Faculty of Life Sciences and Medicine, School of Immunology & Microbial Sciences, Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London , London, UK.
Expert Rev Respir Med. 2020 Aug;14(8):807-816. doi: 10.1080/17476348.2020.1756779. Epub 2020 May 5.
Asthma afflicts more than 300 million people. Contemporary mainstay therapies (inhaled corticosteroids and bronchodilators), prescribed empirically, control symptoms resulting from airways obstruction tolerably well in many patients but it is less clear that they alter the natural history of progressive airways inflammation and remodeling resulting in severe, therapy-resistant obstruction in a significant minority (5-10%), causing lifelong symptoms and elevated risk of recurrent hospital admission and death. Furthermore, no current anti-asthma drug targets bronchial smooth muscle hyperresponsiveness, a critical contributor to airways obstruction and the fundamental physiological abnormality characterizing asthma. Recent monoclonal antibody (biological) therapies reduce obstruction and exacerbations in some, but not all treated patients to an unpredictable extent, but are further limited by administration logistics and cost.
An overview of the cellular and molecular immunopathology of asthma, highlighting the need and logic for the development of a novel, non-steroidal, small molecule drug for topical delivery targeting bronchial smooth muscle hyperresponsiveness and airways inflammation, particularly corticosteroid-refractory inflammation.
This article elaborates evidence supporting the hypothesis that topically delivered, inhaled antagonists of the calcium-sensing receptor (CaSR) have the potential to meet these requirements, and the practicality of repurposing existing, small molecule CaSR antagonists (calcilytics) for this purpose.
哮喘影响着超过 3 亿人。目前的主要治疗方法（吸入皮质类固醇和支气管扩张剂）是根据经验开的，在许多患者中可以很好地控制气道阻塞引起的症状，但它们是否能改变气道炎症和重塑的自然进程，从而导致少数患者（5-10%）出现严重、难以治疗的阻塞，导致终身症状和反复发作的住院和死亡风险增加，这一点就不太清楚了。此外，目前没有针对支气管平滑肌高反应性的抗哮喘药物，而支气管平滑肌高反应性是气道阻塞的关键因素，也是哮喘的基本生理异常特征。最近的单克隆抗体（生物）疗法在一定程度上减轻了一些患者的阻塞和恶化，但不能预测所有治疗患者的程度，而且由于给药后勤和成本的限制，这些疗法进一步受到限制。
本文概述了哮喘的细胞和分子免疫病理学，强调了开发一种新型非甾体小分子药物用于靶向支气管平滑肌高反应性和气道炎症的必要性和逻辑，特别是针对皮质类固醇难治性炎症。
本文详细阐述了支持这样一种假设的证据，即局部给予、吸入钙敏感受体（CaSR）拮抗剂有可能满足这些要求，以及为了达到这个目的，重新利用现有的小分子 CaSR 拮抗剂（calcilytics）的实用性。
