Role of mast cells in the induction of dry skin in a mouse model of rheumatoid arthritis

Purpose: Rheumatoid arthritis (RA) is known to induce dry skin as an extra-articular symptom. However, the mechanisms behind the induction are unclear. In this study, we utilized an arthritis mouse model to simulate RA to reveal the relationship between arthritis and dry skin.

Materials and methods: DBA/1JJmsSlc control mice (n?=?5) and DBA/1JJmsSlc collagen-induced arthritis mouse model (arthritis mice; n?=?5) were used. We measured transepidermal water loss (TEWL) and capacitance to reveal the effect of arthritis on skin barrier function. In addition, we measured the expression of biomarkers of skin barrier function.

Results: We found that the hind limb volume of the arthritis mice was higher than that of the control mice. Our results showed that the arthritis mice had higher TEWL and lower capacitance when compared to the control mice. When compared to that of the control mice, the skin of the arthritis mice was thicker with more leukocyte infiltration. In the skin of arthritis mice, we observed lower expression of type I and IV collagens, but higher expression of matrix metalloproteinases (MMP)-1 and -9 when compared to that of the control mice. The levels of mast cells, histamine, substance P, and tryptase were higher in the arthritis mice than in the control mice. This study showed that the arthritis mice exhibited a disruption of skin barrier function (i.e. dry skin), which was improved following treatment with a mast cell inhibitor.

Conclusions: Our results on mast cells suggested that an improvement of dry skin is important for RA management.     

Cactus cladodes (Opuntia humifusa) extract minimizes the effects of UV irradiation on keratinocytes and hairless mice

Context: Cactus cladodes [Opuntia humifusa (Raf.) Raf. (Cactaceae)] is one of the cactus genera, which has long been used as a folk medicine for skin disorders.

Objective: This study investigated the skincare potential of cactus cladodes extract (OHE), including its ability to regulate ultraviolet B (UVB)-induced hyaluronic acid (HA) production.

Materials and methods: Gene expression levels of hyaluronic acid synthases (HASs) and hyaluronidase (HYAL) were measured in UVB-irradiated HaCaT cells with OHE treatment (10, 25, 50, 100?μg/mL) by real-time polymerase chain reaction (PCR). The HA content was analyzed in hairless mice (SKH-1, male, 6 weeks old) treated with OHE for 10 weeks by using enzyme-linked immunosorbent assay (ELISA). Haematoxylin and eosin (H&;E) and immunohistological staining were performed to examine epidermal thickness and levels of CD44 and hyaluronic acid-binding protein (HABP).

Results: HA synthases (HAS,1 HAS2, HAS3) mRNA levels were increased by 1.9-, 2.2- and 1.6-fold, respectively, with OHE treatment (100?μg/mL), while UVB-induced increase of hyaluronidase mRNA significantly decreased by 35%. HA content in animal was decreased from 42.9 to 27.1?ng/mL by OHE treatment. HAS mRNA levels were decreased by 39%, but HYAL mRNA was increased by 50% in OHE group. CD44 and HABP levels, which were greatly increased by UVB-irradiation, were reduced by 64 and 60%, respectively. Epidermal thickness, transepidermal water loss (TEWL), and erythema formation was also decreased by 45 (45.7 to 24.2?μm), 48 (48.8 to 25?g/h/m²) and 33%, respectively.

Conclusion: OHE protects skin from UVB-induced skin degeneration in HaCaT cells and hairless mice.     

