Dose-response evaluation of the antisecretory effect of continuous infusion intravenous lansoprazole regimens over 48 h.

BACKGROUND: Attainment of intragastric pH < 6.0 may require high-dose continuously infused proton pump therapy. AIM: To assess the pharmacokinetic and pharmacodynamic dose-responses of continuous infusion regimens of lansoprazole. METHODS: Healthy adult subjects were assigned to lansoprazole 60-mg intravenous bolus, followed by 6-mg/h continuous infusion; a 90-mg intravenous bolus followed by 6-, 7.5-, or 9-mg/h continuous infusion; or placebo. RESULTS: Mean intragastric pH values for lansoprazole regimens ranged from 4.8 to 5.2 (0-24 h), 5.5 to 6.0 (>24 to 48 h) and 5.2 to 5.6 (0-48 h). Within these three intervals, the percentages of time intragastric pH exceeded 4, 5 and 6 ranged from 65% to 96%, 54% to 88% and 30% to 61% respectively. Pharmacokinetic parameters were dose-independent with steady-state plasma concentrations achieved within 6-12 h postdose and maintained over 48 h. The mean systemic clearance of lansoprazole was lower in CYP2C19 heterozygous metabolizers than in homozygous extensive metabolizers (9.2 vs. 16.5 L/h), with substantial variability resulting in overlapping ranges of clearance values for both subpopulations. All lansoprazole regimens were well-tolerated. CONCLUSIONS: Lansoprazole administered as a 60-mg intravenous bolus followed by 6-mg/h continuous infusion produced intragastric pH effects comparable with those of higher dosage regimens.

In situ hybridization for Helicobacter pylori in gastric mucosal biopsy specimens: quantitative evaluation of test performance in comparison with the CLOtest and thiazine stain.

Numerous detection methods for Helicobacter Pylori (H. pylori) have been developed with varying degrees of purported diagnostic utility. We have developed a rapid nonradioactive in situ hybridization (ISH) method for H. pylori detection in paraffin-embedded tissue and assessed its relative diagnostic performance by receiver operator characteristics (ROC) in comparison to the thiazine stain and CLOtest. Forty-five patients undergoing endoscopy had antral biopsies and concomitant CLOtest performed. ISH for H. pylori was done using a 22-base, biotin-labeled oligonucleotide probe complementary to a portion of H. pylori 16s rRNA with the following sequence: 5'-GGACATAGGCTGATCTTAGC-3'. ISH using this probe was specific for H. pylori with no crossreactivity with other bacterial or fungal organisms. Receiver operator characteristic analysis was used to assess the diagnostic performance of ISH and thiazine techniques. ISH and thiazine stains were done on serial sections, reviewed independently, and scored on a graded scale from 1-5 based upon the degree of assurance of H. pylori presence. Diagnostic performance was assessed in "expert" and "nonexpert" pathologist groups with the CLOtest serving as the invariant test for relative test comparison. The ISH test performed slightly better (ROC area 0.9) than the thiazine (ROC area 0.8) in the nonexpert population, but equally well in the "expert" group (ROC area 0.95, 0.95). ISH followed by routine hematoxylin and eosin staining showed detailed mucosal histology with a dramatic visualization of H. pylori along the surface of the foveolar cells with no evidence of lamina propria invasion. In summary, ISH for H. pylori is an excellent test that is specific, easily read, and allows concomitant detailed histologic mucosal examination.

Pilot study of the oral omeprazole test for reflux laryngitis.

BACKGROUND: Gastroesophageal reflux disease occasionally presents with laryngeal symptoms. Such patients are often referred for a gastroenterology evaluation. This study was designed to determine whether an empiric trial of high-dose omeprazole therapy could reliably identify patients with reflux laryngitis and thus obviate the need for a gastroenterology workup. METHODS: Patients were evaluated with a history, physical examination, esophageal manometry, upper endoscopy, and 24-hour pH-metry for determination of the presence of absence of underlying gastroesophageal reflux disease and then received an empiric trial of oral omeprazole therapy (20 mg twice daily for 1 month). A positive omeprazole test result was defined as resolution of all laryngeal symptoms on completion of the empiric trial of therapy. RESULTS: Two patients were classified as having no reflux, and eight were classified as having reflux. Omeprazole test results were positive in six patients. Five of six had reflux, but one patient had no evidence for reflux. Omeprazole test results were negative in four patients. Three of four had reflux, and one did not. Despite the absence of antisecretory therapy, laryngeal symptoms did not recur in either patient without reflux during follow-up. Laryngeal symptoms were managed in two of the three patients with reflux who had negative omeprazole test results and who were using inhalers in combination with histamine H2 receptor antagonist therapy for their reflux disease. One patient with reflux who had a negative omeprazole test result responded to higher doses of omeprazole, and the five patients with reflux who had positive omeprazole test results all responded to continuation of omeprazole. CONCLUSIONS: The omeprazole test may be useful in confirming the suspicion of reflux laryngitis in patients suspected of having this disease after an otolaryngology evaluation. However, there is a potential for false-positive and false-negative test results. A gastroenterology evaluation may aid in the identification of false-positive test results by documenting the absence of reflux in certain responders.

