Deanne Daigle

Drug safety assessment of oral formulations of ketoconazole.

Introduction: Ketoconazole was the first broad-spectrum oral antifungal approved by the FDA in 1981. Post-marketing reports of drug-related hepatotoxicity, endocrine dysregulation and drug interactions resulted in market withdrawal of the drug in some countries and strict product relabeling in others. Areas covered: This drug safety review summarizes reports of oral ketoconazole-related adverse events retrieved from a search of the PubMed database using the search strategy ‘ketoconazole OR Nizoral AND hepat*’, references from relevant publications, and data from the FDA Adverse Event Reporting System. Expert opinion: Although oral ketoconazole is effective in treating fungal infections, the potential for drug interactions, endocrine dysregulation, and hepatotoxicity may outweigh its benefits. Newer oral antifungals have similar or greater efficacy in treating dermatologic conditions and are associated with less risk. Likewise, newer agents with specific targets and fewer drug interactions have been developed to treat systemic fungal infections. Therefore, by the time ketoconazole prescribing guidelines were amended, its use had already largely been replaced with newer antifungals. Being that ketoconazole was the first broad-spectrum oral antifungal, experience with the drug made patient safety, and especially hepatic safety, an important consideration in future antifungal development.

The role of biofilms in onychomycosis

Onychomycosis is a fungal infection of nails primarily caused by dermatophyte fungi. Fungi are traditionally understood as existing in the environment as planktonic organisms; however, recent advancements in microbiology suggest that fungi form biofilms-complex sessile microbial communities irreversibly attached to epithelial surfaces by means of an extracellular matrix. The extracellular matrix also acts as a protective barrier to the organisms within the biofilm. The biofilm is surprisingly resistant to injury and may act as a persistent source of infection possibly accounting for antifungal resistance in onychomycosis.

Tavaborole (AN-2690) for the treatment of onychomycosis of the toenail in adults.

Onychomycosis is a challenging nail disease that is difficult to treat due to the thickness and impermeability of the nail plate. At present, systemic agents are the first-line of treatment for this type of infection; however, topical treatment is recommended in milder cases (<50% involvement) or when oral treatment is contraindicated. Effective topical treatments capable of penetrating the nail plate and reaching the site of infection continue to be sought. Tavaborole, the first member of a new class of boron-containing antifungals, is a lightweight, water-soluble topical nail solution for the treatment of toenail onychomycosis. Tavaborole has a unique mechanism of action against fungal organisms and retains antifungal properties in the presence of keratin. Tavaborole 5.0% nail solution has shown a favourable safety and efficacy profile in Phase II/III clinical trials and is currently under review for licensing in the US by the US Food and Drug Administration.

The use of low-level light therapy in the treatment of androgenetic alopecia and female pattern hair loss

Abstract Androgenetic alopecia (AGA) or female pattern hair loss (FPHL) is the most common form of hair loss in men and women. Despite its common occurrence, our understanding of the etiology of AGA and FPHL remains incomplete. As such, traditional therapies demonstrate modest efficacies and new therapies continue to be sought. Low-level light therapy (LLLT) is a relatively new technique used to promote hair growth in both men and women with AGA and FPHL. Currently, there exist several LLLT devices marketed for the treatment of alopecia, which claim to stimulate hair growth; yet marketing these devices only requires that safety, not efficacy, be established. A handful of studies have since investigated the efficacy of LLLT for alopecia with mixed results. These studies suffered from power, confounding and analysis issues which resulted in a high risk of bias in LLLT studies. Due to the paucity of well-conducted randomized controlled trials, the efficacy of LLLT devices remains unclear. Randomized controlled trials of LLLT conducted and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement would greatly increase the credibility of the evidence and clarify the ambiguity of the effectiveness of LLLT in the treatment of AGA and FPHL.

Therapies for onychomycosis a systematic review and network meta-analysis of mycological cure.

New therapies for onychomycosis continue to be developed, yet treatments are seldom directly compared in randomized controlled trials. The objective of this study was to compare the rates of mycological cure for oral and topical onychomycosis treatments using network meta-analysis. A systematic review of the literature on onychomycosis treatments published before March 25, 2013, was performed, and data were analyzed using network meta-analysis. Terbinafine, 250 mg, therapy was significantly superior to all treatments except itraconazole, 400 mg, pulse therapy; itraconazole, 200 mg, therapy was significantly superior to fluconazole and the topical treatments; and fluconazole, efinaconazole, ciclopirox, terbinafine nail solution, and amorolfine treatments were significantly superior to only placebo. These results support the superiority of 12-week continuous terbinafine, 250 mg, therapy and itraconazole, 400 mg, pulse therapy (1 week per month for 3 months) while suggesting the equivalence of topical therapies. These results reflect findings from the literature and treatment efficacy observed in clinical practice.

