Sepsis-induced gastric injury is associated with reflux of bile acid

April 2000

AGAA23

repeated dose administration, suggesting a potential for improved clinical efficacy in the treatment of acid related diseases.

should be considered in GERD patients when greater gastric acid control is desirable.

355 Day 1 %of24-hr with pH>4' %of 24·hrwitll pH>3' 24-hr medIan pH' %ofpts.witIlpH>4 for>12 hr %of pts.withpH>4 for>16 hr Day 5 %of24·hr with pH>4' %of 24·hr with pH>3' 24·hr median pH' %of pts. with pH>4 for>12hr %of pts. with pH>4 for>16hr

E

P

E·P

50 (43-58) 66(59-73) 39 (35-4.3) 39 26

29(22-36) 45(38-53) 2.9 (2.5-3.3) 10 3

21 (15-27)" 21 (14-27)" 1.0(0.7-1.4)"

66 (61-72) 80(75-85) 4.7 (44-4.9) 90 50

44 (39-49) 62(58-67) 37 (3.4-39) 30 10

22 (19-26)" 18(14-21)" to(0.8-1.2)"

• Mean (95% Cl) .. p
353 COMPARISON OF 24-HR INTRAGASTRIC PH PROFILE OF OMEPRAZOLE AND LANSOPRAZOLE IN HEALTHY VOLUNTEERS. Shuwen Xue, Philip O. Katz, Maria DiPietro, June A. Castell, Donald O. Castell, Graduate Hosp, Philadelphia, PA. Sufficient acid suppression is crucial in healing reflux esophagitis. Single daily doses of proton pump inhibitors (PPIs), omeprazole (Orne) and lansoprazole (Lanso) provide effective acid suppression and equal healing and symptom relief in patients with GERD. Despite this, controversy exists as to the efficacy of available PPIs in control of gastric acidity. Aim: To assess the efficacy of Orne 20mg vs Lanso 30mg and Orne 40mg vs Lanso 30mg in intragastric pH control. Methods: Group A: 12 healthy H. pylori negative volunteers (mean age 33, range 24-48 yr) treated with Orne 20 mg and Lanso 30 mg in random order before breakfast for 7 days. Group B: 24 subjects (mean age 36, range 24-54 yr) also treated in random order before breakfast with Orne 40 mg and Lanso 30 mg for 7 days after baseline pH study. One week washout before taking the second drug. Subjects had the same meal on each study day. On day 7 of drug administration, a 24-hr intragastric pH study was performed. Data: The % time gastric pH >4 analyzed (Gastrosoft, Synectics Medical Inc.) and expressed as mean±SD. Nocturnal gastric acid breakthrough is defined as decrease of gastric pH <4 lasting for more than I hr overnight. Results: I) Group A: Orne 20mg and Lanso 30mg showed no significant difference in % time gastric pH >4 in daytime and nocturnal period. 2) Group B: % time pH >4 with Orne 40mg was significantly greater than Lanso 30mg in both daytime (61 ± 19% vs 48±14%, p4 in daytime (69± 18% vs 51 ± 15% p =0.015 and 77±17% vs 61±15% p=0.OO7, respectively) than Orne 20mg. Summary: A single daily dose of Lanso 30mg and Orne 20mg are similar in control of gastric pH despite wide intersubject variations. Orne 40 mg is superior to Lanso 30mg. Conclusion: These pH data support the therapeutic equivalency of FDA approved doses of omeprazole and lansoprazole.