Effective topical delivery systems for corticosteroids: dermatological and histological evaluations

Abstract

Atopic dermatitis (AD) is a chronic and relapsing skin disease with severe eczematous lesions. Long-term topical corticosteroid treatment can induce skin atrophy, hypopigmentation and transepidermal water loss (TEWL) increase. A new treatment approach was needed to reduce the risk by dermal targeting. For this purpose, Betamethasone valerate (BMV)/Diflucortolone valerate (DFV)-loaded liposomes (220–350?nm) were prepared and incorporated into chitosan gel to obtain adequate viscosity (～13?000 cps). Drugs were localized in stratum corneum?+?epidermis of rat skin in ex-vivo permeation studies. The toxicity was assessed on human fibroblast cells. In point of in-vivo studies, pharmacodynamic responses, treatment efficacy and skin irritation were evaluated and compared with previously prepared nanoparticles. Liposome/nanoparticle in gel formulations produced higher paw edema inhibition in rats with respect to the commercial cream. Similar skin blanching effect with commercial creams was obtained via liposome in gels although they contain 10 times less drug. Dermatological scoring results, prognostic histological parameters and suppression of mast cell numbers showed higher treatment efficiency of liposome/nanoparticle in gel formulations in AD-induced rats. TEWL and erythema measurements confirmed these results. Overview of obtained results showed that liposomes might be an effective and safe carrier for corticosteroids in skin disease treatment.     

Has dry/cold weather an impact on the skin condition of cleanroom workers?

ABSTRACT

In previous epidemiological studies irritant skin changes were reported significantly more frequently under dry/cold ambient air conditions. The aim of this study was to assess whether a similar effect might be observed in cleanroom workers, occupationally exposed to strictly controlled ambient conditions. This investigation examined 690 employees of a semiconductor production company in Germany, one half in winter (n = 358) and the other half in spring (n = 332). In both waves, both cleanroom workers, who used occlusive gloves predominantly during the entire shift, and employees in the administration, serving as the control group, were included. Ambient outdoor temperature and relative humidity (RH) were measured and absolute humidity (AH) was calculated. Hands were dermatologically examined with quantitative clinical skin score HEROS, supplemented by transepidermal water loss (TEWL) and stratum corneum hydration measurements. Temperature ranged from –5.41 to 6.51°C in winter (RH 71.04–92.38%; AH 2.85–6.7 g/m³) and from 6.35 to 10.26°C in spring (RH 76.17–82.79%; AH 5.66–7.92 g/m³). Regarding HEROS, TEWL, and corneometry, no marked consistent pattern regarding an enhanced or decreased risk of irritant skin changes was found. Work in a strictly controlled environment with prolonged wearing of occlusive gloves, with clean hands and without exposure to additional hazardous substances, did not seem to negatively affect the skin. In this particular setting, meteorological conditions also did not appear to adversely affect the skin. It is conceivable that wearing of gloves and air conditioning in the plant protect skin of the hands from adverse effects due to dry and cold air encountered when not working.     

Role of Appendages in Skin Resistance and lontophoretic Peptide Flux: Human Versus Snake Skin

