Cutaneous penetration of soft nanoparticles via photodamaged skin: Lipid-based and polymer-based nanocarriers for drug delivery

Photoaging is recognized as the factor damaging skin-barrier function. The aim of this study was to examine the impact of ultraviolet (UV) irradiation on the cutaneous penetration of soft nanoparticles, including nanostructured lipid carriers (NLCs) and poly(lactic-co-glycolic acid) polymer nanoparticles (PNs). In vitro cutaneous permeation of retinoic acid (RA) carried by nanoparticles was evaluated. In vivo nude mouse skin distribution of topically applied nanoparticles was observed by fluorescence and confocal microscopies. The association of nanoparticles with cultured keratinocytes was measured by flow cytometry and fluorescence microscopy. The average diameter and surface charge were 236 nm and −32 mV for NLCs, and 207 nm and −12 mV for PNs. The ultrastructural images of skin demonstrated that the application of UV produced a loss of Odland bodies and desmosomes, the organelles regulating skin-barrier function. UVA exposure increased skin deposition of RA regardless of nanoparticle formulation. UVB did not alter RA deposition from nanoparticles as compared to the non-treated group. Exposure to UVA promoted RA delivery into hair follicles from NLCs and PNs by 4.2- and 4.9-fold, respectively. The in vivo skin distribution also showed a large accumulation of Nile red-loaded nanoparticles in follicles after UVA treatment. The soft nanoparticles were observed deep in the dermis. PNs with higher lipophilicity showed a greater association with keratinocytes compared to NLCs. The cell association of PNs was increased by UVA application, whereas the association between NLCs and keratinocytes was reduced two times by UVA. It was concluded that both follicles and intercellular spaces were the main pathways for nanoparticle diffusion into photodamaged skin.     

Inhibition of UVB-induced skin phototoxicity by a grape seed extract as modulator of nitrosative stress,ERK/NF-kB signaling pathway and apoptosis,in SKH-1 mice

Molecular mechanisms concerning the modulation of nitrosative stress, signal transduction and proliferation/apoptosis by a grape seed extract, Burgund Mare variety (BM), in SKH-1 mice exposed to UVB, were investigated. The animals were irradiated with single and multiple doses of UVB in 10 consecutive days. In each experiment were used five groups of animals: control, vehicle, UVB irradiated, vehicle + UVB, BM + UVB. The extract was applied topically, 30 min before each UVB exposure, in a dose of 4 mg total polyphenols/cm². BM remarkably inhibited UVB-induced activation of inducible nitric oxide synthase (iNOS) and therefore generation of nitric oxide (NO) and nitrotyrosine, in a UVB single dose regimen. BM also suppressed NF-kB activation by UVB but did not affect the activity of total ERK 1/2. In multiple UVB irradiations, BM increased NO formation and total ERK 1/2 activity and reduced iNOS activity and nitrotyrosine levels, inhibited cell proliferation, diminished p53 and caspase-3 immunoreactivities and increased the percentage of Bcl-2 positive cells. We concluded that BM modulates the apoptotic response of SKH-1 mice skin in UVB irradiation by the inhibition of p53, caspase-3, Bax/Bcl-2 and proliferating cell nuclear antigen expressions, as well as by reducing the activation of iNOS and NF-kB.     

Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm²) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E₂ (P < 0.01), and PGE₂ receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser⁴⁷³ in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors.     

A comparative evaluation of photo-toxic effect of fractionated melanin and chlorpromazine hydrochloride on human (dermal fibroblasts and epidermal keratinocytes) and mouse cell line/s (fibroblast Balb/c 3T3)

