Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.¹ Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.² It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.³ Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.⁴ Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.⁵

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.⁶ This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.⁷ Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.⁶

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.⁸ In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.⁹ Patients also may present with aesthetic concerns that may impact their quality of life.¹⁰

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.¹¹ Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.¹² Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.¹³ For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.¹³

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.¹⁴Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.¹⁵ In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.¹⁶ Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.¹⁷ Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.¹⁸

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.¹⁹ Tea tree oil has been shown to be an effective treatment of tinea pedis,²⁰ and it is widely used in Australia as well as in Europe and North America.²¹ Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro^22-28 and in clinical trials.^29,30

In Vitro Data

Because TTO is composed of more than 100 active components,²³ the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.²² The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.²⁴ Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,²⁴ which are the 2 most common etiologies of onychomycosis.⁵ In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.²⁵ Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.³¹

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.⁵ In C albicans, TTO causes altered permeability of plasma membranes,³² dose-dependent alteration of respiration,³³ decreased glucose-induced acidification of media surrounding fungi,³² and reversible inhibition of germ tube formation.^19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.²⁹ Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.²⁹

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.³⁰ Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.³⁰

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.³⁵ The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.³⁵ Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,^36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.^36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.⁴⁰

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.³⁶ The in vitro activity of thymol, a component of TCS, was tested against Candida species.³⁷ The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.³⁷ It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.³⁸

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.³⁶ Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.³⁶

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.⁴⁰ The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.⁴⁰

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.⁴¹ Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.^42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.^45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.^49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.⁴⁶ In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.⁴⁷ In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.⁴²

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.⁴⁹ Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.⁴⁹

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.⁵⁰ The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.⁵⁰

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.^51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.⁵³ Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.^54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.⁵⁷ Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.^53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,⁵⁹ was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.⁵⁴ It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.⁵⁵ In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.⁵⁶

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).⁵⁸ Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).⁵⁸ A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.⁵⁸

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.⁵³ One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.⁵³

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O₃) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.⁶⁰ It was originally shown to have antibacterial properties in vitro,⁶¹ and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.^62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.⁶⁵ The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.⁶⁵

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.⁶² Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.⁶⁴

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.⁶⁵ Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.⁶⁵

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.²⁹ Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.³⁰ Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.⁴⁰ Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.⁴⁹ No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.⁴⁹ In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.⁵⁰ A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,⁵⁸ AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.⁵³

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.⁶⁵ Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.¹ Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.² It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.³ Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.⁴ Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.⁵

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.⁶ This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.⁷ Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.⁶

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.⁸ In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.⁹ Patients also may present with aesthetic concerns that may impact their quality of life.¹⁰

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.¹¹ Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.¹² Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.¹³ For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.¹³

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.¹⁴Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.¹⁵ In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.¹⁶ Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.¹⁷ Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.¹⁸

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.¹⁹ Tea tree oil has been shown to be an effective treatment of tinea pedis,²⁰ and it is widely used in Australia as well as in Europe and North America.²¹ Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro^22-28 and in clinical trials.^29,30

In Vitro Data

Because TTO is composed of more than 100 active components,²³ the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.²² The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.²⁴ Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,²⁴ which are the 2 most common etiologies of onychomycosis.⁵ In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.²⁵ Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.³¹

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.⁵ In C albicans, TTO causes altered permeability of plasma membranes,³² dose-dependent alteration of respiration,³³ decreased glucose-induced acidification of media surrounding fungi,³² and reversible inhibition of germ tube formation.^19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.²⁹ Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.²⁹

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.³⁰ Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.³⁰

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.³⁵ The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.³⁵ Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,^36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.^36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.⁴⁰

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.³⁶ The in vitro activity of thymol, a component of TCS, was tested against Candida species.³⁷ The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.³⁷ It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.³⁸

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.³⁶ Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.³⁶

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.⁴⁰ The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.⁴⁰

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.⁴¹ Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.^42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.^45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.^49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.⁴⁶ In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.⁴⁷ In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.⁴²

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.⁴⁹ Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.⁴⁹

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.⁵⁰ The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.⁵⁰

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.^51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.⁵³ Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.^54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.⁵⁷ Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.^53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,⁵⁹ was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.⁵⁴ It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.⁵⁵ In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.⁵⁶

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).⁵⁸ Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).⁵⁸ A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.⁵⁸

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.⁵³ One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.⁵³

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O₃) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.⁶⁰ It was originally shown to have antibacterial properties in vitro,⁶¹ and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.^62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.⁶⁵ The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.⁶⁵

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.⁶² Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.⁶⁴

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.⁶⁵ Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.⁶⁵

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.²⁹ Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.³⁰ Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.⁴⁰ Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.⁴⁹ No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.⁴⁹ In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.⁵⁰ A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,⁵⁸ AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.⁵³

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.⁶⁵ Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Onychomycosis is a fungal infection of the nail unit by dermatophytes, yeasts, and nondermatophyte molds. It is characterized by a white or yellow discoloration of the nail plate; hyperkeratosis of the nail bed; distal detachment of the nail plate from its bed (onycholysis); and nail plate dystrophy, including thickening, crumbling, and ridging. Onychomycosis is an important problem, representing 30% of all superficial fungal infections and an estimated 50% of all nail diseases.¹ Reported prevalence rates of onychomycosis in the United States and worldwide are varied, but the mean prevalence based on population-based studies in Europe and North America is estimated to be 4.3%.² It is more common in older individuals, with an incidence rate of 20% in those older than 60 years and 50% in those older than 70 years.³ Onychomycosis is more common in patients with diabetes and 1.9 to 2.8 times higher than the general population.⁴ Dermatophytes are responsible for the majority of cases of onychomycosis, particularly Trichophyton rubrum and Trichophyton mentagrophytes.⁵

Onychomycosis is divided into different subtypes based on clinical presentation, which in turn are characterized by varying infecting organisms and prognoses. The subtypes of onychomycosis are distal and lateral subungual (DLSO), proximal subungual, superficial, endonyx, mixed pattern, total dystrophic, and secondary. Distal and lateral subungual onychomycosis are by far the most common presentation and begins when the infecting organism invades the hyponychium and distal or lateral nail bed. Trichophyton rubrum is the most common organism and T mentagrophytes is second, but Candida parapsilosis and Candida albicans also are possibilities. Proximal subungual onychomycosis is far less frequent than DLSO and is usually caused by T rubrum. The fungus invades the proximal nail folds and penetrates the newly growing nail plate.⁶ This pattern is more common in immunosuppressed patients and should prompt testing for human immunodeficiency virus.⁷ Total dystrophic onychomycosis is the end stage of fungal nail plate invasion, may follow DLSO or proximal subungual onychomycosis, and is difficult to treat.⁶

Onychomycosis causes pain, paresthesia, and difficulty with ambulation.⁸ In patients with peripheral neuropathy and vascular problems, including diabetes, onychomycosis can increase the risk for foot ulcers, with amputation in severe cases.⁹ Patients also may present with aesthetic concerns that may impact their quality of life.¹⁰

Given the effect on quality of life along with medical risks associated with onychomycosis, a safe and successful treatment modality with a low risk of recurrence is desirable. Unfortunately, treatment of nail fungus is quite challenging for a number of reasons. First, the thickness of the nail and/or the fungal mass may be a barrier to the delivery of topical and systemic drugs at the source of the infection. In addition, the nail plate does not have intrinsic immunity. Also, recurrence after treatment is common due to residual hyphae or spores that were not previously eliminated.¹¹ Finally, many topical medications require long treatment courses, which may limit patient compliance, especially in patients who want to use nail polish for cosmesis or camouflage.

Currently Approved Therapies for Onychomycosis

Several definitions are needed to better interpret the results of onychomycosis clinical trials. Complete cure is defined as a negative potassium hydroxide preparation and negative fungal culture with a completely normal appearance of the nail. Mycological cure is defined as potassium hydroxide microscopy and fungal culture negative. Clinical cure is stated as 0% nail plate involvement but at times is reported as less than 5% and less than 10% involvement.

Terbinafine and itraconazole are the only US Food and Drug Administration (FDA)–approved systemic therapies, and ciclopirox, efinaconazole, and tavaborole are the only FDA-approved topicals. Advantages of systemic agents generally are higher cure rates and shorter treatment courses, thus better compliance. Disadvantages include greater incidence of systemic side effects and drug-drug interactions as well as the need for laboratory monitoring. Pros of topical therapies are low potential for adverse effects, no drug-drug interactions, and no monitoring of blood work. Cons include lower efficacy, long treatment courses, and poor patient compliance.

Terbinafine, an allylamine, taken orally once daily (250 mg) for 12 weeks for toenails and 6 weeks for fingernails currently is the preferred systemic treatment of onychomycosis, with complete cure rates of 38% and 59% and mycological cure rates of 70% and 79% for toenails and fingernails, respectively.¹² Itraconazole, an azole, is dosed orally at 200 mg daily for 3 months for toenails, with a complete cure rate of 14% and mycological cure rate of 54%.¹³ For fingernail onychomycosis only, itraconazole is dosed at 200 mg twice daily for 1 week, followed by a treatment-free period of 3 weeks, and then another 1-week course at thesame dose. The complete cure rate is 47% and the mycological cure is 61% for this pulse regimen.¹³

Ciclopirox is a hydroxypyridone and the 8% nail lacquer formulation was approved in 1999, making it the first topical medication to gain FDA approval for the treatment of toenail onychomycosis. Based on 2 clinical trials, complete cure rates for toenails are 5.5% and 8.5% and mycological cure rates are 29% and 36% at 48 weeks with removal of residual lacquer and debridement.¹⁴Efinaconazole is an azole and the 10% solution was FDA approved for the treatment of toenail onychomycosis in 2014.¹⁵ In 2 clinical trials, complete cure rates were 17.8% and 15.2% and mycological cure rates were 55.2% and 53.4% with once daily toenail application for 48 weeks.¹⁶ Tavaborole is a benzoxaborole and the 5% solution also was approved for the treatment of toenail onychomycosis in 2014.¹⁷ Two clinical trials reported complete cure rates of 6.5% and 9.1% and mycological cure rates of 31.1% and 35.9% with once daily toenail application for 48 weeks.¹⁸

Given the poor efficacy, systemic side effects, potential for drug-drug interactions, long-term treatment courses, and cost associated with current systemic and/or topical treatments, there has been a renewed interest in natural remedies and over-the-counter (OTC) therapies for onychomycosis. This review summarizes the in vitro and in vivo data, mechanisms of action, and clinical efficacy of various natural and OTC agents for the treatment of onychomycosis. Specifically, we summarize the data on tea tree oil (TTO), a popular topical cough suppressant (TCS), natural coniferous resin (NCR) lacquer, Ageratina pichinchensis (AP) extract, and ozonized sunflower oil.

