Ebselen oxide attenuates mechlorethamine dermatotoxicity in the mouse ear vesicant model.

Mechlorethamine (HN2) is an alkylating agent and sulfur mustard mimetic. Topical exposure to HN2 is associated with tissue blistering. Previous work in our laboratory has shown that ebselen (EB-1) possesses anti-vesicant, anti-inflammatory, anti-bacterial, anti-fungal, and cytoprotective properties, both in vivo and in vitro. We recently reported that ebselen oxide (EB-2), an analog of EB-1 with a tetravalent selenium atom, also possesses anti-bacterial and anti-fungal activity and confers cytoprotection against HN2 in vitro. The purpose of the present study was to determine the vesicant countermeasure potential of EB-2 using the mouse ear vesicant model (MEVM). Compared to control ears, mouse ears exposed to a single dose of HN2 (0.500 µmol/ear) showed an increase in wet weights, ear thickness, hyperplasia, vesication, and inflammatory cell infiltration after 24 h. Fluorescence microscopy of terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL)-stained sections showed that the occurrence of apoptosis extended from the epidermis of the HN2-treated side, all the way to the contralateral epidermis. In contrast, HN2-exposed ears treated topically with EB-2 at a test dose of 0.250 mg/ear showed a significant decrease in wet weight (12% less vs. HN2 alone), morphometric thickness (13% less vs. HN2 alone), and vesication. In addition, TUNEL staining revealed that HN2 ears treated with EB-2 (0.250 mg/ear) showed a decrease in apoptosis as compared to the HN2 group. EB-2 also reduced the abundance of matrix metalloproteinase-9 (MMP-9) in ear tissues exposed to HN2. Taken together, our study demonstrates that EB-2 is an efficacious countermeasure to HN2.

Effect of massage on percutaneous penetration and skin decontamination: man and animal.

CONTEXT: At least 15 factors of percutaneous penetration exist that should be considered when investigating dermal absorption profiles of chemicals. Rubbing is one variable that has been understudied, but may play an important role in understanding overall exposure rates, chemical toxicity, dermal absorption and skin's barrier abilities. OBJECTIVE: This reviews current data related to the role of massage in enhancing percutaneous penetration and skin decontamination as well as highlights the need for further investigation of its role. RESULTS: An in vivo study in rhesus monkeys and guinea pigs measuring amount of drug excreted after being topically applied showed no effect with massage. However, studies measuring permeation rates directly through human and animal skin ex vivo showed rubbing increased flux, reduced skin impedance and increased drug retention in skin. Rubbing also increased effectiveness of reactive skin decontamination lotion (RSDL). CONCLUSION: Massage sometimes influences chemical penetration rates and should be studied thoroughly to clarify the mechanisms and factors involved in the possible enhancing effect. This will also reveal more insight regarding the skin's ability to act as a barrier to exogenous substances and its role in risk assessment. How ex vivo results translate to in vivo behaviors still requires further investigation.

Microplastics in dermatology: Potential effects on skin homeostasis.

BACKGROUND: Microplastics (MPs) and nanoplastics (NPs) have become a growing concern in dermatology due to their widespread presence in cosmetic formulations and the environment. These minuscule synthetic polymer particles prompt an essential exploration of their potential impact on dermatological homeostasis. AIMS: This study aims to investigate the effects of MPs and NPs on the integumentary system. Specifically, it seeks to understand the potential cutaneous alterations, inflammatory responses, and disruptions to the skin's physiological functions caused by these synthetic particles. PATIENTS/METHODS: The investigation involves a comprehensive analysis of emerging research on MPs and NPs. This includes their presence in cosmetic formulations and environmental pervasiveness. The study delves into their capacity to breach the cutaneous barrier, raising concerns about the implications of prolonged exposure. RESULTS: Evidence suggests that MPs and NPs may indeed incite cutaneous alterations, provoke inflammatory responses, and disturb the homeostasis of the skin's physiological functions. Their small dimensions enhance their capability to breach the cutaneous barrier, further emphasizing the apprehensions associated with prolonged exposure. CONCLUSIONS: While a precise understanding of the implications of MPs and NPs on dermatological health remains an ongoing scientific endeavor, this study underscores the growing significance of these synthetic particles. The findings emphasize the need for proactive measures to safeguard both individual well-being and environmental preservation in the context of dermatological health.

Skin Models Used to Define Mechanisms of Action of Sulfur Mustard.

Sulfur mustard (SM) is a threat to both civilian and military populations. Human skin is highly sensitive to SM, causing delayed erythema, edema, and inflammatory cell infiltration, followed by the appearance of large fluid-filled blisters. Skin wound repair is prolonged following blistering, which can result in impaired barrier function. Key to understanding the action of SM in the skin is the development of animal models that have a pathophysiology comparable to humans such that quantitative assessments of therapeutic drugs efficacy can be assessed. Two animal models, hairless guinea pigs and swine, are preferred to evaluate dermal products because their skin is morphologically similar to human skin. In these animal models, SM induces degradation of epidermal and dermal tissues but does not induce overt blistering, only microblistering. Mechanisms of wound healing are distinct in these animal models. Whereas a guinea pig heals by contraction, swine skin, like humans, heals by re-epithelialization. Mice, rats, and rabbits are also used for SM mechanistic studies. However, healing is also mediated by contraction; moreover, only microblistering is observed. Improvements in animal models are essential for the development of therapeutics to mitigate toxicity resulting from dermal exposure to SM.

