Safety assessment for nail cosmetics: Framework for the estimation of systemic exposure through the nail plate.

All cosmetics products, including nail care products, must be evaluated for their safety. The assessment of systemic exposure is a key component of the safety assessment. However, data on the exposure, especially via ungual route (nail plate) are limited. Based on the physicochemical properties of human nails and permeability data of topical onychomycosis drugs, the nail plate is considered a good barrier to chemicals. We examine factors impacting penetration of nail care ingredients through the nail plate, including properties of the nails of the ingredients and formulations. The molecular weight, vapor pressure, logP, water solubility, and keratin binding, as well as formulations properties e.g., polymerization of acrylate monomers are considered important factors affecting penetration. To estimate systemic exposure of nail care ingredients through the nail plate, a standardized framework is applied that quantifies the impacts of these properties on penetration with an adjustment factor for each of these influencing properties. All the adjustment factors are then consolidated to derive an integrated adjustment factor which can be used for calculation of the systemic exposure dose for the ingredient. Several case studies are presented to reflect how this framework can be used in the exposure assessment for nail cosmetic products.

Biomarkers of disease in human nails: a comprehensive review.

Diagnostic, monitoring, response, predictive, risk, and prognostic biomarkers of disease are all widely studied, for the most part in biological fluids or tissues, but there is steadily growing interest in alternative matrices such as nails. Here we comprehensively review studies dealing with molecular or elemental biomarkers of disease, as opposed to semiological, pharmacological, toxicological, or biomonitoring studies. Nails have a long history of use in medicine as indicators of pathological processes and have also been used extensively as a matrix for monitoring exposure to environmental pollution. Nail clippings are simple to collect noninvasively as well as to transport and store, and the matrix itself is relatively stable. Nails incorporate, and are influenced by, circulating molecules and elements over their several months of growth, and it is widely held that markers of biological processes will remain in the nail, even when their levels in blood have declined. Nails thus offer the possibility to not only look back into a subject's metabolic history but also to study biomarkers of processes that operate over a longer time scale such as the post-translational modification of proteins. Reports on ungual biomarkers of metabolic and endocrine diseases, cancer, and psychological and neurological disorders will be presented, and an overview of the sampling and analytical techniques provided.

Malignant onychopapilloma.

Onychopapilloma is a fairly common lesion that is clinically typical enough to make the diagnosis. It is unique in that it stretches from the distal matrix all along the nailbed to the hyponychium. A case is described that developed pain eventually resulting in total excision. Histopathology revealed a malignant onychopapilloma. The differential diagnosis of this lesion is discussed.

Congenital malalignment of the great toenail: Conservative and definitive treatment.

Congenital malalignment of the great toenail, or ungual malalignment, is a rarely recognized disorder. It is characterized by lateral deviation of the longitudinal axis of the nail plate with respect to the distal phalanx, and if untreated, complications in the late teens and adulthood may arise. In this study, we have reviewed conservative and definitive treatments for this disorder.

A novel technique to evaluate nail softening effects of different urea formulations.

Urea has been incorporated into several topical ungual formulations to hydrate and soften the nail plate. In this study, we employed various characterization techniques (visual observation, scanning electron microscopy, measurement of thickness, transonychial water loss, nail electrical resistance, and mechanical study) to investigate the effect of urea concentration on the hydration of bovine hoof membranes - an in vitro model of infected human nails. We obtained inconsistent results in the thickness, transonychial water loss, nail electrical resistance, and scanning electron microscopy studies. In the mechanical study using a modified Texture Analyzer method, we reported an inverse and linear correlation between urea concentrations in the formulations and the force required to puncture the treated membrane (R2 = 0.9582, n ≥ 8). As the urea concentration decreased from 4x to 2x, 1x, and 0x % w/w, the puncture force increased significantly from 0.47 ± 0.07 to 0.77 ± 0.07, 0.91 ± 0.09, and 1.33 ± 0.26 N, respectively (p < 0.05). Thus, urea provided a positive softening effect on the membranes and the puncture force could indicate the urea level in topical formulations. In this study, we provided a novel, efficient, and reliable tool to evaluate the hydration level and physical properties of bovine hoof membranes.

[Ungual lesions in lupus erythematosus: A literature review]. / Lupus érythémateux et atteinte unguéale : revue de la littérature.

