Review article New insights into the effect of amorolfine nail lacquer C. Flagothier, C. Pie´ rard-Franchimont and G. E. Pie´ rard Department of Dermatopathology, University Hospital of Lie`ge, Lie`ge, Belgium Summary Despite improvements in antifungal strategies, the outcome of treating onychomycoses often remains uncertain. Several factors account for treatment failure, of which the pharmacokinetics and pharmacodynamics of the antifungal are of importance. The taxonomic nature and ungual location of the fungus cannot be neglected, besides the type of nail and its growth rate. In addition, the biological cycle of the fungus and the metabolic activity of the pathogen likely play a marked influence in drug response. The presence of natural antimicrobial peptides in the nail is also probably a key feature controlling the cure rates. There are many outstanding publications that cover the full spectrum of the field. The purpose of this review is to put in perspective some facets of activity of the topical treatment using amorolfine nail laquer. The antifungal activity of the drug is likely less pronounced in onychomycosis than that expected from conventional in vitro studies. However, the nail laquer formulation should reduce the propensity to form antifungal-resistant spores and limit the risk of reinfection. Key words: amorolfine, antifungal, fungus, onychomycosis, spore. Topical treatments are often considered to be less Introduction efficacious than current oral treatments. However, some During the last 2 decades, the efficacy of treating topical formulations may provide effects that cannot be onychomycoses has been considerably improved by achieved by other treatments. In discussing the treat- the introduction of new generations of potent antifun- ment of onychomycosis, it should not be forgotten that gals. In general, antifungal therapy has taken a all systemic antifungals exert only fungistatic activity in quantum leap forward in response to the physiciansÕ clinical conditions. Radical elimination of the causal need to control the ever growing number of diagnosed microorganism from the nail does not occur fre- mycotic infections. At the same time, the existence of quently.1, 2 In fact, if antifungals were to exert several different treatment plans with drugs that differ fungicidal activity, completely destroying fungi in the in many of their characteristics has led to disagreements nail, the duration of treatment of toenail and fingernail in formulating indications for their use and assessing onychomycoses would be identical. However, this does their clinical efficacy. Opinions have been expressed not happen in practice, and treatment plans for toenail attempting to link the overall efficacy of the drugs with onychomycosis are always more prolonged compared its pharmacokinetic and pharmacodynamic character- with those for fingernail onychomycosis. The overall istics. Furthermore, these parameters have themselves difference in duration between these treatment plans sometimes been put forward as significant advantages corresponds overall to the difference in the complete or disadvantages for one or another of the antifungals regrowth rate of nail plates on the feet and hands. compared with others. Antifungal activity of amorolfine Correspondence: Professor G. E. Pierard, Department of Dermatopathology, Amorolfine is a potent antifungal drug exhibiting a CHU Sart Tilman, B-4000 Lie` ge, Belgium. large spectrum of in vitro activity.3, 4 However, in the Tel.: +32 4 3662408. Fax: +32 4 3662976. field of onychomycosis, data gained by conventional E-mail: [email protected] in vitro testing5 cannot be taken at face value and 6 Accepted for publication 29 November 2004 extrapolated to the in vivo situation. This is probably Ó 2005 Blackwell Publishing Ltd • Mycoses, 48, 91–94 91 C. Flagothier et al. due to drug interference with natural compounds that facilitating or inhibitory effects of endogenous molecules can influence fungal growth. In addition, contrasting and products from other saprophytic microorganisms with the in vitro testing in culture medium, fungi in already colonizing the skin. Furthermore, the importance onychomycosis utilize the nail as their sole nutrition of carbon dioxide (CO2) cannot be neglected due to its source. Therefore they have to change their metabolism, essential role in both the formation of fungal propagules activating for instance the secretion of keratinases.7 As and also the germination of the arthroconidia, resulting a result of the specific nail environment and fungal in hyphal penetration of the cornified structures. High condition, the activity of antifungals may be consider- CO2 concentrations facilitate subsequent formation of ably decreased in nails compared with standard in vitro