Tea Tree Oil

Background

Tea tree oil is a volatile oil whose medicinal use dates back to the early 20th century when the Bundjabung aborigines of North and New South Wales extracted TTO from the dried leaves of the Melaleuca alternifolia plant and used it to treat superficial wounds.¹⁹ Tea tree oil has been shown to be an effective treatment of tinea pedis,²⁰ and it is widely used in Australia as well as in Europe and North America.²¹ Tea tree oil also has been investigated as an antifungal agent for the treatment of onychomycosis, both in vitro^22-28 and in clinical trials.^29,30

In Vitro Data

Because TTO is composed of more than 100 active components,²³ the antifungal activity of these individual components was investigated against 14 fungal isolates, including C albicans, T mentagrophytes, and Aspergillus species. The minimum inhibitory concentration (MIC) for α-pinene was less than 0.004% for T mentagrophytes and the components with the greatest MIC and minimum fungicidal concentration for the fungi tested were terpinen-4-ol and α-terpineol, respectively.²² The antifungal activity of TTO also was tested using disk diffusion assay experiments with 58 clinical isolates of fungi including C albicans, T rubrum, T mentagrophytes, and Aspergillus niger.²⁴ Tea tree oil was most effective at inhibiting T rubrum followed by T mentagrophytes,²⁴ which are the 2 most common etiologies of onychomycosis.⁵ In another report, the authors determined the MIC of TTO utilizing 4 different experiments with T rubrum as the infecting organism. Because TTO inhibited the growth of T rubrum at all concentrations greater than 0.1%, they found that the MIC was 0.1%.²⁵ Given the lack of adequate nail penetration of most topical therapies, TTO in nanocapsules (TTO-NC), TTO nanoemulsions, and normal emulsions were tested in vitro for their ability to inhibit the growth of T rubrum inoculated into nail shavings. Colony growth decreased significantly within the first week of treatment, with TTO-NC showing maximum efficacy (P<.001). This study showed that TTO, particularly TTO-NC, was effective in inhibiting the growth of T rubrum in vitro and that using nanocapsule technology may increase nail penetration and bioavailability.³¹

Much of what we know about TTO’s antifungal mechanism of action comes from experiments involving C albicans. To date, it has not been studied in T rubrum or T mentagrophytes, the 2 most common etiologies of onychomycosis.⁵ In C albicans, TTO causes altered permeability of plasma membranes,³² dose-dependent alteration of respiration,³³ decreased glucose-induced acidification of media surrounding fungi,³² and reversible inhibition of germ tube formation.^19,34

Clinical Trials

A randomized, double-blind, multicenter trial was performed on 117 patients with culture-proven DLSO who were randomized to receive TTO 100% or clotrimazole solution 1% applied twice daily to affected toenails for 6 months.²⁹ Primary outcome measures were mycologic cure, clinical assessment, and patient subjective assessment (Table 1). There were no statistical differences between the 2 treatment groups. Erythema and irritation were the most common adverse reactions occurring in 7.8% (5/64) of the TTO group.²⁹

Another study was a double-blind, placebo-controlled trial involving 60 patients with clinical and mycologic evidence of DLSO who were randomized to treatment with a cream containing butenafine hydrochloride 2% and TTO 5% (n=40) or a control cream containing only TTO (n=20), with active treatment for 8 weeks and final follow-up at 36 weeks.³⁰ Patients were instructed to apply the cream 3 times daily under occlusion for 8 weeks and the nail was debrided between weeks 4 and 6 if feasible. If the nail could not be debrided after 8 weeks, it was considered resistant to treatment. At the end of the study, the complete cure rate was 80% in the active group compared to 0% in the placebo group (P<.0001), and the mean time to complete healing with progressive nail growth was 29 weeks. There were no adverse effects in the placebo group, but 4 patients in the active group had mild skin inflammation.³⁰

Topical Cough Suppressant

Background

Topical cough suppressants, which are made up of several natural ingredients, are OTC ointments for adults and children 2 years and older that are indicated as cough suppressants when applied to the chest and throat and as relief of mild muscle and joint pains.³⁵ The active ingredients are camphor 4.8%, eucalyptus oil 1.2%, and menthol 2.6%, while the inactive ingredients are cedarleaf oil, nutmeg oil, petrolatum, thymol, and turpentine oil.³⁵ Some of the active and inactive ingredients in TCSs have shown efficacy against dermatophytes in vitro,^36-38 and although they are not specifically indicated for onychomycosis, they have been popularized as home remedies for fungal nail infections.^36,39 A TCS has been evaluated for its efficacy for the treatment of onychomycosis in one clinical trial.⁴⁰

In Vitro Data

An in vitro study was performed to evaluate the antifungal activity of the individual and combined components of TCS on 16 different dermatophytes, nondermatophytes, and molds. The zones of inhibition against these organisms were greatest for camphor, menthol, thymol, and eucalyptus oil. Interestingly, there were large zones of inhibition and a synergistic effect when a mixture of components was used against T rubrum and T mentagrophytes.³⁶ The in vitro activity of thymol, a component of TCS, was tested against Candida species.³⁷ The essential oil subtypes Thymus vulgaris and Thymus zygis (subspecies zygis) showed similar antifungal activity, which was superior to Thymus mastichina, and all 3 compounds had similar MIC and minimal lethal concentration values. The authors showed that the antifungal mechanism was due to cell membrane damage and inhibition of germ tube formation.³⁷ It should be noted that Candida species are less common causes of onychomycosis, and it is not known whether this data is applicable to T rubrum. In another study, the authors investigated the antifungal activity of Thymus pulegioides and found that MIC ranged from 0.16 to 0.32 μL/mL for dermatophytes and Aspergillus strains and 0.32 to 0.64 μL/mL for Candida species. When an essential oil concentration of 0.08 μL/mL was used against T rubrum, ergosterol content decreased by 70 %, indicating that T pulegioides inhibits ergosterol biosynthesis in T rubrum.³⁸

Clinical Observations and Clinical Trial

There is one report documenting the clinical observations on a group of patients with a clinical diagnosis of onychomycosis who were instructed to apply TCS to affected nail(s) once daily.³⁶ Eighty-five charts were reviewed (mean age, 77 years), and although follow-up was not complete or standardized, the following data were reported: 32 (38%) cleared their fungal infection, 21 (25%) had no record of change but also no record of compliance, 19 (22%) had only 1 documented follow-up visit, 9 (11%) reported they did not use the treatment, and 4 (5%) did not return for a follow-up visit. Of the 32 patients whose nails were cured, 3 (9%) had clearance within 5 months, 8 (25%) within 7 months, 11 (34%) within 9 months, 4 (13%) within 11 months, and 6 (19%) within 16 months.³⁶

A small pilot study was performed to evaluate the efficacy of daily application of TCS in the treatment of onychomycosis in patients 18 years and older with at least 1 great toenail affected.⁴⁰ The primary end points were mycologic cure at 48 weeks and clinical cure at the end of the study graded as complete, partial, or no change. The secondary end point was patient satisfaction with the appearance of the affected nail at 48 weeks. Eighteen participants completed the study; 55% (10/18) were male, with an average age of 51 years (age range, 30–85 years). The mean initial amount of affected nail was 62% (range, 16%–100%), and cultures included dermatophytes, nondermatophytes, and molds. With TCS treatment, 27.8% (5/18) showed mycologic cure of which 4 (22.2%) had a complete clinical cure. Ten participants (55.6%) had partial clinical cure and 3 (16.7%) had no clinical improvement. Interestingly, the 4 participants who had complete clinical cure had baseline cultures positive for either T mentagrophytes or C parapsilosis. Most patients were content with the treatment, as 9 participants stated that they were very satisfied and 9 stated that they were satisfied. The average ratio of affected to total nail area declined from 63% at screening to 41% at the end of the study (P<.001). No adverse effects were reported with study drug.⁴⁰

NCR Lacquer

Background

Resins are natural products derived from coniferous trees and are believed to protect trees against insects and microbial pathogens.⁴¹ Natural coniferous resin derived from the Norway spruce tree (Picea abies) mixed with boiled animal fat or butter has been used topically for centuries in Finland and Sweden to treat infections and wounds.^42-44 The activity of NCR has been studied against a wide range of microbes, demonstrating broad-spectrum antimicrobial activity against both gram-positive bacteria and fungi.^45-48 There are 2 published clinical trials evaluating NCR in the treatment of onychomycosis.^49,50

In Vitro Data

Natural coniferous resin has shown antifungal activity against T mentagrophytes, Trichophyton tonsurans, and T rubrum in vitro, which was demonstrated using medicated disks of resin on petri dishes inoculated with these organisms.⁴⁶ In another study, the authors evaluated the antifungal activity of NCR against human pathogenic fungi and yeasts using agar plate diffusion tests and showed that the resin had antifungal activity against Trichophyton species but not against Fusarium and most Candida species. Electron microscopy of T mentagrophytes exposed to NCR showed that all cells were dead inside the inhibition zone, with striking changes seen in the hyphal cell walls, while fungal cells outside the inhibition zone were morphologically normal.⁴⁷ In another report, utilizing the European Pharmacopoeia challenge test, NCR was highly effective against gram-positive and gram-negative bacteria as well as C albicans.⁴²