INTRODUCTION: There are few studies focusing on ungual lesions in patients with lupus erythematosus (LE). The aim of this study is to describe the type and the prevalence of ungual lesions among LE patients. PATIENTS AND METHODS: A systematic literature review with analysis of individual data was performed by searching the MEDLINE database for scientific articles using the keywords "lupus erythematosus" and "nail". RESULTS: Two-hundred and eighty-seven cases were collated including 55.1% women, with an average age of 32.2±11 years. The most common ungual or peri-ungual lesions were longitudinal ridging (83 patients, 28.9%), peri-ungual erythema (62 patients, 21.6%), onycholysis (60 patients, 20.9%), melanonychia (34 patients, 11.8%) and dyschromia (33 patients, 11.5%). An association between the presence of onycholysis and peri-ungual erythema and disease activity was noted [respectively 33 (38.8%) and 26 (30.6%) patients out of 85 with active disease versus 3 (5.8%) and 4 (7.7%) patients out of 52 with non-active disease, P<0.001 and P=0.018]. Screening for fungal infection was performed in one third of the cases, with proven onychomycosis in 34.7% of cases. DISCUSSION: Ungual lesions are not specific and do not permit diagnosis of LE. They can in fact occur in other diseases such as connective tissue disorders. However, their diagnosis is important because they may be the presenting sign in LE, and certain of them may be associated with more active disease. Onychomycosis is frequently a confounding factor in such immunocompromised patients.

Prevalence of Nail Scabies: A French Prospective Multicenter Study.

INTRODUCTION: To assess the prevalence of nail involvement in children <16 years old with a confirmed diagnosis of scabies. STUDY DESIGN: Observational, prospective study in 7 French dermatology departments between June 2015 and January 2017. Children were included if they had scabies confirmed by dermoscopy and/or microscopy and if nails could be sampled. The first toenails and thumbnails as well as clinically affected nails were systematically sampled for microscopic examination. Individual data were recorded via a standardized questionnaire. RESULTS: A total of 47 children with scabies were included (26 females [55.3%], mean age 3.6 ± 4.0 years). Pruritus was present in 42 children (89.3%); the relapse rate was 38.3% (n = 18). In 3 infants (6.4%), Sarcoptes mites were revealed by dermoscopy or microscopy of the first toenails (2 cases) and a thumbnail (1 case), but nails were normal in 2 children. Two of the 3 infants had already received treatment for scabies in the previous weeks. CONCLUSION: Prevalence of nail involvement in children with confirmed scabies was 6.4%. Nails should not be overlooked during scabies treatment.

Investigation of a correlation between taxane-based chemotherapy and the ultrasonic time-of-flight of human fingernails.

BACKGROUND: Medical practitioners have long associated the physical appearance of human fingernails with certain underlying health conditions due to their direct connection to the vascular system. The objective of this study was to demonstrate how human fingernails can potentially be used as a biomarker to determine the severity of a patient's reaction to chemotherapy. METHODS: Quantitative investigation of fingernails in patients undergoing taxane-based chemotherapy was conducted using a high-frequency 50 MHz ultrasound device in B-mode in the form of a pilot study. Time-of-Flight (TOF) ultrasonic signal measurements were recorded longitudinally across fingernails over three time intervals; (before treatment, in the middle of treatment, and on the last day of treatment); a neuropathy assessment and photographs were also taken for comparison. RESULTS: A total of 17 patients were examined in this study with ages ranging from 35-69 years old with both weekly and biweekly chemotherapy regimens. Onycholysis and fingernail discoloration were observed in 8 of the 17 patients. White transverse lines and white lunula were observed on 4 of the 17 patients. Quantitative assessment revealed a TOF median decrease in fingernails during the first half of chemotherapy treatment; conversely, TOF median was found to have increased during the second half. Median TOF measurements at the end of treatment were found to return to approximately that of the baseline value. CONCLUSION: This was a novel application of ultrasound in fingernails as chemotherapy biomarkers and further studies should be considered to verify and expand on the results obtained in this study.

Chemical and physical strategies in onychomycosis topical treatment: A review.

