Effects of topical corticosteroid versus tacrolimus on insulin sensitivity and bone homeostasis in adults with atopic dermatitis-A randomized controlled study.

INTRODUCTION: Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption. OBJECTIVES: We examined whether intensive daily whole-body TCS treatment over 2 weeks followed by twice weekly application for 4 weeks could elicit insulin resistance and increase bone resorption in adults with AD. METHODS: A randomized parallel-group double-blind double-dummy non-corticosteroid-based active comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after 2 weeks of daily treatment and after further 4 weeks of twice-weekly maintenance treatment. RESULTS: AD severity improved with both treatments and systemic inflammation was reduced. After 2 weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n = 18) and tacrolimus (n = 18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both 2 and 6 weeks but remained unchanged in the tacrolimus arm. CONCLUSIONS: Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.

Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT3A Receptor.

5-Hydroxytryptamine3 (5-HT3) receptors are ligand-gated ion channels that mediate neurotransmission by serotonin in the central nervous system. Pharmacological inhibition of 5-HT3 receptor activity has therapeutic potential in several psychiatric diseases, including depression and anxiety. The recently approved multimodal antidepressant vortioxetine has potent inhibitory activity at 5-HT3 receptors. Vortioxetine has an inhibitory mechanism that differs from classic 5-HT3 receptor competitive antagonists despite being believed to bind in the same binding site. Specifically, vortioxetine shows partial agonist activity followed by persistent and insurmountable inhibition. We have investigated the binding mode of vortioxetine at the human 5-HT3A receptor through computational and in vitro experiments to provide insight into the molecular mechanisms behind the unique pharmacological profile of the drug. We find that vortioxetine binds in a manner different from currently known 5-HT3A orthosteric ligands. Specifically, while the binding pattern of vortioxetine mimics some aspects of both the setron class of competitive antagonists and 5-hydroxytryptamine (5-HT) with regards to interactions with residues of the aromatic box motif in the orthosteric binding site, vortioxetine also forms interactions with residues not previously described to be important for the binding of either setrons or 5-HT such as Val202 on Loop F. Our results expand the framework for understanding how orthosteric ligands drive 5-HT3 receptor function, which is of importance for the potential future development of novel classes of 5-HT3 receptor antagonists.

Combination of MALDI-MSI and cassette dosing for evaluation of drug distribution in human skin explant.

Study of skin penetration and distribution of the drug compounds in the skin is a major challenge in the development of topical drug products for treatment of skin diseases. It is crucial to have fast and efficacious screening methods which can provide information concerning the skin penetration and the distribution of the drug molecules in the region of the target. Mass spectrometry imaging (MSI) such as matrix-assisted laser desorption/ionization (MALDI)-MSI offers the opportunity to analyze the drug distribution at micrometer scale, but is a low throughput technique. Cassette dosing of drug molecules has been widely used for two decades as a high throughput screening tool for plasma pharmacokinetic analysis. The purpose of this study is to evaluate the utility of combining MALDI-MSI with cassette dosing to obtain a medium throughput screening technique for drug distribution in the skin directly from thin tissue sections. Excised fresh human skin was treated with two different formulation types containing both single drugs and a cassette with four drugs. Biopsies were taken and analyzed with traditional UHPLC-MS/MS and MALDI-MSI. The results reveal that skin penetration data of the four drugs administered together were in agreement with skin penetration data obtained when the molecules were administered individually. Furthermore, the MALDI-MSI data reveal different distribution profiles of the four drugs which were not possible to deduce from the UHPLC-MS/MS bioanalysis. These findings suggest that combination of MALDI-MSI and cassette dosing can be used as a medium throughput screening tool at an early stage in the drug discovery/development process. Graphical abstract Investigation of drug distribution in human skin explant by MALDI-MSI after cassette dosing.