组胺
微透析
离体
肥大细胞
脱颗粒
药理学
免疫球蛋白E
化学
体内
人体皮肤
免疫学
医学
受体
体外
生物
抗体
生物化学
细胞外
遗传学
生物技术
作者
César Ramírez Molina,Sidsel Falkencrone,Per Stahl Skov,Edward Hooper‐Greenhill,Mike D. Barker,Marion C. Dickson
摘要
Background and Purpose Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6 weeks. Spleen tyrosine kinase mediates allergen‐induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE‐mediated histamine release from mast cells in an ex vivo human skin model. Experimental Approach Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti‐IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC–MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed. Key Results Perfused GSK2646264 significantly inhibited anti‐IgE (but not C5a)‐induced histamine release in a concentration‐dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC 90 and dose‐dependently attenuated anti‐IgE‐induced histamine release. Conclusions and Implications GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8 μM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.
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