Introduction

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.

Areas covered

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.

Expert opinion

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.

中文翻译：

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溶钙剂：吸入性类固醇和SABA / LABA治疗人类哮喘的非类固醇替代品？

介绍

哮喘困扰着3亿多人。根据经验开出的现代主流疗法（吸入皮质类固醇和支气管扩张剂）可以很好地控制因气道阻塞而引起的症状，但在许多患者中尚不清楚，因为它们改变了进行性气道炎症和重塑的自然病史，从而导致严重的耐治疗性阻塞少数（5-10％），会导致终身症状，增加再次住院和死亡的风险。此外，目前没有抗哮喘药针对支气管平滑肌反应过度，气道阻塞的关键因素和哮喘的基本生理异常。最近的单克隆抗体（生物）疗法可减少某些情况下的阻塞和急性发作，

覆盖区域

哮喘的细胞和分子免疫病理学概述，突显了开发新型非甾体小分子药物用于局部递送的需求和逻辑，该药物可靶向支气管平滑肌高反应性和气道炎症，尤其是皮质类固醇难治性炎症。

专家意见

本文详细阐述了支持以下假设的证据：即局部递送的，吸入的钙敏感受体（CaSR）拮抗剂有可能满足这些要求，并且为此目的重新利用了现有的小分子CaSR拮抗剂（分解剂）的实用性。