Validation of the cantharidin‐induced skin blister as an in vivo model of inflammation

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Techniques to create aseptic inflammatory reactions provide information regarding acute inflammatory pathways and may be used to assess the anti-inflammatory properties of novel drugs. WHAT THIS STUDY ADDS• In this study, we have shown that the cantharidin-induced blister is a local inflammatory reaction, safe and well tolerated, with a good intra-subject inter-day reproducibility. This induced blister is inhibited by specific (anti-tumour necrosis factor (TNF)) and non specific (corticosteroids) systemic anti-inflammatory agents. This model could be of interest to evaluate anti-inflammatory agents in their early phase development. AIMPharmacological profiling techniques, such as the cantharidin-induced skin blister, may be used to assess the anti-inflammatory properties of novel drugs. However, no data are available on the reproducibility of this technique or on the blocking effect of anti-inflammatory drugs, such as anti-TNF and corticosteroids. METHODSA group of 30 healthy subjects were randomized into three parallel groups treated with placebo, oral methylprednisolone 20 mg day -1 for 7 days or anti-tumour necrosis factor (TNF) (adalimumab, Humira®, Abbott) 40 mg s.c. single dose. A first blister was induced at baseline and collected, immediately before the start of treatment and a second blister was obtained 7 days after the start of treatment. The total number of cells, the cell viability and the differential cell count were evaluated by two independent observers, who were blind to treatment. ANOVA was used to compare change from baseline among the three groups before pairwise comparisons. RESULTSAmong the placebo group, there was no significant difference in the total cell count, neutrophils, eosinophils and monocytes between day 1 and day 7. Methylprednisolone inhibited the eosinophil influx in mean % (95% CI) (-1.0 (-1.7, -0.3); P < 0.02) and absolute (P < 0.02) values, while anti-TNF inhibited the neutrophil influx in mean % (95% CI) (-19.3 (-29.5, -9.1); P < 0.01) and absolute (P < 0.05) values. CONCLUSIONSThe cantharidin-induced skin blister is a safe, well tolerated and reproducible procedure. Pre-treatment with anti-TNF or methylprednisolone inhibited the neutrophilic or eosinophilic trafficking, respectively. It could be useful in profiling anti-inflammatory drugs regarding their effects on the cellular inflammatory response.

Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans

“…To explore more closely whether differences in inflammatory cells between males and females observed with typhoid vaccination might reflect sex-based differences in acute inflammatory responses, we used a validated cantharidin-based model of inflammation (20, 23). We chose this model since there is no noninvasive method in vivo to explore organ-specific cell and humoral components; therefore, we moved to an easily accessible organ-based model using skin inflammation.…”

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

“…The resulting fluid-filled blisters serve as a surrogate of interstitial fluid. In addition to drug sampling, the technique has also been used to quantify concentrations of endogenous, inflammatory mediators (105)(106)(107). Limitations of this technique include the discomfort resulting from skin blister formation, limited sampling times, difficulties related to standardization, and the presence of inflammatory proteins and mediators in the blister fluid (40,104,105).…”

Interferon-Gamma and Interlukin-4 Patterns in BALB/c Mice Suffering From Cutaneous Leishmaniasis Treated With Cantharidin

“…Neutrophils produce and secret myeloperoxidase causing tissue damage (19-21). Cantharidin induces neutrophils infiltration into the blister site in the first 24 hours and macrophages from 24 to 72 hours (19, 21). Infiltrating neutrophils did not destroy the parasite.…”