Clinical Trials

In one preliminary observational and prospective clinical trial, 15 participants with clinical and mycologic evidence of onychomycosis were instructed to apply NCR lacquer once daily for 9 months with a 4-week washout period, with the primary outcome measures being clinical and mycologic cure.⁴⁹ Thirteen (87%) enrolled participants were male and the average age was 65 years (age range, 37–80 years). The DLSO subtype was present in 9 (60%) participants. The mycologic cure rate at the end of the study was 65% (95% CI, 42%-87%), and none achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail.⁴⁹

The second trial was a prospective, controlled, investigator-blinded study of 73 patients with clinical and mycologic evidence of toenail onychomycosis who were randomized to receive NCR 30%, amorolfine lacquer 5%, or 250 mg oral terbinafine.⁵⁰ The primary end point was mycologic cure at 10 months, and secondary end points were clinical efficacy, cost-effectiveness, and patient compliance. Clinical efficacy was based on the proximal linear growth of healthy nail and was classified as unchanged, partial, or complete. Partial responses were described as substantial decreases in onycholysis, subungual hyperkeratosis, and streaks. A complete response was defined as a fully normal appearance of the toenail. Most patients were male in the NCR (91% [21/23]), amorolfine (80% [20/25]), and terbinafine (68% [17/25]) groups; the average ages were 64, 63, and 64 years, respectively. Trichophyton rubrum was cultured most often in all 3 groups: NCR, 87% (20/23); amorolfine, 96% (24/25); and terbinafine, 84% (21/25). The remaining cases were from T mentagrophytes. A summary of the results is shown in Table 2. Patient compliance was 100% in all except 1 patient in the amorolfine treatment group with moderate compliance. There were no adverse events, except for 2 in the terbinafine group: diarrhea and rash.⁵⁰

AP Extract

Background

Ageratina pichinchensis, a member of the Asteraceae family, has been used historically in Mexico for fungal infections of the skin.^51,52 Fresh or dried leaves were extracted with alcohol and the product was administered topically onto damaged skin without considerable skin irritation.⁵³ Multiple studies have demonstrated that AP extract has in vitro antifungal activity along with other members of the Asteraceae family.^54-56 There also is evidence from clinical trials that AP extract is effective against superficial dermatophyte infections such as tinea pedis.⁵⁷ Given the positive antifungal in vitro data, the potential use of this agent was investigated for onychomycosis treatment.^53,58

In Vitro Data

The antifungal properties of the Asteraceae family have been tested in several in vitro experiments. Eupatorium aschenbornianum, described as synonymous with A pichinchensis,⁵⁹ was found to be most active against the dermatophytes T rubrum and T mentagrophytes with MICs of 0.3 and 0.03 mg/mL, respectively.⁵⁴ It is thought that the primary antimycotic activity is due to encecalin, an acetylchromene compound that was identified in other plants from the Asteraceae family and has activity against dermatophytes.⁵⁵ In another study, Ageratum houstanianum Mill, a comparable member of the Asteraceae family, had fungitoxic activity against T rubrum and C albicans isolated from nail infections.⁵⁶

Clinical Trials

A double-blind controlled trial was performed on 110 patients with clinical and mycologic evidence of mild to moderate toenail onychomycosis randomized to treatment with AP lacquer or ciclopirox lacquer 8% (control).⁵⁸ Primary end points were clinical effectiveness (completely normal nails) and mycologic cure. Patients were instructed to apply the lacquer once every third day during the first month, twice a week for the second month, and once a week for 16 weeks, with removal of the lacquer weekly. Demographics were similar between the AP lacquer and control groups, with mean ages of 44.6 and 46.5 years, respectively; women made up 74.5% and 67.2%, respectively, of each treatment group, with most patients having a 2- to 5-year history of disease (41.8% and 40.1%, respectively).⁵⁸ A summary of the data is shown in Table 3. No severe side effects were documented, but minimal nail fold skin pain was reported in 3 patients in the control group in the first week, resolving later in the trial.⁵⁸

A follow-up study was performed to determine the optimal concentration of AP lacquer for the treatment of onychomycosis.⁵³ One hundred twenty-two patients aged 19 to 65 years with clinical and mycologic evidence of mild to moderate DLSO were randomized to receive 12.6% or 16.8% AP lacquer applied once daily to the affected nails for 6 months. The nails were graded as healthy, mild, or moderately affected before and after treatment. There were no significant differences in demographics between the 2 treatment groups, and 77% of patients were women with a median age of 47 years. There were no significant side effects from either concentration of AP lacquer.⁵³

Ozonized Sunflower Oil

Background

Ozonized sunflower oil is derived by reacting ozone (O₃) with sunflower plant (Helianthus annuus) oil to form a petroleum jelly–like material.⁶⁰ It was originally shown to have antibacterial properties in vitro,⁶¹ and further studies have confirmed these findings and demonstrated anti-inflammatory, wound healing, and antifungal properties.^62-64 A formulation of ozonized sunflower oil used in Cuba is clinically indicated for the treatment of tinea pedis and impetigo.⁶⁵ The clinical efficacy of this product has been evaluated in a clinical trial for the treatment of onychomycosis.⁶⁵

In Vitro Data

A compound made up of 30% ozonized sunflower oil with 0.5% of α-lipoic acid was found to have antifungal activity against C albicans using the disk diffusion method, in addition to other bacterial organisms. The MIC values ranged from 2.0 to 3.5 mg/mL.⁶² Another study was designed to evaluate the in vitro antifungal activity of this formulation on samples cultured from patients with onychomycosis using the disk diffusion method. They found inhibition of growth of C albicans, C parapsilosis, and Candida tropicalis, which was inferior to amphotericin B, ketoconazole, fluconazole, and itraconazole.⁶⁴

Clinical Trial

A single-blind, controlled, phase 3 study was performed on 400 patients with clinical and mycologic evidence of onychomycosis. Patients were randomized to treatment with an ozonized sunflower oil solution or ketoconazole cream 2% applied to affected nails twice daily for 3 months, with filing and massage of the affected nails upon application of treatment.⁶⁵ Cured was defined as mycologic cure in addition to a healthy appearing nail, improved as an increase in healthy appearing nail in addition to a decrease in symptoms (ie, paresthesia, pain, itching) but positive mycological testing, same as no clinical change in appearance with positive mycological findings, and worse as increasing diseased nail involvement in the presence of positive mycological findings. Demographics were similar between groups with a mean age of 35 years. Men accounted for 80% of the study population, and 65% of the study population was white. The mean duration of disease was 30 months. They also reported on a 1-year follow-up, with 2.8% of patients in the ozonized sunflower oil solution group and 37.0% of patients in the ketoconazole group describing relapses. Trichophyton rubrum and C albicans were cultured from these patients.⁶⁵

Comment

Due to the poor efficacy, long-term treatment courses, inability to use nail polish, and high cost associated with many FDA-approved topical treatments, along with the systemic side effects, potential for drug-drug interactions, and cost associated with many oral therapies approved for onychomycosis, there has been a renewed interest in natural remedies and OTC treatments. Overall, TTO, TCS, NCR, AP extract, and ozonized sunflower oil have shown efficacy in vitro against some dermatophytes, nondermatophytes, and molds responsible for onychomycosis. One or more clinical trials were performed with each of these agents for the treatment of onychomycosis. They were mostly small pilot studies, and due to differences in trial design, the results cannot be compared with each other or with currently FDA-approved treatments. We can conclude that because adverse events were rare with all of these therapies—most commonly skin irritation or mild skin pain—they exhibit good safety.

For TTO, there was no statistical difference between the clotrimazole and TTO treatment groups in mycologic cure, clinical assessment, or patient subjective assessment of the nails.²⁹ Although there was an 80% complete cure in the butenafine and TTO group, it was 0% in the TTO group at week 36.³⁰ Trial design, longer treatment periods, incorporation into nanocapsules, or combination treatment with other antifungal agents may influence our future use of TTO for onychomycosis, but based on the present data we cannot recommend this treatment in clinical practice.

With TCS, 27.8% of participants had a mycologic cure and 22.2% had complete clinical cure.⁴⁰ Although it is difficult to draw firm conclusions from this small pilot study, there may be some benefit to treating toenail onychomycosis due to T mentagrophytes or C parapsilosis with TCS but no benefit in treating onychomycosis due to T rubrum, the more common cause of onychomycosis. Limitations of this study were lack of a placebo group, small sample size, wide variety of represented pathogens that may not be representative of the true population, and lack of stratification by baseline severity or involvement of nail. A larger randomized controlled clinical trial would be necessary to confirm the results of this small study and make formal recommendations.

In one clinical trial with NCR, mycologic cure was 65% at the end of the study.⁴⁹ No participants achieved clinical cure, but 6 participants showed some improvement in the appearance of the nail. Because this study was small (N=15), it is difficult to draw firm conclusions.⁴⁹ In another study with NCR, mycologic cure rates with NCR, amorolfine, and terbinafine were 13%, 8%, and 56%, respectively. Based on these results, NCR has similar antifungal efficacy to amorolfine but was inferior to oral terbinafine.⁵⁰ A larger randomized controlled clinical trial with more homogenous and less severely affected patients and longer treatment periods would be necessary to confirm the results of these small studies and make formal recommendations.

Because there were no significant differences in clinical effectiveness of mycologic cure rates between AP lacquer 10% and ciclopirox lacquer 8% in one clinical trial,⁵⁸ AP does not seem to be more effective than at least one of the current FDA-approved topical treatments; however, because AP lacquer 16.8% was shown to be more effective than AP lacquer 12.6% in one onychomycosis clinical trial, using higher concentrations of AP may yield better results in future trials.⁵³

One trial comparing ozonized sunflower oil to ketoconazole cream 2% showed 90.5% and 13.5% cure rates, respectively.⁶⁵ Although there is good in vitro antifungal activity and a clinical trial showing efficacy using ozonized sunflower oil for the treatment of onychomycosis, confirmatory studies are necessary before we can recommend this OTC treatment to our patients. Specifically, we will get the most data from large randomized controlled trials with strict inclusion/exclusion and efficacy criteria.

