NVP-QBE170

An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

K. J. Coote, D. Paisley, S. Czarnecki, M. Tweed, H. Watson, A. Young, R. Sugar, M. Vyas, N. J. Smith, U. Baettig, P. J. Groot-Kormelink, M. Gosling, R. Lock, B. Ethell, G. Williams, A. Schumacher, J. Harris, W. M. Abraham, J. Sabater, C. T. Poll & 3 others T. Faller, S. P. Collingwood, H. Danahay

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) 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 In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 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-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.

Original languageEnglish (US)
Pages (from-to)2814-2826
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number11
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

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Epithelial Sodium Channel Blockers
Hyperkalemia
Mucociliary Clearance
Amiloride
Guinea Pigs
Cystic Fibrosis
Sheep
Epithelial Cells
NVP-QBE170
Powders
Inhalation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Coote, K. J., Paisley, D., Czarnecki, S., Tweed, M., Watson, H., Young, A., ... Danahay, H. (2015). NVP-QBE170: An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia. British Journal of Pharmacology, 172(11), 2814-2826. https://doi.org/10.1111/bph.13075

NVP-QBE170 : An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia. / Coote, K. J.; Paisley, D.; Czarnecki, S.; Tweed, M.; Watson, H.; Young, A.; Sugar, R.; Vyas, M.; Smith, N. J.; Baettig, U.; Groot-Kormelink, 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.

In: British Journal of Pharmacology, Vol. 172, No. 11, 01.06.2015, p. 2814-2826.

Research output: Contribution to journalArticle

Coote, KJ, Paisley, D, Czarnecki, S, Tweed, M, Watson, H, Young, A, Sugar, R, Vyas, M, Smith, NJ, Baettig, U, Groot-Kormelink, PJ, Gosling, M, Lock, R, Ethell, B, Williams, G, Schumacher, A, Harris, J, Abraham, WM, Sabater, J, Poll, CT, Faller, T, Collingwood, SP & Danahay, H 2015, 'NVP-QBE170: An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia', British Journal of Pharmacology, vol. 172, no. 11, pp. 2814-2826. https://doi.org/10.1111/bph.13075
Coote, K. J. ; Paisley, D. ; Czarnecki, S. ; Tweed, M. ; Watson, H. ; Young, A. ; Sugar, R. ; Vyas, M. ; Smith, N. J. ; Baettig, U. ; Groot-Kormelink, 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. / NVP-QBE170 : An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 11. pp. 2814-2826.
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abstract = "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-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) 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 In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 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-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.",
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T2 - An inhaled blocker of the epithelial sodium channel with a reduced potential to induce hyperkalaemia

AU - Coote, K. J.

AU - Paisley, D.

AU - Czarnecki, S.

AU - Tweed, M.

AU - Watson, H.

AU - Young, A.

AU - Sugar, R.

AU - Vyas, M.

AU - Smith, N. J.

AU - Baettig, U.

AU - Groot-Kormelink, P. J.

AU - Gosling, M.

AU - Lock, R.

AU - Ethell, B.

AU - Williams, G.

AU - Schumacher, A.

AU - Harris, J.

AU - Abraham, W. M.

AU - Sabater, J.

AU - Poll, C. T.

AU - Faller, T.

AU - Collingwood, S. P.

AU - Danahay, H.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) 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 In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 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-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.

AB - 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-QBE170, designed for inhaled delivery, with a reduced potential to induce hyperkalaemia. Experimental Approach The in vitro potency and duration of action of NVP-QBE170 were compared with amiloride and a newer ENaC blocker, P552-02, in primary human bronchial epithelial cells (HBECs) 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 In vitro, NVP-QBE170 potently inhibited ENaC function in HBEC and showed a longer duration of action to comparator molecules. In vivo, intratracheal (i.t.) instillation of NVP-QBE170 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-QBE170 by conscious sheep increased MCC and was better than inhaled hypertonic saline in terms of efficacy and duration of action. Conclusions and Implications NVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.

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