On the Basis of Sex: Impact and Treatment of Toenail Onychomycosis in Female Patients.

Onychomycosis is a fungal infection of the nail unit affecting approximately five percent of the global population and representing 50 percent of all nail dystrophies seen in clinical practice. Patients with onychomycosis can suffer significant pain in addition to physical and psychological distress, which may seriously impair their quality of life (QoL). It is well established that onychomycosis prevalence is impacted by patient characteristics, including age and systemic comorbidities. However, the impact of patient sex on onychomycosis occurrence and treatment is not well characterized. This narrative review of the literature was conducted to address a dearth of published information on epidemiology, QoL, clinical trial participation, and treatment success specifically in female patients with onychomycosis. Additionally, an analysis of real-world treatment of onychomycosis in female patients is reported, including prescription patterns and the impact of toenail polish on topical treatments for onychomycosis. Understanding sex as a clinically relevant variable may inform onychomycosis treatment strategies and improve treatment outcomes.

Influence of Season on Efficacy and Tolerability of Tazarotene 0.045% Lotion for the Treatment of Acne.

Objective: The condition of the skin can vary due to weather fluctuations. Therefore, this post-hoc analysis evaluated efficacy and safety of tazarotene 0.045% lotion in warmer versus colder months. Methods: In two Phase III, double-blind, 12-week studies, participants aged nine years or older with moderate-to-severe acne were randomized 1:1 to once-daily tazarotene or vehicle lotion. The pooled population (N=1,614) was stratified by randomization date (warmer=May to September; colder=October to April). Evaluations included inflammatory/noninflammatory lesion counts, treatment success, adverse events, and safety/tolerability. Results: Tazarotene 0.045% lotion was similarly efficacious over colder and warmer months. Compared with vehicle, tazarotene demonstrated significantly greater least-squares mean absolute reductions from baseline to Week 12 in inflammatory (colder/warmer tazarotene vs. vehicle: -16.6/-15.8 vs. -13.2/-12.9) and noninflammatory lesions (-23.2/-22.6 vs. -17.5/-15.1); treatment success rates were also significantly higher (30.1/30.8% vs. 18.2/17.6%) (P<0.001, all). No strong seasonal trends in safety were observed, though tazarotene led to slightly more discontinuations (3.4% vs. 1.9%) and related adverse events (12.0% vs. 10.3%) in colder versus warmer months. Transient increases in scaling, erythema, and itching at Weeks 2 to 8 of tazarotene treatment were slightly higher in colder versus warmer months but returned to baseline/improved by Week 12. Limitations: Geographical variation across study sites can lead to varying temperatures and humidity within the same months. Conclusion: Tazarotene 0.045% lotion was efficacious and well tolerated for acne treatment, regardless of season. Year-round tolerability of tazarotene 0.045% lotion may be due to its lower tazarotene concentration and polymeric emulsion technology, which simultaneously delivers moisturizers/humectants/emollients to skin.

Triple-combination clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% gel for moderate-to-severe acne in children and adolescents: Randomized phase 2 study.

BACKGROUND/OBJECTIVES: Topical clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% gel (IDP-126) is the first fixed-dose triple-combination formulation in development for acne. This post hoc analysis investigated efficacy and safety of IDP-126 in children and adolescents with moderate-to-severe acne. METHODS: In a randomized, double-blind phase 2 study (NCT03170388), participants ≥9 years of age with moderate-to-severe acne were eligible for randomization (1:1:1:1:1) to once-daily IDP-126, one of three dyad combination gels, or vehicle gel for 12 weeks. This post hoc analysis of pediatric participants (n = 394) included children and adolescents up to 17 years of age. Assessments included treatment success, inflammatory/noninflammatory lesion counts, Acne-Specific Quality of Life (Acne-QoL) questionnaire, treatment-emergent adverse events (TEAEs), and cutaneous safety/tolerability. RESULTS: At Week 12, treatment success rates were significantly greater with IDP-126 (55.8%) than with vehicle (5.7%; p < .001) or any of the dyad combinations (range: 30.8%-33.9%; p < .01, all). Lesion reductions with IDP-126 were also significantly greater than with vehicle (inflammatory: 78.3% vs. 45.1%; noninflammatory: 70.0% vs. 37.6%; p < .001, both) and 9.2%-16.6% greater than with any of the dyad combinations. Increases (improvements) from baseline in Acne-QoL domain scores were generally greater with IDP-126 than in any other treatment group. The most common treatment-related TEAEs across treatment groups were application site pain and dryness. Most treatment-related TEAEs were of mild-to-moderate severity. CONCLUSION: IDP-126 gel-a novel fixed-dose, triple-combination topical formulation for acne-demonstrated superior efficacy to vehicle and three dyad component gels and was well tolerated in children and adolescents with moderate-to-severe acne.

