Assessment of the nail penetration of antifungal agents, with different physico-chemical properties.

Onychomycosis, or fungal nail infection, is a common fungal infection largely caused by dermatophyte fungi, such as Trichophyton rubrum or Trichophyton mentagrophytes, which affects a significant number of people. Treatment is either through oral antifungal medicines, which are efficacious but have significant safety concerns, or with topical antifungal treatments that require long treatment regimens and have only limited efficacy. Thus, an efficacious topical therapy remains an unmet medical need. Among the barriers to topical delivery through the nail are the physico-chemical properties of the antifungal drugs. Here, we explore the ability of a range of antifungal compounds with different hydrophilicities to penetrate the nail. Human nail discs were clamped within static diffusion (Franz) cells and dosed with equimolar concentrations of antifungal drugs. Using LC-MS/MS we quantified the amount of drug that passed through the nail disc and that which remained associated with the nail. Our data identified increased drug flux through the nail for the more hydrophilic compounds (caffeine as a hydrophilic control and fluconazole, with LogP -0.07 and 0.5, respectively), while less hydrophilic efinaconazole, amorolfine and terbinafine (LogP 2.7, 5.6 and 5.9 respectively) had much lower flux through the nail. On the other hand, hydrophilicity alone did not account for the amount of drug associated with/bound to the nail itself. While there are other factors that are likely to combine to dictate nail penetration, this work supports earlier studies that implicate compound hydrophilicity as a critical factor for nail penetration.

Efinaconazole topical solution 10%: Formulation and efficacy assessment in the treatment of toenail onychomycosis.

BACKGROUND: Efinaconazole is non-lacquer-based with a low surface tension that efficiently targets delivery of active ingredient into the nail and nail bed. OBJECTIVES: To develop an optimal, stable formulation of efinaconazole topical solution 10% (ETS10). METHODS: We evaluated the safety and efficacy of ETS10 on 10 Iranian participants in a pilot, single-group and before-after clinical study, for up to 8 weeks in onychomycosis. RESULTS: The study showed reasonable results concerning the short period of treatment. During the period of storage, the formulation showed no variation in colour, odour and pH. The average pH at initial, 1st, 6th and 12th months was 4.65, 4.64, 4.65 and 4.64, respectively. The assay of an active pharmaceutical ingredient in the formulation was desired over the whole period. This indicates that antimicrobial activity has been adequate and efficient. A significant decrease in Investigator Global Assessment (IGA) of the target toenails was also defined as the efficacy endpoint. The median score for IGA at baseline visit was 3 out of 5 which decreased to 2 out of 5 and the decrease was statistically significant. CONCLUSION: The study clarifies the new efficacy of ETS10 in subjects with onychomycosis and passed the safety study successfully. These properties may develop the potentiality of ETS10 as a good treatment option for patients with onychomycosis.

Effect of secukinumab on the clinical activity and disease burden of nail psoriasis: 32-week results from the randomized placebo-controlled TRANSFIGURE trial.

BACKGROUND: Nail psoriasis is associated with functional impairment, pain and reduced quality of life. OBJECTIVES: To demonstrate the superiority of secukinumab over placebo in clearing nail psoriasis as assessed by the Nail Psoriasis Severity Index (NAPSI) at week 16 and over time up to week 132. Presented here is the week 32 interim analysis. Impact on quality of life was assessed by Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA) patient questionnaires. METHODS: TRANSFIGURE is a double-blind, randomized, placebo-controlled study in patients with moderate-to-severe plaque and nail psoriasis. RESULTS: The primary objective of this study was met: both doses of secukinumab were superior to placebo at week 16 (NAPSI improvements of -45·3%, -37·9% and -10·8% for secukinumab 300 mg and 150 mg and placebo, respectively, P < 0·001). Significant improvements were seen in patients' quality of life: the NAPPA-Quality of Life total score median decreases at week 16 were 60·9%, 49·9% and 15·8% for secukinumab 300 mg and 150 mg and placebo, respectively (P < 0·001). Improvement in nail psoriasis continued to week 32: NAPSI percentage change reached -63·2% and -52·6% for secukinumab 300 mg and 150 mg, respectively. Skin clearance measured by ≥ 90% improvement in Psoriasis Area and Severity Index was significant (rates of 72·5%, 54·0% and 1·7% for secukinumab 300 mg and 150 mg and placebo at week 16, respectively, P < 0·001) and was sustained to week 32. The most common adverse events were nasopharyngitis, headache and upper respiratory tract infections. CONCLUSIONS: Secukinumab demonstrated significant and clinically meaningful efficacy and quality-of-life improvements for patients with nail psoriasis up to week 32. What's already known about this topic? Nail psoriasis is understudied and there is a lack of effective treatment options. Nail psoriasis is correlated with more severe psoriatic disease and the development of psoriatic arthritis. What does this study add? TRANSFIGURE is one of the few prospective placebo-controlled trials specifically in nail psoriasis and includes nail-specific quality-of-life measures such as Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA)-Quality of Life and NAPPA-Patient Benefit Index. In this trial, secukinumab demonstrates significant efficacy and quality-of-life improvements in this difficult-to-treat population.

