Document Detail


Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis.
MedLine Citation:
PMID:  23412700     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Steven M Rowe; Ginger Reeves; Heather Hathorne; G Martin Solomon; Smita Abbi; Didier Renard; Ruth Lock; Ping Zhou; Henry Danahay; John P Clancy; David A Waltz
Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chest     Volume:  144     ISSN:  1931-3543     ISO Abbreviation:  Chest     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-24     Completed Date:  2013-09-30     Revised Date:  2014-07-01    
Medline Journal Info:
Nlm Unique ID:  0231335     Medline TA:  Chest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  200-7     Citation Subset:  AIM; IM    
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00506792
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Administration, Intranasal
Adult
Biological Transport / drug effects
Chlorides / metabolism
Cross-Over Studies
Cystic Fibrosis / metabolism*
Dose-Response Relationship, Drug
Double-Blind Method
Drug Tolerance
Female
Gabexate / administration & dosage,  analogs & derivatives*,  pharmacokinetics,  pharmacology
Humans
Male
Middle Aged
Protease Inhibitors / administration & dosage,  pharmacokinetics,  pharmacology*
Respiratory System / metabolism*
Serine Endopeptidases / drug effects*
Sodium / metabolism*
Treatment Outcome
Grant Support
ID/Acronym/Agency:
5UL1 RR025777/RR/NCRR NIH HHS; K23 DK075788/DK/NIDDK NIH HHS; P30 DK072482/DK/NIDDK NIH HHS; T32 HL105346/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Chlorides; 0/Protease Inhibitors; 0FD207WKDU/camostat; 4V7M9137X9/Gabexate; 9NEZ333N27/Sodium; EC 3.4.21.-/Serine Endopeptidases; EC 3.4.21.-/prostasin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  From the board of editors: on plagiarism.
Next Document:  Studies on diversity and evolution of Iridaceae species in southern Brazil.