Fractionated melanin (Mel-HEV), a bleached version of natural melanin, offers protection against the high energy visible (HEV/UVA) and ultraviolet (specifically UVA) irradiation making it a potential compound to be added to skin care and sunscreen formulations and other cosmetic and personal care products. Chlorpromazine (CPZ) has been shown to exhibit photosensitivity and phototoxicity reaction in vitro and in vivo. Comparative evaluation of chemotoxicity and phototoxicity using Mel-HEV and CPZ (as positive control) was performed on mouse fibroblast cell line ‘Balb/c 3T3’. This is the recommended method for evaluating the phototoxic potential of compounds under the European Center of Validation of Alternative Methods (ECVAM) guidelines (OECD, 2004). This study was expanded from a mouse cell line – Balb 3T3/c to two human cell lines – HDF and HEKn for two reasons: to compare the difference between the sensitivity and behavior of two fibroblast cell lines (Balb/c 3T3 vs. HDF) and to compare the differences between two fibroblast cell lines with the keratinocyte cell line (HDF & Balb/c 3T3 vs. HEKn). It was found that Balb/c 3T3 and HEKn were both sensitive to the phototoxic potential of CPZ. However, HDF showed insensitivity to phototoxic evaluation. The test compound, Mel-HEV, was found to be non-phototoxic. The mean toxic concentration (MTC) for CPZ during HEV and UVA exposure conditions was found to be similar using Balb/c 3T3 (36.25 μg/ml) and HEKn (39.99 μg/ml) showing that cells exhibit similar responses at HEV/UVA? conditions. However, Balb/c 3T3 showed more sensitivity to CPZ at HEV/UVA+ condition (MTC = 0.87 μg/ml; mean PIF = 55.33; MPE = 0.395) than HEKn (MTC = 5.35 μg/ml; PIF = 7.61; MPE = 0.276) making it the preferred cell line for phototoxicity evaluations.     

Skin Laser Treatments Enhancing Transdermal Delivery of ALA

Drug delivery across skin has been limited due to barrier properties of the skin, especially those of the stratum corneum (SC). Use of the laser radiation has been suggested for the controlled removal of the SC. The purpose of this study was to study in vitro the influence of infrared radiation from the erbium:yttrium–aluminum–garnet (Er:YAG) laser (λ = 2940 nm), and visible from the 2nd harmonic of a neodymium:yttrium–aluminum–garnet (Nd:YAG) laser (λ = 532 nm) on transdermal delivery of 5-aminolevulinic acid (ALA). Pinna skin of the inner side of rabbit ear was used for skin permeation. The light sources were an Er:YAG laser (Key III Plus KaVo) and a Q-switched Nd:YAG laser (Lotis TII SL-2132). Permeation study, morphological and structural skin examination by histology and differential scanning calorimetry (DSC) were carried out. Permeation profiles and histological observations obtained after irradiation with infrared and visible laser radiation differed due to different biophysical effects on irradiated skin. Wavelength of 2940 nm required lower energy contribution to produce the same level of permeation than visible radiation at 532 nm. Structural analysis by DSC shows a selective impact on the lipidic structure. Laser pretreatment enhanced the delivery of ALA trough the skin by SC ablation.     

Cytotoxicity and mutagenicity of retinol with ultraviolet A irradiation in mouse lymphoma cells

Vitamin A (all-trans-retinol; retinol) is an essential human nutrient and plays an important role in several biological functions. However, under certain circumstances, retinol treatment can cause free radical generation and induce oxidative stress. In this study, we investigated photocytotoxicity and photomutagenicity of retinol using L5178Y/Tk^+/− mouse lymphoma cells concomitantly exposed to retinol and ultraviolet A (UVA) light. While the cells treated with retinol alone at the doses of 5 or 10 μg/ml in the absence of light did not increase the mutant frequency (MF) in the Tk gene, the treatment of the cells with 1–4 μg/ml retinol under UVA light (1.38 mW/cm² for 30 min) increased the MF in the Tk gene in a dose–responsive manner. To elucidate the underlying mechanism of action, we also examined the mutational types of the Tk mutants by determining their loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 on which the Tk gene is located. The mutational spectrum for the retinol + UVA treatment was significantly different from those of the control and UVA alone. More than 93% of the mutants from retinol + UVA treatment lost heterozygosity at the Tk1 locus and the major type (58%) of mutations was LOHs extending to D11Mit42, an alternation involving approximately 6 cM of the chromosome, whereas the main type of mutations in the control was non-LOH mutations. These results suggest that retinol is mutagenic when exposed to UVA in mouse lymphoma cells through a clastogenic mode-of-action.     

