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Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g., asthma and atherosclerosis. Anti-inflammatory drugs come with side effects that may be aggravated by high and fluctuating drug concentrations. To remedy this, an anti-inflammatory drug should have an appropriate pharmacokinetic half-life or better still, a sustained anti-inflammatory drug response. However, we still lack a quantitative mechanistic understanding of such sustained effects. Here, we study the anti-inflammatory response to a common glucocorticoid drug, dexamethasone. We find a sustained response 22 hours after drug removal. With hypothesis testing using mathematical modeling, we unravel the underlying mechanism-a slow release of dexamethasone from the receptor-drug complex. The developed model is in agreement with time-resolved training and testing data and is used to simulate hypothetical treatment schemes. This work opens up for a more knowledge-driven drug development to find sustained anti-inflammatory responses and fewer side effects., (© 2020 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Ethosomes and liposomes are ultra-small vesicles capable of encapsulating drugs and cosmetic ingredients for topical use, thereby potentially increasing bioavailability and clinical efficacy. So far, few reports have suggested that formulation of cosmetic ingredients in vesicular carrier systems may increase the allergenicity potential., Objectives: To investigate the effect of ethosome formulation of isoeugenol and methyldibromo glutaronitrile on the elicitation response under patch test conditions and by repeated open applications., Patients/materials/methods: A total of 27 volunteer patients with a previous positive patch test reaction to either isoeugenol or methyldibromo glutaronitrile were included in the study. In all patients, a serial dilution patch test was performed with the allergen in question formulated in ethosomes and in an ethanol/water solution. In addition, a repeated open application test (ROAT) was performed in a subset of 16 patients, and lag time until a positive response was recorded., Results: Both contact allergens encapsulated in ethosomes showed significantly enhanced patch test reactions as compared with the allergen preparation in ethanol/water without ethosomes. No significant difference in the median lag time was recorded between preparations in the ROAT., Conclusions: Encapsulating potential contact allergens in ethosomes may increase the challenge response as compared with the same concentrations in an ethanol/water base without ethosomes., (© 2010 John Wiley & Sons A/S.)

Background: The allergenic potency of a hapten is related to its skin penetration properties, but little is known about the distribution of haptens in the skin following topical application., Objectives: The aim of this study was to investigate the diffusion and epidermal distribution using two-photon microscopy (TPM) of two fluorescent compounds., Methods: Sensitizing capacities of fluorescein isothiocyanate (FITC) and fluorescein were investigated using the local lymph node assay. Chemical reactivity of the compounds was analysed, and their distribution in human epidermis was visualized using TPM and confocal microscopy. Also the in vitro diffusion through epidermis of FITC and fluorescein has been examined., Results: FITC was classified as an extreme sensitizer, whereas fluorescein was non-sensitizing. TPM and confocal microscopy showed an accumulation of FITC in stratum corneum (SC), whereas fluorescein was more evenly distributed in epidermis. The diffusion of fluorescein through epidermis was three times higher than that of FITC., Conclusions: TPM, which has never been used in this context before, is a promising tool for visualizing the distribution of fluorescent compounds of varying reactivity in intact skin. The strong allergen FITC is mainly retained in or adjacent to SC, whereas most fluorescein diffused through the epidermis.