Purpose. 1. The assessment of the role of hair follicles and sweat glands in skin resistance and percutaneous iontophoretic flux of 9-desglycinamide, 8-arginine vasopressin (DGAVP) by comparing two skin species: human stratum corneum which contained hair follicles, sweat and sebaceous glands, and shed snake skin which lacked all appendages. 2. The effect of l-dodecylazacycloheptan-2-one (dodecyl-Azone, a lipid perturbing agent) on the iontophoretic DGAVP flux. Methods. Iontophoresis in vitro was performed in a transport cell (0.79 cm² area available for percutaneous transport) by 8-hours application of a pulsed constant current of 100 Hz, 50% duty cycle and 0.26 mA.cm^–2 current density delivered by a pair of Ag/AgCl electrodes, of which the anode was facing the anatomical surface of the skin samples. Results. The initial resistances of human stratum corneum and shed snake skin samples were of the same order of magnitude (20–24 k.cm²) and both skin species showed a comparable resistance-decrease profile during 8-hours iontophoresis, indicating that the resistances were mainly determined by the stratum corneum and not greatly influenced by the appendageal structures. The initial resistances of the skin samples pretreated with dodecyl-azone were less than 50% of the values of untreated samples. Because dodecyl-azone is known to perturb the ordering of the intercellular lipids, the effect of azone on the resistance confirms that the resistance mainly resides within the intercellular lipids of the stratum corneum. No correlation was found between the iontophoretic DGAVP-flux and the conductance of human skin. For shed snake skin, however, a good correlation was found, indicating that the iontophoretic permeability of human skin in vitro for a peptide such as DGAVP is, unlike shed snake skin, not related to its overall permeability to ions. While the initial resistances of both human and snake skin were in the same order of magnitude and showed the same declining profile during iontophoresis, the steady state iontophoretic DGAVP flux across human stratum corneum was approximately 140 times larger than through shed snake skin. These findings suggest that small ions follow pathways common to both skin types, presumably the intercellular route, while the peptide on the other hand is transported differently: across snake skin presumably along intercellular pathways only, but across human stratum corneum along additional pathways (most likely of appendageal origin) as well. This interpretation is supported by the observations made of the effects of dodecyl-azone on DGAVP-iontophoresis. Pretreatment with dodecyl-azone did not significantly change steady state fluxes and lag times of DGAVP-iontophoresis across human stratum corneum, but resulted in a significant 3-fold lag time decrease and a 3-fold flux increase of DGAVP-iontophoresis across snake skin. Conclusions. The results of these in vitro studies emphasize the importance of the appendageal pathway for iontophoretic peptide transport across human stratum corneum.     

In vivo antibacterial activity of Garcinia mangostana pericarp extract against methicillin-resistant Staphylococcus aureus in a mouse superficial skin infection model

Context: Garcinia mangostana Linn. (Guttiferae) (GM) pericarp has been shown to exhibit good in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA); however, there is currently no available information regarding its in vivo antibacterial activity.

Objective: To examine in vivo antibacterial activity of G. mangostana extract against MRSA.

Materials and methods: GM pericarp was extracted by ethanol (GM-EtOH) and methanol (GM-MeOH). The crude extracts were examined for in vitro antibacterial activity against MRSA using broth microdilution assay. The in vivo antibacterial activity of 10% GM-EtOH against MRSA was determined in a tape stripping mouse model of superficial skin infection for 9 days by evaluating transepidermal water loss (TEWL) and performing colony counts from cultured swabs.

Results: GM-EtOH showed greater in vitro activity against MRSA than GM-MeOH in broth microdilution assay with minimum inhibitory concentration 17 versus 20?μg/mL and minimum bactericidal concentration 30 versus 35?μg/mL, respectively. The GM-EtOH (13.20?±?0.49%) contained α-mangostin more than the GM-MeOH (9.83?±?0.30%). In the tape stripping mouse model, 10% GM-EtOH reduced the number of MRSA colonies (0–1) recovered from infected wounds (>100 colonies) on the first day of treatment, restored TEWL to normal levels on the fourth day, and had completely healed the wounds by day 9.

Conclusion: GM-EtOH showed promising in vivo antibacterial activity against MRSA in a superficial skin infection model in mice. It is of interest to develop a topical formulation of GM-EtOH to further study its potential as a novel antibacterial agent.     

Ethosomes-based topical delivery system of antihistaminic drug for treatment of skin allergies

Abstract

Cetirizine is indicated for the treatment of allergic conditions such as insect bites and stings, atopic and contact dermatitis, eczema, urticaria. This investigation deals with development of a novel ethosome-based topical formulation of cetirizine dihydrochloride for effective delivery. The optimised formulation consisting of drug, phospholipon 90 G? and ethanol was characterised for drug content, entrapment efficiency, pH, vesicular size, spreadability and rheological behaviour. The ex vivo permeation studies through mice skin showed highest permeation flux (16.300?±?0.300?µg/h/cm²) and skin retention (20.686?±?0.517?µg/cm²) for cetirizine-loaded ethosomal vesicles as compared to conventional formulations. The in vivo pharmacodynamic evaluation of optimised formulation was assessed against oxazolone-induced atopic dermatitis (AD) in mice. The parameters evaluated were reduction in scratching score, erythema score, skin hyperplasia and dermal eosinophil count. Our results suggest that ethosomes are effective carriers for dermal delivery of antihistaminic drug, cetirizine, for the treatment of AD.     