Strategies for the enhancement of nail plate permeation of drugs to treat onychomycosis.

Onychomycosis is caused by dermatophytes, non-dermatophytes and yeasts. It has a global prevalence of 5.5%, requires long treatment periods, and has high relapse rates following therapy. Oral antifungals are generally the most common treatment. While effective, they have limitations such as drug-drug interactions, hepatotoxicity and adverse side effects; thus, they cannot be used in several populations. Topical antifungals do not have the safety limitations but are typically not as effective. The primary challenge of topical treatment is the permeation of drug molecules across the nail plate barrier, which is a highly cross-linked keratin network. The use of drugs and formulations with favourable characteristics such as small size, absence of lipophilicity, hydrophilic nature, hydrating properties and appropriate pH can greatly improve permeation. Here, we review physical, nanoparticle-based, formulation-based, mechanical and chemical drug delivery strategies to improve the permeation of drugs across the nail plate.

Enhancing Skin Uptake of Topical Antioxidants With 1,440-nm Nonablative Fractional Diode Laser Pretreatment.

BACKGROUND: Energy-based devices, such as nonablative lasers, are a promising method to enhance the delivery and absorption of topically applied molecules. OBJECTIVE: To characterize ex vivo uptake of common antioxidant topicals after pretreatment with a nonablative laser wavelength. MATERIALS AND METHODS: Using donor human skin tissue, uptake of 3 topical antioxidants was analyzed (C E Ferulic with 15% l-ascorbic acid [15% vitamin C serum], Phloretin CF with ferulic acid [10% vitamin C serum], and Phyto+ [botanical serum]; SkinCeuticals, Dallas, TX; 2010 formulations) after pretreatment with a 1,440-nm nonablative fractional diode laser. RESULTS: Pretreatment with the 1,440-nm laser enhanced uptake of 15% and 10% vitamin C serums by approximately 10 and 21 times, respectively, compared to controls. Laser pretreatment also enhanced uptake of botanical serum by approximately 6 times relative to controls. Permeation of vitamin C and botanical serums was also enhanced through laser pretreatment. CONCLUSION: Nonablative laser pretreatment increased uptake and permeation of topical antioxidants. Optimizing treatment requires consideration of the device and treatment parameters as well as the properties of the topical formulation.

Enhanced Uptake and Retention of 0.03% Bimatoprost, 0.5% 5-Fluorouracil, and 5% Minoxidil After 1,550-nm or 1,927-nm Nonablative Laser Pretreatment.

BACKGROUND: Laser pretreatment with cosmeceutical topicals is growing in popularity. However, lasers may also enhance the uptake of medical topicals that treat dermatologic conditions, such as vitiligo, alopecia, and cancerous and precancerous lesions. Permeation of these topicals must be quantified to optimize treatment protocols. OBJECTIVE: To analyze transdermal uptake of 3 topicals after nonablative fractional 1,550-nm erbium-doped glass or 1,927-nm thulium fiber laser pretreatment. METHODS AND MATERIALS: Human donor tissue was pretreated with a nonablative fractional 1,550-nm erbium-doped glass or 1,927-nm thulium fiber laser followed by application of 0.03% bimatoprost, 0.5% 5-fluorouracil, or 5% minoxidil. Permeation and retention were measured over 24 hours (bimatoprost and 5-fluorouracil) or 90 minutes (minoxidil), and uptake was calculated. RESULTS: Pretreatment with 1,927-nm thulium laser (500 MTZ/cm2; 5 mJ; 5 W) enhanced uptake and retention of bimatoprost versus untreated control at 24 hours post-treatment. Pretreatment with 1,550-nm erbium-doped glass laser (2,000 MTZ/cm2; 10 mJ; 30 W) enhanced permeation, uptake, and retention of 5-fluorouracil at 24 hours post-treatment and enhanced permeation and uptake of minoxidil at 90 minutes post-treatment. CONCLUSION: Nonablative laser pretreatment may enhance topical treatment of dermatologic conditions. Device settings must be optimized to maximize topical permeation while minimizing laser-associated thermal side effects.

