Amorolfine

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Abstract
Amorolfine is a structurally unique, topically active antifungal agent, which possesses both fungistatic and fungicidal activity in vitro. Its spectrum of in vitro activity includes dermatophyte, dimorphic, some dematiaceous and filamentous fungi, and some yeasts. In clinical trials, application of amorolfine 5% nail lacquer once or twice weekly for up to 6 months produced mycological and clinical cure in approximately 40 to 55% of patients with mild onychomycosis 3 months after cessation of therapy. Overall cure and improvement was observed in approximately 85 to 90% of patients with superficial dermatomycoses following treatment with amorolfine 0.25% cream for up to 6 weeks. However, few controlled, comparative trials are available for these different mycoses, and only small numbers of patients have been evaluated to date. Both preparations appear to be well tolerated; only minor localised adverse events have been reported in clinical trials. At present, the major potential indication for topical amorolfine appears to be onychomycosis. Within this clinical setting, amorolfine should be reserved for patients with mild infection without nail matrix involvement. Systemic therapy, however, remains essential for patients with severe intractable onychomycosis involving the nail bed. Evidence to date does not clarify whether the use of adjuvant topical amorolfine reduces the need for systemic therapy in patients with severely infected nails, or whether amorolfine is beneficial in individuals unresponsive to other treatment options. Amorolfine is a morpholine derivative which is chemically distinct from other currently available antifungal agents. It acts primarily by inhibiting ergosterol biosynthesis, a component of fungal cell membrane, and possesses both fungistatic and fungicidal activity. Despite in vitro activity against various fungi, animal test models indicate that amorolfine is inactive when given systemically for life-threatening mycoses. Conventional in vitro susceptibility tests indicate that amorolfine has greatest fungistatic activity against dermatophyte and dimorphic fungi. It is also active against some dematiaceous and filamentous fungi, and against some yeasts. Fungicidal activity is also highest against Trichophyton mentagrophytes. In the guinea-pig, topical amorolfine 0.01% was effective against cutaneous infection induced by T. mentagrophytes. On a concentration basis, amorolfine showed greater activity in clearing fungal lesions in this model than naftifine, oxiconazole, ketoconazole, bifonazole and clotrimazole, but lower activity than terbinafine. In rats, a dose-dependent log reduction in vaginal yeast cell counts was also observed with topical amorolfine starting at concentrations of 0.01%; vaginal candidiasis was completely cleared at a concentration of 1%. Amorolfine penetration through human nail follows an exponential relationship between drug concentration and nail layer. In vitro data suggest that soft diseased nails will retain less drug than hard compact nails. After a single application of nail lacquer (formulated with methylene chloride), permeation of [3H]amorolfine 5% through the thumbnail ranged from 20 to 100 μg/L/h. Mean percutaneous absorption of amorolfine through healthy human skin following a single application of 0.25% cream did not exceed 10% of the total administered dose. Systemically absorbed radioactive amorolfine was slowly excreted via urine and faeces over 3 weeks; plasma concentrations of <0.5 μg/L were detected in all samples. Further studies in volunteers indicate that active concentrations of amorolfine may be retained in healthy skin for 2 or 3 days after single applications of 0.5% cream or alcohol solution, respectively. The therapeutic efficacy of amorolfine has been investigated in patients with onychomycosis, dermatomycoses and vulvovaginal candidiasis. In total, only small patient numbers have been evaluated, and comparative data are minimal. Available noncomparative data in approximately 600 patients suggest that amorolfine 5% nail lacquer applied once or twice weekly for up to 6 months may be effective in mild onychomycosis without nail matrix involvement. Mycological and clinical cure rates of about 40 to 55% were observed in treated patients 3 months after cessation of therapy; fingernails responded consistently better than toenails. Preliminary data in patients with mild disease suggest that topical amorolfine may also be useful in conjunction with oral griseofulvin to enhance cure; further double-blind studies are, however, required to ascertain the potential benefits of combined therapy. Amorolfine 0.25% cream may be beneficial in patients with other superficial skin infections; in 208 patients, it appeared to be comparable in efficacy with bifonazole 1% cream. Amorolfine alcohol aerosol solutions 0.5 and 2% may also be useful in patients with foot mycoses. Similarly, a single vaginal dose of amorolfine 50 or 100mg appeared to be as effective as one clotrimazole 500mg pessary in 118 women with vulvovaginal candidiasis. In clinical trials, topical amorolfine (5% nail lacquer and 0.25% cream) appeared to be well tolerated, with up to 5% of patients reporting minor symptoms. In patients using the nail lacquer, these events included burning, itching, redness and local pain which were tolerable and confined to the site of application. Additional events of scaling, weeping, blistering and oedema were also described for the cream. A similar adverse event profile was reported for both the alcohol solution and vaginal tablets. Amorolfine 5% nail lacquer should be applied to the affected nail once or twice weekly. Treatment should be continued without...