Skip to main content
Top
Published in: Infectious Diseases and Therapy 6/2024

Open Access 04-05-2024 | Onychomycosis | Original Research

Penetration Profiles of Four Topical Antifungals in Mycotic Human Toenails Quantified by Matrix-Assisted Laser Desorption Ionization–Fourier Transform Ion Cyclotron Resonance Imaging

Authors: Nicolas Joly-Tonetti, Raphael Legouffe, Aurore Tomezyk, Clémence Gumez, Mathieu Gaudin, David Bonnel, Martin Schaller

Published in: Infectious Diseases and Therapy | Issue 6/2024

Login to get access

Abstract

Introduction

Onychomycosis is a fungal infection of the nails that can be challenging to treat. Here, matrix-assisted laser desorption ionization–Fourier transform ion cyclotron resonance (MALDI-FTICR) imaging was applied to the quantitative analysis of the penetration profile of the antifungal compound, amorolfine, in human mycotic toenails. The amorolfine profile was compared with those of three other antifungals, ciclopirox, naftifine, and tioconazole.

Methods

Antifungal compounds (amorolfine 5% lacquer, ciclopirox 8% lacquer, naftifine 1% solution, and tioconazole 28% solution) were applied to mycotic nails (n = 42). Nail sections were prepared, and MALDI-FTICR analysis was performed on the sections at a spatial resolution of 70 μm to compare the distribution profiles. Based on the minimum inhibitory concentrations of the four test compounds needed to kill 90% (MIC90) of the fungal organism, Trichophyton rubrum, the fold differences between the MIC90 and the antifungal concentrations in the nails (termed the multiplicity of the MIC90) were calculated for each.

Results

The penetration profiles indicated higher concentrations of amorolfine and ciclopirox in the deeper layers of the nails 3 h after treatment, compared with naftifine and tioconazole. The mean concentrations across the entire nail sections at 3 h were significantly different among the four antifungals: amorolfine, 2.46 mM; ciclopirox, 0.95 mM; naftifine, 0.63 mM; and tioconazole, 1.36 mM (p = 0.016; n = 8 per compound). The median multiplicity of the MIC90 at 3 h was 191-fold for amorolfine, tenfold for ciclopirox, 52-fold for naftifine, and 208-fold for tioconazole.

