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NVP ‐ QBE 170: an inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia
Author(s) -
Coote K J,
Paisley D,
Czarnecki S,
Tweed M,
Watson H,
Young A,
Sugar R,
Vyas M,
Smith N J,
Baettig U,
GrootKormelink P J,
Gosling M,
Lock R,
Ethell B,
Williams G,
Schumacher A,
Harris J,
Abraham W M,
Sabater J,
Poll C T,
Faller T,
Collingwood S P,
Danahay H
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13075
Subject(s) - amiloride , epithelial sodium channel , pharmacology , medicine , inhalation , potency , blockade , in vivo , channel blocker , sodium channel blocker , ex vivo , sodium channel , anesthesia , sodium , in vitro , chemistry , biology , receptor , biochemistry , microbiology and biotechnology , organic chemistry , calcium
Background and Purpose Inhaled amiloride, a blocker of the epithelial sodium channel ( ENaC ), enhances mucociliary clearance ( MCC ) in cystic fibrosis ( CF ) patients. However, the dose of amiloride is limited by the mechanism‐based side effect of hyperkalaemia resulting from renal ENaC blockade. Inhaled ENaC blockers with a reduced potential to induce hyperkalaemia provide a therapeutic strategy to improve mucosal hydration and MCC in the lungs of CF patients. The present study describes the preclinical profile of a novel ENaC blocker, NVP ‐ QBE 170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP ‐ QBE 170 were compared with amiloride and a newer ENaC blocker, P552‐02, in primary human bronchial epithelial cells ( HBEC s) by short‐circuit current. In vivo efficacy and safety were assessed in guinea pig (tracheal potential difference/hyperkalaemia), rat (hyperkalaemia) and sheep ( MCC ). Key Results I n vitro , NVP ‐ QBE 170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo , intratracheal (i.t.) instillation of NVP ‐ QBE 170 attenuated ENaC activity in the guinea pig airways with greater potency and duration of action than that of amiloride without inducing hyperkalaemia in either guinea pig or rat. Dry powder inhalation of NVP ‐ QBE 170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP ‐ QBE 170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.