Network Meta-Analysis of Onychomycosis Treatments

Background: Many onychomycosis treatments have not been directly compared in head-to-head clinical trials. Objective: To determine the relative efficacy of onychomycosis treatments using network meta-analysis (NMA). Methods: We conducted a systematic review and NMA of mycological cure rates. Results: Nineteen trials were included in the network. Terbinafine 250 mg was significantly superior to all treatments except itraconazole 400 mg pulse therapy. The itraconazole 400 mg pulse regimen was significantly superior to all topicals except efinaconazole 10% nail solution. Itraconazole 200 mg was significantly superior to all topical treatments, while fluconazole 150-450 mg, efinaconazole 10% nail solution, tavaborole 5% nail solution, ciclopirox nail lacquer 8%, terbinafine nail solution, and amorolfine 5% nail lacquer were significantly superior to placebo. Conclusions: Newly developed topicals have improved the odds ratios (ORs) of mycological cure, yet these ORs were not significantly greater than preexisting topical treatments. Further experience with these agents will reveal their clinical significance, and head-to-head trials are warranted.

Clinical trials of lasers for toenail onychomycosis: The implications of new regulatory guidance

Abstract Background: Despite the fact that lasers are presently indicated for the cosmetic outcome “temporary increase in clear nail”, these devices are increasingly used to treat onychomycosis and particularly in patients who are unwilling or unable to take oral antifungal medication. The US Food and Drug Administration (FDA) recently issued draft guidance for medical device trials for onychomycosis. Objective: This review evaluates the quality of laser trials for onychomycosis and compares the design guidelines for medical devices and antifungal drugs. Method: The PubMed database up to 29 May 2015 was searched for clinical studies of laser treatment for onychomycosis. Results: The evidence demonstrating that lasers eradicate pathogenic fungi is limited and published laser trials suffer from limitations such as incomplete reporting of randomization and lack of stratified analyzes for fingernail/toenail data and infecting organisms. Differences in inclusion criteria and efficacy outcomes between drug and device guidelines may prevent the comparison of results from device and drug trials. Conclusion: We propose the standardization of device guidelines to match those of antifungal drug trials. Patients and physicians need to be aware of the capabilities and limitations of laser treatment for onychomycosis.

Potential role of tavaborole for the treatment of onychomycosis

Systemic antifungal treatments are believed to be more effective than topicals for the treatment of onychomycosis; however, they are associated with more risks of adverse events. Tavaborole is the first member of a new class of antifungals that has been developed as a new topical nail solution for the treatment of toenail onychomycosis caused by dermatophytes. During Phase I-III clinical trials, tavaborole 5.0% nail solution showed a favorable safety and efficacy profile. Tavaborole 5.0% received US FDA market approval on 8 July 2014.

A critical appraisal of once-daily topical luliconazole for the treatment of superficial fungal infections

Luliconazole is a novel imidazole derivative, which has demonstrated in vitro efficacy against dermatophytes and Candida. The results from Phase III trials show that luliconazole 1% cream applied once daily for 2 weeks successfully resolved the clinical signs and symptoms as well as eradicated the pathologic fungi, which cause tinea pedis. A 1-week treatment with luliconazole 1% cream also produced favorable clinical and mycological results in clinical trials for tinea corporis and tinea cruris. Across trials, adverse events consisted mainly of localized reactions following application. The development of a new antifungal agent is timely due to mounting resistance among existing treatments. Because luliconazole requires a short duration of treatment, it may assist in reducing disease recurrence as a result of patient nonadherence.

Progression of Surgical Hair Restoration Techniques

Background: Early surgical hair restoration (SHR) techniques were fraught with limitations. Major advancements and refinements have taken place yielding minimally invasive, relatively scar-free, and natural-looking hair transplantations. Objective: Our aim was to review the origins and advancements of SHR and to discuss future directions for the field. Methods: Searches were performed using: Pubmed, Scopus, and the International Society of Hair Restoration Surgery’s Hair Transplant Forum International for articles related to SHR. Reference sections of articles obtained were reviewed. Relevant textbooks obtained were reviewed. Results and Conclusion: SHR techniques originated as macro-level graft transplantations and excision of scalp tissue. They progressed toward micro-level graft transplantations performed with extreme caution and precision. However, all SHR techniques are limited by their reliance on existing donor hair to fill balding areas. Further advancements in hair follicle cell cloning and regeneration of growth may offer a solution to this overarching limitation.