Conclusion

In this study, MALDI-FTICR was successfully applied to the quantitative analysis of antifungal distribution in human mycotic nails. The findings suggest that amorolfine penetrates deeper layers of the nail and accumulates at concentrations far exceeding the MIC needed to exert antimycotic activity.
Literature
1.
go back to reference Baswan S, Kasting GB, Li SK, et al. Understanding the formidable nail barrier: a review of the nail microstructure, composition and diseases. Mycoses. 2017;60(5):284–95.CrossRefPubMedPubMedCentral Baswan S, Kasting GB, Li SK, et al. Understanding the formidable nail barrier: a review of the nail microstructure, composition and diseases. Mycoses. 2017;60(5):284–95.CrossRefPubMedPubMedCentral
2.
3.
go back to reference Porta Siegel T, Hamm G, Bunch J, Cappell J, Fletcher JS, Schwamborn K. Mass spectrometry imaging and integration with other imaging modalities for greater molecular understanding of biological tissues. Mol Imaging Biol. 2018;20(6):888–901.CrossRefPubMedPubMedCentral Porta Siegel T, Hamm G, Bunch J, Cappell J, Fletcher JS, Schwamborn K. Mass spectrometry imaging and integration with other imaging modalities for greater molecular understanding of biological tissues. Mol Imaging Biol. 2018;20(6):888–901.CrossRefPubMedPubMedCentral
4.
go back to reference LaBonia GJ, Lockwood SY, Heller AA, Spence DM, Hummon AB. Drug penetration and metabolism in 3-dimensional cell cultures treated in a 3D printed fluidic device: assessment of irinotecan via MALDI imaging mass spectrometry. Proteomics. 2016;16(11–12):1814–21.CrossRefPubMedPubMedCentral LaBonia GJ, Lockwood SY, Heller AA, Spence DM, Hummon AB. Drug penetration and metabolism in 3-dimensional cell cultures treated in a 3D printed fluidic device: assessment of irinotecan via MALDI imaging mass spectrometry. Proteomics. 2016;16(11–12):1814–21.CrossRefPubMedPubMedCentral
5.
go back to reference Russo C, Lewis EEL, Flint L, Clench MR. Mass spectrometry imaging of 3D tissue models. Proteomics. 2018;18(14):1700462.CrossRef Russo C, Lewis EEL, Flint L, Clench MR. Mass spectrometry imaging of 3D tissue models. Proteomics. 2018;18(14):1700462.CrossRef
6.
go back to reference Reyzer ML, Chaurand P, Angel PM, Caprioli RM. Direct molecular analysis of whole-body animal tissue sections by MALDI imaging mass spectrometry. Methods Mol Biol. 2010;656:285–301.CrossRefPubMedPubMedCentral Reyzer ML, Chaurand P, Angel PM, Caprioli RM. Direct molecular analysis of whole-body animal tissue sections by MALDI imaging mass spectrometry. Methods Mol Biol. 2010;656:285–301.CrossRefPubMedPubMedCentral
7.
go back to reference Jove M, Spencer J, Clench M, Loadman PM, Twelves C. Precision pharmacology: mass spectrometry imaging and pharmacokinetic drug resistance. Crit Rev Oncol Hematol. 2019;141:153–62.CrossRefPubMed Jove M, Spencer J, Clench M, Loadman PM, Twelves C. Precision pharmacology: mass spectrometry imaging and pharmacokinetic drug resistance. Crit Rev Oncol Hematol. 2019;141:153–62.CrossRefPubMed
8.
go back to reference Granborg JR, Handler AM, Janfelt C. Mass spectrometry imaging in drug distribution and drug metabolism studies—principles, applications and perspectives. Trends Anal Chem. 2022;146: 116482.CrossRef Granborg JR, Handler AM, Janfelt C. Mass spectrometry imaging in drug distribution and drug metabolism studies—principles, applications and perspectives. Trends Anal Chem. 2022;146: 116482.CrossRef
9.
go back to reference Schulz S, Becker M, Groseclose MR, Schadt S, Hopf C. Advanced MALDI mass spectrometry imaging in pharmaceutical research and drug development. Curr Opin Biotechnol. 2019;55:51–9.CrossRefPubMed Schulz S, Becker M, Groseclose MR, Schadt S, Hopf C. Advanced MALDI mass spectrometry imaging in pharmaceutical research and drug development. Curr Opin Biotechnol. 2019;55:51–9.CrossRefPubMed
10.
