Pretreatment of skin using an abrasive skin preparation pad, a microneedling device or iontophoresis improves absorption of methyl aminolevulinate in ex vivo human skin.

BACKGROUND: Pretreatment of skin to remove scales/crusts and roughen the surface is essential to enhance the penetration of topically applied methyl aminolevulinate (MAL) prior to photodynamic therapy and to permit daylight to access all parts of the skin lesions. Numerous procedures of skin preparation are currently available. This study compared the in vitro penetration of MAL into ex vivo human skin pretreated with skin preparation pad abrasion or a microneedling device, and evaluated the effectiveness of an iontophoretic device in delivering MAL into ex vivo human skin. METHODS: Human skin samples, obtained from aesthetic surgeries, were used in this study. The thickness of the skin samples ranged between 1.44-2.87mm. Pretreatment of samples was performed with 10 passages of the Ambu® Unilect™ 2121M (Ambu A/S, Denmark) skin preparation pad, 8 rolling repetitions using the microneedling device Dermaroller® HC 902 (Dermaroller GmbH, Germany), or by an iontophoresis device (Feeligreen SA, France) for 1.5h. The effect of these pretreatment procedures on the penetration of MAL into the skin was assessed. RESULTS: Penetration in the total skin, liquid receptor and total penetration was most increased by skin preparation pad treatment, followed by microneedling and iontophoresis. Overall, MAL total penetration was increased up to 103-fold by skin preparation pad treatment, 4-fold by microneedling and 1.8-fold by iontophoresis. CONCLUSIONS: Abrasion with skin preparation pad was shown to be superior to microneedling and iontophoresis for increasing MAL penetration in ex vivo human skin.

Fixed-Combination Gels of Adapalene and Benzoyl Peroxide Provide Optimal Percutaneous Absorption Compared to Monad Formulations of These Compounds: Results from Two In Vitro Studies.

INTRODUCTION: Adapalene 0.1%/benzoyl peroxide 2.5% (0.1% A/BPO) and adapalene 0.3%/BPO 2.5% (0.3% A/BPO) gels are fixed-combination options for the topical treatment of acne. However, the active compounds of these combinations are also available as monads, to be used in association or as monotherapy. These two in vitro studies determined the effect of different treatment regimens on the percutaneous absorption of adapalene (0.1% and 0.3%) gels and BPO 2.5% gel in ex vivo human skin. METHODS: In vitro percutaneous absorption studies were conducted using full-thickness human skin from six donors. Treatment regimens included the application of 0.1% A/BPO, 0.3% A/BPO, or four free-combination regimens of the monads. Skin samples were incubated for 24 h. Concentrations of adapalene and BPO equivalent (BPO-eq) (i.e. benzoic acid after chemical transformation of BPO) were measured using high-performance liquid chromatography. Comparison of regimens was performed using a bioequivalence criterion (estimated ratio bewteen 0.8 and 1.25). RESULTS: The fixed combination 0.3% A/BPO regimen demonstrated more than three times higher absorption of adapalene versus the fixed-combination 0.1% A/BPO. Based on the bioequivalence acceptance criterion, all four free-combination regimens were different from 0.1% A/BPO and 0.3% A/BPO, with higher adapalene release delivered by the fixed combinations versus the free combinations. For BPO-eq, the results showed that the free-combination regimens where adapalene 0.1% was applied first were different from 0.1% A/BPO, with lower BPO-eq release delivered by these regimens compared to the fixed combination. The regimen adapalene 0.3% for 10 h followed by BPO 2.5% delivered lower BPO-eq release compared to the fixed combination. CONCLUSION: The fixed-combination A/BPO gels provide optimal percutaneous absorption of the active compounds compared to free combinations of adapalene 0.1%, adapalene 0.3%, and BPO 2.5%. The higher concentration of adapalene in the 0.3% A/BPO gel and the resulting higher absorption may explain higher clinical efficacy.

Lack of effect of selected sunscreens applied on ex vivo human skin for 5-methyl-aminolevulinic acid penetration and protoporphyrin IX photoactivation.

BACKGROUND: Photodynamic therapy (PDT) is a successful treatment for non-melanoma skin cancers. Methyl-aminolevulinate (MAL) is metabolized to protoporphyrin IX (PpIX) which accumulates in the skin lesion and which generates a painful photochemical toxic reaction upon red light exposure. PDT using daylight (DL) exposure is now used to reduce pain and subjects are advised to protect the areas with sunscreen. This work investigated the effect of sunscreen on MAL penetration and PpIX photoactivation in ex vivo human skin. METHODS: To measure skin penetration of MAL, particle-free sunscreens were applied on ex vivo human skin samples mounted on diffusion cells before application of Metvix cream containing [14C]-MAL for 2.5h. To circumvent the absence of skin penetration of PpIX, skin samples were first treated with microneedles and mounted on diffusion cells before the application of PpIX solution for 1h followed by sunscreens. Skin samples were then exposed to solar simulator for 1h. Concentrations of [14C]-MAL or PpIX were measured in both total skin and receptor liquid. RESULTS AND CONCLUSIONS: The results showed that the in vitro skin penetration of MAL and the PpIX photoactivation on ex vivo human skin samples are not modified by pretreatments of ex vivo human skin with sunscreens. This study demonstrates that neither in vitro skin penetration of MAL nor PpIX photoactivation were modified by pretreatments with Cetaphil SPF 30 Dermacontrol and Actinica® Lotion SPF 50+. This supports the efficacy and safety of MAL DL-PDT in the clinical situation.

