Dermatotoxicology

Willard-Mack, Cynthia L.; Ramani, T V; Auletta, Carol

doi:10.1177/0192623315622585

Cited by 14 publications

(3 citation statements)

References 10 publications

(9 reference statements)

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“…However, topical antifungal drugs have proven effective for treating various fungal infections without systemic adverse effects. Minipig skin has immunological, anatomical, and physiological similarities with human skin; thus, the use of minpigs in dermal toxicity studies has increased in recent years [ 18 , 20 , 22 ]. In addition, the skin of pigs has similar characteristics with that of humans, including firm attachment to the subcutaneous tissue, sparse hair coat, thick epidermis and dermis, similar dermal epidermal thickness ratio, absence of panniculus carnosus, epidermal turnover time, re-epithelialization as a healing mechanism, vascular anatomy, and collagen structure [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

Kim,

Kang,

Yang

et al. 2024

Toxicol Res.

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ATB1651 gel is an antifungal drug candidate that enhances antifungal activity through substitution of several aryl rings, alkyl chains, and methyl groups. To ensure safety of use of ATB1651 gel, assessment of its potentially toxic side effects is necessary. In this study, we examined the repeated-dose toxicity of ATB1651 gel to Yucatan minipigs (Sus scrofa) in accordance with the Good Laboratory Practice guidelines. Five doses of ATB1651 gel (0%, 0.2%, 0.5%, 1.0%, 3.0%) were administered dermally to the left and right flanks of 38 minipigs daily for 4 weeks. Mortality, clinical symptoms, dermal scores, body weights, and physiological, biochemical, pathological, and toxicokinetic analyses were performed after the treatment period. No systemic toxicological damage was observed in either male or female minipigs regardless of dose; however, dermal application of ATB1651 gel caused some skin alterations at the application sites. Specifically, erythema and eschar formation, edema, and scabs or raise spots were observed at the application site(s) in males in the 3.0% ATB1651 gel treatment group and in females at ATB1651 gel concentrations ≥ 1.0%, with dermal scores ranging from grade 1 to 2. Additionally, histopathological assay indicated infiltration of different types of inflammatory cells and the presence of pustule/crust at the application site(s) in both males and females at ATB1651 gel concentrations ≥ 0.5%. However, these changes were reversible after a 2-week recovery period and were considered a local irritation effect of ATB1651 gel. The no-observed-adverse-effect level of ATB1651 gel was 3.0% with regard to topical and systemic toxicity in both male and female minipigs. Collectively, our results imply that ATB1651 gel is a safe candidate for clinical development as an antifungal drug with a wide therapeutic window.

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Section: Discussionmentioning

confidence: 99%

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

Kim,

Kang,

Yang

et al. 2024

Toxicol Res.

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“…In addition, the pig syndrome is short in duration, comparable to herpes labialis lip injury in humans. The investigations are also of great interest, because the similarity between the skin of humans and pigs makes the pig an ideal model for use in nonclinical dermal studies [ 57 ]. Features of swine skin that are similar to that of humans include a firm attachment to underlying structures, relatively thick epidermis, dermal to epidermal thickness ratios, similar dermal collagen and elastin content, and variance in cutaneous pigment [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

First virological and pathological study of Göttingen Minipigs with Dippity Pig Syndrome (DPS)

