BACKGROUND AND PURPOSEInhaled 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 APPROACHThe 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 RESULTSIn 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 IMPLICATIONSNVP-QBE170 highlights the potential for inhaled ENaC blockers to exhibit efficacy in the airways with a reduced risk of hyperkalaemia, relative to existing compounds.

The aim of this study was to evaluate the efficacy of tropisetron, a selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, versus placebo in the prevention of postoperative nausea and vomiting in patients undergoing general anesthesia for gynecologic surgery. Ten minutes before induction of general anesthesia, 80 patients received in a double-blind manner a single intravenous (IV) injection of either 5 mg tropisetron or a matching placebo. Anesthesia was induced with thiopental and maintained with nitrous oxide and enflurane in oxygen. In the first 24 h postoperatively 7 of 40 patients (17.5%) given tropisetron and 16 of 40 patients (40%) receiving placebo vomited (P < 0.05). The incidence of nausea was 30% (12/40) in the tropisetron group and 52% (21/40) in the placebo group (P < 0.05). A total effective antiemetic response showed 26 patients (65%) in the tropisetron group and 16 patients (40%) in the placebo group (P < 0.05). We conclude that tropisetron given IV prior to gynecologic procedures in general anesthesia significantly reduces postoperative nausea and vomiting when compared to placebo without causing any adverse effect.

No abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7–33 to establish structure–activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

No abstract