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

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 The US Food and Drug Administration (FDA) recently issued draft guidance for medical device trials for onychomycosis.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.

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.

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.

Attention Deficit Hyperactivity Disorder Symptoms, Comorbidities, Substance Use, and Social Outcomes among Men and Women in a Canadian Sample.

Background. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that can persist in adolescence and adulthood. Aim. To examine prevalence of ADHD symptoms and correlates in a representative sample of adults 18 years and older living in Ontario, Canada. Method. We used the Centre for Addiction and Mental Health Monitor, an ongoing cross-sectional telephone survey, to examine the relationships between ADHD positive symptoms and comorbidities, substance use, medication use, social outcomes, and sociodemographics. Results. Of 4014 residents sampled in 2011-2012, 3.30% (2.75%-3.85%) screened positively for ADHD symptoms (women = 3.6%; men = 3.0%). For men, distress, antisocial symptoms, cocaine use, antianxiety medication use, antidepressant medication use, and criminal offence arrest were associated with positive ADHD screen. For women, distress, cocaine use, antianxiety medication use, antidepressant medication use, pain medication use, and motor vehicle collision in the past year were associated with positive ADHD screen. Conclusions. ADHD symptoms are associated with adverse medical and social outcomes that are in some cases gender specific.

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.

Sinecatechins 10% ointment: a green tea extract for the treatment of external genital warts.

External genital warts (EGWs) resulting from the human papilloma virus (HPV) are a common sexually transmitted infection and cause significant impairments in patient quality of life and sexual well-being. Therapeutic options for EGWs can be provider-assisted, but many patients opt for treatment that can be applied at home. Sinecatechins 10% ointment is a new botanically based patient-administered therapy for EGWs. It is comprised of >85% catechins, green tea polyphenols that have been shown to possess antioxidant, antiproliferative, antiviral, and antitumor properties. Phase III trials of sinecatechins 10% ointment have demonstrated higher efficacy and lower recurrence rates compared to currently available patient-applied treatments. Therefore, sinecatechins 10% ointment presents an alternative self-administered topical treatment for EGWs.

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. © 2015 S. Karger AG, Basel.

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.

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.

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.

Surgical hair restoration and the advent of a robotic-assisted extraction device.

The number of surgical hair restorations performed worldwide is ever-increasing. Today's gold standard in surgical hair restoration is follicular unit transplantation (FUT). FUT refers to the transplantation of individual follicular units (FUs) from the donor region to the recipient region. Strip extraction and manual FU extraction (FUE) are the most common methods for FU production. While strip extraction and manual FUE both hold individual merits, they are also associated with a number of limitations. The introduction of a robotic surgical assistive device may circumvent many of the limitations associated with traditional strip and manual FUE methods. As with all new technologies, however, the robotic device will require further independently funded, peer-reviewed, clinical testing to establish its efficacy relative to existing hair restoration methods in clinical practice.

Network Meta-analysis of Treatments for Chronic Plaque Psoriasis in Canada.

BACKGROUND: Psoriasis affects approximately 500,000 Canadians. Eight treatments are currently licensed for chronic plaque psoriasis in Canada. OBJECTIVE: To compare the efficacy of systemic treatments for chronic plaque psoriasis for the outcome > 75% reduction in the Psoriasis Area and Severity Index (PASI) using network meta-analysis. METHODS: PubMed and clinicaltrials.gov databases were searched up until October 15, 2013, for phase III clinical trials. A consistency model based on a random-effects bayesian statistical framework was used to compare the rates of > 75% PASI reduction across trials. RESULTS: Twenty-one studies were included in the network analysis. Infliximab had significantly greater odds of producing > 75% reduction in the PASI compared to all treatments. All treatments conferred greater odds of > 75% PASI reduction compared to placebo. CONCLUSION: Although infliximab had the highest efficacy relative to other systemic treatments for psoriasis, adverse effects, cost, and patient preferences should also be considered when deciding on treatment.

Topical therapy for toenail onychomycosis: an evidence-based review.

BACKGROUND: Managing toenail onychomycosis with topical treatments is challenging. It is difficult for topical medication to penetrate the nail plate, and this is reflected in lower cure rates with topical treatment than with oral treatment. However, oral medications may not be suitable for some patients, because of drug interactions; therefore, topical treatments are critical in managing the disease in certain patient populations. OBJECTIVE: This paper reviews the quality and content of the scientific literature on topical treatments for toenail onychomycosis. METHODS: PubMed, Ovid (Medline and Embase), Scopus, Cochrane library, and clinicaltrials.gov databases were searched for original clinical reports of topical monotherapy for microscopy and/or culture-confirmed toenail onychomycosis in adults. Studies were evaluated using an onychomycosis study quality scale, which was based on the CONSORT guidelines. RESULTS: Twenty-five publications (28 studies) were identified and met the inclusion criteria. Thirteen studies scored high ratings on the quality scale. These were randomized controlled trials or randomized comparative trials. Low-quality studies were nonrandomized, open studies that prevented statistical analysis. Most studies reported clinical and mycological cure. The most variation was observed with reporting outcomes of clinical improvement. Amorolfine, ciclopirox, tavaborole, and efinaconazole produced clinical and mycological cure in patients with mild to moderate toenail onychomycosis (<50-65 % nail involvement), with efinaconazole showing the highest rates. Treatments were generally applied daily for 24-48 weeks, with longer treatment and follow-up showing better outcomes. CONCLUSION: Topical treatment with amorolfine, ciclopirox, tavaborole, or efinaconazole is appropriate for cases of mild to moderate toenail onychomycosis due to dermatophyte or mixed dermatophyte/Candida infection.

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.

Basal cell carcinoma.

Basal cell carcinoma (BCC) is a relatively common form of cancer with a favorable prognosis when treated early. Although most BCCs are easily treated by surgical methods, these lesions occasionally progress to an advanced state that is no longer conducive to surgery or radiation therapy. Even more rarely, the lesions spread to distant sites. Until recently, treatment for locally advanced and metastatic BCC were restricted to chemotherapy and radiation; however, the effectiveness of traditional chemotherapeutic methods in treating locally advanced or metastatic BCC is limited at best. Recent discoveries in the fields of molecular biology have found important pathways implicated in the pathogenesis of BCC. Among these are the epidermal growth factor receptor and hedgehog pathways, which are now being targeted by new biologic therapies. Despite a paucity of phase II and III trial data, preliminary evidence demonstrating the disease-stabilizing ability of biologic therapies in locally advanced and metastatic BCC appears promising.

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

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.