Effects of topical pimecrolimus 1% on high-dose ultraviolet B-irradiated epidermal Langerhans cells

Some studies reported no changes in the number of epidermal Langerhans cells (LC) that were observed in mice treated with pimecrolimus, and low-dose stimulated solar radiation (once)-induced changers in LC are minimally affected by pimecrolimus. This study is to investigate the effects of topical pimecrolimus 1% on high-dose ultraviolet B (UVB)-irradiated epidermal LC. Forty human foreskin tissues were randomly divided into 4 groups of 10 tissues each: Group A, control; Group B, pimecrolimus 1% (once)-only; Group C, 180 mJ/cm² UVB (once)-only; Group D, UVB + pimecrolimus. Each tissue was cut into 4 pieces corresponding to 4 time points. All the tissues were cultured at 37 °C. After being treated, the tissues were collected respectively and processed for immunohistochemical staining and immunofluorescence staining. For UVB-only group, epidermal CD1a⁺ LC number at 18 h decreased from 39.6 ± 8.30 to 22.3 ± 2.26/5 high magnification, compared to CD1a⁺ LC number at 0 h (P < 0.01). The CD1a⁺ LC number of UVB-only group was significantly less than other groups at 18 h, 24 h and 48 h (P < 0.05, respectively). Similar results were obtained with immunofluorescence staining for CD 1a and immunohistochemical staining for Langerin. The numbers of epidermal HLA-DR⁺ LC had no significant differences among all groups at different time points. Our study found a single 180 mJ/cm² UVB irradiation significantly reduced epidermal LC numbers at 18 h, 24 h and 48 h, however, topical pimecrolimus could reverse these changes. UVB plus pimecrolimus treatment did not affect human LC maturation.     

Nanoencapsulation of rice bran oil increases its protective effects against UVB radiation-induced skin injury in mice

Excessive UV-B radiation by sunlight produces inflammatory and oxidative damage of skin, which can lead to sunburn, photoaging, and cancer. This study evaluated whether nanoencapsulation improves the protective effects of rice bran oil against UVB radiation-induced skin damage in mice. Lipid-core nanocapsules containing rice bran oil were prepared, and had mean size around 200 nm, negative zeta potential (∼−9 mV), and low polydispersity index (<0.20). In order to allow application on the skin, a hydrogel containing the nanoencapsulated rice bran oil was prepared. This formulation was able to prevent ear edema induced by UVB irradiation by 60 ± 9%, when compared with a hydrogel containing LNC prepared with a mixture of medium chain triglycerides instead of rice bran oil. Protein carbonylation levels (biomarker of oxidative stress) and NF-κB nuclear translocation (biomarker of pro-inflammatory and carcinogenesis response) were reduced (81% and 87%, respectively) in animals treated with the hydrogel containing the nanoencapsulated rice bran oil. These in vivo results demonstrate the beneficial effects of nanoencapsulation to improve the protective properties of rice bran oil on skin damage caused by UVB exposure.     

Photoprotective effects of Romanian propolis on skin of mice exposed to UVB irradiation