Use of in vitro performance models in the assessment of drug delivery across the human nail for nail disorders.

INTRODUCTION: Onychomycosis is the most prevalent nail condition, affecting between 5% and 20% of the population in western countries. Oral therapies are not the treatment of choice due to poor patient compliance, high relapse rates, severe side effects, and contraindication. However, the difficultly in curing the condition using topical delivery is partly due to both the nail structure presenting a complex barrier and the lack of understanding of how best to achieve delivery of drug to the nail bed. AREAS COVERED: Several novel in vitro models incorporating human nails discussed in this article have been developed in recent years that allow for the study of the mechanisms of ungual drug absorption and formulation efficacy to be assessed. EXPERT OPINION: The TurChub zone of inhibition model is a high-throughput performance screen for prototype formulations during development, while the robustness of the ChubTur nail permeation, TurSh nail penetration, and RoMar antifungal efficacy models ensure these can be validated for in vitro bioequivalence testing of generic products to reference listed drugs. With clinical trials being a costly and high-risk approach to generic approval, the described novel in vitro screening and performance testing techniques offer a de-risked and less-expensive route to market.

A Review of Indigo Naturalis as an Alternative Treatment for Nail Psoriasis.

INTRODUCTION: Nail psoriasis is challenging to treat. The few currently available therapies are limited in efficacy, and often produce unfavorable side effects. A plant extract widely used in Traditional Chinese Medicine, indigo naturalis (Qing Dai), is presented in this review as an alternative topical treatment for skin and nail psoriasis. The purpose of this article is to present information on a viable alternative treatment with a favorable side effect profile for a difficult disease to treat. METHODS: A PubMed search for the term "indigo naturalis" was performed, and literature from 2006 to the present relevant to indigo naturalis and treatment of psoriasis and nail psoriasis was reviewed. RESULTS: Indigo naturalis shares several therapeutic mechanisms with current psoriasis treatments, such as regulation of keratinocyte proliferation and differentiation, restoration of epidermal barrier function, and reduction of inflammatory processes. Clinically, it is well tolerated. CONCLUSION: Recent research of indigo naturalis suggests that it is a safe, inexpensive, and effective alternative topical treatment for skin and nail psoriasis.

Pachyonychia congenita. Electron microscopic and epidermal glycoprotein assessment before and during isotretinoin treatment.

Two patients, a father and son, with pachyonychia congenita were treated with orally administered isotretinoin because the extreme deformity and discomfort associated with their massive keratoderma interfered with their work and school, respectively. While clinical benefits could not be sustained, electron microscopic findings compatible with suppression of abnormal keratinization were observed. In addition, skin biopsy samples were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the gels were then subjected to a lectin overlay technique with concanavalin A labeled with iodine 125. The distribution of specific glycoproteins was found to be different for lesional as against normal epidermis. The procedure was repeated after oral treatment with isotretinoin. The labeled glycoprotein pattern of the lesional epidermis was clearly distinguishable from both the pretreatment lesional and the normal epidermis; it was mostly intermediate between the two. The normal epidermis was virtually unaffected by the retinoid treatment.