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REVIEW ARTICLE Preclinical pharmacological profile of Eberconazole: A review and update

Latha Subramanya Moodahadu, Ashis Patnaik, Vakati Venkat Arvind, Ranjit Madhukar Bhide1, Kavitha Katta2, Binny Krishnankutty3, Shantala Bellary

ABSTRACT Eberconazole is a broad-spectrum 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 and 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 . Key Words: Animal toxicity, dermatophytoses, eberconazole, inflamed cutaneous mycoses, no observed effect level, penetration study

Introduction and investigated in Spain by Centro de Investigacion Wassermann, marketed by Salvat, was launched in 2005 Medical fraternity has witnessed an increase in the and since then is available in the market. It is relatively incidence[1] and change in the spectrum of superficial new in Indian pharmaceutical market, available since fungal incidence worldwide in the recent past due to 2007. In this paper, we have reviewed its preclinical changes in the lifestyle, increased migration, increase pharmacology and toxicology. in clinical conditions such as diabetes mellitus and other immunocompromised states.[1,2] Eberconazole Topical agents are preferred in the management of Eberconazole ((1-(2,4-dichloro-10,11-dihydro-5H- fungal infections of the skin due to the advantages they dibenzo[a,d]cyclohepten-5-yl)-1H-imidazole) [Figure 1] is offer i.e., ease of application, better local bioavailability, an imidazole antifungal with a broad spectrum of activity, less systemic toxicity, shorter treatment period and effective against a wide range of yeast and fungi such as reduced rate of recurrence. Among various available dermatophytes, candidiasis, yeasts (Malassezzia furfur) topical antifungal agents, azoles are the primary local and Pityriasis versicolor in in vitro and animal studies.[3-6] antifungal agents due to their well-established efficacy Its antifungal activity has been demonstrated in Candida and safety. Eberconazole, an imidazole derivative and albicans serotype B membrane protoplasts. This study effective topical antifungal agent, initially designed also showed that minimal inhibitory concentration (MIC)

Access this article online Dr. Reddy’s Laboratories Ltd., Hyderabad, Andhra Pradesh, 1Director of Research and Study Director, Indian Institute of Toxicology, Pune, Quick Response Code 2 Website: Maharashtra, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science, Hyderabad, Andhra Pradesh, 3Department of www.mjmsr.net Pharmacology, Azeezia Medical College, Kollam, Kerala, India Address for correspondence: Dr. Latha Subramanya Moodahadu, DOI: G5, Mount Meru Apt, Road 5, Avenue 7, Banjara Hills, 10.4103/0975-9727.135757 Hyderabad - 500 034, Andhra Pradesh, India. E-mail: [email protected]

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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 SD50 of 65.5 mg/mL, which was comparable to that with acetyl Figure 1: Stuctural formula of eberconazole (70.1 mg/mL) and ketoprofen (41.7 mg/ml).[9]

of eberconazole increased 14-fold in the presence of In vitro studies have shown that eberconazole is isolated membrane phospholipids.[7] In vitro studies effective against disease causing Candida including have demonstrated its efficacy against eight species of C. parapsilosis (minimum inhibitory concentration