Conclusion

Over-the-counter and natural remedies may be an emerging area of research in the treatment of onychomycosis. This review summarizes the laboratory data and clinical trials on several of these agents and, when available, compares their clinical and mycologic efficacy with FDA-approved therapies. Shortcomings of some of these studies include a small study population, lack of adequate controls, nonstandardized mycologic testing, and abbreviated posttreatment evaluation times. It may be concluded that these products have varying degrees of efficacy and appear to be safe in the studies cited; however, at present, we cannot recommend any of them to our patients until there are larger randomized clinical trials with appropriate controls demonstrating their efficacy.

Maternal influenza infection during pregnancy does not increase the risk for autism spectrum disorder (ASD) in children, according to Ousseny Zerbo, PhD, and associates.

In a study of 196,929 mother-child pairs (the children were born at Kaiser Permanente Northern California between Jan. 1, 2000, and Dec. 31, 2010), 1.6% of the children were diagnosed with ASD. Influenza was diagnosed in 0.7% of mothers during their pregnancy, and 23% received an influenza vaccination during pregnancy.

©Devonyu/thinkstockphotos.com

[email protected]

Maternal influenza infection during pregnancy does not increase the risk for autism spectrum disorder (ASD) in children, according to Ousseny Zerbo, PhD, and associates.

In a study of 196,929 mother-child pairs (the children were born at Kaiser Permanente Northern California between Jan. 1, 2000, and Dec. 31, 2010), 1.6% of the children were diagnosed with ASD. Influenza was diagnosed in 0.7% of mothers during their pregnancy, and 23% received an influenza vaccination during pregnancy.

©Devonyu/thinkstockphotos.com

[email protected]

Maternal influenza infection during pregnancy does not increase the risk for autism spectrum disorder (ASD) in children, according to Ousseny Zerbo, PhD, and associates.

In a study of 196,929 mother-child pairs (the children were born at Kaiser Permanente Northern California between Jan. 1, 2000, and Dec. 31, 2010), 1.6% of the children were diagnosed with ASD. Influenza was diagnosed in 0.7% of mothers during their pregnancy, and 23% received an influenza vaccination during pregnancy.

©Devonyu/thinkstockphotos.com

[email protected]

Pembrolizumab (Keytruda)

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted priority review to the supplemental biologics license application (sBLA) for pembrolizumab (Keytruda®) as a treatment for patients with refractory classical Hodgkin lymphoma (cHL) and for cHL patients who have relapsed after 3 or more prior lines of therapy.

The sBLA will be reviewed under the FDA’s accelerated approval program. The target action date is March 15, 2017.

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

The drug, which is being developed by Merck, already has FDA approval as a treatment for melanoma, lung cancer, and head and neck cancer.

Pembrolizumab also has breakthrough therapy designation as a treatment for relapsed/refractory cHL.

The current sBLA for pembrolizumab is seeking approval for the drug at a fixed dose of 200 mg, administered intravenously every 3 weeks.

This is the first application for regulatory approval of pembrolizumab in a hematologic malignancy.

The sBLA is supported by data from the phase 1 KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.

Results from KEYNOTE-013 (in cHL patients) were presented at the 2014 ASH Annual Meeting, and results from KEYNOTE-087 were presented at the 2016 ASCO Annual Meeting.

Pembrolizumab (Keytruda)

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted priority review to the supplemental biologics license application (sBLA) for pembrolizumab (Keytruda®) as a treatment for patients with refractory classical Hodgkin lymphoma (cHL) and for cHL patients who have relapsed after 3 or more prior lines of therapy.

The sBLA will be reviewed under the FDA’s accelerated approval program. The target action date is March 15, 2017.

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

The drug, which is being developed by Merck, already has FDA approval as a treatment for melanoma, lung cancer, and head and neck cancer.

Pembrolizumab also has breakthrough therapy designation as a treatment for relapsed/refractory cHL.

The current sBLA for pembrolizumab is seeking approval for the drug at a fixed dose of 200 mg, administered intravenously every 3 weeks.

This is the first application for regulatory approval of pembrolizumab in a hematologic malignancy.

The sBLA is supported by data from the phase 1 KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.

Results from KEYNOTE-013 (in cHL patients) were presented at the 2014 ASH Annual Meeting, and results from KEYNOTE-087 were presented at the 2016 ASCO Annual Meeting.

Pembrolizumab (Keytruda)

Photo courtesy of Merck

The US Food and Drug Administration (FDA) has granted priority review to the supplemental biologics license application (sBLA) for pembrolizumab (Keytruda®) as a treatment for patients with refractory classical Hodgkin lymphoma (cHL) and for cHL patients who have relapsed after 3 or more prior lines of therapy.

The sBLA will be reviewed under the FDA’s accelerated approval program. The target action date is March 15, 2017.

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response.

The drug, which is being developed by Merck, already has FDA approval as a treatment for melanoma, lung cancer, and head and neck cancer.

Pembrolizumab also has breakthrough therapy designation as a treatment for relapsed/refractory cHL.

The current sBLA for pembrolizumab is seeking approval for the drug at a fixed dose of 200 mg, administered intravenously every 3 weeks.

This is the first application for regulatory approval of pembrolizumab in a hematologic malignancy.

The sBLA is supported by data from the phase 1 KEYNOTE-013 trial and the phase 2 KEYNOTE-087 trial.

Results from KEYNOTE-013 (in cHL patients) were presented at the 2014 ASH Annual Meeting, and results from KEYNOTE-087 were presented at the 2016 ASCO Annual Meeting.

Blood sample

Photo by Juan D. Alfonso

The US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for Abbott Molecular Inc.’s RealTime ZIKA assay.

The EUA means the assay can be used by certified laboratories for the qualitative detection of RNA from Zika virus in human serum, EDTA plasma, and urine (collected alongside a patient-matched serum or plasma specimen).

Zika virus RNA is generally detectable in these specimens during the acute phase of infection.

According to updated guidance from the US Centers for Disease Control and Prevention (CDC), Zika virus RNA is detectable up to 14 days in serum and urine (possibly longer in urine), following the onset of symptoms, if present. Positive results are indicative of current infection.

The FDA’s decision to grant an EUA means Abbott’s RealTime ZIKA assay can be used in individuals who meet CDC Zika virus clinical criteria (eg, clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiological criteria for which Zika virus testing may be indicated).

The assay can be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a, to perform high complexity tests, or by similarly qualified non-US laboratories, pursuant to section 564 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 360bbb-3).

The EUA does not mean Abbott’s RealTime ZIKA assay is FDA cleared or approved.

An EUA allows for the use of unapproved medical products or unapproved uses of approved medical products in an emergency.

The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.

This means Abbott’s RealTime ZIKA assay is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.

Blood sample

Photo by Juan D. Alfonso

The US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for Abbott Molecular Inc.’s RealTime ZIKA assay.

The EUA means the assay can be used by certified laboratories for the qualitative detection of RNA from Zika virus in human serum, EDTA plasma, and urine (collected alongside a patient-matched serum or plasma specimen).

Zika virus RNA is generally detectable in these specimens during the acute phase of infection.

According to updated guidance from the US Centers for Disease Control and Prevention (CDC), Zika virus RNA is detectable up to 14 days in serum and urine (possibly longer in urine), following the onset of symptoms, if present. Positive results are indicative of current infection.

The FDA’s decision to grant an EUA means Abbott’s RealTime ZIKA assay can be used in individuals who meet CDC Zika virus clinical criteria (eg, clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiological criteria for which Zika virus testing may be indicated).

The assay can be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a, to perform high complexity tests, or by similarly qualified non-US laboratories, pursuant to section 564 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 360bbb-3).

The EUA does not mean Abbott’s RealTime ZIKA assay is FDA cleared or approved.

An EUA allows for the use of unapproved medical products or unapproved uses of approved medical products in an emergency.

The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.

This means Abbott’s RealTime ZIKA assay is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.

Blood sample

Photo by Juan D. Alfonso

The US Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) for Abbott Molecular Inc.’s RealTime ZIKA assay.

The EUA means the assay can be used by certified laboratories for the qualitative detection of RNA from Zika virus in human serum, EDTA plasma, and urine (collected alongside a patient-matched serum or plasma specimen).

Zika virus RNA is generally detectable in these specimens during the acute phase of infection.

According to updated guidance from the US Centers for Disease Control and Prevention (CDC), Zika virus RNA is detectable up to 14 days in serum and urine (possibly longer in urine), following the onset of symptoms, if present. Positive results are indicative of current infection.

The FDA’s decision to grant an EUA means Abbott’s RealTime ZIKA assay can be used in individuals who meet CDC Zika virus clinical criteria (eg, clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (eg, history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiological criteria for which Zika virus testing may be indicated).

The assay can be used by laboratories in the US that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), 42 U.S.C. §263a, to perform high complexity tests, or by similarly qualified non-US laboratories, pursuant to section 564 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. § 360bbb-3).

The EUA does not mean Abbott’s RealTime ZIKA assay is FDA cleared or approved.

An EUA allows for the use of unapproved medical products or unapproved uses of approved medical products in an emergency.

The products must be used to diagnose, treat, or prevent serious or life-threatening conditions caused by chemical, biological, radiological, or nuclear threat agents, when there are no adequate alternatives.

This means Abbott’s RealTime ZIKA assay is only authorized as long as circumstances exist to justify the emergency use of in vitro diagnostics for the detection of Zika virus, unless the authorization is terminated or revoked sooner.

Q)How is complementary and alternative medicine used in multiple sclerosis, and how can I safely recommend it to my patients?

