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.
Funder
American Asthma Foundation
HHS | NIH | National Institute of Allergy and Infectious Diseases
Publisher
Proceedings of the National Academy of Sciences
Reference27 articles.
1. Murphy SL Xu J Kochanek KD (2013) Deaths: Final Data for 2010. National Vital Statistics Reports (Centers for Disease Control and Prevention, Atlanta), Vol 61, No 4.
2. A look at the pathogenesis of asthma: The need for a change in direction;Holgate;Discov Med,2010
3. A brief history of inhaled asthma therapy over the last fifty years
4. Inhaled corticosteroid and long-acting β2-agonist pharmacological profiles: Effective asthma therapy in practice;Tamm;Respir Med,2012
5. The mechanisms, diagnosis, and management of severe asthma in adults
Cited by
44 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献