We aimed at investigating the antioxidant, antiinflamatory, antiapoptotic and antigenotoxic effects of a Romanian Propolis (RP) extract in two concentrations (RP1 3 mg, respectively RP2 1.5 mg polyphenols/cm²), topically administered, either prior to or after UVB exposure, in a Swiss mouse model. Our results showed that both concentrations of RP extract, independent of the time of administration, significantly attenuated the malondialdehyde (MDA) formation and restored glutathione peroxidase (GPx) activity. However, the 8-hydroxy-2-deoxy-guanosine (8-oxo-dG), nitric oxide (NO) and glutathione (GSH) levels were not influenced by UVB exposure and RP treatment. Interleukin (IL)-6 levels were significantly decreased by RP treatment, both before and after UVB-exposure. RP2 extract, in both regimens, significantly reduced the epidermal hyperplasia and dermal inflammation, whereas RP1 pre-treatment diminished only the dermal inflammation. The effect of our RP extract in terms of reduction of sunburn cell formation and of activated caspase-3 and TUNEL-positive cells was observed in both subsets of the experiment, RP2 having a slightly better protective effect as compared to RP1. The antigenotoxic effect of RP was demonstrated by significantly reduced cyclobutane pyrimidine dimers (CPDs) formation. Our results suggest that RP extract might be a potential chemopreventive candidate by modulation of multiple UVB-induced signaling pathways in skin.     

Artocarpin attenuates ultraviolet B-induced skin damage in hairless mice by antioxidant and anti-inflammatory effect

Artocarpin, a prenylated flavonoid isolated from an agricultural plant Artocarpus communis, has been documented to possess anti-inflammation and anticancer activities. As oxidative stress and inflammation promote the development of ultraviolet B (UVB) irradiation-induced photodamage, the aim of the present study was to evaluate the photoprotective effect of artocarpin on UVB-induced skin damage in hairless mice. Artocarpin at a topical dose of 0.05% and 0.1% showed a significant photoprotective effect by decreasing histopathological changes, such as desquamation, epidermal thicken and sunburn cell formation, but 0.1% of artocarpin administration did not show better effect. Regarding the antioxidant activities, artocarpin exhibited a significant effect (P < 0.05) by decreasing levels of reactive species oxygen and lipid peroxidation. In addition, artocarpin can significantdecrease the level of tumor necrosis factor-α and interleukin-1β for downregulating the inflammation protein, including the synthesis of cytosolic phospholipase A2 and cyclooxygenase-2 (P < 0.05). In conclusion, these data suggest that artocarpin can prevent skin damage from UVB irradiation-induced photodamage in hairless mice and this is likely mediated through its antioxidant and anti-inflammation mechanisms. Therefore, we suggested that artocarpin could be a useful photoprotective agent in medicine and/or cosmetics.     

Evaluation of the impact of a continuing professional development worksheet on sustained learning and implementing change after a continuing pharmacy education activity

BackgroundContinuing professional development (CPD) continues to gain acceptance as a model for health care professionals to engage in lifelong learning. Little is known about how CPD participants use the experience to develop learning plans and implement new knowledge into practice.ObjectiveThe primary objective of this study was to evaluate the effectiveness of instruments designed to guide the pharmacist through a CPD process to plan and participate in continuing professional education activities at a national meeting.MethodsThe study was a case-control study of pharmacists randomized from the participants of the 2010 American Pharmacists Association Annual Meeting. The test group (n = 47) was instructed to complete CPD planning worksheets designed to facilitate planning of their continuing pharmacy education activities before the meeting. The control group (n = 58) did not have instructions beyond the meeting program. Both groups completed 3 surveys assessing components of the CPD processes: 1 before and 2 after the meeting. The surveys focused on confidence in abilities to identify, plan, and evaluate learning as well as implementation of practice change.ResultsNearly all the test groups reported successful application of learning (95%) and achieving their designed learning plan (87%). Practice changes were implemented in more than half (60%) of the test groups after using a CPD process to plan their learning activities. There were no significant differences among groups regarding the outcome measures.ConclusionsParticipants successfully used a CPD approach to meet their learning plans and achieve meaningful learning outcomes. Integration of CPD components into educational activities may help to promote practice change.     