Complementary and alternative medicine (CAM) is a non-mainstream practice used in conjunction with conventional medicine.¹ Its use is prevalent among people with and without chronic illnesses, including those living with multiple sclerosis (MS). Up to 70% of Americans with MS have used some type of CAM therapy, compared with 36% of the general population.^1,2 CAM use is higher in women than in men and is highest among persons ages 35 to 49—two demographics also associated with MS.³

CAM practices include a myriad of therapies from different disciplines (see Table 1).³ Because most people who use CAM do not discuss it with their health care providers, it is important that providers inquire about patient use and are armed with basic safety and efficacy information.

Office visits for MS should include safety and efficacy discussions about all therapeutic treatments (disease modifying, relapse, and symptom management). Some issues—such as adverse effects—are obvious, while others, such as cost, are less so. A patient with MS may pursue an extremely expensive CAM therapy that lacks substantial evidence for the condition. Providers should therefore consider cost as part of the safety equation and be aware that while some CAM therapies have been studied in MS, most have not (or the research has been of poor quality).⁴

For many commonly used therapies, there is insufficient scientific evidence to support their usefulness in MS. These include acupuncture, biofeedback, Chinese medicine, chiropractic care, replacing amalgam dental fillings, equine therapy, hyperbaric oxygen treatment, low-dose naltrexone, massage therapy, tai chi, and yoga. While many of these practices are relatively safe and inexpensive, others may cause financial harm. Conversely, something considered safe and inexpensive (eg, a low-fat diet with omega-3 supplementation) may be found to be ineffective. Although recommending this type of diet for a person with MS is safe, realistic expectations must be discussed regarding its effect (or lack thereof) on the condition.⁴

The effectiveness of medical marijuana for MS is another popular deliberation. While data suggest that several administration methods of oral cannabinoids may be effective for spasticity and pain reduction, there is inadequate evidence to support the use of smoked cannabis. The deleterious effects of cannabis on cognition also need to be considered.⁵

Dietary supplements (eg, vitamins, minerals, botanicals, dietary substances) are often regarded as safe by patients because they are “natural.” As clinicians, we must be direct in asking patients about everything they are taking—many dietary supplements have drug interactions and/or toxic effects and may adversely stimulate the immune system. Vitamin D, for example, is one supplement that has been heavily studied in MS; lower levels of vitamin D have been shown to increase the risk for MS, and higher levels may be associated with lower relapse and disability rates. Therefore, standard of practice is to monitor vitamin D levels and supplement accordingly.

CAM can be safely and effectively recommended to people living with MS with due diligence. A question guide to aid recommendations is listed in Table 2.

Currently, no CAM therapies have been shown to modify MS, and CAM should not be recommended in place of disease-modifying treatment. However, if the proper questions are addressed, many CAM therapies can be safely recommended for common MS symptoms. Insurance coverage varies significantly among policies, but some treatments (eg, acupuncture and chiropractic care) are gaining coverage.

Finally, it is safe and a good standard of care to recommend a healthy anti-inflammatory diet, such as the Mediterranean diet, to people living with MS in order to improve general health. —MW

Megan Weigel, DNP, ARNP-C, MSCN
President of IOMSN
Baptist Neurology, Jacksonville Beach, Florida

Q)How is complementary and alternative medicine used in multiple sclerosis, and how can I safely recommend it to my patients?

Complementary and alternative medicine (CAM) is a non-mainstream practice used in conjunction with conventional medicine.¹ Its use is prevalent among people with and without chronic illnesses, including those living with multiple sclerosis (MS). Up to 70% of Americans with MS have used some type of CAM therapy, compared with 36% of the general population.^1,2 CAM use is higher in women than in men and is highest among persons ages 35 to 49—two demographics also associated with MS.³

CAM practices include a myriad of therapies from different disciplines (see Table 1).³ Because most people who use CAM do not discuss it with their health care providers, it is important that providers inquire about patient use and are armed with basic safety and efficacy information.

Office visits for MS should include safety and efficacy discussions about all therapeutic treatments (disease modifying, relapse, and symptom management). Some issues—such as adverse effects—are obvious, while others, such as cost, are less so. A patient with MS may pursue an extremely expensive CAM therapy that lacks substantial evidence for the condition. Providers should therefore consider cost as part of the safety equation and be aware that while some CAM therapies have been studied in MS, most have not (or the research has been of poor quality).⁴

For many commonly used therapies, there is insufficient scientific evidence to support their usefulness in MS. These include acupuncture, biofeedback, Chinese medicine, chiropractic care, replacing amalgam dental fillings, equine therapy, hyperbaric oxygen treatment, low-dose naltrexone, massage therapy, tai chi, and yoga. While many of these practices are relatively safe and inexpensive, others may cause financial harm. Conversely, something considered safe and inexpensive (eg, a low-fat diet with omega-3 supplementation) may be found to be ineffective. Although recommending this type of diet for a person with MS is safe, realistic expectations must be discussed regarding its effect (or lack thereof) on the condition.⁴

The effectiveness of medical marijuana for MS is another popular deliberation. While data suggest that several administration methods of oral cannabinoids may be effective for spasticity and pain reduction, there is inadequate evidence to support the use of smoked cannabis. The deleterious effects of cannabis on cognition also need to be considered.⁵

Dietary supplements (eg, vitamins, minerals, botanicals, dietary substances) are often regarded as safe by patients because they are “natural.” As clinicians, we must be direct in asking patients about everything they are taking—many dietary supplements have drug interactions and/or toxic effects and may adversely stimulate the immune system. Vitamin D, for example, is one supplement that has been heavily studied in MS; lower levels of vitamin D have been shown to increase the risk for MS, and higher levels may be associated with lower relapse and disability rates. Therefore, standard of practice is to monitor vitamin D levels and supplement accordingly.

CAM can be safely and effectively recommended to people living with MS with due diligence. A question guide to aid recommendations is listed in Table 2.

Currently, no CAM therapies have been shown to modify MS, and CAM should not be recommended in place of disease-modifying treatment. However, if the proper questions are addressed, many CAM therapies can be safely recommended for common MS symptoms. Insurance coverage varies significantly among policies, but some treatments (eg, acupuncture and chiropractic care) are gaining coverage.

Finally, it is safe and a good standard of care to recommend a healthy anti-inflammatory diet, such as the Mediterranean diet, to people living with MS in order to improve general health. —MW

Megan Weigel, DNP, ARNP-C, MSCN
President of IOMSN
Baptist Neurology, Jacksonville Beach, Florida

Q)How is complementary and alternative medicine used in multiple sclerosis, and how can I safely recommend it to my patients?

Complementary and alternative medicine (CAM) is a non-mainstream practice used in conjunction with conventional medicine.¹ Its use is prevalent among people with and without chronic illnesses, including those living with multiple sclerosis (MS). Up to 70% of Americans with MS have used some type of CAM therapy, compared with 36% of the general population.^1,2 CAM use is higher in women than in men and is highest among persons ages 35 to 49—two demographics also associated with MS.³

CAM practices include a myriad of therapies from different disciplines (see Table 1).³ Because most people who use CAM do not discuss it with their health care providers, it is important that providers inquire about patient use and are armed with basic safety and efficacy information.

Office visits for MS should include safety and efficacy discussions about all therapeutic treatments (disease modifying, relapse, and symptom management). Some issues—such as adverse effects—are obvious, while others, such as cost, are less so. A patient with MS may pursue an extremely expensive CAM therapy that lacks substantial evidence for the condition. Providers should therefore consider cost as part of the safety equation and be aware that while some CAM therapies have been studied in MS, most have not (or the research has been of poor quality).⁴

For many commonly used therapies, there is insufficient scientific evidence to support their usefulness in MS. These include acupuncture, biofeedback, Chinese medicine, chiropractic care, replacing amalgam dental fillings, equine therapy, hyperbaric oxygen treatment, low-dose naltrexone, massage therapy, tai chi, and yoga. While many of these practices are relatively safe and inexpensive, others may cause financial harm. Conversely, something considered safe and inexpensive (eg, a low-fat diet with omega-3 supplementation) may be found to be ineffective. Although recommending this type of diet for a person with MS is safe, realistic expectations must be discussed regarding its effect (or lack thereof) on the condition.⁴

The effectiveness of medical marijuana for MS is another popular deliberation. While data suggest that several administration methods of oral cannabinoids may be effective for spasticity and pain reduction, there is inadequate evidence to support the use of smoked cannabis. The deleterious effects of cannabis on cognition also need to be considered.⁵

Dietary supplements (eg, vitamins, minerals, botanicals, dietary substances) are often regarded as safe by patients because they are “natural.” As clinicians, we must be direct in asking patients about everything they are taking—many dietary supplements have drug interactions and/or toxic effects and may adversely stimulate the immune system. Vitamin D, for example, is one supplement that has been heavily studied in MS; lower levels of vitamin D have been shown to increase the risk for MS, and higher levels may be associated with lower relapse and disability rates. Therefore, standard of practice is to monitor vitamin D levels and supplement accordingly.

CAM can be safely and effectively recommended to people living with MS with due diligence. A question guide to aid recommendations is listed in Table 2.

Currently, no CAM therapies have been shown to modify MS, and CAM should not be recommended in place of disease-modifying treatment. However, if the proper questions are addressed, many CAM therapies can be safely recommended for common MS symptoms. Insurance coverage varies significantly among policies, but some treatments (eg, acupuncture and chiropractic care) are gaining coverage.

Finally, it is safe and a good standard of care to recommend a healthy anti-inflammatory diet, such as the Mediterranean diet, to people living with MS in order to improve general health. —MW

Megan Weigel, DNP, ARNP-C, MSCN
President of IOMSN
Baptist Neurology, Jacksonville Beach, Florida

Consumption of dietary fiber at the recommended average intake of 25 g per day was associated with lower risks of developing symptomatic knee osteoarthritis and moderate or severe knee pain over 4-8 years in two separate analyses of Osteoarthritis Initiative participants conducted by investigators at Boston University.

