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Inhaled Calcilytics: Effects on Airway Inflammation and Remodeling

Yarova PL, Davies C, Price SA, Huang Q, Graca JA, Maleki-Toyserkani S, Lowe AP, Kidd EJ, Ford WR, Broadley KJ, Ward JT, Corrigan CJ, Prakash YS, Kemp PJ, Riccardi D.

Respiratory Drug Delivery 2016. Volume 1, 2016: 1-12.

Abstract:

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and there is a lack of available drugs that reduce the decline in lung function seen with disease progression. Therefore, there is clearly an unmet need for new therapeutics. Previously, we have shown that calcium sensing receptor (CaSR) activation elicits airways hyper-responsiveness and inflammation in pre-clinical in vivo murine models of asthma. However, the role of CaSR in the progression of COPD is currently unknown. In this article, a role for CaSR and topical calcilytic therapies will be proposed and discussed to reduce COPD pathogenesis and disease progression. The proposal is supported by new data on the anti-inflammatory effects of the inhaled negative allosteric CaSR modulator or calcilytic, NPS89636. The effects of NPS89636 were studied in an in vivo model of COPD induced in guinea pigs by inhalation of lipopolysaccharide (LPS); as in human subjects with COPD, pulmonary inflammation in the guinea pig lungs were shown to be insensitive to inhaled corticosteroids. Here, we show that treatment with NPS89636 reduced inflammation, specifically leukocyte and neutrophil infiltration, in the airways of LPS-treated animals. In addition, calcilytic treatment reduced lung interstitial wall thickening. These effects were unlikely attributable to off-target calcilytic actions on the parathyroid glands, as free ionized blood calcium levels were not altered for up to 24 hours after calcilytic inhalation. Together, these observations suggested that topically delivered calcilytics may represent a novel treatment strategy for COPD.