354 BEDTIME H2 BLOCKERS CONTROL NOCTURNAL GASTRIC ACID BREAKTHROUGH IN GERD PATmNTS. Shuwen Xue, Philip O. Katz, June A. Castell, Donald 0_ Castell, Graduate Hosp, Philadelphia, PA. Proton pump inhibitors (PPI) twice daily (BID AC) effectively control daytime gastric pH. However nocturnal acid breakthrough (NAB), defined as gastric pH >4 for more than I hr, occurs in >75% of patients on PPI BID. H2 blockers decrease NAB in normals. Efficacy of PPI BID plus Hz blockers HS has not been evaluated in patients. Aim: to assess intragastric pH control and NAB on PPI BID with and without bedtime Hz blockers in GERD patients. Methods: Intragastric 24 hr pH studies in GERD patients were reviewed. Group A = 57 patients (mean age 48, male 27) on PPI at least BID (omeprazole 20mg or lansoprazole 30mg) plus Hz blockers HS (Zantac 300mg, Pepcid 40mg or Axid 300mg). Group B = 60 patients (mean age 53, male 30) taking only PPI BID. The % time nocturnal and daytime gastric pH > 4, and % of patients with NAB analyzed. Results: I) Median % time pH>4 overnight was 96% in group A, and only 51% in group B (p4 was 83% in group A and 73% in group B, (p=0.02). 2) % of patients with a median % time pH >4 greater than 90% overnight was 63% in group A and 22% in group B (p4 less than 50% was 11% in group A and 48% in group B (p4 greater than 90% in daytime was 33% in group A and 30% in group B (NS); pH >4 less than 50% was 11% in group A and 18% in group B (NS). 3) NAB occurred in 33% patients in group A and 82% in group B (p
SEPSIS-INDUCED GASTRIC INJURY IS ASSOCIATED WITH REFLUX OF BILE ACID. Elizabeth J. Dial, Jimmy J. Romero, Xavier Villa, Lenard M. Lichtenberger, Univ of Texas Med Sch, Houston, TX. Background: The causes of sepsis-associated gastric bleeding and ulceration are incompletelyunderstood. We previously reported that in a model of sepsis, the lipopolysaccharide (LPS)-treated rat, there was a reduction of gastric surface hydrophobicity which was indicative of a damaged mucosal barrier (Gastroenterology 114:AI02, 1998). For the present study, we tested the hypothesisthat damage to the stomach from LPS was due to refluxof intestinal bile acid. Methods: Sprague-Dawley rats (N=8-IO/group) were fasted overnight and subjected to either sham surgery or bile duct ligation. Two hours later, after recovery from the surgery, the rats were treated with saline or E. coli LPS (0III :B4) at 5mg/kg, ip. Four hours later, the rats were euthanized and fluid in the stomach was collected for assay of bile acid and hemoglobin (a measure of bleeding), and gastric tissue was collected for contact angle analysis (a measure of surface hydrophobicity and barrier integrity). To investigate whether LPS treatment induced the reflux of bile into the stomach in unoperated animals, other rats were treated with LPS (5mg/kg, ip), sacrificed after 2 or 4 hours, and had their stomach fluid collected and assayed for bile acid. Results: As seen in the table, LPS induced a significant increase in bile acid and hemoglobin in the stomach, an effect which was blocked by bile duct ligation (BDL). Similarly, the LPS-induced reduction in gastric contact angle was prevented by prior bile duct ligation. In non-surgically treated rats, LPS induced a 2-3 fold increase in gastric bile acid at 2-4 hours after injection. Conclusions: LPS treatment of rats caused a reflux of bile into the stomach which damaged the surface barrier and contributed to bleeding. Monitoring for the presence of bile in the gastric contents of potentially septic patients may identify a previously unrecognized risk for gastric bleeding.

Treatment Sham+sallne Sham+LPS BLD+saline BDL+LPS

Bileacid(nmol)

Hemoglobin (fIg)

Contact angle

271±141 883±159 • 257±116 311±75

11±3 509±207 ' 19±9 24±4

49±4 37±4 • 45±3 45±5

Values are expressed asthe mean ± standard error. • p
356 EXPRESSION OF P16I NK4 ON GASTRIC EPITHELIAL CELLS IN H PYLORI POSITIVE GASTRITIS BEFORE AND AFTER ERADICATION OF H PYLORI. Periklis Foukas, Stavros Sougioultzis, Michalis Tzivras, Pantelis Grigoriadis, Panagiotis Davaris, Athanasios Archimandritis, Dept of pathophysiology, Med Sch, Univ of Athens, Athens, Greece; Dept of Pathology, Med Sch, Univ of Athens, Athens, Greece. Background: H pylori(Hp)infection induces hyperproliferation of the gastric epithelium that is considered a major factor for gastric carcinogenesis.INK4 is a putative tumor suppressor gene and its product, p161N K 4, inhibits the kinase activity of the cdk4/cyclin D complex blocking the progression of the cell cycle. Aim: To evaluate the expression of p16l N K 4 on gastric epithelial cells in Hp gastritis before and after Hp eradication.Patients-Methods:Thirty patients with dyspepsia with and without ulcers were prospectively studied. At least 4 biopsies were obtained on endoscopy (antral:2,corpus:2)for CLO-test and histo]ogy(H&E, Giemsa, Alcian blue for Sydney classification). Formalin-fixed paraffin embedded tissue sections were stained by the ABC immunoalkaline phosphatase rnethod.Rabbit polyclonaI anti-p16 (Santa-Cruz)was used. Staining intensity was graded from 0 to 2 +. 23 patients were Hp( + )by both methods and 7 Hp(-)(controls).Hp eradication therapy was given to Hp( +) and all patients were endoscoped 116±9 days after; biopsies were obtained and treated as previously.Results:Hp was eradicated in 20 of 23 patients.Normal mucosa: Cytoplasmic staining for p16lNK 4 was observed on epithelial cells (proliferation zone 1 +, surface epithelium I + )with less or no stain on epithelial cells between these zones;no staining was observed on glandular epithelium.Hp gastritis:Intense(2 + )cytoplasmic staining on epithelial cells in the proliferation zone with nuclear staining in some of them;surface epithelium and glandular cells stained like normal After Hp eradication the staining pattern became like the normal mucosa.In gastric pits with intestinal metaplasia, intense(2 +), only cytoplasmic staining was observed before and after eradication.Conclusions:Significance of cytoplasmic staining for p16l N K 4 remains unclear but staining of epithelial cells in the proliferating zone of normal mucosa suggests association with the proliferation of normal cells;expression on surface epithelium is compatible with the observation of p16l N K 4 accumulation in senescent cells. In Hp gastritis the pattern of staining for p16l N K 4 seems reasonable:substrate partners (cdk4/ cyclin D,pRb)are in the nuclei and GI arrest is needed for DNA repair mechanisms.In intestinal metaplasia,loss of nuclear p16l N K4 expression may confer to the intense growth potential of these cells. *Supported by grant 70-3-2945/95ED-1909PENED/KA,Greek Ministry of Industry.Energy,Technology