The studies are the first to describe an association between total dietary fiber and lower risk of symptomatic OA and pain worsening in the knee, as well as a lower risk of moderate and severe pain patterns. The lowered risks were partially mediated by body mass index (BMI) but persisted even after adjustment for the variable.

Nic_Ol/Thinkstock

In both studies, the investigators estimated dietary fiber intake by using a validated food frequency questionnaire at baseline that summed the fibers from grains, fruits and vegetables, and nuts and legumes.

Fiber and symptomatic knee OA

At the end of 4 years of follow-up, Dr. Dai and her colleagues identified 152 knees with incident radiographic OA (defined as a knee newly developing a Kellgren and Lawrence grade of 2 or higher), 869 knees with incident symptomatic OA (defined as new onset of both radiographic OA and a painful knee on most days in past month), and 1,964 knees with pain worsening as defined by an increase of at least 14% of the baseline Western Ontario and McMaster Universities (WOMAC) Index pain subscale score at each annual exam. This analysis excluded 540 people who were lost to follow-up and 205 who had invalid caloric intake recordings, leaving 4,051 in the study. The outcomes also excluded people with prevalent radiographic or symptomatic knee OA or knee pain worsening at baseline.

There was a significant trend for lower risk of both symptomatic OA (P less than .002) and pain worsening (P = .005) across four quartiles of daily total dietary fiber intake (mean of 9.1 g, 13 g, 16 g, and 21.9 g in quartiles 1-4). Quartile 4 daily intake was associated with a statistically significant 30% reduction (95% confidence interval, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening. Both comparisons were adjusted for age, sex, race, total energy intake, education, smoking status, physical activity, intake of other dietary factors (including polyunsaturated fat and other fats, vitamin C, vitamin D, vitamin E, vitamin K, dairy products, sweets, and soda), and nonsteroidal anti-inflammatory drug use (for the pain-worsening comparison).

Even though approximately 34% of the association between total fiber intake and symptomatic OA and 22% of the association between total fiber intake and pain worsening were mediated through reduced BMI, further adjustment of the comparisons for baseline BMI yielded similarly significant results.

The investigators found no associations between total dietary fiber intake and radiographic knee OA or for other fiber intake with either symptomatic or radiographic knee OA.

“The strongest protection was suggested at the highest quartile, which is in line with the current dietary guidelines for daily fiber intake. For older people [aged 51 years and older], for women it’s 22 g per day and for men it’s 28 g per day,” Dr. Dai said at the meeting.

Fiber and knee pain trajectories

Dr. Dai and her associates identified distinct, relatively homogeneous clusters of WOMAC pain trajectories over the 8-year study course in patients with and without radiographic knee OA at baseline in the Arthritis Care & Research study, and then examined their relationship to participants’ total dietary fiber intake, divided into quartiles (Arthritis Res Care. 2016; Nov 29. doi: 10.1002/acr.23158). The investigators found four pain trajectory patterns, including no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%).

Individuals who consumed the most total fiber also had the highest representation in the no pain pattern (38.1%) and the lowest representation in the severe pain pattern (4.3%). A high total fiber intake was associated with lower risk of having a moderate or severe pain pattern when compared with those in the no pain trajectory (both P for trend less than .01). Intake of fiber in the highest quartile was associated with a 24% lower likelihood (95% CI, 7%-39%) of belonging to the moderate pain pattern and a 44% lower likelihood (95% CI, 2%-59%) of being in the severe pain pattern, compared with individuals in the lowest intake quartile.

The same four pain trajectory patterns existed in individuals with radiographic knee OA at baseline, but the proportions were shifted slightly lower for no pain (26.1%) and higher for severe pain (7.9%). There was an even greater effect magnitude for the association between dietary total fiber and moderate or severe pain pattern among individuals with radiographic knee OA at baseline. Similar results were found for participants without radiographic knee OA at baseline. The relationships between total dietary fiber intake and pain patterns were somewhat attenuated after adjustment for depression scores and BMI at baseline but still remained statistically significant.

In each of the comparisons and sensitivity analyses, the highest quartile of cereal grain fiber intake was also significant on its own in lowering risk for being in the moderate or severe pain trajectory patterns. However, no significant results were found for fiber from fruits and vegetables or from nuts and legumes.

The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.

[email protected]

Consumption of dietary fiber at the recommended average intake of 25 g per day was associated with lower risks of developing symptomatic knee osteoarthritis and moderate or severe knee pain over 4-8 years in two separate analyses of Osteoarthritis Initiative participants conducted by investigators at Boston University.

The studies are the first to describe an association between total dietary fiber and lower risk of symptomatic OA and pain worsening in the knee, as well as a lower risk of moderate and severe pain patterns. The lowered risks were partially mediated by body mass index (BMI) but persisted even after adjustment for the variable.

Nic_Ol/Thinkstock

In both studies, the investigators estimated dietary fiber intake by using a validated food frequency questionnaire at baseline that summed the fibers from grains, fruits and vegetables, and nuts and legumes.

Fiber and symptomatic knee OA

At the end of 4 years of follow-up, Dr. Dai and her colleagues identified 152 knees with incident radiographic OA (defined as a knee newly developing a Kellgren and Lawrence grade of 2 or higher), 869 knees with incident symptomatic OA (defined as new onset of both radiographic OA and a painful knee on most days in past month), and 1,964 knees with pain worsening as defined by an increase of at least 14% of the baseline Western Ontario and McMaster Universities (WOMAC) Index pain subscale score at each annual exam. This analysis excluded 540 people who were lost to follow-up and 205 who had invalid caloric intake recordings, leaving 4,051 in the study. The outcomes also excluded people with prevalent radiographic or symptomatic knee OA or knee pain worsening at baseline.

There was a significant trend for lower risk of both symptomatic OA (P less than .002) and pain worsening (P = .005) across four quartiles of daily total dietary fiber intake (mean of 9.1 g, 13 g, 16 g, and 21.9 g in quartiles 1-4). Quartile 4 daily intake was associated with a statistically significant 30% reduction (95% confidence interval, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening. Both comparisons were adjusted for age, sex, race, total energy intake, education, smoking status, physical activity, intake of other dietary factors (including polyunsaturated fat and other fats, vitamin C, vitamin D, vitamin E, vitamin K, dairy products, sweets, and soda), and nonsteroidal anti-inflammatory drug use (for the pain-worsening comparison).

Even though approximately 34% of the association between total fiber intake and symptomatic OA and 22% of the association between total fiber intake and pain worsening were mediated through reduced BMI, further adjustment of the comparisons for baseline BMI yielded similarly significant results.

The investigators found no associations between total dietary fiber intake and radiographic knee OA or for other fiber intake with either symptomatic or radiographic knee OA.

“The strongest protection was suggested at the highest quartile, which is in line with the current dietary guidelines for daily fiber intake. For older people [aged 51 years and older], for women it’s 22 g per day and for men it’s 28 g per day,” Dr. Dai said at the meeting.

Fiber and knee pain trajectories

Dr. Dai and her associates identified distinct, relatively homogeneous clusters of WOMAC pain trajectories over the 8-year study course in patients with and without radiographic knee OA at baseline in the Arthritis Care & Research study, and then examined their relationship to participants’ total dietary fiber intake, divided into quartiles (Arthritis Res Care. 2016; Nov 29. doi: 10.1002/acr.23158). The investigators found four pain trajectory patterns, including no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%).

Individuals who consumed the most total fiber also had the highest representation in the no pain pattern (38.1%) and the lowest representation in the severe pain pattern (4.3%). A high total fiber intake was associated with lower risk of having a moderate or severe pain pattern when compared with those in the no pain trajectory (both P for trend less than .01). Intake of fiber in the highest quartile was associated with a 24% lower likelihood (95% CI, 7%-39%) of belonging to the moderate pain pattern and a 44% lower likelihood (95% CI, 2%-59%) of being in the severe pain pattern, compared with individuals in the lowest intake quartile.

The same four pain trajectory patterns existed in individuals with radiographic knee OA at baseline, but the proportions were shifted slightly lower for no pain (26.1%) and higher for severe pain (7.9%). There was an even greater effect magnitude for the association between dietary total fiber and moderate or severe pain pattern among individuals with radiographic knee OA at baseline. Similar results were found for participants without radiographic knee OA at baseline. The relationships between total dietary fiber intake and pain patterns were somewhat attenuated after adjustment for depression scores and BMI at baseline but still remained statistically significant.

In each of the comparisons and sensitivity analyses, the highest quartile of cereal grain fiber intake was also significant on its own in lowering risk for being in the moderate or severe pain trajectory patterns. However, no significant results were found for fiber from fruits and vegetables or from nuts and legumes.

The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.

[email protected]

Consumption of dietary fiber at the recommended average intake of 25 g per day was associated with lower risks of developing symptomatic knee osteoarthritis and moderate or severe knee pain over 4-8 years in two separate analyses of Osteoarthritis Initiative participants conducted by investigators at Boston University.

The studies are the first to describe an association between total dietary fiber and lower risk of symptomatic OA and pain worsening in the knee, as well as a lower risk of moderate and severe pain patterns. The lowered risks were partially mediated by body mass index (BMI) but persisted even after adjustment for the variable.

Nic_Ol/Thinkstock

In both studies, the investigators estimated dietary fiber intake by using a validated food frequency questionnaire at baseline that summed the fibers from grains, fruits and vegetables, and nuts and legumes.

Fiber and symptomatic knee OA

At the end of 4 years of follow-up, Dr. Dai and her colleagues identified 152 knees with incident radiographic OA (defined as a knee newly developing a Kellgren and Lawrence grade of 2 or higher), 869 knees with incident symptomatic OA (defined as new onset of both radiographic OA and a painful knee on most days in past month), and 1,964 knees with pain worsening as defined by an increase of at least 14% of the baseline Western Ontario and McMaster Universities (WOMAC) Index pain subscale score at each annual exam. This analysis excluded 540 people who were lost to follow-up and 205 who had invalid caloric intake recordings, leaving 4,051 in the study. The outcomes also excluded people with prevalent radiographic or symptomatic knee OA or knee pain worsening at baseline.