滚轮微针处理次数对药物皮肤渗透、分布及皮肤刺激性的影响

目的 考察用于皮肤促透研究的滚轮微针处理次数。方法 以维A酸为模型药物,Franz扩散池、组织匀浆法研究裸鼠皮肤的促透效果,用亚甲蓝染色法、激光共聚焦显微镜法等考察裸鼠皮肤的药物分布,经皮水分流失（TEWL）测量法、激光多普勒血流量法评价皮肤刺激性。结果 滚轮微针处理次数为1、3、5、8、10次时,处理次数越多,促透效果越好,皮肤中滞留药量也越高,但是皮肤中滞留药量在处理8次和10次时无显著性差异（P>0.05）。亚甲基蓝染色和激光共聚焦实验均显示处理次数增加,针孔分布均匀度提高;亚甲基蓝染色显示,处理5次以上时,出现部分针眼重叠而皮肤破损现象。在体皮肤内药物吸收实验显示处理1次时,裸鼠皮肤中滞留药量均匀性较差,但是处理3次以上时,皮肤中滞留药量均匀性明显改善。TEWL测量法显示处理5次以下,皮肤屏障功能恢复时间为24 h,处理8次以上为36 h。激光多普勒血流量法显示处理5次以下,皮肤屏障功能恢复时间为1 h,处理8次以上为2 h。结论 滚轮微针处理5次可确保裸鼠皮肤促透研究的安全性和有效性。     

Absorption,distribution, metabolism and excretion of loxoprofen after dermal application of loxoprofen gel to rats

Abstract

1. Loxoprofen (LX), is a prodrug of the pharmacologically active form, trans-alcohol metabolite (trans-OH form), which shows very potent analgesic effect. In this study, the pharmacokinetics and metabolism of [¹⁴C]LX-derived radioactivity after dermal application of [¹⁴C]LX gel (LX-G) to rats were evaluated.

2. The area under concentration-time curve (AUC_0–∞) of radioactivity in the plasma after the dermal application was 13.6% of that of the oral administration (p?<?0.05).

3. After the dermal application, the radioactivity remained in the skin and skeletal muscle at the treated site for 168?h, whereas the AUC_0–168?h of the radioactivity concentration in every tissue examined except the treated site was statistically lower than that after the oral administration (p?<?0.05).

4. The trans-OH form was observed at high levels in the treated skin site at 0.5?h. Metabolite profiles in plasma, non-treated skin site and urine after the dermal application were comparable with those after the oral administration.

5. Renal excretion was the main route of elimination after the dermal application.

6. In conclusion, compared to the oral administration, the dermal application of [¹⁴C]LX-G showed lower systemic and tissue exposure with higher exposure in the therapeutic target site. The radioactivity revealed similar metabolite profiles in both administration routes.     

In vitro skin decontamination model: comparison of salicylic acid and aminophylline

Objective: This study compared three model decontaminant solutions (distilled water, 10% distilled water and soap and methanol) for their ability to remove salicylic acid and aminophylline from an in vitro skin model.

Materials and methods: Human abdominal skin was dosed with 20?µL of either [¹⁴C]-aminophylline or [¹⁴C]-salicylic acid on 1?cm² per skin. After each exposure time (5, 30 and 60?min post-dosing, respectively), surface skin was washed three times with each solution and tape stripped 10 times. Wash solutions, tape strips, receptor fluid and remaining skin were then analyzed with liquid scintillation counting to quantify the amount of salicylic acid and aminophylline.