Bullous Pemphigoid Occurring after Stopping Imatinib Therapy of CML: Is a Continuation of Post-Treatment Follow-Up Needed?

Advancements and the use of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of Chronic Myeloid Leukemia (CML), achieving unprecedented success rates and expanding their applications to various neoplasms. However, the use of TKIs is not without its drawbacks. Skin, gastrointestinal, and central nervous systems are particularly susceptible to adverse effects, including a higher incidence of autoimmune responses in treated individuals. In this report, we present a unique case of bullous pemphigoid, a rare autoimmune disease, which has not been previously associated with TKI therapy as an adverse effect, particularly appearing after discontinuing Imatinib® treatment.

Combination of ebselen and hydrocortisone substantially reduces nitrogen mustard-induced cutaneous injury.

The purpose of the present study was to investigate the vesicant countermeasure effects of hydrocortisone (HC) and ebselen (EB-1), administered as monotherapy or as a combination treatment. The mouse ear vesicant model (MEVM) was utilized and test doses of HC (0.016, 0.023, 0.031, 0.047, 0.063, 0.125 or 0.250 mg/ear), EB-1 (0.125, 0.187, 0.250, 0.375 or 0.500 mg/ear) or the combination of HC + EB-1 were topically applied at 15 min, 4 h and 8 h after nitrogen mustard exposure. Ear punch biopsies were obtained 24 h after mechlorethamine (HN2) exposure. Compared to control ears, ear tissues exposed topically to HN2 (0.500 µmol/ear) presented with an increase in ear thickness, vesication, TUNEL fluorescence and expression of matrix metalloproteinase 9 (MMP-9) and inducible nitric oxide synthase (iNOS). In contrast, HN2 exposed ears treated topically with EB-1 showed a significant decrease in morphometric thickness and vesication vs. HN2 alone. Ear tissues exposed to HN2 and then treated with HC also demonstrated reductions in morphometric thickness and vesication. Combination treatment of HC + EB-1 was found to be the most effective at reducing HN2-induced ear edema and vesication. The combination also dramatically decreased HN2-mediated cutaneous expression of iNOS and MMP-9 and decreased HN2-induced TUNEL staining. Taken together, our study demonstrates that the combination of HC + EB-1 is an efficacious countermeasure to HN2.

Assessment of the time-dependent dermatotoxicity of mechlorethamine using the mouse ear vesicant model.

Mechlorethamine (HN2) is an alkylating agent and sulfur mustard gas mimetic which is also used in anticancer therapy. HN2 is associated with skin inflammation and blistering which can lead to secondary infections. The purpose of the present study was to investigate the time-dependent dermatotoxicity of HN2 using the mouse ear vesicant model (MEVM). To this end, our operational definition of dermatotoxicity included tissue responses to HN2 consistent with an increase in the wet weights of mouse ear punch biopsies, an increase in the morphometric thickness of H&E stained ear sections and histopathologic observations including tissue edema, inflammatory cell infiltration and vesication. The ears of male Swiss Webster mice were topically exposed to a single dose of HN2 (0.5 µmol/ear) or DMSO vehicle (5 µl/ear) or left untreated (naive). Mice were then euthanized at 15 min, 1, 2, 4, 8 or 24 hr following HN2 exposure. Compared to control ears, mouse ears exposed to HN2 at all time points showed an increase in wet weights, morphometric thickness, edema, inflammatory cell infiltration and signs of vesication. The incidence in tissue vesication sharply increased between 4 and 8 hr after exposure, revealing that tissue vesication is well established by 8 hr and remains elevated at 24 hr after exposure. It is noteworthy that, compared to control ears, mouse ears treated with DMSO vehicle alone also exhibited an increase in wet weights and morphometric thickness at 15 min, 1, 2 and 4 hr following treatment; however, these vehicle effects begin to subside after 4 hr. The results obtained here using the MEVM provide a more holistic understanding of the kinetics of vesication, and indicate that time points earlier than 24 hr may prove useful not only for investigating the complex mechanisms involved in vesication but also for assessing the effects of vesicant countermeasures.

Paclitaxel-induced cutaneous change mimicking malignancy in a previous cutaneous eruption.

Taxanes are antineoplastic drugs that can cause dermatotoxicity which can mimic an intraepidermal carcinoma. A 65-year-old woman presented with a cutaneous eruption suggestive of a paraneoplastic syndrome. Imaging studies showed multiple peritoneal nodules and associated ascites. A sample taken from the greater omentum revealed an adenocarcinoma. Clinical data and family history pointed to a gynecological origin of the tumor and the patient was treated with carboplatin and paclitaxel. A new cutaneous biopsy showed that the epidermis was acanthotic with atypical keratinocytes, abundant mitoses, and apoptotic figures, arising concerns of malignancy. According to the Plummer and Shea criteria, the lesion was ultimately interpreted as reactive cutaneous hyperplasia and expression of the taxane effect. We report, for the first time, paclitaxel-induced histologic changes on a previous cutaneous eruption. Pathologists should be aware of the profound cytopathic effects of taxane therapy in order to interpret skin biopsies of patients undergoing this treatment.