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Understanding drug behavior within the skin, especially for photosensitive compounds, is crucial for developing effective and safe topical therapies. This study employs Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) to investigate the skin permeation and photostability of selumetinib, a MEK inhibitor used in treating type 1 neurofibromatosis (NF1). The highest amounts of selumetinib in the skin sections were obtained when using the gel formulation, suggesting that it is to be preferred to cream formulations to achieve higher permeation of the drug. Our study also revealed that selumetinib is amenable to photodegradation in ex vivo skin explants, and yields one main degradation product, whose degradation is likely triggered by hydrogen abstraction. MALDI-MSI results showed selumetinib and its degradation product concentrate in skin appendages, indicating these structures might serve as drug reservoirs, potentially prolonging retention and efficacy. This study demonstrates that combining MALDI-MSI with LC/MS-MS can highly contribute to the characterization of the fate of photosensitive compounds in the skin, an essential prerequisite to the development of compound-specific photoprotective measures. It will also pave the way for innovative topical delivery strategies for NF1 treatment. [ABSTRACT FROM AUTHOR]

Résumé: En oncologie, l'antalgie est un enjeu majeur de la prise en charge du patient. La « Patient-controlled analgesia » est une méthode permettant au patient de gérer lui-même sa douleur, mais elle n'est pas toujours applicable en cas de transfert des patients. L'objectif de ce travail a été de valider l'utilisation d'un dispositif portable d'intérêt permettant de mimer l'action de pompes électriques pour deux molécules : morphine et oxycodone. Des études de stabilités ainsi que la vérification de la conformité des spécificités vis-à-vis du débit ont été étudiées, en parallèle une réflexion sur le circuit de dispensation a été menée. Les deux molécules sont stables sur une durée d'au moins 30 heures. Une conformité de la valeur des débits a pu être montrée. Le circuit « prescription – dispensation – administration » a été définit et sécurisé. Ceci a pu permettre de valider et de mettre en place l'utilisation de ce dispositif. In oncology, analgesia is a major issue in patient management. "Patient-controlled analgesia" (PCA) is a method that allows patients to manage their own pain, but it is not always applicable when patients are transferred. The objective of this work was to validate the use of a portable device allowing to mimic the action of electric pumps use for PCA. For this purpose, two drugs were studied and analyzed. Stability studies, as well as the verification of the conformity of the specificities with regard to the flow rate were studied, in parallel a reflection on the dispensing circuit was carried out. Both molecules are stable for at least 30 hours. Compliance of the flow rates was demonstrated. The "prescription – dispensation – administration" circuit was defined and secured. These tests allowed us to "validate" this device and to use it in real life. [ABSTRACT FROM AUTHOR]

Objective: Based on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS., Methods: We investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing., Results: We show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction ( r = -0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001)., Conclusions: Gut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)