Size-dependent biodistribution of carbon nanohorns in vivo

Carbon nanotubules, such as nanotubes and nanohorns, are potentially useful as drug delivery or hyperthermia agents for cancer therapy. However, the biokinetics of variously sized nanocarbons are important for their medical application and risk assessment. To examine the time course of the biodistribution of carbon nanohorns (CNHs) in mice, CNH aggregates of 100 nm (L-CNHs) or CNHs of 30–50 nm (S-CNHs) were dispersed with lipid polyethylene glycol and administered to mice through tail vein injection. Histological observation revealed that S-CNHs accumulated more slowly than did L-CNHs in the liver and spleen. The accumulation of L- and S-CNHs in spleen reached saturation within 1 and 48 h, respectively, and the accumulation in liver reached saturation within 48 h and > 7 days, respectively. CNHs did not accumulate appreciably in the lung, skin, or kidney. Histologic, hematologic, and immunologic (IL-6, TNF-α, and IFN-γ) tests did not reveal obvious toxicologic lesions at any time point.From the Clinical EditorIn this study the biodistribution and accumulation characteristics of small and large carbon nanohorns were characterized in mice. Data demonstrate slower accumulation of small carbon nanohorns in liver and spleen, no accumulation in skin, lung, or kidney, and no obvious hematologic or immunologic toxicity.     

Pig and guinea pig skin as surrogates for human in vitro penetration studies: A quantitative review

Both human and animal skin in vitro models are used to predict percutaneous penetration in humans. The objective of this review is a quantitative comparison of permeability and lag time measurements between human and animal skin, including an evaluation of the intra and inter species variability. We limit our focus to domestic pig and rodent guinea pig skin as surrogates for human skin, and consider only studies in which both animal and human penetration of a given chemical were measured jointly in the same lab. When the in vitro permeability of pig and human skin were compared, the Pearson product moment correlation coefficient (r) was 0.88 (P < 0.0001), with an intra species average coefficient of variation of skin permeability of 21% for pig and 35% for human, and an inter species average coefficient of variation of 37% for the set of studied compounds (n = 41). The lag times of pig skin and human skin did not correlate (r = 0.35, P = 0.26). When the in vitro permeability of guinea pig and human skin were compared, r = 0.96 (P < 0.0001), with an average intra species coefficient of variation of 19% for guinea pig and 24% for human, and an inter species coefficient of variation of permeability of 41% for the set of studied compounds (n = 15). Lag times of guinea pig and human skin correlated (r = 0.90, P < 0.0001, n = 12). When permeability data was not reported a factor of difference (FOD) of animal to human skin was calculated for pig skin (n = 50) and guinea pig skin (n = 25). For pig skin, 80% of measurements fell within the range 0.3 < FOD < 3. For guinea pig skin, 65% fell within that range. Both pig and guinea pig are good models for human skin permeability and have less variability than the human skin model. The skin model of choice will depend on the final purpose of the study and the compound under investigation.     

The effects of sulfur mustard exposure and freezing on transdermal penetration of tritiated water through ex vivo pig skin

The percutaneous absorption of tritiated water (³H₂O) through sulfur mustard (SM) exposed abdominal pig skin was measured using in vitro Franz-type static diffusion cells. The barrier function to water permeation following exposure to liquid SM for 8 min and excision 3 h later did not change significantly. A small, but statistically significant difference (P < 0.05) in steady state penetration (Jss), permeability coefficient (Kp) and lag time (t_L) of ³H₂O was observed between fresh skin and skin stored frozen (?20 °C) for up to two weeks. Steady-state penetration and Kp values were significantly higher (P < 0.05) in skin stored frozen compared with fresh skin. Fresh naïve skin had an average Kp of 1.65 × 10^?3 cm h^?1, whereas frozen naïve skin was 2.04 × 10^?3 cm h^?1. Fresh SM exposed skin had a mean Kp of 1.72 × 10^?3 cm h^?1, whereas frozen SM exposed skin was 2.31 × 10^?3 cm h^?1. Lag times were also shorter (P < 0.05) in skin that had been stored frozen. Frozen, SM-exposed porcine abdominal skin may be used for in vitro penetration studies, but effects of treatment and storage on the barrier layer should be taken into account.     