Amorolfine 5% Nail Lacquer Exhibits Potent Antifungal Activity Compared to Three Acid-Based Devices Indicated for the Treatment of Onychomycosis: An In Vitro Nail Penetration Assay.

INTRODUCTION: Onychomycosis is the most common infectious disease involving nails. The aim of this study was to evaluate the antifungal activity of amorolfine 5% nail lacquer and three different acid-based medical devices indicated in the treatment of onychomycosis using an in vitro nail penetration assay. METHODS: Four products were tested in vitro: (a) amorolfine 5% nail lacquer; (b) ethyl lactate and acetic acid; (c) citric acid and urea; (d) ethyl lactate, glycerin, lactic acid, and citric acid. Test products were applied to healthy human cadaver nails and allowed to dry. Disks were cut from each piece of nail and placed on seeded agar plates of Trichophyton rubrum. Following incubation at 30 °C, zones of inhibition were measured. RESULTS: Amorolfine-treated nails exhibited inhibitory activity against T. rubrum with a mean zone of inhibition of 59.2 mm in diameter. In contrast, all three acid-based medical devices and the untreated controls showed no zones of inhibition (mean effective zones of 0 mm). CONCLUSION: In this in vitro nail penetration model, head-on, comparative study, we showed that amorolfine 5% nail lacquer possesses potent antifungal activity, whereas no antifungal activity was detected for three commercially available acid-based medical devices under identical assay conditions. FUNDING: Galderma.

Variability of PCB burden in 5 fish and sharks species of the French Mediterranean continental slope.

Despite being generally located far from contamination sources, deep marine ecosystems are impacted by chemicals like PCB. The PCB contamination in five fish and shark species collected in the continental slope of the Gulf of Lions (NW Mediterranean Sea) was measured, with a special focus on intra- and interspecific variability and on the driving factors. Significant differences occurred between species. Higher values were measured in Scyliorhinus canicula, Galeus melastomus and Helicolenus dactylopterus and lower values in Phycis blennoides and Lepidorhombus boscii. These differences might be explained by specific abilities to accumulate and eliminate contaminant, mostly through cytochrome P450 pathway. Interindividual variation was also high and no correlation was observed between contamination and length, age or trophic level. Despite its major importance, actual bioaccumulation of PCB in deep fish is not as documented as in other marine ecosystems, calling for a better assessment of the factors driving individual bioaccumulation mechanisms and originating high variability in PCB contamination.

Characterization of ABC transporters in human skin.

BACKGROUND: Most identified drug transporters belong to the ATP-binding cassette (ABC) and solute carrier (SLC) families. Recent research indicates that these transporters play an important role in the absorption, distribution and excretion of drugs, and are involved in clinically relevant drug-drug interactions for systemic drugs. However, very little is known about the role of drug transporters in human skin, especially in the disposition of topically applied drugs, and their involvement in drug-drug interactions. The aim of this work was to characterize the ABC transporters in human skin. METHODS: Expressions of ABCB1 multidrug resistance protein 1 (MDR1) also known as P-gp, ABCC1 and ABCC2 multidrug resistance-associated protein 1 and 2 (MRP1 and MRP2), and ABCG2 brest cancer resistance protein (BCRP) in human skin tissues were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). The modulations of ABCB1 and ABCC1 expressions were analyzed after ex vivo treatment of human skin with rifampicin and dexamethasone. The localization of the major transporter MRP1 in human skin was analyzed by immunohistochemistry. Finally, functional analysis of MRP1 in human skin was performed using different specific substrates and inhibitors. RESULTS: The expressions of ABCB1, ABCC1, ABCC2, and ABCG2 were all detected in human skin, of which the expression of ABCC1 was considered the most important. The comparison of human skin with human hepatocytes and kidneys shows that the expression of ABCC1 increased 15-fold in skin than in hepatocytes. Immunohistochemistry revealed marked expressions of MRP1 within the hair follicle, sweat gland and muscle, as well as moderate expression in the basal epidermis. Functional analysis demonstrated that the skin absorptions of rhodamine 123, [3H]-vinblastine, and [3H]-LTC4 were markedly decreased in the presence of MRP1 inhibitors (verapamil and MK571), thus supporting the role of MRP1 in the uptake of compounds from the epidermal compartment as well as their secretion into the bloodstream and sweat ducts. CONCLUSIONS: The present findings are the first to demonstrate the involvement of MRP1 in drug uptake in human skin.