Results: Total mass balance recovery for each chemical at three time exposure points was between 73.6 and 101.5%, except at 60?min where aminophylline was only 42.5%. Majority of salicylic acid and aminophylline were recovered from washing solution when compared to stratum corneum, epidermis, dermis, surrounding skin and receptor fluid.

Conclusion: The three tested decontaminates possessed similar effectiveness in removing lipophilic and hydrophilic chemicals from the skin. Due to diminishing decontamination efficacy with time, it is suggested that skin should be washed as soon as possible following contamination to minimize percutaneous penetration and the deleterious effects associated with skin reservoir content.     

Nanocarrier-based topical drug delivery for the treatment of skin diseases

Introduction: Skin disorders will continue to cause complications in patients. At present, there is an expansion of research into dermatologic treatment due to a critical need for new treatment options to treat skin diseases.

Areas covered: The skin itself provides a natural barrier against particle penetration for topical delivery. However, it also offers a potential approach for the delivery of therapeutics, especially in diseased skin and via the openings of hair follicles. Recent innovation might be achieved in the field of dermatological treatment with improvement in the dermal localization of bioactives into the affected skin region, via novel nanocarriers that deliver the drugs directly to the target cells. After application, these nanocarriers can penetrate through the stratum corneum into viable skin and accumulate at the target site. However, noteworthy uptake does occur after damage and in certain diseased skin.

Expert opinion: Skin-targeted topical delivery by means of nanosystems, in order to produce sustained release and maintain a localized effect, will result in an effective treatment of various life-threatening dermatological conditions. In addition, research continues into the interactions between novel particles, skin and skin lipid, and the influence of particle composition on drug distribution within the skin strata.     

Localized delivery of a lipophilic proteasome inhibitor into human skin for treatment of psoriasis

Purpose: Pentaerythritol tetrakis (3,5-di-tert-butyl-4-hydroxyhydrocinnamate) (PTTC) is a cinnamate tetraester with proteasome inhibitor activity, which may be used as a topical treatment in psoriasis, but has a computed log?P of 23. The objective of this in vitro study was to determine the intradermal delivery, skin irritation and potential efficacy of PTTC in treating psoriasis.

Methods: Solubility studies were performed to find a suitable vehicle for PTTC. Permeation studies were performed with microneedle-treated skin. A cell culture irritation test was dosed with a positive control, negative control and PTTC. An MTT assay was performed to evaluate cell viability and irritancy. Psoriatic cell culture was also dosed with PTTC and IL-6 levels were determined by ELISA.

Results: Solubility was greatest in dimethyl sulfoxide and ethyl pyruvate, with dimethyl sulfoxide delivering a greater amount (2343.41?±?384.26?µg) into stratum corneum. PTTC alone as well as topical PTTC emulsion formulation were found to be non-irritant with cell viability of 69.0?±?5.64% and 74.6?±?5.03%, respectively. Treatment with neat PTTC slightly reduced IL-6 levels and PTTC emulsion significantly reduced IL-6 levels to 92.53?±?12.74?pg/ml compared to basal levels (141.69?±?8.41?pg/ml).

Conclusion: PTTC can be delivered intradermally to potentially treat psoriasis.     

Collagen loaded nano-sized surfactant based dispersion for topical application: formulation development,characterization and safety study