clinically relevant disease causing organisms such as 90, MIC90 = 0.125 μg/ml). In this study, effects of Candida including Candida parapsilosis. In vitro studies eberconazole on clinical isolates of yeast including C. have also demonstrated its efficacy against many krusei, C. glabrata, C. albicans, and C. parapsilosis triazole-resistant yeasts (Candida krusei and Candida was studied. Eberconazole showed lower MIC values glabrata)[8] and also -resistantC. albicans.[4,5] and excellent activity against triazole-resistant Candida Studies have shown its efficacy against Gram-positive species such as C. krusei and C. glabrata compared bacteria.[5] However, its broad spectrum action is limited to ketoconazole and clotrimazole, with a statistically compared to other agents such as echinocandins and significant difference between eberconazole and the next generation triazoles.[5] ketoconazole. Majority of triazole-resistant yeasts (C. krusei and C. glabrata) and fluconazole-resistant C. Eberconazole is either fungicidal or fungistatic based albicans showed sensitivity to eberconazole. This on its concentration, having fungicidal activity at higher study demonstrated excellent activity of eberconazole concentrations. It inhibits the ergosterol synthesis against C. krusei and T. glabrata; comparable efficacy to (inhibition of fungal lanosterol 14α-demethylase), an that of comparators was noted against C. albicans and [4,11] essential component of the cytoplasmic membrane C. parapsilosis. Although Cryptococcus neoformans thus leading to structural and functional changes, isolates were less sensitive to eberconazole than thereby inhibiting fungal growth. At high concentrations, to ketoconazole and clotrimazole, lower MIC values [5] it promotes leakage of smaller molecules from the (0.162 μg/ml) were observed. The antifungal activity of eberconazole against 124 clinical isolates of Candida, cell membrane. It has also shown to possess anti- which included eight different species and 34 isolates inflammatory activity in vivo, which is attributed to the of Cryptococcus neoformans was determined and was inhibition of 5-lipoxygenase; it is also known to inhibit compared to that of clotrimazole and ketoconazole.[4,11] cyclooxygenase-2, though to a lesser extent, whereas it In vitro activity of eberconazole was compared with has not proved to inhibit cyclooxygenase-1. This property clotrimazole, ketoconazole and miconaozole against is useful in conditions such as inflamed cutaneous 200 strains of dermatophytes. Eberconazole was more mycoses, thus favoring the reduction of inflammatory active (P < 0.05) than the other agents, against the symptoms and enhancing treatment compliance.[9] majority of the species tested.[12] Eberconazole 1% cream is available in the market as Similar MICs were observed with eberconazole an antifungal agent having characteristic molecular and clotrimazole in 116 strains of yeast and 45 structure, which is both lipophilic-hydrophilic. This helps dermatophytes, whereas bifonazoles produced in better penetration of cell membrane by the drug and [10] different results with higher MICs and resistant strains, prolongs its duration of action. i.e., growth at concentrations above 40 μg/mlin C. tropicalis and C. albicans. Eberconazole produced the Preclinical Pharmacology lowest MICs with Torulopsis. glabrata although they Studies with the strain, Candida vaginalis serogroup B are only fungicidal in slightly >50% of the cases. It have shown that eberconazole binds to the lipid fraction also demonstrated lowest MICs for T. mentagrophytes of fungal membrane. The phospholipids sub-fraction and fungicidal activity was not seen in the majority of

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strains. In M. canis and T. rubrum, it also appeared to Animal Pharmacokinetics be the antifungal with the greatest MIC in relation to Pharmacokinetic (PK) tests and bioavailability (BA) other comparator .[9] assay of eberconazole lotion was carried out on four minipigs in France, procured from Charles River. Two Efficacy male and two female miniature pigs of the YUCATAN There has been encouraging results of anti-dermatophytic breed aged approximately 8-10 months were used. PK efficacy of various antifungal agents in optimized guinea and BA were tested following topical application, using pig models, which, were found to be highly reproducible radiolabelled eberconazole (with C14) and intravenous and therefore, a useful tool in the primary screening of a administration. For topical application 10 g of cream compound.[13] The therapeutic efficacy of eberconazole was applied on about 100 cm2 of the skin surface in the 1% was similar with an excellent tolerance when interscapular region and spread by gentle massage to compared to clotrimazole 1% in an experimental model favor the absorption. Its effect on applied on scarified of cutaneous candidiasis in guinea pigs, suggesting skin (lanced used for finger pricking) was also studied. feasibility of the use of eberconazole in the management Blood and urine samples were collected at baseline and of skin infections in humans caused by C. albicans.[4,9] at subsequent intervals. Blood samples were taken after Efficacy of eberconazole 1% cream was compared 30, 60, 90, 120, 240 and 480 minutes and 24, 32, 48, with clotrimazole 1% cream in experimentally produced and 72 h post-administration. Urine and fecal samples candidiasis through a double blind comparative study in were collected at 0-4 h, 4-8 h, 8-24 h and 48-72 h. The 22 male guinea pigs. Ten animals were in each study results of animal pharmacokinetic parameters studied group and two animals did not receive treatment for the are tabulated in Table 1.[9] lesions caused. Eberconazole or comparator cream was applied at a dose of 1-1.3 g by means of finger massage. In urine, 17.2% of the injected product was obtained Treatment was suspended on 6th day to collect samples whereas, 29.4% was obtained in feces. After 72 hrs on the following day. Treatment was reinitiated for 5 days. of assessment (AUC72 = 28.03), 46.6% of the injected Samples were collected once again after a 2-day rest product was recovered in urine and feces. On parenteral period. This study has shown that there was clinical administration, 46.6% of the injected eberconazole was recovery (disappearance of lesions and negative culture) recovered in feces and urine.[9] in 9/10 animals in the group treated with eberconazole, whereas, clotrimazole produced lower cure rate (3/10). After topical administration on normal skin, area under No clinical improvement of the lesion was observed in curve (AUC) was 15.09 mm2 in the 0-72 h period, which two cases in the clotrimazole group. In eberconazole was remarkably low compared to that of intravenous group, mycological cultures were negative in all except administration. The elimination or recovery of the product one animal, which showed a lesser number of colonies in urine was 0.44% and 0.31% in feces in 0-72-h period; of C. albicans. Eberconazole’s antimicrobial activity urinary elimination was significant in males in first few was greater than clotrimazole against yeast, mould, and bacteria. It was more effective than clotrimazole Table 1: Animal pharmacokinetic parameters of in eliminating exogenous contamination on carriers in eberconazole yeast, mould and bacteria. The antimicrobial activity of Parameters IV eberconazole was greater in yeasts and moulds than in Cmax: 1.684 μg/ml plasma

