Successful In Vitro and In Vivo Treatment of Tinea Pedis with a Nitric Oxide-releasing Gel

Abstract

Introduction: 

Tinea pedis (athlete’s foot) is among the most common superficial fungal infections worldwide, affecting up to 70% of individuals in their lifetime. Caused primarily by Trichophyton rubrum and Trichophyton interdigitale, it manifests as interdigital maceration, hyperkeratotic scaling, or vesiculobullous eruptions. Treatment is often complicated by increasing resistance to standard antifungal therapies. Nitric oxide (NO), a broad-spectrum antimicrobial with multiple cellular targets, represents a promising alternative. Previous work with a nitric oxide releasing solution (NORS) demonstrated fungicidal efficacy in keratin-rich environments and clinical utility in foot bath studies, but real-world application was limited by treatment logistics. This study evaluates a novel nitric oxide releasing gel (NORS-gel) designed for practical patient use. 

Aim: 

To investigate the antifungal efficacy, dermal penetration, mechanism of action, and preliminary clinical performance of NORS-gel in refractory tinea pedis. 

Methods: 

Antifungal activity was assessed against T. rubrum and T. mentagrophytes using (1) time-kill assays, (2) zone of inhibition tests across synthetic dermal membranes, and (3) scanning electron microscopy (SEM) for morphological effects. A single-patient case study evaluated safety, tolerability, and clinical efficacy. Treatment involved twice-daily topical application for one week, followed by once-daily use for four weeks. Symptom severity was measured using the Athlete’s Foot Severity Score (AFSS). 

Results: 

NORS-gel demonstrated rapid fungicidal activity, achieving complete kill of T. rubrum within one minute and T. mentagrophytes within an average of 2.8 minutes, while placebo had no effect. In dermal membrane assays, NORS-gel penetrated the synthetic barrier and maintained fungicidal efficacy, producing zones of inhibition 57% larger than those with Tolcylen and significantly outperforming tolnaftate, which failed to penetrate. SEM revealed extensive structural disruption, impaired hyphal formation, and fungal cell wall perforations, confirming a fungicidal—not fungistatic—mechanism. 
 
In the clinical case, a 37-year-old male with refractory interdigital tinea pedis unresponsive to terbinafine and clotrimazole achieved complete symptomatic resolution after five weeks. AFSS decreased from 24 at baseline to 0 at week 5. Adverse effects were limited to mild, transient yellow skin discoloration and dryness, managed with moisturizer. 

Conclusions: 

NORS-gel exhibited rapid, potent fungicidal activity in vitro, effective dermal penetration with sustained efficacy, and striking morphological disruption of fungal structures. Clinically, a refractory case of tinea pedis resolved completely within five weeks of treatment. Nitric oxide’s multifaceted antimicrobial mechanism may reduce risk of resistance development and confer added benefits in wound healing. While these findings are preliminary, they highlight the therapeutic potential of NORS-gel as a novel topical antifungal agent. Larger randomized controlled trials are warranted to confirm efficacy, optimize dosing regimens, and establish long-term safety. 

Sponsored: SaNOtize Research and Development Corporation