Abstract

Collagen, a high molecular weight, hydrophilic and highly abundant protein is known to have anti-ageing, anti-wrinkle, anti-acne, anti-scar and wound healing properties. High molecular weight and hydrophilic nature hinder its effective topical delivery. So, the objective of present study was to develop effective topical nano-surfactant dispersion (NSD) for collagen delivery. NSD was prepared from sorbitan monostearate (Span60) and cholesterol using ethanol injection method followed by probe sonication. NSD was characterized for entrapment efficiency (%EE), size and size distribution (Z-avg and polydispersity index (PDI)), shape, zeta-potential (ζ), in vitro drug release, skin hydration and skin irritation test and histopathological examination. Optimized NSD (NSD3) had %EE, z-avg, PDI and ζ-potential of 77.56%?±?1.09%, 158.1?±?2.31?nm, 0.211 and ?17.2?±?0.64?mV, respectively. In in vivo skin hydration test, NSD treatment showed nearly 2.5-fold and 3-fold increase in the thickness of stratum corneum (SC) as compared to the collagen gel treated and untreated skin, respectively. The mean scores of skin irritation test in two animal species, rats and rabbits, were found to be 1.42?±?1.01 and 1.71?±?0.29, respectively, indicating the non-irritant nature of collagen loaded NSD. Histopathology of the skin after application of developed NSD showed non-significant changes in skin anatomy indicating its safe nature.     

Evolution of the percutaneous penetration and distribution of uranyl nitrate as a function of skin-barrier integrity: an in vitro assessment

As recommended by OECD Guidelines, percutaneous penetration studies consider intact skin, but rarely injured skin. Recent years have witnessed a growing concern for these two types of dermal exposure in the industry, particularly in the nuclear industry. The aim of this study was to show that a method based on an in vitro device can be used to realistically assess how skin-barrier alterations caused by occupational accidents can modify the percutaneous penetration and distribution of radionuclides, particularly uranium. Wounds encountered in the nuclear industry (i.e., nitric acid burns and abrasion) were simulated on hairless rat skin. Skin-barrier alterations were characterized by means of a histological study and by measuring transepidermal water loss (TEWL) and skin thickness. The percutaneous penetration of uranyl nitrate through intact or injured skin biopsies was then measured in vitro. The maximum uranium flux values obtained for intact skin, skin abrasion with stratum corneum removal, and skin exposed to 2 N HNO₃, 5 N HNO₃, and 14 N HNO₃ were, respectively, 0.6?±?0.02, 1.2?±?0.03, 1.2?±?0.04, 42.0?±?1.0, and 174.0?±?8.7?ng.cm^?2.h^?1. These results demonstrated that the percutaneous absorption of uranium increased with the increased impairment of the stratum corneum. TEWL, combined with maximum uranium flux values measured in vitro, yielded a good prediction of the percutaneous penetration of uranium through injured skin, previously observed in vivo. To conclude, this in vitro assay provides a conservative estimate of the percutaneous diffusion of uranium through intact or injured skin, making it a good alternative method for toxicological studies and risk assessments.     

Short term study of human skin irritation by single application closed patch test: assessment of four multiple emulsion formulations loaded with botanical extracts

Background: Assessment of skin irritation potential is a major concern in safety assessment of cosmetics, when long-term use of these products are expected. Non-invasive bioengineering probes have been used previously to measure skin irritation potential of cosmetic ingredients.

Objectives: Experimentation carried out to weigh up the skin irritation potential of four multiple emulsion formulations via visual and non-invasive measurements. Immediate effects of formulations and comparison of two assessment techniques were also tried to establish.

Methods: Four multiple emulsion formulations one control (without botanical active) and three containing the functional botanical actives plus additives were tested in this study using the following techniques: transepidermal water loss (TEWL), COLIPA visual scoring method (CVSM), Mexameter MPA 5 (Courage + Khazaka, Germany) and capacitance [Corneometer MPA 5 (Courage + Khazaka, Germany)]. Visual examination and non-invasive measurements were performed at baseline and after 24?h. The formulations were applied on the forearm of 12 healthy volunteers of same sexes aged 20–25 years.

Results: We found that none of the formulation produced irritation both on visual and instrumental evaluation. However, formulations MeB and MeC have comparable immediate effects on dryness, erythema, melanin and TEWL. Formulation MeC produced more effective results on different parameters, may be due to synergistic effect of two extracts, while MeA failed to produce any immediate effects on skin parameters. Moreover results of both assessment methods are parallel to each other.

