title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov.
authors: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL; Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL. Electronic address: smrowe@uab.edu.
authors: Steven M
authors: SM
authors: Rowe
authors: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL.
authors: Ginger
authors: G
authors: Reeves
authors: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL.
authors: Heather
authors: H
authors: Hathorne
authors: Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL.
authors: G Martin
authors: GM
authors: Solomon
authors: Novartis Institutes for BioMedical Research, East Hanover, NJ.
authors: Smita
authors: S
authors: Abbi
authors: Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors: Didier
authors: D
authors: Renard
authors: Novartis Institutes for BioMedical Research, Horsham, England.
authors: Ruth
authors: R
authors: Lock
authors: Novartis Institutes for BioMedical Research, Horsham, England.
authors: Ping
authors: P
authors: Zhou
authors: Novartis Institutes for BioMedical Research, Horsham, England.
authors: Henry
authors: H
authors: Danahay
authors: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, and University of Cincinnati, Cincinnati, OH.
authors: John P
authors: JP
authors: Clancy
authors: Novartis Institutes for BioMedical Research, Cambridge, MA.
authors: David A
authors: DA
authors: Waltz
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D018592:Cross-Over Studies; D003550:Cystic Fibrosis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D004952:Esters; D005260:Female; D016670:Gabexate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006146:Guanidines; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012137:Respiratory System / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism*; D016896:Treatment Outcome; D000099271:Prostasin
chemical_list: D002712:Chlorides; D004952:Esters; D016670:Gabexate; D006146:Guanidines; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D012964:Sodium; D000099271:Prostasin; C034532:camostat