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Currently available topical antifungals are often not satisfactory for the treatment of nail infections, because of the inability to penetrate the nail plate. Terbinafine HCl nail solution is a novel antifungal formulation containing a nail penetration enhancer dodecyl-2-N,N-dimethylaminopropionate hydrochloride (DDAIP HCl, trade name NexACT®-88). In this study, we used a guinea pig model of Trichophyton mentagrophytes dermatophytosis and evaluated the clinical and mycological efficacy of different terbinafine HCl nail solutions (TNS) formulated with or without DDAIP HCl. Ciclopirox (8%) nail lacquer (Penlac®), the only Food and Drug Administration approved topical treatment for onychomycosis, was used as a comparator. Following the IACUC Guidelines, the skin of male albino guinea pigs was abraded under anaesthesia. Each animal was infected with T. mentagrophytes ATCC 24953 (cell suspension containing 1 × 107 conidia). The experimental animals were divided into 11 groups (five animals per group) and tested with the following formulations: vehicle control, 0.5% DDAIP HCl, 1%, 5% and 10% TNS (without DDAIP HCl), 1% TNS with 0.5%, 2.5% and 5.0% DDAIP HCl, 5% and 10% TNS with 0.5% DDAIP HCl, 8% ciclopirox nail lacquer and an untreated control group. Evaluation of clinical and mycological efficacy was performed 72 h after completion of a 7-day treatment regimen. Skin biopsy samples were processed for histopathological examination. The infected untreated control guinea pigs showed patches of hair loss and ulcerated or scaly skin and fungal invasion of hair roots. The vehicle and 0.5% DDAIP HCl treated groups showed minimal clinical efficacy (only 11% and 5%, respectively). In contrast, all three concentrations of TNS (1%, 5% and 10% terbinafine HCl) formulated with or without 0.5% DDAIP HCl showed 100% mycological efficacy by the hair root invasion test. Clinical efficacy of the 5% and 10% TNS improved with addition of 0.5% DDAIP HCl (47.4% and 73.8% vs. 68.4% and 89.5%, respectively). In addition, no fungal elements were detected in the treated guinea pig skin. All formulations of TNS resulted in a higher clinical and mycological efficacy compared with the 8% ciclopirox nail lacquer (P=0.0444). In conclusion, TNS containing 1%, 5% and 10% terbinafine HCl formulated with and without DDAIP HCl demonstrated high antifungal efficacy in experimental dermatophytosis. Addition of 0.5% DDAIP HCl to 5% and 10% TNS significantly enhanced the clinical and mycological efficacy of these formulations which were superior compared with the 8% ciclopirox nail lacquer. Evaluation of the 1%, 5% and 10% TNS in clinical trials for the treatment of dermatophytosis and onychomycosis is warranted.