There was a significant trend for lower risk of both symptomatic OA (P less than .002) and pain worsening (P = .005) across four quartiles of daily total dietary fiber intake (mean of 9.1 g, 13 g, 16 g, and 21.9 g in quartiles 1-4). Quartile 4 daily intake was associated with a statistically significant 30% reduction (95% confidence interval, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening. Both comparisons were adjusted for age, sex, race, total energy intake, education, smoking status, physical activity, intake of other dietary factors (including polyunsaturated fat and other fats, vitamin C, vitamin D, vitamin E, vitamin K, dairy products, sweets, and soda), and nonsteroidal anti-inflammatory drug use (for the pain-worsening comparison).

Even though approximately 34% of the association between total fiber intake and symptomatic OA and 22% of the association between total fiber intake and pain worsening were mediated through reduced BMI, further adjustment of the comparisons for baseline BMI yielded similarly significant results.

The investigators found no associations between total dietary fiber intake and radiographic knee OA or for other fiber intake with either symptomatic or radiographic knee OA.

“The strongest protection was suggested at the highest quartile, which is in line with the current dietary guidelines for daily fiber intake. For older people [aged 51 years and older], for women it’s 22 g per day and for men it’s 28 g per day,” Dr. Dai said at the meeting.

Fiber and knee pain trajectories

Dr. Dai and her associates identified distinct, relatively homogeneous clusters of WOMAC pain trajectories over the 8-year study course in patients with and without radiographic knee OA at baseline in the Arthritis Care & Research study, and then examined their relationship to participants’ total dietary fiber intake, divided into quartiles (Arthritis Res Care. 2016; Nov 29. doi: 10.1002/acr.23158). The investigators found four pain trajectory patterns, including no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%).

Individuals who consumed the most total fiber also had the highest representation in the no pain pattern (38.1%) and the lowest representation in the severe pain pattern (4.3%). A high total fiber intake was associated with lower risk of having a moderate or severe pain pattern when compared with those in the no pain trajectory (both P for trend less than .01). Intake of fiber in the highest quartile was associated with a 24% lower likelihood (95% CI, 7%-39%) of belonging to the moderate pain pattern and a 44% lower likelihood (95% CI, 2%-59%) of being in the severe pain pattern, compared with individuals in the lowest intake quartile.

The same four pain trajectory patterns existed in individuals with radiographic knee OA at baseline, but the proportions were shifted slightly lower for no pain (26.1%) and higher for severe pain (7.9%). There was an even greater effect magnitude for the association between dietary total fiber and moderate or severe pain pattern among individuals with radiographic knee OA at baseline. Similar results were found for participants without radiographic knee OA at baseline. The relationships between total dietary fiber intake and pain patterns were somewhat attenuated after adjustment for depression scores and BMI at baseline but still remained statistically significant.

In each of the comparisons and sensitivity analyses, the highest quartile of cereal grain fiber intake was also significant on its own in lowering risk for being in the moderate or severe pain trajectory patterns. However, no significant results were found for fiber from fruits and vegetables or from nuts and legumes.

The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.

[email protected]

WASHINGTON – The nation’s political sea-change won’t wash Alzheimer’s disease research funding offtrack, two legislators vowed at a Washington briefing.

Rather than descend into partisan budget-bickering under the new administration, lawmakers should reach across the aisle and pass funding bills to vigorously propel the nation toward its goal of having an effective disease-modifying Alzheimer’s disease therapy by 2025.

“If we make this a high-enough priority, we can meet that goal,” Rep. Paul Tonko (D-NY) said at a briefing sponsored by The Hill newspaper, with support by Eli Lilly. “We should prioritize the work we need to do to achieve it in both the House and Senate, and move forward both aggressively and progressively.”

Michele G. Sullivan/Frontline Medical News

“I am a strong proponent of investing in research. We simply must continue to put research dollars into Alzheimer’s. If we don’t invest, try to find a cure or treatment, Alzheimer’s will become the single largest driver of health care costs on both a federal and state level. We have to recognize this: We could, potentially, not even be able to provide care for all patients we will have, unless we find a treatment or a cure.”

After a decade of struggle, federal dollars for Alzheimer’s research have begun to creep up. Last year, Congress passed a historic $350 million increase in Alzheimer’s research funding at the National Institutes of Health, raising the total spending to $991 million for fiscal year 2016. Then, in June, the Senate Appropriations Committee approved a landmark $400 million funding increase. In July, the House Appropriations Committee approved its own $350 million bump.

In August, the NIH recommended a $414 million increase for fiscal year 2018. If both the fiscal year 2017 increase and fiscal year 2018 request are ultimately passed, funding levels would be very close to the $2 billion/year federal commitment that researchers and Alzheimer’s policy mavens say is necessary to achieve the 2025 goal, set forth in the National Plan to Address Alzheimer’s Disease.

“There’s no such thing as too much research funding,” Sen. Tillis said during the briefing. But, he added, that federal generosity must be wisely husbanded.

“There must also be a sense of discipline along with the funding. Money like that should be targeted in terms of which diseases we go after – they should be areas that have the broadest impact. In a world of scarce resources, we can’t afford to simply throw money around.”

Alzheimer’s research is a perfect example of this careful resource management, he said. The NIH has prepared its second “bypass budget,” a funding proposal that passes the normal legislative channels and goes directly to the President.

Based on the consensus of scientists involved in search for a disease-modifying therapy, this budget proposal estimates the additional money needed to meet the 2025 goal, above the NIH’s baseline Alzheimer’s funding.

Only two other areas of medicine have such a budget: cancer and HIV-AIDS, said Robert J. Egge, chief public policy officer of the Alzheimer’s Association.

“This budget goes right from the scientists to Congress with no filter by the Office of Management and Budget, and lands directly on the President’s desk,” he said in an interview. “It tells legislators what scientists need in order to accomplish that 2025 goal.”

The $2 billion/year figure, Mr. Egge noted, is a ground-floor suggestion. “That’s what we need right now to stay on track. We think the best way to figure out where we need to be in the long-term is to let the scientists at NIH tell us what they need, and we need Congress and the Administration to follow this year to year.”

Like Sen. Tillis and Rep. Tonko, Mr. Egge was upbeat in anticipating steady funding progress.

“The champions of Alzheimer’s funding who have made such a difference for us are all back and in their same positions,” with unstinting commitment to the cause.

Those legislators include:

• Rep. Tom Cole (R-OK), chairman of the House Appropriations Committee’s Subcommittee on Labor, Health and Human Services, Education and Related Agencies, which funds the NIH. In 2015, Rep. Cole shepherded through a $300 million appropriation for Alzheimer’s research, and the pending $350 million appropriation for fiscal year 2017.

• Sen. Roy Blunt (R-MO), who, as chairman of the Senate Appropriations Committee’s Subcommittee on Labor, Health and Human Services, Education and Related Agencies, secured June’s $400 million and a $350 million bump in 2015.

• Ranking member Sen. Patty Murray (D-WA), who cosponsored the Alzheimer’s Breakthrough Act of 2009, and who worked with Sen. Blunt to secure the recent Alzheimer’s funding increases.

Mr. Egge is not overly troubled about the antiscience rhetoric bandied about by some potential members of President-elect Trump’s administration. He predicted those rumblings will settle down and not negatively affect Alzheimer’s funding.

“I think all the talk of not believing in the science of biomedical research was premature,” he said. “I think it’s completely appropriate to say ‘We are going to watch closely and form opinions,’ but I have never been overly alarmed by this. As an Alzheimer’s advocate for strong science, I am waiting to see what the next steps are. President-elect Trump has said on the campaign trail that Alzheimer’s would be a top priority. Our champions from both parties are fully committed to this fight and recognize that science is the fundamental path to do so. I share this optimism. It’s not complacent optimism – it’s vigilant optimism that we will continue with the momentum we need to finally, squarely and effectively, address this disease.”

[email protected]
On Twitter @alz_gal

WASHINGTON – The nation’s political sea-change won’t wash Alzheimer’s disease research funding offtrack, two legislators vowed at a Washington briefing.

Rather than descend into partisan budget-bickering under the new administration, lawmakers should reach across the aisle and pass funding bills to vigorously propel the nation toward its goal of having an effective disease-modifying Alzheimer’s disease therapy by 2025.

“If we make this a high-enough priority, we can meet that goal,” Rep. Paul Tonko (D-NY) said at a briefing sponsored by The Hill newspaper, with support by Eli Lilly. “We should prioritize the work we need to do to achieve it in both the House and Senate, and move forward both aggressively and progressively.”

Michele G. Sullivan/Frontline Medical News

“I am a strong proponent of investing in research. We simply must continue to put research dollars into Alzheimer’s. If we don’t invest, try to find a cure or treatment, Alzheimer’s will become the single largest driver of health care costs on both a federal and state level. We have to recognize this: We could, potentially, not even be able to provide care for all patients we will have, unless we find a treatment or a cure.”

After a decade of struggle, federal dollars for Alzheimer’s research have begun to creep up. Last year, Congress passed a historic $350 million increase in Alzheimer’s research funding at the National Institutes of Health, raising the total spending to $991 million for fiscal year 2016. Then, in June, the Senate Appropriations Committee approved a landmark $400 million funding increase. In July, the House Appropriations Committee approved its own $350 million bump.

In August, the NIH recommended a $414 million increase for fiscal year 2018. If both the fiscal year 2017 increase and fiscal year 2018 request are ultimately passed, funding levels would be very close to the $2 billion/year federal commitment that researchers and Alzheimer’s policy mavens say is necessary to achieve the 2025 goal, set forth in the National Plan to Address Alzheimer’s Disease.

