Therapeutic Efficacy of Topically Applied KP-103 against Experimental Tinea Unguium in Guinea Pigs in Comparison with Amorolfine and Terbinafine

Abstract

The therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation of Trichophyton mentagrophytes SM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine against T. mentagrophytes SM-110 were 8-and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.

Establishment of a Novel Model of Onychomycosis in Rabbits for Evaluation of Antifungal Agents

“…These authors also used this model to evaluate the efficacy of a topical antifungal agent, but the article did not describe the pathophysiological findings in detail, omitting how the gross appearance changed as well as the histopathological findings on the examination of the infected nails (21). Thus, it was not clear whether the drug efficacy found using the animal model reflected the drug's therapeutic effect against onychomycosis in clinical practice.…”

“…The first report of an animal model for onychomycosis was described by Tatsumi et al in 2002, with the use of guinea pigs. These authors also used this model to evaluate the efficacy of a topical antifungal agent, but the article did not describe the pathophysiological findings in detail, omitting how the gross appearance changed as well as the histopathological findings on the examination of the infected nails (21).…”

“…Tatsumi et al (21) reported the evaluation of some antifungal agents using an in vivo experimental model of onychomycosis, but detailed histological examination was limited, and they did not describe whether fungal infection occurred near the nail bed, as occurs in the clinical setting. Drug efficacy tests that used this model were useful in the evaluation of orally administered drugs but not for topical agents.…”

Progressive development in experimental models of transungual drug delivery of anti‐fungal agents

“…Along with this, terbinafine was also orally administered at a daily dose of 40 mg kg À1 of body weight for 30 consecutive days, starting on day 60 post-infection. The fungal burdens of nails and plantar skin were then assessed 2 days subsequent to the last treatment after sacrificing them [83]. The main drawback of this study was that the drug efficacy tests used in this model were useful in evaluating orally administered drugs and not topical agents.…”

“…In vivo permeation models Tatsumi et al (2002) evaluated the therapeutic effect of a novel triazole anti-mycotic (KP-103) and compared it with amorolfine and terbinafine in a guinea pig tinea unguium model. For evaluating the efficacy anti-fungal drugs, paper discs that were previously immersed in fungal suspension (T. mentagrophytes SM-110) were placed between the toes of the hind paw with the help of selfadhering foam pads to produce tinea unguium and tinea pedis.…”