go back to reference Pinto F, Bagger C, Kunze G, et al. Visualisation of penetration of topical antifungal drug substances through mycosis-infected nails by matrix-assisted laser desorption ionisation mass spectrometry imaging. Mycoses. 2020;63(8):869–75.CrossRef Pinto F, Bagger C, Kunze G, et al. Visualisation of penetration of topical antifungal drug substances through mycosis-infected nails by matrix-assisted laser desorption ionisation mass spectrometry imaging. Mycoses. 2020;63(8):869–75.CrossRef
11.
go back to reference Bowman AP, Blakney GT, Hendrickson CL, Ellis SR, Heeren RMA, Smith DF. Ultra-high mass resolving power, mass accuracy, and dynamic range MALDI mass spectrometry imaging by 21-T FT-ICR MS. Anal Chem. 2020;92(4):3133–42.CrossRefPubMedPubMedCentral Bowman AP, Blakney GT, Hendrickson CL, Ellis SR, Heeren RMA, Smith DF. Ultra-high mass resolving power, mass accuracy, and dynamic range MALDI mass spectrometry imaging by 21-T FT-ICR MS. Anal Chem. 2020;92(4):3133–42.CrossRefPubMedPubMedCentral
12.
go back to reference Hamm G, Bonnel D, Legouffe R, et al. Quantitative mass spectrometry imaging of propranolol and olanzapine using tissue extinction calculation as normalization factor. J Proteomics. 2012;75(16):4952–61.CrossRefPubMed Hamm G, Bonnel D, Legouffe R, et al. Quantitative mass spectrometry imaging of propranolol and olanzapine using tissue extinction calculation as normalization factor. J Proteomics. 2012;75(16):4952–61.CrossRefPubMed
13.
go back to reference Adimi P, Hashemi SJ, Mahmoudi M, et al. In-vitro activity of 10 antifungal agents against 320 dermatophyte strains using microdilution method in Tehran, Iran. J Pharm Res. 2013;12(3):537–45. Adimi P, Hashemi SJ, Mahmoudi M, et al. In-vitro activity of 10 antifungal agents against 320 dermatophyte strains using microdilution method in Tehran, Iran. J Pharm Res. 2013;12(3):537–45.
14.
go back to reference Fachin A, Maffei C, Martinez-Rossi N. In vitro susceptibility of Trichophyton rubrum isolates to griseofulvin and tioconazole. Induction and isolation of a resistant mutant to both antimycotic drugs: mutant of Trichophyton rubrum resistant to griseofulvin and tioconazole. Mycopathologia. 1996;135(3):141–3.CrossRefPubMed Fachin A, Maffei C, Martinez-Rossi N. In vitro susceptibility of Trichophyton rubrum isolates to griseofulvin and tioconazole. Induction and isolation of a resistant mutant to both antimycotic drugs: mutant of Trichophyton rubrum resistant to griseofulvin and tioconazole. Mycopathologia. 1996;135(3):141–3.CrossRefPubMed
15.
go back to reference Pittrof F, Gerhards J, Erni W, Klecak G. Loceryl nail lacquer–realization of a new galenical approach to onychomycosis therapy. Clin Exp Dermatol. 1992;17:26–8.CrossRefPubMed Pittrof F, Gerhards J, Erni W, Klecak G. Loceryl nail lacquer–realization of a new galenical approach to onychomycosis therapy. Clin Exp Dermatol. 1992;17:26–8.CrossRefPubMed
16.
go back to reference Reinel D, Clarke C. Comparative efficacy and safety of amorolfine nail lacquer 5% in onychomycosis, once-weekly versus twice-weekly. Clin Exp Dermatol. 1992;17:44–9.CrossRefPubMed Reinel D, Clarke C. Comparative efficacy and safety of amorolfine nail lacquer 5% in onychomycosis, once-weekly versus twice-weekly. Clin Exp Dermatol. 1992;17:44–9.CrossRefPubMed
20.
go back to reference Clissold SP, Heel RC. Tioconazole: a review of its antimicrobial activity and therapeutic use in superficial mycoses. Drugs. 1986;31:29–51.CrossRefPubMed Clissold SP, Heel RC. Tioconazole: a review of its antimicrobial activity and therapeutic use in superficial mycoses. Drugs. 1986;31:29–51.CrossRefPubMed
21.
go back to reference Hay RJ. Antifungal drugs. In: Katsambas AD, Lotti TM, Dessinioti C, D’Erme AM, editors. European handbook of dermatological treatments. Cham: Springer International Publishing; 2023. p. 1543–54.CrossRef Hay RJ. Antifungal drugs. In: Katsambas AD, Lotti TM, Dessinioti C, D’Erme AM, editors. European handbook of dermatological treatments. Cham: Springer International Publishing; 2023. p. 1543–54.CrossRef
22.