“There’s no such thing as too much research funding,” Sen. Tillis said during the briefing. But, he added, that federal generosity must be wisely husbanded.

“There must also be a sense of discipline along with the funding. Money like that should be targeted in terms of which diseases we go after – they should be areas that have the broadest impact. In a world of scarce resources, we can’t afford to simply throw money around.”

Alzheimer’s research is a perfect example of this careful resource management, he said. The NIH has prepared its second “bypass budget,” a funding proposal that passes the normal legislative channels and goes directly to the President.

Based on the consensus of scientists involved in search for a disease-modifying therapy, this budget proposal estimates the additional money needed to meet the 2025 goal, above the NIH’s baseline Alzheimer’s funding.

Only two other areas of medicine have such a budget: cancer and HIV-AIDS, said Robert J. Egge, chief public policy officer of the Alzheimer’s Association.

“This budget goes right from the scientists to Congress with no filter by the Office of Management and Budget, and lands directly on the President’s desk,” he said in an interview. “It tells legislators what scientists need in order to accomplish that 2025 goal.”

The $2 billion/year figure, Mr. Egge noted, is a ground-floor suggestion. “That’s what we need right now to stay on track. We think the best way to figure out where we need to be in the long-term is to let the scientists at NIH tell us what they need, and we need Congress and the Administration to follow this year to year.”

Like Sen. Tillis and Rep. Tonko, Mr. Egge was upbeat in anticipating steady funding progress.

“The champions of Alzheimer’s funding who have made such a difference for us are all back and in their same positions,” with unstinting commitment to the cause.

Those legislators include:

• Rep. Tom Cole (R-OK), chairman of the House Appropriations Committee’s Subcommittee on Labor, Health and Human Services, Education and Related Agencies, which funds the NIH. In 2015, Rep. Cole shepherded through a $300 million appropriation for Alzheimer’s research, and the pending $350 million appropriation for fiscal year 2017.

• Sen. Roy Blunt (R-MO), who, as chairman of the Senate Appropriations Committee’s Subcommittee on Labor, Health and Human Services, Education and Related Agencies, secured June’s $400 million and a $350 million bump in 2015.

• Ranking member Sen. Patty Murray (D-WA), who cosponsored the Alzheimer’s Breakthrough Act of 2009, and who worked with Sen. Blunt to secure the recent Alzheimer’s funding increases.

Mr. Egge is not overly troubled about the antiscience rhetoric bandied about by some potential members of President-elect Trump’s administration. He predicted those rumblings will settle down and not negatively affect Alzheimer’s funding.

“I think all the talk of not believing in the science of biomedical research was premature,” he said. “I think it’s completely appropriate to say ‘We are going to watch closely and form opinions,’ but I have never been overly alarmed by this. As an Alzheimer’s advocate for strong science, I am waiting to see what the next steps are. President-elect Trump has said on the campaign trail that Alzheimer’s would be a top priority. Our champions from both parties are fully committed to this fight and recognize that science is the fundamental path to do so. I share this optimism. It’s not complacent optimism – it’s vigilant optimism that we will continue with the momentum we need to finally, squarely and effectively, address this disease.”

[email protected]
On Twitter @alz_gal

WASHINGTON – The nation’s political sea-change won’t wash Alzheimer’s disease research funding offtrack, two legislators vowed at a Washington briefing.

Rather than descend into partisan budget-bickering under the new administration, lawmakers should reach across the aisle and pass funding bills to vigorously propel the nation toward its goal of having an effective disease-modifying Alzheimer’s disease therapy by 2025.

“If we make this a high-enough priority, we can meet that goal,” Rep. Paul Tonko (D-NY) said at a briefing sponsored by The Hill newspaper, with support by Eli Lilly. “We should prioritize the work we need to do to achieve it in both the House and Senate, and move forward both aggressively and progressively.”

Michele G. Sullivan/Frontline Medical News

“I am a strong proponent of investing in research. We simply must continue to put research dollars into Alzheimer’s. If we don’t invest, try to find a cure or treatment, Alzheimer’s will become the single largest driver of health care costs on both a federal and state level. We have to recognize this: We could, potentially, not even be able to provide care for all patients we will have, unless we find a treatment or a cure.”

After a decade of struggle, federal dollars for Alzheimer’s research have begun to creep up. Last year, Congress passed a historic $350 million increase in Alzheimer’s research funding at the National Institutes of Health, raising the total spending to $991 million for fiscal year 2016. Then, in June, the Senate Appropriations Committee approved a landmark $400 million funding increase. In July, the House Appropriations Committee approved its own $350 million bump.

In August, the NIH recommended a $414 million increase for fiscal year 2018. If both the fiscal year 2017 increase and fiscal year 2018 request are ultimately passed, funding levels would be very close to the $2 billion/year federal commitment that researchers and Alzheimer’s policy mavens say is necessary to achieve the 2025 goal, set forth in the National Plan to Address Alzheimer’s Disease.

“There’s no such thing as too much research funding,” Sen. Tillis said during the briefing. But, he added, that federal generosity must be wisely husbanded.

“There must also be a sense of discipline along with the funding. Money like that should be targeted in terms of which diseases we go after – they should be areas that have the broadest impact. In a world of scarce resources, we can’t afford to simply throw money around.”

Alzheimer’s research is a perfect example of this careful resource management, he said. The NIH has prepared its second “bypass budget,” a funding proposal that passes the normal legislative channels and goes directly to the President.

Based on the consensus of scientists involved in search for a disease-modifying therapy, this budget proposal estimates the additional money needed to meet the 2025 goal, above the NIH’s baseline Alzheimer’s funding.

Only two other areas of medicine have such a budget: cancer and HIV-AIDS, said Robert J. Egge, chief public policy officer of the Alzheimer’s Association.

“This budget goes right from the scientists to Congress with no filter by the Office of Management and Budget, and lands directly on the President’s desk,” he said in an interview. “It tells legislators what scientists need in order to accomplish that 2025 goal.”

The $2 billion/year figure, Mr. Egge noted, is a ground-floor suggestion. “That’s what we need right now to stay on track. We think the best way to figure out where we need to be in the long-term is to let the scientists at NIH tell us what they need, and we need Congress and the Administration to follow this year to year.”

Like Sen. Tillis and Rep. Tonko, Mr. Egge was upbeat in anticipating steady funding progress.

“The champions of Alzheimer’s funding who have made such a difference for us are all back and in their same positions,” with unstinting commitment to the cause.

Those legislators include:

• Rep. Tom Cole (R-OK), chairman of the House Appropriations Committee’s Subcommittee on Labor, Health and Human Services, Education and Related Agencies, which funds the NIH. In 2015, Rep. Cole shepherded through a $300 million appropriation for Alzheimer’s research, and the pending $350 million appropriation for fiscal year 2017.

• Sen. Roy Blunt (R-MO), who, as chairman of the Senate Appropriations Committee’s Subcommittee on Labor, Health and Human Services, Education and Related Agencies, secured June’s $400 million and a $350 million bump in 2015.

• Ranking member Sen. Patty Murray (D-WA), who cosponsored the Alzheimer’s Breakthrough Act of 2009, and who worked with Sen. Blunt to secure the recent Alzheimer’s funding increases.

Mr. Egge is not overly troubled about the antiscience rhetoric bandied about by some potential members of President-elect Trump’s administration. He predicted those rumblings will settle down and not negatively affect Alzheimer’s funding.

“I think all the talk of not believing in the science of biomedical research was premature,” he said. “I think it’s completely appropriate to say ‘We are going to watch closely and form opinions,’ but I have never been overly alarmed by this. As an Alzheimer’s advocate for strong science, I am waiting to see what the next steps are. President-elect Trump has said on the campaign trail that Alzheimer’s would be a top priority. Our champions from both parties are fully committed to this fight and recognize that science is the fundamental path to do so. I share this optimism. It’s not complacent optimism – it’s vigilant optimism that we will continue with the momentum we need to finally, squarely and effectively, address this disease.”

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Developing interventions to address vaccine hesitancy in these communities may require a significantly different approach than it would in fully assimilated groups, with a need to start by learning about the culture, fears, values and priorities of that particular community.

Fibonacci Blue [CC BY 2.0

ATLANTA – Research into vaccine hesitancy in the United States tends to focus on overall trends among native-born Americans or immigrants who have mostly assimilated into American culture. But the nation is dotted with tight-knit ethnic communities which have immigrated to the United States, including refugee communities that retain much of the culture and practices of their home country.

Developing interventions to address vaccine hesitancy in these communities may require a significantly different approach than it would in fully assimilated groups, with a need to start by learning about the culture, fears, values and priorities of that particular community.

Fibonacci Blue [CC BY 2.0

ATLANTA – Research into vaccine hesitancy in the United States tends to focus on overall trends among native-born Americans or immigrants who have mostly assimilated into American culture. But the nation is dotted with tight-knit ethnic communities which have immigrated to the United States, including refugee communities that retain much of the culture and practices of their home country.

Developing interventions to address vaccine hesitancy in these communities may require a significantly different approach than it would in fully assimilated groups, with a need to start by learning about the culture, fears, values and priorities of that particular community.

Fibonacci Blue [CC BY 2.0

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National Cancer Institute

ATLANTA – A multifaceted comprehensive intervention significantly improved human papillomavirus (HPV) vaccination rates in a Florida pediatric health care group practice.

Alix G. Casler, MD, chief of pediatrics at Orlando Health Physician Associates, described how her practice put into place practices to improve the overall HPV vaccination rate of their clients.

National Cancer Institute

ATLANTA – A multifaceted comprehensive intervention significantly improved human papillomavirus (HPV) vaccination rates in a Florida pediatric health care group practice.

Alix G. Casler, MD, chief of pediatrics at Orlando Health Physician Associates, described how her practice put into place practices to improve the overall HPV vaccination rate of their clients.

National Cancer Institute