Onychomycosis is a fungal infection of the fingernails or toenails caused by dermatophytes, nondermatophytes, moulds, and yeasts. This condition affects around 10-30% people worldwide, negatively influencing patients' quality of life, with severe outcomes in some cases. Since the nail unit acts as a barrier to exogenous substances, its physiological features hampers drug penetration, turning the onychomycosis treatment a challenge. Currently, there are several oral and topical therapies available; nevertheless, cure rates are still low and relapse rates achieves 10-53%. Also, serious side effects may be developed due to long-term treatment. In light of these facts, researchers have focused on improving topical treatments, either by modifying the vehicle or by using some physical technique to improve drug delivery trough the nail plate, hence increasing therapy effectiveness. Therefore, the aim of this paper is to explain these novel alternative approaches. First, the challenges for drug ungual penetration are presented. Then, the chemical and physical strategies developed for overcoming the barriers for drug penetration are discussed. We hope that the information gathered may be useful for the development of safer and more effective treatments for onychomycosis.

Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients.

BACKGROUND: Data on long-term topical sirolimus treatment of the cutaneous manifestations of tuberous sclerosis complex are rare. OBJECTIVE: To evaluate the long-term benefit and tolerance of topical 1% sirolimus in tuberous sclerosis complex. METHODS: In this 18-month prospective single-center study, 1% sirolimus cream was applied daily to facial angiofibromas (FAs), fibrous cephalic plaques (FCPs), shagreen patches, hypomelanotic macules, and ungual fibromas. After complete clearance (CC) of FAs, we evaluated a maintenance protocol of 3 applications weekly. RESULTS: Twenty-five patients were enrolled. Fifty percent obtained CC of FAs within 9 months. Of 7 patients with CC (58%) who were following the maintenance protocol, 6 relapsed within 7 months and 1 was still responding at 1 year. Of 16 patients with FCPs, 7 (44%) remained stable at 12 months and 9 (56%) improved after 3 to 9 months of treatment. Only 1 of 5 patients treated for shagreen patches showed improvement at 12 months. Treatment was well tolerated with no serious adverse events. LIMITATIONS: The small number of patients was a limitation. CONCLUSIONS: Topical 1% sirolimus applied daily produced positive responses in treatment of FAs, FCPs, and facial hypomelanotic macules and was well tolerated. A 3-times-weekly maintenance protocol did not prevent FA relapses.

Trans-ungual Delivery of AR-12, a Novel Antifungal Drug.

AR-12 is a novel small molecule with broad spectrum antifungal activity. Recently, AR-12 was found to be highly active against Trichophyton rubrum, one of the predominantly responsible organisms that cause onychomycosis. The primary objective of this project was to investigate the ability of AR-12 to penetrate into and across the human nail plate followed by improving its trans-ungual permeation using different penetration enhancers. TranScreen-N™, a high throughput screening method was utilized to explore the potential nail penetration enhancers to facilitate the drug delivery through the nail. This screen demonstrated that dexpanthenol and PEG 400 were the most efficient enhancers. The in vitro permeation studies were performed across the human cadaver nail plates for 7 days with three AR-12 (5% w/v) formulations containing 10% w/v dexpanthenol (Formulation A), 10% w/v PEG 400 (Formulation B), and a combination of 10% w/v dexpanthenol + 10% w/v PEG 400 (Formulation C). The in vitro studies concluded that dexpanthenol and PEG 400 were able to deliver a significant amount of AR-12 into and across the nail plate that was found to be more than MIC 50 level of the drug.

Terbinafine Hydrochloride Trans-ungual Delivery via Nanovesicular Systems: In Vitro Characterization and Ex Vivo Evaluation.

Treating a nail infection like onychomycosis is challenging as the human nail plate acts as a formidable barrier against all drug permeation. Available oral and topical treatments have several setbacks. Terbinafine hydrochloride (TBH), belonging to the allylamine class, is mainly used for treatment of onychomycosis. This study aims to formulate TBH in a nanobased spanlastic vesicular carrier that enables and enhances the drug delivery through the nail. The nanovesicles were formulated by ethanol injection method, using either Span® 60 or Span® 65, together with Tween 80 or sodium deoxycholate as an edge activator. A full factorial design was implemented to study the effect of different formulation and process variables on the prepared TBH-loaded spanlastic nanovesicles. TBH entrapment efficiency percentages, particle size diameter, percentage drug released after 2 h and 8 h were selected as dependent variables. Optimization was performed using Design-Expert® software to obtain an optimized formulation with high entrapment efficiency (62.35 ± 8.91%), average particle size of 438.45 ± 70.5 nm, and 29.57 ± 0.93 and 59.53 ± 1.73% TBH released after 2 and 8 h, respectively. The optimized formula was evaluated using differential scanning calorimetry and X-ray diffraction and was also morphologically examined using transmission electron microscopy. An ex vivo study was conducted to determine the permeation and retainment of the optimized formulation in a human cadaver nail plate, and confocal laser scanning microscope was used to show the extent of formulation permeation. In conclusion, the results confirmed that spanlastics exhibit promising results for the trans-ungual delivery of TBH.