Conclusions: None of the formulation produce irritant effects, barrier impairment effects or immediate effects except for the formulation MeC which produced appreciable results than other formulations but statistically these results were insignificant (p?>?0.05). Based on these results, it could be concluded that formulations may be implied safely as skin rejuvenating candidates.     

Healing effect of Dillenia indica fruit extracts standardized to betulinic acid on ultraviolet radiation-induced psoriasis-like wounds in rats

Context: Dillenia indica Linn. (Dilleniaceae) is traditionally used to treat skin inflammation.

Objective: This study evaluated the healing effect of Dillenia indica fruit extracts on induced psoriasis-like wounds in Wistar rats.

Materials and methods: Extracts were standardized to betulinic acid, including an aqueous ethanolic extract (AEE), ethyl acetate extract (EAE) and petroleum ether extract. Effects against lipid peroxidation were assessed in vitro. Wounds were created at rat tails (n?=?12). Topical treatments were applied once daily for 7 days (1?mL of AEE or EAE at 5 or 50?mg/mL). Maximal dose was defined by the extract solubility. A 10-fold lower dose was also tested. Positive and negative controls were treated with clobetasol (0.5?mg/mL) or excipient. Half of each group was euthanized for histology. The remaining animals were observed for 20 days for wound measurements.

Results: Yields of AEE and EAE were 4.3 and 0.7%, respectively. Betulinic acid concentrations in AEE and EAE were 4.6 and 107.6?mg/g. Extracts neutralized lipid peroxidation in vitro at 0.02?μg/mL, accelerating healing at 50?mg/mL. Complete healing in mice treated with AEE occurred 16 days after wound induction. This time was 14 and 12 days in mice treated with EAE and clobetasol. Compared to orthokeratosis, parakeratosis was reduced by AEE (25%), EAE (45%) and clobetasol (55%). EAE caused superior protection against biomolecules oxidation of skin compared to AEE.

Discussion and conclusion: EAE exhibited activity closer to that of clobetasol. Betulinic acid may be an active constituent, which should be assessed in future studies.     

Assessment of Skin Barrier Function Using Transepidermal Water Loss: Effect of Age

To probe age-related changes in skin barrier function, transepidermal water loss (TEWL) rates have been measured in young (19–42 years) and old (69–85 years) subjects. TEWL was determined at ventral forearm skin sites, which had been occluded for 24 hr with polypropylene chambers. Baseline TEWL rates (J , which showed no dependence on age, were measured for each subject before and after the experiment. Following removal of the occlusive chamber, TEWL was monitored continuously from t = 0.5 min until its return to the baseline (preocclusion) level, which was typically in the range of 2–7 g/m²/hr. Initial TEWL rates (mean ± SD) were found to differ significantly between young (28.6 ± 7.5 g/m²/hr; n = 26) and old (36.9 ± 10.5 g/m²/hr; n = 18) subjects (P < 0.01). Relaxation of TEWL to J was significantly slower in the aged cohort, such that the characteristic time for diffusion of water in the stratum corneum was estimated to be (mean ± SD) 176 ± 59 min for the young subjects, compared to 360 ± 76 min for the old (P < 0.001.). Thus, the initial TEWL value following removal of occlusion is significantly greater, and the excessive stratum corneum hydration produced by occlusion is dissipated more slowly, in old skin than in young. A hypothesis to explain the slower relaxation of perturbed TEWL in old skin is proposed.     