arthroconidia. In contrast, onychocytes and corneocytes testing procedures.8 may contain certain soluble factors that induce arthro- The pharmacokinetic properties of amorolfine in nails conidia germination. Amino acids from human corneo- suggest a good penetration deep into the subungual cytes are important in this process. Some endogenous compartment.4, 9, 10 Therapeutic results in onychomy- antimicrobial peptides exert the apposite effect and act in cosis have been reported on several occasions.11–15 The the scope of innate immunity.16–21 patient’s ability to use the treatment correctly and his/ her compliance should not be overlooked in selecting The conidia–hyphae–conidia loop the treatment. If an infected skin scale is released in a swimming pool or shower cubicle, attachment of the fungus to corneo- Fungal adherence and invasiveness cytes allows its activation. The state of dormancy is In addition to the antifungal and nail characteristics, the broken due to increased moisture levels that lead to the taxonomic nature and life cycle of the offending fungi are initiation of germination and penetration of the corni- important. Numerous types of fungal propagules (spores) fied structures. Along the invasive fungal path, germi- are present in the environment, some of which can be nation after propagule attachment must be rapid, responsible for onychomycosis. The first step in the otherwise the fungus is expelled by continuous desqu- complex pathogenic path of onychomycosis consists of amation, nail growth and regular body cleansing. propagule adherence to the surface of the nail or the During the invasive hyphal phase, arthrocondiia are surrounding skin. Invasion may follow, leading to eventually formed again, through asexual reproduc- hyphae and conidia formation, and subsequent dispersal tion.1, 2, 22–24 This process involves the division of of propagules, thus closing the pathogenic circle. hyphae into strings of short segments separated by Intact skin and nail usually prevent the penetration of double septa. This situation represents the resting state most pathogenic fungi. Contact with skin scales har- of an otherwise filamentous fungus. In this state of boring the fungus is commonly an essential step in the dormancy arthroconidia can survive for very long development of superficial fungal infections. Indeed, the periods of time, protected to a large extent from harsh adherence of tiny infected scales or fungal propagules is environmental conditions. These cells are also less the primary mechanism of fungal transmission. Discrete sensitive to the vast majority of antifungals.2 abrasion of the stratum corneum and presence of soft At this stage, the fungal life is already approaching keratin accumulation under the distal part or the lateral full circle. Indeed, the pathogenic loop begins with the margins of the nail plate are friendly niches for formation of hyphae that, in turn, disarticulate into adherence of fungal propagules. Occlusion also helps arthroconidia, and concludes with the release of infec- these infectious cells to cling to the cornified structures. tious propagules again. This cycle lends itself to elegant As fungal cells can survive for up to 2 years in a viable studies with antimycotics, using the corneofungimetry state in scales, nail fragments and hair, the original bioassay performed on small strips of stratum cor- contact with an infective fungus is therefore indirect in neum.6, 25–28This model permits the study of adherence, many instances. germination and penetration of fungi in the human Most experimental fungal invasions of the stratum stratum corneum. The effect of topical or oral antifun- corneum rely on abrasion of the skin surface or gals can be established as well.6, 25, 27–29 occlusion before dermatophytes can be induced to establish themselves effectively as pathogens. How- Amorolfine nail lacquer and fungal adherence ever, the fungal inocula must usually be far heavier than is usually experienced in an in vivo situation. In The ability of fungi to attach themselves to body addition, these studies do not take into account the surfaces is the first incident in the chain of events that 92 Ó 2005 Blackwell Publishing Ltd • Mycoses, 48, 91–94 Insights into amorolfine eventually results in the requirement for antimycotic Conclusion treatment. Identifying the organism and understanding the successive steps of its pathogenic path are important It is a problem familiar for all dermatologists that a to improve therapeutic outcome. number of cases of onychomycoses can be alleviated or We performed an in vitro study using non-infected big improved but not cured. There is ample evidence that toenails obtained at autopsy. Samples coated or uncoa- some broad-spectrum antifungals including amorolfine ted