New Hope for Patients  with Onychomycosis 

Onychomycosis, a non-self-healing fungal infection of the toenails or fingernails, is a common infection accounting for 20% of all nail diseases in adults, affecting 5% of the worldwide population.¹

Dermatophytes, non-dermatophyte molds and yeast cause infected nails to become thick, discolored, and brittle, resulting in separation of the nail from the nailbed. Toenails are more frequently affected than fingernails, with dermatophytes identified in 90% of the toenail and 50% of fingernail onychomycosis.² Trichophyton rubrum is a dermatophytic fungus responsible for the majority of nail fungus although other dermatophytes, including Trichophyton mentagrophytes and Epidermophyton floccosum, have been identified.² Risk factors for developing onychomycosis include older age, diabetes, tinea pedis, psoriasis, immunodeficiency, and living with family members with active onychomycosis.² 

The infection starts with a low-grade inflammatory response and progresses to a chronic phase, resulting in total dystrophic onychomycosis. The most effective treatments for onychomycosis are systemic antifungals, although combination therapy with topical agents, periodic debridement, or chemical nail avulsion may produce better results than systemic medication alone.²

Cure remains challenging with existing therapies due to poor adherence, duration of treatment, oral medication side effects, drug-drug interactions, and lack of visible results in a short period of time.^2,3 Additionally, thickened nails may prevent topical and systemic drugs from penetrating the nail and cure rates are lower in older adults and those with underlying medical conditions that impede nail growth, circulation, and immunity. Reinfection is also common, with 6.5% to 53% of patients experiencing a recurrence;³ fungal resistance to current medications is increasing, highlighting the need for a broad-spectrum antifungal approach that overcomes resistance issues.⁴

Nitric oxide (NO) is a small molecule with diverse physiological, cellular, and molecular functions.⁵ Exogenous topically applied NO has broad-spectrum antimicrobial activity against bacteria, viruses, and fungi through multiple mechanisms^6-13 and has shown efficacy in tinea pedis and other dermal fungal infections.^7,14 Antimicrobial resistance to NO is unlikely. 

 Acidified nitrites release NO and several different topical NO-releasing solution (NORS) formulations have been developed to support skin wellness and homeostasis. An in vitro study of NORS effectively eradicated Trichophyton rubrum and Trichophyton mentagrophytes.¹² Finnen et al showed acidified nitrite produced antifungal effects in the nail plate of 13 human volunteers and surmised this effect was likely mediated by S-nitrosothiols formed by reaction of thiol groups with acidified nitrite.¹⁵ The formulation was well tolerated and benign and temporary discoloration of the nail was observed.¹⁵ Of the 13 subjects with onychomycosis treated once daily with an acidified nitrite cream, all were culture negative for Trichophyton rubrum at Week 16 (end of study) with most culture negative as early as Week 2 (11/13).¹⁵

A non-prescription NORS gel formulation has been developed for onychomycosis (SaNOtize, Vancouver, BC). Besides NORS showing strong antifungal properties, NO being a small molecule makes it ideal to penetrate thickened nails, so it was hypothesized that once-daily application of NORS gel would improve nail clearance in those with onychomycosis. 

Case Vignettes

A 65-year-old female with a 4-year history of onychomycosis of the great toe presented to clinic for evaluation. She reported the nail fungus was extremely bothersome and had tried topical application of tea tree oil and castor oil and oral calcium supplements; she also unsuccessfully employed a variety of other over-the-counter products intended for nail clearance. Her physician offered oral antifungals, but she refused due to concerns about side effects, liver damage, duration of treatment, and the need for blood draws to monitor liver function. 

She was offered NORS gel and instructed to apply it once a day to the affected nail for 1 month. By the third week (Figure 1, Week 3), there was an expected, temporary discoloration of the nail and surrounding skin due to the contact of the NORS with dead keratinocytes. By Month 2, this discoloration was visibly absent from new nail growth. By Month 5, the nail was clear and culture negative. She reported no side effects during treatment other than discoloration. 

A 59-year-old male experienced nail fungus on two toenails for 2 months following an injury to the toenails. Infected toenails became thick, developed hard ridges, and were discolored. (Figure 2). The presence of dermatophytes was confirmed via laboratory testing of nail clippings. Before bed, the patient applied NORS gel to the infected nails by mixing the gel on the nail surface with a toothpick and then added a piece of corn pad to create a small air pocket. Treated nails were wrapped with plastic wrap and the patient wore clean socks to bed. Nails were covered in plastic wrap for about 6 to 8 hours each night for an average of 6 nights per week for 30 to 40 days. He reported one occurrence of a mild and uncomfortable stinging sensation surrounding a treated nail; he removed the plastic wrap and discontinued treatment for 2 days. Upon reapplication and covering, he did not experience any pain and noticed some nail discoloration. New smooth nail growth at the cuticle was observed 1 to 2 weeks after treatment termination. 

Hope for Those with Onychomycosis?

Onychomycosis is frustrating for both patient and provider with limited therapeutic options, low cure rates, and prolonged duration of treatment.^2,3 NORS gel has shown anecdotal success in laboratory-confirmed onychomycosis, with the convenience of once-daily application for 1 month and no prescription.^16,17 Studies suggest NORS gel is likely antifungal and penetrates the nail, supporting nail clearance with clearer nails seen in 3 months after 1 month of daily application.^7,16 It is well tolerated with mild discoloration reported during and after use but not observed in new nail growth. NORS gel is being offered in a user experience program to determine its impact on supporting nail health.