bacteria. In a similar study in guinea pigs, eberconazole T1/2alpha 37.7h T beta 0.34h 1% cream showed a better clinical response as early 1/2 72 as one week that became obvious from 14 days, and AUC 28.03 K 0.06 reduction of dermatophyte colonies isolated per culture 10 K 0.63/h. compared to 1%.[9] 21 K12 1.38/h V 29685.81 ml Eberconazole 1% was similar in efficacy when compared C VB 866.48 ml to ketoconazole 1% cream in experimentally produced Cl 1781.15 ml pityriasis in guinea pigs. The animals in both groups fc 31.26% showed significant improvement and in many cases the Animal PK parameters Cmax (peak concentration), T1/2alpha and T1/2beta (biological half lifetime referring to each elimination rate constant), AUC (Area under lesions disappeared totally. Eberconazole also showed curve from 0-72h), K10 (apparent first order elimination rate constant of the central good local anti-inflammatory activity on application on compartment), K21 and K12 (intercompartmental distribution rate constant), VC (Volume of Distribution corresponding to central compartment), VB (Volume of the external ear [rats], which was comparable to that of Distribution corresponding to peripheral compartment), Cl (total body clearance) and acetyl salicylic acid and ketoprofen.[9] fc (Bioavailability central compartment)

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hours and fecal route of elimination was more significant no significant difference between the cytotoxicity of in females. These results imply that topical administration eberconazole and other imidazole antifungal agents of eberconazole does not reach the central compartment tested (, , and clotrimazole).[9] in quantifiable values.[9] Local Toxicity of Eberconazole After topical administration to scarified skin, the AUC in It was non-irritant in the primary ocular tolerance test 2 the plasma according to time was 2.77 mm compared with index of acute ocular irritation of 1.33. Local toxicity 2 with the 856.99 mm of the AUC of intravenous of eberconazole cream was compared to bifonazole in administration, and bioavailability was 0.32%. Elimination albino rats. Both produced similar degree of irritation, but of eberconazole in urine was 0.31% of the total eberconazole found to be slightly lesser irritant compared administered. Its elimination in feces of female mini to bifonazole. It was non-irritant to vaginal mucosa of pigs was notable. Following the 72-h period, 0.42% of New Zealand rabbits. No allergy or hypersensitivity was the product administered was recovered in feces. Total observed as Buehler test was negative in guinea pigs. [9] recovery was 0.72%. It shared similar cytotoxicity profile with other imidazole antifungal products studied i.e., miconazole, econazole, In albino rabbits, in therapeutic doses, eberconazole 1% and clotrimazole when studied using BALB/3T3 cell line. [9] cream, when applied on healthy skin was not absorbed. Skin reaction score was measured using eberconazole 1% w/w lotion in Sprague Dawley rats (method of Animal Toxicity of Eberconazole Draize).[9]

The LD50 (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 Vitro Penetration Studies in Swiss albino male mice and 685.7 mg/kg p.o. with limits In vitro penetration studies were conducted for of 517.2 and 909.1 mg/kg p.o. in female mice. Testicular eberconazole cream 1% w/w and the data was compared atrophy was noted in autopsy in male mice with relative with that of clotrimazole 1% w/w [Table 2] and terbinafine reduction in testicular weight, which was 3.15 in control HCl 1% w/w [Table 3]. The studies were done using 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 Table 2: Comparison of penetration of eberconazole 1% [9] in females except for a greater toxicity of the product. cream and clotrimazole 1% cream Eberconazole cream Clotrimazole cream In subchronic dermal toxicity tests at different doses, no 1%w/w 1%w/w toxic effects were seen when eberconazole lotion was µg/cm2 released µg/cm2 released applied to rats, rabbits and dogs in 28-day dermal toxicity Time (h) Set 1 Set 2 Set 1 Set 2 study indicating a good safety profile. Histopathological 0.5 1.3 1.8 1.2 0.5 toxicity tests did not show any significant lesions of 1 3.6 4.0 2.9 1.1 2 6.9 7.2 5.0 2.1 nosological importance. No lesions or alterations 4 10.6 11.6 6.5 3.6 attributable to the application of the eberconazole 6 16.3 15.9 7.9 5.3 were observed. No neoplastic or degenerative necrotic Comparison of 2 sets of experiments showing less intraset variation among lesions were noted in the animals studied. No systemic eberconazole and clotrimazole and overall amount of eberconazole released is greater than clotrimazole 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 Table 3: Comparison of penetration of eberconazole 1% typhimurium reverse mutation assay of eberconazole cream and terbinafine1% cream lotion was negative. No mutations were noted in the Eberconazole cream Terbinafine cream 1%w/w 1%w/w mouse lymphoma thymidine kinase locus assay.[5] µg/cm2 released µg/cm2 released Eberconazole 1% w/w lotion was found to be safe in Time (h) Set 1 Set 2 Set 1 Set 2 rabbits and rats when applied over a period of 28 days 0.5 1.6 1.7 0.6 0.3 and the no observed effect level (NOEL) was 2 ml/kg in 1 3.6 3.7 1.3 0.8 male and female animals.[14] 2 6.4 6.7 2.6 2.0 4 10.2 11.0 4.8 4.0 Eberconazole cream did not present allergic effects of 6 14.1 15.1 7.2 6.7 skin sensitization (Buchler test) in guinea pigs under Flux 2.35 2.52 1.21 1.12 Comparison of 2 sets of experiments showing less intraset variation among experimental conditions. No significant cytotoxic effects eberconazole and terbinafine and overall amount of eberconazole released is greater were seen in the BALB/3T3 cell lines and there was than Terbinafine

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synthetic membranes through Franz diffusion cell. Two was higher than clotrimazole, the penetration of sets of three cells were tested with eberconazole against ebrconazole was also significantly higher than clotrimazole and terbinafine, separately and subjected clotrimazole. to permeation. Solubility and sink conditions were tested using different media and back diffusion studies were In vitro penetration studies conducted (on synthetic also conducted. membranes) have shown that the release of the drug molecule from eberconazole cream was less variable These studies revealed that the release of the drug when compared to clotrimazole and Terbinafine. The from eberconazole intra sets (set 1 and 2) showed less comparators had high variability in the release. As variation as compared to clotrimazole and terbinafine indicated by the flux ratio, the overall amount of drug intrasets. Overall amount of eberconazole released was released from eberconazole cream was comparatively more compared to the other two drugs. more than clotrimazole [Figures 2 and 3] and Terbinafine [Figures 4 and 5]. It can be concluded that eberconazole Viscosity of eberconazole was between 8.7 and 5.8 cream has comparatively more penetrative ability than poise at 60-110 rpm whereas that of clotrimazole clotrimazole or terbinafine cream and may result in was between 6.6 and 4.8 poise at the same rpm. improved efficacy outcome.[15] Flux ratio i.e., amount of drug released in µg/cm2 for eberconazole with respect to clotrimazole ranged from Discussion 2.3 to 2.9 and that with respect to Terbinafine ranged Preclinical tests are required to prove the safety of the from 1.8 to 2.01. Although viscosity of eberconazole product prior to its use in humans in Phase I studies. These studies should prove the higher therapeutic