Formulation,optimization and evaluation of transferosomal gel for transdermal insulin delivery

The present study deals with the development of transferosomal gel containing insulin by reverse phase evaporation method for painless insulin delivery for use in the treatment of insulin dependent diabetes mellitus. The effect of independent process variables like ratio of lipids (soya lecithin:cholesterol), ratio of lipids and surfactants, and ratio of surfactants (Tween 80:sodium deoxycholate) on the in vitro permeation flux (μg/cm²/h) of formulated transferosomal gels containing insulin through porcine ear skin was optimized using 2³ factorial design. The optimal permeation flux was achieved as 13.50 ± 0.22 μg/cm²/h with drug entrapment efficiency of 56.55 ± 0.37% and average vesicle diameter range, 625–815 nm. The in vitro insulin permeation through porcine ear skin from these transferosomal gel followed zero-order kinetics (R² = 0.9232–0.9989) over a period of 24 h with case-II transport mechanism. The in vitro skin permeation of insulin from optimized transferosomal gel by iontophoretic influence (with 0.5 mA/cm² current supply) also provided further enhancement of permeation flux to 17.60 ± 0.03 μg/cm²/h. The in vivo study of optimized transferosomal gel in alloxan-induced diabetic rat has demonstrated prolonged hypoglycemic effect in diabetic rats over 24 h after transdermal administration.     

Studies on percutaneous penetration of chemicals – Impact of storage conditions for excised human skin

According to international guidelines skin penetration experiments can be carried out using freshly excised or frozen stored skin. However, this recommendation refers to data obtained in experiments with human cadaver skin. In our study, the percutaneous penetration of the occupationally relevant chemicals anisole, cyclohexanone and 1,4-dioxane was investigated for freshly excised as well as for 4 and 30 days at ?20 °C stored human skin using the diffusion cell technique. As indicator for the impairment of skin barrier by freezing cholesterol dissolution was determined in the solvents in exposure chambers of diffusion cells. Considering the percutaneously penetrated amounts, the following ranking was determined: 1,4-dioxane > anisole > cyclohexanone (decline to a factor of 5.9). The differences of fluxes between freshly excised and frozen stored skin (4 and 30 days) were not significant (p > 0.05). Cholesterol dissolved from the skin indicates no significant differences between freshly excised and frozen stored skin. This study shows that freezing of human skin for up to 30 days does not alter the skin barrier function and the permeability of chemicals.     

Evaluation of EpiDerm full thickness-300 (EFT-300) as an in vitro model for skin irritation: Studies on aliphatic hydrocarbons

The aim of this study was to understand the skin irritation effects of saturated aliphatic hydrocarbons (HCs), C9–C16, found jet fuels using in vitro 3-dimensional EpiDerm full thickness-300 (EFT-300) skin cultures. The EFT-300 cultures were treated with 2.5 μl of HCs and the culture medium and skin samples were collected at 24 and 48 h to measure the release of various inflammatory biomarkers (IL-1α, IL-6 and IL-8). To validate the in vitro results, in vivo skin irritation studies were carried out in hairless rats by measuring trans epidermal water loss (TEWL) and erythema following un-occlusive dermal exposure of HCs for 72 h. The MTT tissue viability assay results with the EFT-300 tissue show that 2.5 μl/tissue (≈4.1 μl/cm²) of the HCs did not induce any significant changes in the tissue viability for exposure times up to 48 h of exposure. Microscopic observation of the EFT-300 cross-sections indicated that there were no obvious changes in the tissue morphology of the samples at 24 h, but after 48 h of exposure, tridecane, tetradecane and hexadecane produced a slight thickening and disruption of stratum corneum. Dermal exposures of C12–C16 HCs for 24 h significantly increased the expression of IL-1α in the skin as well as in the culture medium. Similarly, dermal exposure of all HCs for 24 h significantly increased the expression of interleukin-6 (IL-6) and IL-8 in the skin as well as in the culture medium in proportion to the HC chain length. As the exposure time increased to 48 h, IL-6 concentrations increased 2-fold compared to the IL-6 values at 24 h. The in vivo skin irritation data also showed that both TEWL and erythema scores increased with increased HCs chain length (C9–C16). In conclusion, the EFT-300 showed that the skin irritation profile of HCs was in the order of C9 ⩽ C10 ⩽ C11 ⩽ C12 < C13 ≈ C14 ≈ C16 and that the tissue was an excellent in vitro model to predict in vivo irritation and to understand the structural activity relationship of HCs.     