Phase II trial of 5-fluorouracil, leucovorin, interferon-alpha-2a, and cisplatin as neoadjuvant chemotherapy for locally advanced esophageal carcinoma.

BACKGROUND: Most patients with esophageal carcinoma present with locally advanced disease and a poor prognosis. Surgery or radiation provides palliation for locally advanced esophageal carcinoma. The role of neoadjuvant therapy remains to be defined. We administered neoadjuvant chemotherapy consisting of 5-fluorouracil (5-FU), leucovorin, interferon-alpha, and cisplatin to 11 patients with locally advanced disease. METHODS: Eleven patients with squamous cell or adenocarcinoma of the esophagus were treated peroperatively with two to three cycles of combination chemotherapy. Nine patients underwent resection with curative intent. RESULTS: Six patients received three cycles of chemotherapy, and five received two. Dose reduction was necessary for two patients. One patient achieved a pathologic complete response, histologically confirmed. Of the eleven patients, two did not undergo surgery because of progressive disease during chemotherapy. Seven of the 9 patients relapsed after surgery and 2 have been disease free for 27 months. CONCLUSIONS: The combination 5-FU leucovorin, interferon-alpha-2a, and cisplatin administered in a neoadjuvant setting resulted in a median survival of 11.8 months with a median time to relapse of 7 months.

Thapsigargin defines roles of Ca2+ in initial, sustained, and potentiated stimulation of pepsinogen secretion.

The roles of Ca2+ in agonist-induced pepsinogen secretion from guinea pig chief cells remain unclear. We used cholecystokinin octapeptide (CCK-8) or secretin alone or with thapsigargin (TG) to clarify these roles. TG releases Ca2+ from intracellular stores by inhibiting microsomal Ca(2+)-adenosinetriphosphatase (ATPase), thereby depleting intracellular Ca2+ (Cai2+) stores. In most cells TG also causes Ca2+ influx. In the present study, with an extracellular Ca2+ concentration ([Ca2+]o) of 1.5 mM, CCK-8 (0.1 microM) caused a rapid increase in pepsinogen secretion; however, the rate decreased with time. With [Ca2+]o = 0, the initial increase was similar but later secretion was abolished, suggesting that Ca2+ influx was important for sustained secretion. With [Ca2+]o = 1.5 mM, TG (0.1 microM) caused a 2.7-fold sustained increase in in Cai2+ concentration ([Ca2+]i) and a ninefold sustained increase in pepsinogen secretion. With [Ca2+]o = 0, TG caused a transient 66% increase in [Ca2+]i and a 50% increase in pepsinogen secretion. The time course of TG-induced pepsinogen secretion correlated with the time course of TG-induced increases in [Ca2+]i. These data demonstrated that Ca2+ influx itself was a potent stimulant of pepsinogen secretion. We further focused on the roles of increasing [Ca2+]i from Cai2+ stores. With or without extracellular Ca2+ (Cao2+) present, addition of CCK-8 (0.1 microM) 10 min after TG caused no further increase in [Ca2+]i, demonstrating depletion of the inositol 1,4,5-trisphosphate-sensitive pool. The Ca(2+)-mobilizing agent CCK-8 caused no pepsinogen secretion 10 min after TG preincubation, demonstrating that mobilization of Ca2+ from intracellular stores was important in the rapid initial phase stimulation of pepsinogen secretion caused by CCK-8. In contrast, preincubation with TG had no effect on pepsinogen secretion by secretin, an agent that increases adenosine 3',5'-cyclic monophosphate. A 6-min preincubation with TG potentiated the subsequent stimulation of pepsinogen secretion caused by secretin in the presence of Cao2+ where [Ca2+]i remained elevated. However, TG-induced potentiations of secretin-stimulated pepsinogen secretion was abolished once [Ca2+]i had returned to the basal level in the absence of Cao2+.(ABSTRACT TRUNCATED AT 400 WORDS)