Figure 2: Comparison of flux ratio of eberconazole cream and clotrimazole set 1 through franz diffusion cell. Set 1 of experiments to compare of flux ratio Figure 3: Comparison of flux ratio of eberconazole cream and clotrimazole of eberconazole and clotrimazole through Franz diffusion cell. Clotrimazole set 2 through franz diffusion cell. Set 2 of experiments to compare of flux ratio (−♦−) and line of best fit for clotrimazole (−−) and eberconazole (−■−) and of eberconazole and clotrimazole through Franz diffusion cell. Clotrimazole the line of best fit for eberconazole (−−) (−♦−) and line of best fit for clotrimazole (−−) and eberconazole (−■−) and the line of best fit for eberconazole (−−)

Figure 4: Comparison of flux ratio of eberconazole cream and terbinafine Figure 5: Comparison of flux ratio of eberconazole cream and terbinafine set 1 through franz diffusion cell. Set 1 of experiments to compare of flux set 2 through franz diffusion cell. Set 2 of experiments to compare of flux ratio of eberconazole and terbinafine through Franz diffusion cell. Terbinafine ratio of eberconazole and terbinafine through Franz diffusion cell. Terbinafine (−♦−) and line of best fit for terbinafine (−−) and eberconazole (−■−) and (−♦−) and line of best fit for terbinafine (−−) and eberconazole (−■−) and the line of best fit for eberconazole (−−) the line of best fit for eberconazole (−−)

