Emerging Concepts In Treating Onychomycosis

Author(s): 
John D. Mozena, DPM, and Joshua P. Mitnick, DPM

   Ciclopirox is a hydroxypyridone with a unique mechanism of action. It works by chelating the polyvalent cations (Fe+3 or Al+3), resulting in the inhibition of metal dependent enzymes that degrade the toxic peroxides within the fungal cell. Mycological cure rates have been good but clinical cure rates are approximately one-quarter that of oral medications.9

   Other medications that have shown anecdotal success are tea tree oil, Vicks Vapor rub, Listerine and oral medications dissolved in different mediums including dimethyl sulfoxide (DMSO). None of these have FDA approval or are substantiated by evidence-based medicine.9-11

   In regard to new topical agents, Schering Plough has acquired AN2690, a new topical antifungal that targets fungal protein synthesis. An essential enzyme in fungal synthesis is leucyl-transfer RNA synthetase (LeuRS). AN2690 inhibits protein synthesis by denaturing LeurRS, which leads to the termination of cell growth or cell death.12 This inhibition requires a boron molecule to be replaced with a carbon molecule. In theory, this will eliminate fungal infection.

   When it comes to possible side effects for AN2690, initial phase II trials led to little or no detectable drug exposure in urine or blood, negating possible systemic issues. The main side effect was mild to moderate local skin reaction. Schering-Plough will begin phase III clinical trials in 2009. The company claims that this new topical treatment will be 250 times more powerful than Penlac, the only currently approved topical therapy for onychomycosis in the U.S.12

   Another way to improve topical medications is to improve transport technology. Current work is centering on an iontophoretic control device that delivers an electrical current with a dose of terbinafine (Lamisil, Novartis) to the nail bed by electrode. The goal is to drive the drug through the nail as well as saturate the nail and nail bed. This will create a reservoir of antifungal medication, which will allow continual release of terbinafine to the underside of the nail where onychomycosis develops.

   The same features that make drug delivery to the nail difficult (i.e. a lack of blood vessels and a waxy, impermeable surface) improve the half-life of drugs that do penetrate. Also bear in mind that the structure of the nail creates an excellent reservoir for holding drugs and releasing them over time. This will help eliminate high systemic concentrations and drug interaction concerns.

   A double-blind, randomized pilot study of 28 patients using iontophoresis with terbinafine hydrochloride showed a 64 percent clinical improvement in comparison to the placebo group at week 24. Final data is not available at this time.13

   NanoBio Corporation is developing NB-002, a new topical treatment for onchomycosis. This oil-in-water emulsion is currently in phase II development. With this treatment, high-energy nano-sized particles penetrate the skin pores and diffuse through the skin that surrounds the entire nail plate, according to a study by NanoBio Corporation.14 Upon contact with the pathogen, the highly charged particles release their energies to the pathogen’s outer membranes, disrupting the fungus.

   NanoBio states that NB-002 is able to achieve 50 times the minimum drug concentration needed to kill the fungus in the center of the nail bed. Studies conducted in vitro demonstrate that NB-002 has antifungal activity against the organisms (including T. rubrum, T. mentagrophytes, Epidermophyton floccosum and Candida albicans) that cause nail fungus.14

   MacroChem Corporation is currently in the midst of a phase II open-label trial of EcoNail (econazole 5%/SEPA 18% nail lacquer), a topical lacquer with SEPA (2-n-1,3 dioxolane) as a drug release enhancer to increase the delivery of econazole to the nail matrix. A total of 37 patients with mild to moderate great toenail infection underwent treatment for 48 weeks with the topical nail lacquer. After 48 weeks of once-a-day treatment, 100 percent of patients had cultures that were negative for dermatophyte growth.15

Comments

For professionals in the Podiatric community that are interested, here is the current Pivotal Study information on the Noveon from Nomir Medical Technologies

There were 36 subjects (53 Toes) enrolled in the study.

Starting after the completion of the second of the four treatments, all subjects were required to use a non-prescriptive topical agent: 1% topical terbinafine cream applied only between the toes to control or prevent tinea interdigitalis.

Patients were instructed to not get any cream on the nails.

Use of this topical between the toes only, was in accordance with the current listed product information and is neither FDA indicated, nor FDA cleared as a treatment for onychomycosis. Other adjunctive actions that are "standard of care", such as nail debridement or nail trimming, were allowed at each investigator’s discretion.

Control subjects were handled identically in all respects to those who were treated, except for, of course, with sham “treatment” there was no energy delivery. The highest treatment site temperature was 100.5°F.

All study subjects had to have laboratory confirmation of onychomycosis by either positive culture using a selective dermatophyte test medium, or positive periodic acid-Schiff staining (PAS) from a toenail sample.

The mycology was followed and data taken for the 180 day balance of the study.

The top-line preliminary 120-day data analysis that was presented at the Council for Nail Disorders 13th Annual Scientific Meeting, and demonstrated that after Noveon treatment, 76.3 percent of the treated toes showed evidence of clinical improvement (p

This data was based on at least 120 days of follow-up on all enrolled patients. Additionally, no significant adverse events were reported.

The final 180 day data, is currently under review by the FDA in an application for 510(k) approval for Onychomycosis treatment, and has been accepted for publication with a Podiatric peer-review journal.

Completed pilot study data with this device can be found at:

Bornstein, E.S., A.H. Robbins, M. Michelon (2008) Photo-inactivation of fungal pathogens that cause onychomycosis in vitro and in vivo with the noveon dual wavelength laser system. 2008 New Cardiovascular Horizons Meeting Abstracts.

http://www.nomirmedical.com/pdf/NCH_...L_08-26-08.pdf

A lengthy discussion on this and other light-based onychomycosis technologies can be found at:

http://www.podiatry-arena.com/podiat...ad.php?t=22925

Eric Bornstein
Chief Science Officer
Nomir Medical Technologies

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