 Mar 2013. Available from: http://www.prlog.org/12108680-southwest-human-fungal-infections-spike-over-the-past-decade.html [Last accessed on 2013 Aug 20].  Back to cited text no. 1
    
2.Charles AJ. Superficial cutaneous fungal infections in tropical countries. Dermatol Ther 2009;22:550-9.  Back to cited text no. 2
    
3.Zalacain A, Obrador C, Martinez JP, Viñas M, Vinuesa T. Characterization of the antimicrobial susceptibility of fungi responsible for onychomycosis in Spain. Med Mycol 2011;49:495-9.  Back to cited text no. 3
    
4.Torres-Rodríguez JM, Madrenys-Brunet N, Montsant L. Topical treatment with eberconazole of the experimental guinea pig cutaneous candidosis. Rev Iberoam Micol 1999;16:43-5.  Back to cited text no. 4
    
5.Drug report: Eberconazole. Thomson Reuters Pharma™ [Last updated on 2010 Aug 12].  Back to cited text no. 5
    
6.Font E, Freixes J, Julve J. Profile of a new topical antimycotic, eberconazole. Rev Iberoam Micol 1995;12:16-7.  Back to cited text no. 6
    
7.Tomás JM, Camprubí S, Merino S, Parés R, Llauradó X, Julve J. Inhibition of two imidazole antimycotics, eberconazole and clotrimazole, by different components of Candida albicans serotype B membrane protoplasts. Int J Antimicrob Agents 1993;3:61-4.  Back to cited text no. 7
    
8.Torres-Rodríguez JM, Mendez R, López-Jodra O, Morera Y, Espasa M, Jimenez T, et al. In vitro susceptibilities of clinical yeast isolates to the new antifungal eberconazole compared with their susceptibilities to clotrimazole and ketoconazole. Antimicrob Agents Chemother 1999;43:1258-9.  Back to cited text no. 8
    
9.Information from Data on file; from Innovators (Laboratorios Salvat, S.A) product information. Part III. Vol. 2. dated 16 Dec 2001.  Back to cited text no. 9
    
10.Martin Gonzalez B, Vilata-Corell JJ, Linares ML, Laguna Argente C, Roche-Gamon E. Treatment in superficial cutaneous mycoses with eberconazole Tratamiento de lasmicosis superficiales con eberconazol. Med Clin 2006;126:47-50.  Back to cited text no. 10
    
11.Eberconazole (Eberconazol, Eberconazole nitrate, WAS 2160). Drugs R D 2002;3:352-4.  Back to cited text no. 11
    
12.Fernández-Torres B, Inza I, Guarro J. In vitro activities of the new antifungal drug Eberconazole and three other topical agents against 200 strains of dermatophytes. J Clin Microbiol 2003;41:5209-11.  Back to cited text no. 12
    
13.Ghannoum MA, Hossain MA, Long L, Mohamed S, Reyes G, Mukherjee PK. Evaluation of antifungal efficacy in an optimized animal model of Trichophyton mentagrophytes-dermatophytosis. J Chemother 2004;16:139-44.  Back to cited text no. 13
    
14.Eberconazole lotion subchronic dermal toxicity study in rats and rabbits. Information from Data on file Dr. Reddy′s Laboratories Ltd., 2006; Toxicology report on Eberconazole1% w/w lotion. Dr. Reddy′s laboratories Information from data on file dated 12/Jun/2008.  Back to cited text no. 14
    
15.Information from Data on file, Dr. Reddy′s Laboratories, penetration study data dated 22 Apr 2008.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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Eberconazole
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