Key parameters of non-ablative fractional laser pretreatments for enhanced topical uptake.

BACKGROUND: The uptake of topical formulations can be enhanced through laser pretreatments. Newer technologies, such as non-ablative fractional lasers (NAFLs), can target dermal tissues and spare the stratum corneum (SC), which can mitigate common side effects associated with ablative laser treatment. OBJECTIVE: To discuss the parameters of 2 NAFL pretreatment systems (1440-nm/1927-nm diode system or 1550-nm erbium-doped glass/1927-nm thulium system), which can be paired with topicals to improve their cutaneous uptake. METHODS AND MATERIALS: The parameters of the 1440-nm/1927-nm diode system and 1550-nm erbium-doped glass/1927-nm thulium system were reviewed, as well as in vivo experiments using both laser systems. RESULTS: Multiple parameters should be optimized to enhance the uptake of various topical formulations and minimize side effects, including wavelength, spot size, density, pulse duration, thermal properties, and topical formulation. Chosen therapeutic parameters must account for patient-specific factors, such as treatment indication, therapeutic area, and Fitzpatrick skin type. In vivo experiments have demonstrated that both laser systems are effective in enhancing the uptake of various topical therapies relative to untreated controls. CONCLUSION: Individualization of laser system parameters increases efficiency and minimizes risk.

Quantifying Skin Uptake of Topicals After 1,927-nm and 1,440-nm Nonablative Fractional Diode Laser Treatment.

BACKGROUND: Although the stratum corneum limits transdermal absorption of topicals, laser devices can enhance topical uptake by disrupting the skin barrier. Nonablative lasers are commonly used, but their effects on topical uptake should be quantified to optimize outcomes. OBJECTIVE: The objective of this study is to analyze transdermal uptake of 4 topicals after nonablative fractional diode laser pretreatment. METHODS AND MATERIALS: Human donor tissue was pretreated ex vivo with a nonablative fractional diode laser (1,927 nm or 1,440 nm, at varying treatment densities, powers, and peak energies) followed by application of either 2% salicylic acid, 10% ascorbic acid, over-the-counter mineral eye serum, or 4% hydroquinone. Topical uptake was quantified over 24 hours. RESULTS: Despite lower power settings, pretreatment with the 1,927 nm wavelength was associated with greater uptake of 10% ascorbic acid, mineral eye serum, and 4% hydroquinone than the 1,440 nm wavelength. In addition, 1,440-nm laser pretreatment with higher density (320 microscopic treatment zones [MTZ]/cm 2 ) and peak power (3 W) was associated with similar uptake but greater retention of 2% salicylic acid and greater uptake of 10% ascorbic acid than that with lower density (80 MTZ/cm 2 ) and peak power (1.2 W). CONCLUSION: When using laser pretreatment, device settings should be adjusted to balance outcomes with potential side effects.

Androgen Receptor-Mediated Nuclear Transport of NRDP1 in Prostate Cancer Cells Is Associated with Worse Patient Outcomes.

To our knowledge, our group is the first to demonstrate that NRDP1 is located in the nucleus as well as the cytoplasm of CaP cells. Subcellular fractionation, immunohistochemistry, and immunofluorescence analysis combined with confocal microscopy were used to validate this finding. Subcellular fractionation followed by western blot analysis revealed a strong association between AR and NRDP1 localization when AR expression and/or cellular localization was manipulated via treatment with R1881, AR-specific siRNA, or enzalutamide. Transfection of LNCaP with various NRDP1 and AR constructs followed by immunoprecipitation confirmed binding of NRDP1 to AR is possible and determined that binding requires the hinge region of AR. Co-transfection with NRDP1 constructs and HA-ubiquitin followed by subcellular fractionation confirmed that nuclear NRDP1 retains its ubiquitin ligase activity. We also show that increased nuclear NRDP1 is associated with PSA recurrence in CaP patients (n = 162, odds ratio; 1.238, p = 0.007) and that higher levels of nuclear NRDP1 are found in castration resistant cell lines (CWR22Rv1 and PC3) compared to androgen sensitive cell lines (LNCaP and MDA-PCa-3B). The combined data indicate that NRDP1 plays a role in mediating CaP progression and supports further investigation of both the mechanism by which nuclear transport occurs and the identification of specific nuclear targets.