[Downloaded free from http://www.mjmsr.net on Tuesday, August 26, 2014, IP: 218.241.189.21] || Click here to download free Android application for this journal 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 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. 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] Muller Journal of Medical Science and Research | Vol 5 | Issue 2 | Jul - Dec 2014 159 [Downloaded free from http://www.mjmsr.net on Tuesday, August 26, 2014, IP: 218.241.189.21] || Click here to download free Android application for this journal Moodahadu, et al.: Eberconazole preclinical pharmacology 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 salicylic acid 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 fluconazole-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 160 Muller Journal of Medical Science and Research | Vol 5 | Issue 2 | Jul - Dec 2014 [Downloaded free from http://www.mjmsr.net on Tuesday, August 26, 2014, IP: 218.241.189.21] || Click here to download free Android application for this journal Moodahadu, et al.: Eberconazole preclinical pharmacology