title: An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates.
abstract: The treatment of onychomycosis remains problematic even though there are several potent antifungal agents available for patient use. The aim of this investigation was to understand whether the structural modifications that arise when a patient's nail become infected plates influences the permeation of drugs into the nail following topical application. It was hoped that through improving understanding of the nail barrier in the diseased state, the development of more effective topical treatments for onychomycosis could be facilitated. The permeation of three compounds with differing hydrophobicities, caffeine, terbinafine and amorolfine (clogD at pH 7.4 of -0.55, 3.72 and 4.49 respectively), was assessed across both healthy and onychomycosis infected, full thickness, human nail plate sections. Transonychial water loss (TOWL) measurements performed on the healthy and diseased nails supported previous observations that the nail behaves like a porous barrier given the lack of correlation between TOWL values with the thicker, diseased nails. The flux of the more hydrophilic caffeine was twofold greater across diseased in comparison with the healthy nails, whilst the hydrophobic molecules terbinafine and amorolfine showed no statistically significant change in their nail penetration rates. Caffeine flux across the nail was found to correlate with the TOWL measurements, though no correlation existed for the more hydrophobic drugs. These data supported the notion that the nail pores, opened up by the infection, facilitated the passage of hydrophilic molecules, whilst the keratin binding of hydrophobic molecules meant that their transport through the nail plate was unchanged. Therefore, in order to exploit the structural changes induced by nail fungal infection it would be beneficial to develop a small molecular weight, hydrophilic antifungal agent, which exhibits low levels of keratin binding.
authors.affiliation: Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB, UK. Electronic address: w.j.mcauley@herts.ac.uk.
authors.forename: W J
authors.initials: WJ
authors.lastname: McAuley
authors.affiliation: Pharmaceutical Science Division, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Traynor
authors.affiliation: Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB, UK.
authors.forename: S
authors.initials: S
authors.lastname: Guesné
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: S
authors.initials: S
authors.lastname: Murdan
authors.affiliation: Department of Pharmacy, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB, UK; MedPharm Ltd, Unit 3 Chancellor Court, 50 Occam Road, Surrey Research Park, Guildford GU2 7AB, UK.
authors.forename: M B
authors.initials: MB
authors.lastname: Brown
mesh_terms: D000287:Administration, Topical; D000935:Antifungal Agents / Q000008:administration & dosage*; D006801:Humans; D007633:Keratins / Q000378:metabolism; D009025:Morpholines / Q000008:administration & dosage; D009181:Mycoses / Q000188:drug therapy*; D009260:Nail Diseases / Q000188:drug therapy*; D009262:Nails / Q000187:drug effects* / Q000382:microbiology*; D009281:Naphthalenes / Q000008:administration & dosage; D014009:Onychomycosis / Q000188:drug therapy* / Q000382:microbiology; D010539:Permeability; D012867:Skin / Q000187:drug effects / Q000382:microbiology; D000077291:Terbinafine; D014867:Water / Q000008:administration & dosage
chemical_list: D000935:Antifungal Agents; D009025:Morpholines; D009281:Naphthalenes; D014867:Water; D007633:Keratins; C038974:amorolfine; D000077291:Terbinafine
keywords: Barrier; Fungal; Nail; Onychomycosis; Topical drug delivery