Comparison of percutaneous absorption and metabolism of di-n-butylphthalate in various species

An ex vivo study of the percutaneous absorption of di-n-butylphthalate (DBP) showed that DBP was completely hydrolysed by esterases during penetration through rat skin. Fluxes were dependent on the esterase activity in the skin. The aim of this study was to determine the nature of the esterases involved in the hydrolysis of DBP in the skin. The relation between the percutaneous absorption of DBP and the epidermis/dermis esterase activity was determined in human, rat, rabbit, guinea-pig and mouse skin. An animal model was tested to estimate the human percutaneous absorption of lipophilic ester substances such as DBP. The nature of the esterases was determined by inhibition study in epidermis and dermis homogenates. A topical application of neat [¹⁴C]-DBP was used to determine ex vivo fluxes. Monobutylphthalate (MBP) levels in each skin layer were determined by high-performance-liquid-chromatography (HPLC). DBP was mainly hydrolysed by skin carboxyesterases for the all studied species. Unlike MBP levels in the skin, epidermis or whole skin esterase activity was not related to the DBP fluxes (hairless rat > hairy rat > hairless mouse = rabbit > guinea-pig > human) of all studied species. Therefore prediction of the results in the human being by extrapolation from animal data should be done carefully.     

Enhanced Skin Permeation of Naltrexone by Pulsed Electromagnetic Fields in Human Skin In Vitro

The aim of the present study was to evaluate the skin permeation of naltrexone (NTX) under the influence of a pulsed electromagnetic field (PEMF). The permeation of NTX across human epidermis and a silicone membrane in vitro was monitored during and after application of the PEMF and compared to passive application. Enhancement ratios of NTX human epidermis permeation by PEMF over passive diffusion, calculated based on the AUC of cumulative NTX permeation to the receptor compartment verses time for 0–4 h, 4–8 h, and over the entire experiment (0–8 h) were 6.52, 5.25, and 5.66, respectively. Observation of the curve indicated an initial enhancement of NTX permeation compared to passive delivery whilst the PEMF was active (0–4 h). This was followed by a secondary phase after termination of PEMF energy (4–8 h) in which there was a steady increase in NTX permeation. No significant enhancement of NTX penetration across silicone membrane occurred with PEMF application in comparison to passively applied NTX. In a preliminary experiment PEMF enhanced the penetration of 10 nm gold nanoparticles through the stratum corneum as visualized by multiphoton microscopy. This suggests that the channels through which the nanoparticles move must be larger than the 10 nm diameter of these rigid particles.     

Human skin penetration of cobalt nanoparticles through intact and damaged skin

Cobalt nanoparticles (CoNPs) are produced for several industrial and biomedical applications but there is a lack of data on human cutaneous absorption. Cobalt is also a skin sensitizer that can cause allergic contact dermatitis. Co applied as NPs, due to their small size and high surface, can penetrate into the skin in higher amount that bulk material. The aim of this study was to evaluate the absorption of Co applied as NPs in both intact and damaged skin. Experiments were performed using Franz cells and 1.0 mg cm^?2 of CoNPs was applied as donor phase for 24 h. Mean Co content of 8.5 ± 1.2 ng cm^?2 and 1.87 ± 0.86 μg cm^?2 were found in the receiving solutions of Franz cells when the CoNPs suspension was applied on intact skin and on damaged skin, respectively. Twenty-four hours Co flux permeation was 76 ± 49 ng cm^?2 h^?1 in damaged skin with a lag time of 2.8 ± 2.1 h. This study suggests that Co applied as NPs is able to penetrate the human skin in an in vitro diffusion cell system.