Diagnostic criteria for and clinical review of melanonychia in Korean patients.

BACKGROUND: Melanonychia may be the presenting sign of ungual melanoma. However, there are insufficient basic clinical data for melanonychia in Korean patients. OBJECTIVE: We sought to identify basic clinical data and devise a classification algorithm for melanonychia. METHODS: In all, 275 patients with melanonychia who visited our clinic from January 2002 to August 2014 were included in this study. We reviewed medical records, clinical and dermoscopic photographs, and histopathologic findings and we assessed demographics (eg, age); medical (eg, systemic diseases), family, and trauma (eg, nail biting) history; and physical findings (eg, affected number and site). RESULTS: The 5 most common causes of melanonychia in Korean patients were subungual hemorrhage (29.1%), nail matrix nevus (21.8%), trauma-induced pigmentation (14.5%), nail apparatus lentigo (11.6%), and ethnic-type nail pigmentation (8.0%). Melanoma was diagnosed in 6.2% of patients. Ethnic-type nail pigmentation was commonly identified. LIMITATIONS: This is a retrospective study from a single center. CONCLUSION: We propose a revised diagnostic algorithm for melanonychia to assist in the evaluation of this condition.

Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitro and in vivo evaluation.

Onychomycosis is a fungal infection of nail unit that is caused by dermatophytes. Oral Terbinafine hydrochloride (TBF-HCl) is being used for the treatment of onychomycosis since 24 years. The side effects caused by the systemic application and limitations of topical administration of this drug regarding the diffusion through nail lead to the development of a new formulation based on, TBF-HCl-loaded liposome. The newly obtained film formulations were prepared and characterized via several parameters, such as physical appearance, drug content, thickness, bioadhesive properties and tensile strength. In vitro and ex vivo permeation studies were performed to select an optimum film formulation for antifungal activity to show the efficiency of formulations regarding the treatment of onychomycosis. The in vitro release percentages of drug were found 71.6 ± 3.28, 54.4 ± 4.26, 56.1 ± 7.48 and 46.0 ± 2.43 for liposome loaded pullulan films (LI-P, LII-P) and liposome loaded Eudragit films (LI-E, LII-E), respectively. The accumulated drug in the nail plates were found 31.16 ± 4.22, 24.81 ± 5.35, 8.17 ± 1.81 and 8.92 ± 3.37 for LI-P, LII-P, LI-E and LII-E, respectively, which within therapeutic range for all film formulations. The accumulated drug in the nail plate was found within therapeutic range for all film formulations. The efficacy of the selected TBF-HCl-loaded liposome film formulation was compared with TBF-HCl-loaded liposome, ethosome, liposome poloxamer gel and ethosome chitosan gel formulations. It was found that TBF-HCl-loaded liposome film formulation had better antifungal activity on fungal nails which make this liposome film formulation promising for ungual therapy of fungal nail infection.

Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus.

BACKGROUND: Oral mechanistic target of rapamycin inhibitors have been shown to reduce visceral tumor volume in patients with tuberous sclerosis complex (TSC). OBJECTIVE: We sought to evaluate the cutaneous response to oral sirolimus in patients with TSC and an indication for systemic treatment, including long-term effects. METHODS: A retrospective analysis of 14 adult patients with TSC prescribed sirolimus to treat lymphangioleiomyomatosis was performed. Serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before, during, and after the treatment period were blinded, then assessed using the Physician Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment. RESULTS: Sirolimus significantly improved angiofibromas (median treatment duration 12 months; median PGA score 4.5 [range 1.5-5]; Wilcoxon signed rank test, P = .018) and shagreen patches (median treatment duration 10 months; median PGA score 4.5 [range 3.5-5]; Wilcoxon signed rank test, P = .039), whereas ungual fibromas improved in some patients (median treatment duration 6.5 months; median PGA score 4.66 [range 2.75-5]; Wilcoxon signed rank test, P = .109). Clinical, immunohistochemical, or molecular evidence of resistance was not observed (range 5-64 months of treatment). LIMITATIONS: This was a retrospective analysis limited to adult women with lymphangioleiomyomatosis. CONCLUSION: Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.

