Clinical Studies on Bile Acids in Barrett's Esophagus

Patients who have been scheduled for elective endoscopic examination at the Dallas VA
Medical Center for the evaluation of GERD or Barrett's esophagus will be invited to
participate in the study. Patients who provide written, informed consent will have a medical
history taken.

Women of child bearing potential will have a pregnancy test. Eligible subjects will be
treated with omeprazole 20 mg BID for at least four weeks before the scheduled endoscopic
examination. Eight days before the endoscopy, patients will be instructed to discontinue any
aspirin and other non-steroidal anti-inflammatory drugs (unless there is a contraindication
to discontinuing those medications including a history of coronary artery disease,
myocardial infarction, cerebrovascular accident or transient ischemic attacks). The
endoscopic examination, which had been scheduled for clinical purposes, will be performed as
usual, with biopsy specimens taken as required for clinical purposes ..

When the clinical examination has been completed, a perfusion catheter will be passed
through the biopsy channel and positioned 5 cm above the squamocolumnar junction in the
distal esophagus. The distal esophagus will be perfused with 10cc of a 250 M solution of
either deoxycholic acid (DCA) or ursodeoxycholic acid (UDCA) for 5 minutes. Odd-number
patients enrolled in each of the two patient groups (GERD patients with and without
Barrett's esophagus) will receive DCA, whereas even-number patients will receive UDCA. The
catheter position, bile acid concentration and duration of bile acid perfusion are chosen to
simulate a typical episode of gastroesophageal reflux. In all patients, 12 biopsy specimens
of the squamous epithelium will be taken using jumbo biopsy forceps at a level 2 cm proximal
to the squamocolumnar junction at baseline (6 biopsies will be used to establish the primary
cell cultures and six will be used for the molecular analyses); 6 more biopsy specimens will
be taken at the same level immediately after bile acid perfusion for molecular analyses. In
the patients with Barrett's esophagus, 12 biopsy specimens of the specialized intestinal
metaplasia also will be taken using jumbo biopsy forceps at a level

1 cm distal to the squamocolumnar junction at baseline (6 biopsies will be used to establish
the primary cell cultures and six will be used for the molecular analyses); 6 more biopsy
specimens will be taken a t the same level immediately after bile acid perfusion for
molecular analyses. All endoscopic procedures will be performed by S.J. Spechler.

All patients will be maintained on omeprazole 20 mg BID for one year, after which the
endoscopic examinations will be repeated. The endoscopies will be performed with bile acid
perfusions and biopsy sampling exactly as described above, except that patients who received
DCA during the first examination will receive UDCA and vice versa.

After the second endoscopy, patients will be treated with UDCA in a dose of 10 mg/kg for 8
weeks, after which a final endoscopy will be performed.

During this endoscopy, 6 biopsy specimens of the squamous epithelium will be taken using
jumbo biopsy forceps at a level 2 cm proximal to the squamocolumnar junction in all
patients. In the patients with Barrett's esophagus, 6 biopsy specimens of the specialized
intestinal metaplasia also will be taken using jumbo biopsy forceps at a level 1 cm distal
to the squamocolumnar junction at baseline. No bile acid perfusion will be performed during
the final endoscopy, and all biopsy specimens will be used for molecular analyses.