In Vivo Percutaneous Absorption,Skin Barrier Perturbation,and Irritation from JP-8 Jet Fuel Components

Abstract

JP-8 jet fuel has been reported to cause systemic and dermal toxicities in animal models and humans. There is a great potential for human exposure to JP-8. In this study, we determined percutaneous absorption and dermal toxicity of three components of JP-8 (i.e., xylene, heptane, and hexadecane) in vivo in weanling pigs. In vivo percutaneous absorption results suggest a greater absorption of hexadecane (0.43%) than xylene (0.17%) or heptane (0.14%) of the applied dose after 30 min exposure. Transepidermal water loss (TEWL) provides a robust method for assessing damage to the stratum corneum. Heptane showed greater increase in TEWL than the other two chemicals. No significant (p<0.05) increase in temperature was observed at the chemically treated site than the control site. Heptane showed greater TEWL values and erythema score than other two chemicals (xylene and hexadecane). We did not observe any skin reactions or edema from these chemicals. Erythema was completely resolved after 24 h of the patch removal in case of xylene and hexadecane.     

Analysis of Simultaneous Transport and Metabolism of Ethyl Nicotinate in Hairless Rat Skin

Purpose. Simultaneous skin transport and metabolism of ethyl nicotinate (EN), a model drug, were measured and theoretically analyzed. Methods. Several permeation studies of EN or its metabolite nicotinic acid (NA) were done on full-thickness skin or stripped skin with and without an esterase inhibitor. Permeation parameters such as partition coefficient of EN from the donor solution to the stratum corneum and diffusion coefficients of EN and NA in the stratum corneum and the viable epidermis and dermis were determined by these studies. Enzymatic parameters (Michaelis constant K _m and maximum metabolism rate V _max were obtained from the production rate of NA from different concentrations of EN in the skin homogenate. Obtained permeation data were then analyzed by numerical method based on differential equations showing Fick's second law of diffusion in the stratum corneum and the law with Michaelis-Menten metabolism in the viable epidermis and dermis. Results. Fairly good steady-state fluxes of EN and NA through the skin were obtained after a short lag time for all the concentrations of EN applied. These steady-state fluxes were not proportional to the initial donor concentration of EN: EN and NA curves were concave and convex, respectively, which suggests that metabolic saturation from EN to NA takes place in the viable skin at higher EN application. The steady-state fluxes of EN and NA calculated by the differential equations with resulting permeation and enzymatic parameters were very close to the obtained data. Conclusions. The present method is a useful tool to analyze simultaneous transport and metabolism of many drugs and prodrugs, especially those showing Michaelis-Menten type-metabolic saturation in skin.     

Stratum corneum pharmaco­kinetics of the anti-fungal drug,terbinafine, in a novel topical formulation,for single-dose application in dermatophytoses

ABSTRACT

Objective: The stratum corneum (SC) pharmacokinetics of terbinafine following single-dose administration of a novel cutaneous solution (film-forming solution, FFS) containing terbinafine hydrochloride and a film-forming agent, was investigated in three studies. Terbinafine 1% cream (Lamisil) was included as a benchmark in two of these studies.

Research design and methods: Drugs were applied to areas of the back, and skin strips were taken from defined areas at baseline and from 1 to 312?h after application. Samples were analysed using validated liquid chromatography/mass spectrometry.

Results: The residence time of the film on the skin was up to 72?h after application (up to 12?h for the 1% cream). After application of terbinafine FFS, 30% of the total amount of drug delivered into the SC occurred during the first 2?h, 31% from 2–12?h, and 39% thereafter. The C_max was observed as early as 1.5?h (t_max). SC levels were still detected after 13 days (24?ng/cm²) (t_½ was 162?h). Terbinafine 1% cream showed a similar t_max (2?h) with a lower C_max than terbinafine 1% FFS, and mean SC levels after 7 days of treatment were 46?ng/cm² (day 13). The t_½ was 68?h. Washing at 30?min removed 86% of the film still present on the surface; the decrease of terbinafine concentration in the SC was 84%. A later washing at 12?h removed 73% of the film in comparison to non-washed skin and induced a decrease in the terbinafine content in the SC of 27%.

Conclusions: The SC pharmacokinetic profile of terbinafine 1% FFS indicates that this novel formulation is efficient in delivering high amounts of terbinafine to the skin for a prolonged time and supports its use in the treatment of dermatophytoses with a single application.

Introduction