Ignite Creation Date:
2024-05-05 @ 10:24 PM
Last Modification Date:
2024-10-26 @ 10:18 AM
Study NCT ID:
NCT01095133
Status:
COMPLETED
Last Update Posted:
2012-09-20
First Post:
2010-03-05
Brief Title:
Do Acid Sensing Ion Channels Contribute to Heartburn
Sponsor:
University of North Carolina Chapel Hill
Organization:
University of North Carolina Chapel Hill
Study Overview
Official Title:
Do Acid Sensing Ion Channels ASICs Contribute to Heartburn in Proton Pump Inhibitor PPI-Complete Responders or PPI-Partial Responders With Nonerosive Reflux Disease NERD
Status:
COMPLETED
Status Verified Date:
2012-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this research study is to learn about whether treating the esophagus with amiloride reduces either the frequency or the time to onset of acid-induced heartburn in patients with nonerosive reflux disease In particular we are looking at people who have either had complete relief while using a Proton Pump Inhibitor PPI or who have only had some relief of symptoms while on a PPI
Detailed Description:
It is now well established that patients with gastroesophageal reflux disease - both erosive and non-erosive forms - have on esophageal biopsy a lesion in esophageal stratified squamous epithelium known as dilated intercellular spaces DIS This lesion has importance because it reflects an increase in paracellular permeability due to acid damage to the tight junctions 1 Moreover the increase in paracellular permeability in non-eroded esophageal epithelium provides a plausible explanation for why heartburn occurs during episodes of acid reflux or esophageal acid perfusion in those with nonerosive reflux disease NERD but not in healthy subjects and that is because luminal acid is now able to diffuse between cells in quantities sufficient to acidify the intercellular space 2 Further the lowering of intercellular pH is the likely trigger for heartburn by its ability to stimulate pain-sensing neurons nociceptors within the esophageal mucosa with the signal from these neurons being transmitted to the CNS for heartburn perception Clinical and experimental evidence support these concepts in that antacid ingestion relieves and proton pump inhibitors PPIs prevent heartburn in most patients and when PPIs control heartburn they also lead to resolution of DIS in squamous epithelium 3 Moreover it is increasingly likely that many NERD patients classified as PPI-partial responders develop heartburn through the same mechanism as PPI-complete responders with NERD This is because PPIs only raise gastric pH to pH 5 and even such weakly-acidic refluxates have been shown to be associated with heartburn 4 The reason for this is that in the presence of a broken epithelial barrier weakly acidic refluxates are still able to acidify the intercellular space to levels sufficient to activate the nociceptors - the latter the case since the nociceptors can be activated even at pHs as modestly acidic as pH 60-pH 70 see below
The esophageal mucosa has two nociceptors that are candidates to mediate heartburn in NERD These are a a capsaicin-sensitive transient receptor potential vanilloid receptor TRPV-1 and b an amiloride-inhibitable acid-sensing ion channel ASIC subtype 2 Both nociceptor types innervate the esophageal mucosa and are activated by small declines in environmental intercellular pH 56 Recently a role for TRPV-1 was sought in the causation of heartburn during esophageal acid perfusion 7 This was done by perfusing the esophagus with capsaicin in quantities presumed sufficient to desensitize TRPV-1 and then perfusing with acid to see if it blocked heartburn The results however were negative in that acid still elicited heartburn From this one can conclude that heartburn is either not mediated by TRPV-1 or that capsaicin failed to adequately desensitize TRPV-1 We propose to test the hypothesis that capsaicins failure to block heartburn in these subjects was because the actual nociceptors mediating heartburn are mucosal ASICs rather than TRPV-1 The hypothesis will be tested in a double-blind crossover study designed to determine if esophagal perfusion with the ASIC-inhibitor amiloride can block heartburn elicited by acid-perfusion in PPI-complete responders and PPI-partial responders with NERD 8 The expectation is that when compared to placebo amiloride which readily diffuses across intact esophageal epithelium will reduce the frequency and both prolong the onset and reduce the severity of heartburn elicitable by esophageal acid perfusion Such an outcome would provide support for mucosal ASICs rather than TRPV-1 as mediator of heartburn in NERD and raise interest in ASICs as a potential therapeutic target for that subset with NERD that are PPI-partial responders
The esophageal mucosa has two nociceptors that are candidates to mediate heartburn in NERD These are a a capsaicin-sensitive transient receptor potential vanilloid receptor TRPV-1 and b an amiloride-inhibitable acid-sensing ion channel ASIC subtype 2 Both nociceptor types innervate the esophageal mucosa and are activated by small declines in environmental intercellular pH 56 Recently a role for TRPV-1 was sought in the causation of heartburn during esophageal acid perfusion 7 This was done by perfusing the esophagus with capsaicin in quantities presumed sufficient to desensitize TRPV-1 and then perfusing with acid to see if it blocked heartburn The results however were negative in that acid still elicited heartburn From this one can conclude that heartburn is either not mediated by TRPV-1 or that capsaicin failed to adequately desensitize TRPV-1 We propose to test the hypothesis that capsaicins failure to block heartburn in these subjects was because the actual nociceptors mediating heartburn are mucosal ASICs rather than TRPV-1 The hypothesis will be tested in a double-blind crossover study designed to determine if esophagal perfusion with the ASIC-inhibitor amiloride can block heartburn elicited by acid-perfusion in PPI-complete responders and PPI-partial responders with NERD 8 The expectation is that when compared to placebo amiloride which readily diffuses across intact esophageal epithelium will reduce the frequency and both prolong the onset and reduce the severity of heartburn elicitable by esophageal acid perfusion Such an outcome would provide support for mucosal ASICs rather than TRPV-1 as mediator of heartburn in NERD and raise interest in ASICs as a potential therapeutic target for that subset with NERD that are PPI-partial responders
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None