用于类固醇抵抗重症哮喘的高效糖皮质激素的开发
2019/07/11
摘要
吸入糖皮质激素（GCs）在类固醇抵抗重症哮喘中的临床应用中作用有限。为了克服这一局限性，基于对糖皮质激素受体（GR）结构的研究，我们开发了一系列高效的GC，包括VSGC12，VSG158和VSG159。特别是VSG158，在哮喘小鼠模型中其对肺部炎症的抑制效果最好，比目前临床上最有效的GC氟替卡松糠酸酯（FF）的效力高10倍。更重要的是，VSG158在类固醇抵抗气道炎症模型中显示了减少中性粒细胞炎症的独特性质，临床可用的GC（包括地塞米松和FF）对该模型治疗是无效的。 VSG158和VSG159有良好的疗效，能减少脱靶和副作用。此外，这些GC还具有吸入使用的药代动力学特性。总之，这些GC疗效良好、副作用较少，有望用于治疗类固醇抵抗重症哮喘。
Development of highly potent glucocorticoids for steroid-resistant severe asthma.
He Y, Shi J, Nguyen QT, You E, Liu H, Ren X, Wu Z, Li J, Qiu W, Khoo SK, Yang T, Yi W, Sun F, Xi Z, Huang X, Melcher K, Min B, Xu HE.
Abstract
Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.
吸入糖皮质激素（GCs）在类固醇抵抗重症哮喘中的临床应用中作用有限。为了克服这一局限性，基于对糖皮质激素受体（GR）结构的研究，我们开发了一系列高效的GC，包括VSGC12，VSG158和VSG159。特别是VSG158，在哮喘小鼠模型中其对肺部炎症的抑制效果最好，比目前临床上最有效的GC氟替卡松糠酸酯（FF）的效力高10倍。更重要的是，VSG158在类固醇抵抗气道炎症模型中显示了减少中性粒细胞炎症的独特性质，临床可用的GC（包括地塞米松和FF）对该模型治疗是无效的。 VSG158和VSG159有良好的疗效，能减少脱靶和副作用。此外，这些GC还具有吸入使用的药代动力学特性。总之，这些GC疗效良好、副作用较少，有望用于治疗类固醇抵抗重症哮喘。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6932-6937. doi: 10.1073/pnas.1816734116.)
(Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6932-6937. doi: 10.1073/pnas.1816734116.)
Development of highly potent glucocorticoids for steroid-resistant severe asthma.
He Y, Shi J, Nguyen QT, You E, Liu H, Ren X, Wu Z, Li J, Qiu W, Khoo SK, Yang T, Yi W, Sun F, Xi Z, Huang X, Melcher K, Min B, Xu HE.
Abstract
Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.
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支气管扩张剂在哮喘和慢性阻塞性肺疾病中的可逆性：三项大型人群研究的结果
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包括中叶支气管的支气管热成形术显著改善重症哮喘患者肺功能及生活质量