Emerging topical onychomycosis therapies - quo vadis?

INTRODUCTION: Onychomycosis, a common chronic fungal infection affecting fingernails and toenails, globally may affect 10 - 30% of the population. This chronic disease is difficult to eradicate. The goal of developing a highly effective and safe topical treatment has not yet been reached as it depends on the type of onychomycosis and the variety of invaders. AREAS COVERED: Topical drug delivery to the nail is highly desirable in treating nail disorders. However, efficacy of topical therapies is low due to their limited permeability across the nail plate. Advances have especially been made by the development of new therapeutic options including new drug entities, new formulations and reformulations. This overview updates emerging topical treatments for onychomycosis, research progress and future perspectives. EXPERT OPINION: Development of novel effective noninvasive topical therapy for treating onychomycosis and other nail diseases such as psoriasis is long overdue. Previously there was a lack of basic knowledge about nail and its barrier properties, but with the recent increased interest in this field both from industry and academia, we hope extensive research will continue in this field to bring about successful and safe treatments for such chronic diseases.

Ungual Scabies: A Case Report and Review of Literature.

Introduction: Nail unit infestation by scabies mites (ungual scabies) is uncommon. It usually presents with distal subungual lesions, leading to recurrent and persistent disease by acting as a reservoir of infection. Periungual involvement in scabies with nail loss is rare and may lead to severe nail damage. Case Presentation: We report a 14-year-old boy on chemotherapy for acute lymphocytic leukemia (ALL) who presented with extensive scaling and crusted plaques of scabies. Nail unit revealed periungual crusted plaques with paronychia and onychomadesis involving five digits. It was associated with partial to complete nail loss. Dermoscopy of periungual crusted plaques showed greyish-white scales with brown dots and globules. A sinuous burrow with a brown-triangular structure was visualized in the web space. KOH mount from skin scrapings showed the scabies mites. Treatment of scabies led to a marked improvement. Conclusion: Though ungual scabies is generally a benign disease, proximal periungual involvement with damage to nail matrix is possible, leading to nail loss. We review manifestations of nail unit scabies reported in literature. Treatment options used and outcomes are also analyzed. The importance of nail-directed therapy in preventing relapses of scabies cannot be undermined.

Fracture or Not: An Easily Mistaken Benign Finding in a Tuberous Sclerosis Patient.

Tuberous sclerosis (TSC) is a rare autosomal dominant disorder that can affect multiple organ systems, including the brain, heart, lungs, and skin. Cutaneous manifestations are common, including ungual fibromas, however, these may be mistaken for other pathologies. Here, we present the case of a 14-year-old with TSC complaining of traumatic left little finger pain. Radiographic evaluation revealed cortical scalloping of the nailbed, concerning for a non-displaced fracture. Given the history of TSC, however, this defect may have also represented a periungual fibroma. The patient subsequently underwent conservative management and an eight-month radiographic follow-up showed no osseous remodeling, supporting the diagnosis of periungual fibroma. It is imperative for clinicians to understand the cutaneous manifestations of TSC to aid in proper diagnosis and avoidance of unnecessary treatment. In this case, interval follow-up confirmed the diagnosis and excluded fracture.

Dactylitis and Ungual Tuberculosis: An Atypical Presentation of the Disease.

Introduction: Tuberculosis is a common infection caused by Mycobacterium tuberculosis in developing countries. Among the extrapulmonary forms of tuberculosis, cutaneous tuberculosis is rare, and even dermatologists are less familiar with its ungual manifestations. Case Presentation: We present an exuberant case of ungual tuberculosis in a patient with no personal or family history of immunosuppression, which is the first manifestation of the disseminated form of the disease. Conclusion: In our patient, the initial manifestation was related to the nail, probably originating from the progression of bone TB focus, which further progressed with respiratory symptoms and involvement of other organs. We believe this is the first case in which the ungual presentation allowed the diagnosis of disseminated tuberculosis.