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effect of a compound on the organism with minimal Acknowledgments effect on the host for it to become a novel agent. Authors acknowledge Dr. Lalitha Ramani for assisting in Understanding the preclinical data helps the physician editing of this manuscript. Authors acknowledge the support to select the appropriate agent among many in the of their colleagues Mr. Prabhakar Rao, Asst Manager, market. Global Medical Affairs, Dr. Madhusudan Bommanagi, former Associate Director, Project Management and Dr. Satish In vitro studies demonstrated lower MICs with Chava, Asst Manager, Global Medical Affairs, Dr. Reddy’s eberconazole than with comparators against many Laboratories Ltd., Hyderabad, India, and Dr. R. Arunkumar, species of yeast, dermatophytes, T. glabrata, and T. Associate Professor, Dept. of Pharmacology, Chettinad mentagrophytes. It demonstrated higher efficacy against Hospital and Research Institute, Kelambakkam, Tamilnad, the majority of species against which it was tested. Its India. We thank Dr. Akhilesh D Sharma, Senior Vice effectiveness against Gram-positive bacteria is an added President, Global Medical Affairs, Dr. Reddy’s Laboratories advantage in the management of secondary bacterial Ltd., Hyderabad, India for his valuable guidance and infections associated with superficial fungal infections. support. Its antimicrobial activity along with anti-inflammatory actions is thought to be clinically useful in the treatment References of inflamed cutaneous mycoses, thereby minimizing the 1. Southwest Human Fungal Infections Spike over the Past Decade. need of a topical steroid in this condition. 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 Animal PK studies have shown that topical application accessed on 2013 Aug 20]. of eberconazole 1% is not significantly absorbed as 2. Charles AJ. Superficial cutaneous fungal infections in tropical negligible amount of the drug was found in the central countries. Dermatol Ther 2009;22:550-9. compartment; similar observations were made on 3. Zalacain A, Obrador C, Martinez JP, Viñas M, Vinuesa T. administration on scarified skin. Animal toxicity studies Characterization of the antimicrobial susceptibility of fungi have shown that it was safe and, NOEL was 2 ml/kg body responsible for onychomycosis in Spain. Med Mycol 2011;49: 495-9. weight in tested animals. Eberconazole was found be slightly irritant compared to bifonazole in rats; no allergic 4. Torres-Rodríguez JM, Madrenys-Brunet N, Montsant L. Topical treatment with eberconazole of the experimental guinea pig or hypersensitivity reactions were noted when tested for cutaneous candidosis. Rev Iberoam Micol 1999;16:43-5. local toxicity. 5. Drug report: Eberconazole. Thomson Reuters Pharma™ [Last updated on 2010 Aug 12]. In vitro penetration studies conducted on synthetic 6. Font E, Freixes J, Julve J. Profile of a new topical antimycotic, membranes, showed eberconazole has less variation eberconazole. Rev Iberoam Micol 1995;12:16-7. compared to clotrimazole and terbinafine. Overall 7. Tomás JM, Camprubí S, Merino S, Parés R, Llauradó X, release of eberconazole was comparatively more. Julve J. Inhibition of two imidazole antimycotics, eberconazole Viscosity of eberconazole was between 8.7 and 5.8 and clotrimazole, by different components of Candida albicans serotype B membrane protoplasts. Int J Antimicrob Agents poise when compared to 6.6 to 4.8 poise (clotrimazole), 1993;3:61-4. indicating that the higher viscosity did not show any 8. Torres-Rodríguez JM, Mendez R, López-Jodra O, Morera Y, impact on the in vitro permeation of the drug by the test Espasa M, Jimenez T, et al. In vitro susceptibilities of clinical product. Flux ratio indicated that eberconazole shows yeast isolates to the new antifungal eberconazole compared with faster rate of drug release over other two comparative their susceptibilities to clotrimazole and ketoconazole. Antimicrob products. Agents Chemother 1999;43:1258-9. 9. Information from Data on file; from Innovators (Laboratorios Salvat, S.A) product information. Part III. Vol. 2. dated 16 Dec Conclusions 2001. Preclinical data of eberconazole showed that it is well- 10. Martin Gonzalez B, Vilata-Corell JJ, Linares ML, Laguna Argente C, tolerated. It is evident from literature that it is not absorbed Roche-Gamon E. Treatment in superficial cutaneous mycoses systemically. In the preclinical trials, eberconazole, has with eberconazole Tratamiento de lasmicosis superficiales con eberconazol. Med Clin 2006;126:47-50. shown high efficacy and antimycotic activity against yeasts and fungi. It was found to be effective in vitro 11. Eberconazole (Eberconazol, Eberconazole nitrate, WAS 2160). Drugs R D 2002;3:352-4. against a wide range of dermatophyte species than the 12. Fernández-Torres B, Inza I, Guarro J. In vitro activities of the other topical agents thus offering a therapeutic advantage new antifungal drug Eberconazole and three other topical for the treatment of dermatophytosis where topical agents against 200 strains of dermatophytes. J Clin Microbiol therapy is indicated. Animal toxicity studies have proved 2003;41:5209-11. its safety. 13. Ghannoum MA, Hossain MA, Long L, Mohamed S, Reyes G,

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Mukherjee PK. Evaluation of antifungal efficacy in an optimized How to cite this article: Moodahdu LS, Patnaik A, Arvind VV, Bhide animal model of Trichophyton mentagrophytes-dermatophytosis. RM, Katta K, Krishnankutty B, et al. Preclinical pharmacological profile of J Chemother 2004;16:139-44. Eberconazole: A review and update. Muller J Med Sci Res 2014;5:159-65. 14. Eberconazole lotion subchronic dermal toxicity study in rats and Source of Support: Nil, Conflict of Interest: Dr M S Latha, Dr Ashis rabbits. Information from Data on file Dr. Reddy’s Laboratories Ltd., Patnaik, Dr VV Arvind and Dr Shantala B, are the employees of Dr 2006; Toxicology report on Eberconazole1% w/w lotion. Reddy’s Laboratories Ltd., which is marketing Eberconazole in India. These authors are stakeholders having financial stakes in Dr. Reddy’s Dr. Reddy’s laboratories Information from data on file dated Laboratories Ltd. by means of salary, company stocks or both. Dr Binny 12/Jun/2008. Krishnankutty & Dr Katta Kavitha are former employees of Dr Reddy’s 15. Information from Data on file, Dr. Reddy’s Laboratories, penetration Laboratories Ltd and presently not having any stakes in Dr. Reddy’s Laboratories Ltd. Dr RM Bhide is not having any conflict of interest. study data dated 22 Apr 2008.

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