Jhelum

Grand²,

Jacobsen³

et al. 2023

PLoS ONE

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Dippity Pig Syndrome (DPS) is a well-known but rare complex of clinical signs affecting minipigs, which has not been thoroughly investigated yet. Clinically affected animals show acute appearance of red, exudating lesions across the spine. The lesions are painful, evidenced by arching of the back (dipping), and the onset of clinical signs is generally sudden. In order to understand the pathogenesis, histological and virological investigations were performed in affected and unaffected Göttingen Minipigs (GöMPs). The following DNA viruses were screened for using PCR-based methods: Porcine cytomegalovirus (PCMV), which is a porcine roseolovirus (PCMV/PRV), porcine lymphotropic herpesviruses (PLHV-1, PLHV-2, PLHV-3), porcine circoviruses (PCV1, PCV2, PCV3, PCV4), porcine parvovirus 1 (PPV1), and Torque Teno sus viruses (TTSuV1, TTSuV2). Screening was also performed for integrated porcine endogenous retroviruses (PERV-A, PERV-B, PERV-C) and recombinant PERV-A/C and their expression as well as for the RNA viruses hepatitis E virus (HEV) and SARS-CoV-2. Eight clinically affected and one unaffected GöMPs were analyzed. Additional unaffected minipigs had been analyzed in the past. The analyzed GöMPs contained PERV-A and PERV-B integrated in the genome, which are present in all pigs and PERV-C, which is present in most, but not all pigs. In one affected GöMPs recombinant PERV-A/C was detected in blood. In this animal a very high expression of PERV mRNA was observed. PCMV/PRV was found in three affected animals, PCV1 was found in three animals with DPS and in the unaffected minipig, and PCV3 was detected in two animals with DPS and in the unaffected minipig. Most importantly, in one animal only PLHV-3 was detected. It was found in the affected and unaffected skin, and in other organs. Unfortunately, PLHV-3 could not be studied in all other affected minipigs. None of the other viruses were detected and using electron microscopy, no virus particles were found in the affected skin. No porcine virus RNA with exception of PERV and astrovirus RNA were detected in the affected skin by next generation sequencing. This data identified some virus infections in GöMPs with DPS and assign a special role to PLHV-3. Since PCMV/PRV, PCV1, PCV3 and PLHV-3 were also found in unaffected animals, a multifactorial cause of DPS is suggested. However, elimination of the viruses from GöMPs may prevent DPS.

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“…Rabbits have often been used in irritation studies because of their sensitive skin response, but their structure is different from that of humans. Erythema, edema, and histological changes do not always occur in humans, so care should be taken to avoid overestimation 3 , 26 . The epidermis of minipigs was the thickest compared to that of other animals.…”

Section: Epidermismentioning

confidence: 99%

Morphological characteristics and notes of the skin in preclinical toxicity assessment

Moroki

2023

J Toxicol Pathol

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In this review, the histological structures of the skin are summarized for fundamental knowledge for toxicological assessment. The skin is composed of epidermis, dermis, subcutaneous tissue, and associated adnexa. In the epidermis, keratinocytes comprise four layers, and three other cell types, besides keratinocytes, play various roles. Epidermal thickness varies with species and body site. In addition, it can be affected by tissue preparation procedures, which can render toxicity assessments difficult. Bulge stem cells are the origin of sebaceous glands, epidermal basal layer, and hair follicle formation, and they play an important role in the maintenance of the basic structure of the skin. Stem cells and appendages formed from stem cells sometimes become toxic targets, and it is useful to study the origins of the hair follicle/hair cycle to interpret their toxicity. Irritant contact dermatitis and allergic contact dermatitis are the main adverse reactions in topical application studies. The mechanism involves direct chemical irritation of the skin, and histologically, epidermal necrosis and accompanying inflammatory cell infiltration. In allergic contact dermatitis, an inflammatory reaction and intercellular or intracellular edema, histologically represented by lymphocytic infiltration of the epidermis and dermis, are observed. Regional and species differences exist in the dermal absorption of compounds, and differences in the thickness of the stratum corneum substantially contribute to these differences. Learning the basic structures, functions, and possible artifacts will contribute to the evaluation of skin toxicity by topical and systemic applications.

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Dermatotoxicology

Cited by 14 publications

References 10 publications

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

Toxicity of a novel antifungal agent (ATB1651 gel) in Yucatan minipigs (Sus scrofa) following 4 weeks of daily dermal administration

First virological and pathological study of Göttingen Minipigs with Dippity Pig Syndrome (DPS)

Morphological characteristics and notes of the skin in preclinical toxicity assessment

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