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Reduced Sodium Transport with Nasal Administration of the Prostasin Inhibitor Camostat in Cystic Fibrosis Subjects

Rowe, Steven and Reeves, Ginger and Halthorne, Heather and Solomon, G Martin and Abbi, Smita and Renard, Didier and Lock, Ruth and Zhou, Ping and Danahay, Henry and Clancy, JP and Waltz, David (2013) Reduced Sodium Transport with Nasal Administration of the Prostasin Inhibitor Camostat in Cystic Fibrosis Subjects. Chest, 144 (1). pp. 200-207. ISSN None

Abstract

Background: Prostasin (PRSS8), a trypsin-like serine protease, is a channel-activating protease and major regulator of ENaC-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibit sodium transport in CF.
Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reduce Na+ transport in the CF airway, we conducted a two part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered via a nasal spray pump in CF patients. Nasal potential difference was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach.
Results: In Part I, nine subjects were enrolled to complete crossover dosing in six subjects at the maximally tolerated dose. The change in maximal (most polarizing) basal potential difference two hours following administration of camostat was +13.1 mV (1.6 mg dose group), compared to -8.6 mV following placebo (P<0.005). Intrasubject change in Ringer’s PD and amiloride sensitive PD exhibited similar and consistent responses. Bayesian analysis in an additional six subjects within Part II estimated an ED50 of 18 mcg/ml. There was no significant change in chloride transport or total nasal symptom score, nasal exam rating, and laboratory parameters.
Conclusions: This study establishes the proof of concept that reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease.

Item Type: Article
Keywords: prostasin, ENaC, channel activating protease, nasal potential difference
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/7716

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