go back to reference Gotter B, Faubel W, Neubert R. Photothermal imaging in 3D surface analysis of membrane drug delivery. Eur J Pharm Biopharm. 2010;74(1):26–32.CrossRefPubMed Gotter B, Faubel W, Neubert R. Photothermal imaging in 3D surface analysis of membrane drug delivery. Eur J Pharm Biopharm. 2010;74(1):26–32.CrossRefPubMed
23.
go back to reference Dutet J, Delgado-Charro M. Assessment of iontophoretic and passive ungual penetration by laser scanning confocal microscopy. Pharm Res. 2012;29(12):3464–74.CrossRefPubMed Dutet J, Delgado-Charro M. Assessment of iontophoretic and passive ungual penetration by laser scanning confocal microscopy. Pharm Res. 2012;29(12):3464–74.CrossRefPubMed
24.
go back to reference Flores F, Chiu W, Beck R, da Silva C, Delgado-Charro M. Enhancement of tioconazole ungual delivery: combining nanocapsule formulation and nail portion approaches. Int J Pharm. 2018;535(1–2):237–44.CrossRefPubMed Flores F, Chiu W, Beck R, da Silva C, Delgado-Charro M. Enhancement of tioconazole ungual delivery: combining nanocapsule formulation and nail portion approaches. Int J Pharm. 2018;535(1–2):237–44.CrossRefPubMed
25.
go back to reference Ghannoum M, Long L, Kunze G, Sarkany M, Osman-Ponchet H. A pilot, layerwise, ex vivo evaluation of the antifungal efficacy of amorolfine 5% nail lacquer vs other topical antifungal nail formulations in healthy toenails. Mycoses. 2019;62(6):494–501.CrossRefPubMed Ghannoum M, Long L, Kunze G, Sarkany M, Osman-Ponchet H. A pilot, layerwise, ex vivo evaluation of the antifungal efficacy of amorolfine 5% nail lacquer vs other topical antifungal nail formulations in healthy toenails. Mycoses. 2019;62(6):494–501.CrossRefPubMed
27.
go back to reference Matsuda Y, Sugiura K, Hashimoto T, Ueda A, Konno Y, Tatsumi Y. Efficacy coefficients determined using nail permeability and antifungal activity in keratin-containing media are useful for predicting clinical efficacies of topical drugs for onychomycosis. PLoS One. 2016;11(7): e0159661.CrossRefPubMedPubMedCentral Matsuda Y, Sugiura K, Hashimoto T, Ueda A, Konno Y, Tatsumi Y. Efficacy coefficients determined using nail permeability and antifungal activity in keratin-containing media are useful for predicting clinical efficacies of topical drugs for onychomycosis. PLoS One. 2016;11(7): e0159661.CrossRefPubMedPubMedCentral
28.
go back to reference Plaum S, Verma A, Fleischer ABJ, Olayinka B, Hardas B. Detection and relevance of naftifine hydrochloride in the stratum corneum up to four weeks following the last application of naftifine cream and gel, 2%. J Drugs Dermatol. 2013;12(9):1004–8.PubMed Plaum S, Verma A, Fleischer ABJ, Olayinka B, Hardas B. Detection and relevance of naftifine hydrochloride in the stratum corneum up to four weeks following the last application of naftifine cream and gel, 2%. J Drugs Dermatol. 2013;12(9):1004–8.PubMed
Metadata
Title
Penetration Profiles of Four Topical Antifungals in Mycotic Human Toenails Quantified by Matrix-Assisted Laser Desorption Ionization–Fourier Transform Ion Cyclotron Resonance Imaging
Authors
Nicolas Joly-Tonetti
Raphael Legouffe
Aurore Tomezyk
Clémence Gumez
Mathieu Gaudin
David Bonnel
Martin Schaller
Publication date
04-05-2024
Publisher
Springer Healthcare
Published in
Infectious Diseases and Therapy / Issue 6/2024
Print ISSN: 2193-8229
Electronic ISSN: 2193-6382
DOI
https://doi.org/10.1007/s40121-024-00978-3

Other articles of this Issue 6/2024

Infectious Diseases and Therapy 6/2024 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Webinar | 06-02-2024 | 20:00 (CET)

Mastering chronic pancreatitis pain: A multidisciplinary approach and practical solutions

Severe pain is the most common symptom of chronic pancreatitis. In this webinar, experts share the latest insights in pain management for chronic pancreatitis patients. Experts from a range of disciplines discuss pertinent cases and provide practical suggestions for use within clinical practice.

Sponsored by: Viatris

Developed by: Springer Healthcare