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Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis.

Abstract：

BACKGROUND:Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). METHODS:To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing 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 through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. RESULTS:In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with -8.6 mV following placebo (P<.005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. CONCLUSIONS:This study establishes the proof of concept that a 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. TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov.

journal_name

Chest

journal_title

Chest

authors

Rowe SM,Reeves G,Hathorne H,Solomon GM,Abbi S,Renard D,Lock R,Zhou P,Danahay H,Clancy JP,Waltz DA

doi

10.1378/chest.12-2431

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

200-207

issue

eissn

0012-3692

issn

1931-3543

pii

S0012-3692(13)60468-7

journal_volume

144

pub_type

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Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis.