AIM:To demonstrate the pharmacodynamic comparability between oral 40 mg pantoprazole delayed-release granules and tablets.METHODS:This was a multicentre, randomized, open-label, 2-period, 2-sequence, 9-week crossover study in patients aged 18-65 years with gastro-oesophageal reflux disease and documented erosive oesophagitis. The primary endpoint was a comparison of the inhibition of pentagastrin-stimulated maximum acid output (MAO) at steady state after once daily dosing for 1 week and 23 h after the last dose of pantoprazole granules and tablets. Basal acid output was measured prior to MAO. Standard safety evaluations were performed. The one-sided t-test was used to test the null hypothesis that granules - 1.2 x tablet >/= 0 against the alternative hypothesis that this difference was <0 for both MAO and basal acid output values.RESULTS:Sixty patients completed the study. The mean MAO values were 7.11 +/- 4.98 and 7.29 +/- 4.77 mmol/h, while the mean basal acid output values were 0.74 +/- 0.91 and 0.58 +/- 0.63 mmol/h for the granules and tablets, respectively. The two formulations were shown statistically to be pharmacodynamically equivalent in suppressing MAO (P = 0.006), safe and well tolerated.CONCLUSION:Patients with gastro-oesophageal reflux disease who are unable to swallow the tablet may safely be prescribed the pantoprazole sodium granules.

BACKGROUND:Zollinger-Ellison syndrome and idiopathic hypersecretion are gastrointestinal hypersecretory conditions requiring long-term maintenance.AIMS:The safety and efficacy data for short-term (6-month) treatment of Zollinger-Ellison syndrome and idiopathic hypersecretion with oral pantoprazole were previously published. This study extends the initial observations to 3 years.METHODS:The primary efficacy end point for this report was the control of gastric acid secretion in the last hour before the next dose of oral pantoprazole (acid output of <10 mmol/h; <5 mmol/h in subjects with prior acid-reducing surgery). Dose titration was permitted to a maximum of 240 mg per 24 h.RESULTS:Twenty-four subjects completed the study. The acid output of 28 of 34 subjects was controlled at initial enrolment. The mean acid output rates were <10 mmol/h throughout the 36 months of treatment for 90-100% of the patients. The majority of the patients were controlled with b.d. doses of 40 or 80 mg pantoprazole at 36 months (acid output was controlled in 24 of 24 subjects). Pantoprazole was generally well tolerated with minimal adverse events reported.CONCLUSIONS:Maintenance oral pantoprazole therapy up to 3 years at dosages of 40-120 mg b.d. was effective and well tolerated in patients with Zollinger-Ellison syndrome and other hypersecretory conditions.

Purpose: This post hoc pooled analysis of data from 2 identical clinical trials compares the safety and effectiveness of pantoprazole 40 mg once daily vs. ranitidine 150 mg twice daily (the approved US dose levels) on long-term maintenance of healing of erosive esophagitis over 3 years of treatment. Methods: GERD patients with endoscopically documented healed erosive esophagitis (grade 0 or 1 Hetzel-Dent score) were enrolled in two 3-year, double-blind, comparator- controlled clinical studies that compared the efficacy and safety of pantoprazole 40 mg once daily (n = 179) and ranitidine 150 mg twice daily (n = 183) in the maintenance of healing. Upper endoscopy was performed at months 1, 3, 6, 12, 24, and 36, or when GERD symptoms recurred. Relapse was defined as the reappearance of erosive esophagitis with endoscopic grade = 2. Patients who relapsed during year 1 were withdrawn. Patients who relapsed at the end of year 1 or later could receive open-label treatment with pantoprazole 40 mg; if healed, they could then return to their randomized treatment. Time to first relapse was analyzed. Results: Pantoprazole 40 mg once daily was more effective than ranitidine 150 mg twice daily in maintaining healed erosive esophagitis through 36 months of treatment. In study A, 77% of 85 pantoprazole patients maintained healing vs 25% of 88 ranitidine patients; in study B, 74% of 94 pantoprazole patients maintained healing vs 26% of 95 ranitidine patients (both studies p <0.001; Wilcoxon test). Overall, 75% of patients remained healed on pantoprazole compared with 26% on ranitidine. The incidence of adverse events was similar (pantoprazole 6.7%; ranitidine 6.5%). Significantly more discontinuations occurred in the ranitidine groups than in the pantoprazole groups (79.5% vs 46.9%, p <0.001, any reason; 56.2% vs 13.4% lack of efficacy, p <0.001, ranitidine vs pantoprazole). Conclusions: Pantoprazole 40 mg once per day safely and effectively maintains healing of erosive esophagitis with significantly fewer relapses than ranitidine 150 mg twice daily over 3 years of treatment.

with P[21.(Table) Sumraary: Variations in gastric pH over a 24-hour period are non-random and the observed degree of long-term correlation is greater after both 1 and 2 weeks of PPl administration.Conclusinns: The modulation of gastric acidity is a non-linear process; quantification of long-term correlations and their response to experimental interventions, such as acid suppression, will allow more detailed study of the mechanisms underlying the control of gastric acid secretion.

OBJECTIVE:Maintenance proton pump inhibitor (PPI) therapy is effective for gastric acid hypersecretory states, although data with pantoprazole are limited. The aim of this study was to evaluate the safety and efficacy of long term p.o. pantoprazole in individuals with hypersecretion.METHODS:All subjects had Zollinger-Ellison syndrome or idiopathic hypersecretion. Baseline acid output was measured in the presence of prior maintenance antisecretory therapy before pantoprazole exposure. The starting dose was 40 mg b.i.d. in most cases, and the dose was adjusted to document control within the first 2 wk of therapy. The maximal allowable dose was 240 mg daily. Acid output was measured on day 28 and then quarterly from month 3. The primary efficacy endpoint was documented control of acid secretion at 6 months, i.e., acid output in the last 1 h before the next dose of therapy of <10 mEq/h (<5 mEq/h in subjects with prior acid-reducing surgery).RESULTS:A total of 26 subjects had Zollinger-Ellison syndrome (six with multiple endocrine neoplasia syndrome type 1) and nine had idiopathic hypersecretion. Pre-enrollment therapy included omeprazole in 27 subjects and lansoprazole in eight, and 82.4% of subjects were controlled on their prior regimens. With upward dose titration, acid output was controlled in all subjects by day 10 and in all but two (6%) at the 6-month time point. Median acid secretion on therapy at 6 months was <2 mEq/h (mean 2.2 mEq/h; range 0–10.5 mEq/h) at a dose of 40 mg b.i.d. for 24 subjects, 80 mg b.i.d. for seven subjects, and 120 mg b.i.d. for two subjects. During the course of the study, five subjects required doses of 240 mg daily. Pantoprazole was generally well tolerated. No cases of anterior optic ischemic neuropathy occurred. Five subjects died during follow-up, all because of events unrelated to the study drug.CONCLUSIONS:Maintenance p.o. pantoprazole therapy at a dose of 80–240 mg/day in divided doses was both effective and generally well tolerated for patients with Zollinger-Ellison syndrome and idiopathic hypersecretion.

and lgA classes were measured by antibedy in-house enzyme innnunoassay.CagA antibodies of IgG class were determined by an immunoblot method H.pylori was determined positive if histology and/or urease test were positive.Results: The use of NSA1D was significantly more common in bleeding patients (60 vs.37, p = 0.001) and they had siguificantly more often tt.pyloriintectiou (77 vs.40, p < 0,001).Among the bacteria CagA slralns were detected with the similar frequency in both groups (97% vs 96%, NS).H.D'lori inlection (Odds 5.3, 95% CI:2.6-10.9,p<0.001), use of NSA1D or ASA (Odds 2.2, 95%CI 1 1-47, p = 0028) attd previous history of duodenal ulcer (Odds 47, 95%C1: 15-14.3,p = 0.006) were significam risk factors tbr peptic ulcer bleeding when logistic regression analysis was un&rtaken.Furthermore, H.pylori and the consumption of NSA1Ds are independent risk tacmrs (p = 0,018 tot interaction term).There was an increasing dose dependent rgk with ASA, ketoprofen and smoking (>20 cigarettes) for peptic ulcer bleeding.Conchision: H,D, Iori intectinn, use of N SAID or ASA, hea W smoking and history of duodenal ulcer are independent risk factors for peptic ulcer bleeding.However, C.agA strains are common also in non-uker patients and their role in acute hemorrhage remains obscure

Under normal physiological conditions, gastric acid production is controlled by a negative feedback mechanism. Proton pump inhibitors, such as pantoprazole, inhibit gastric acid secretion by irreversibly binding and inactivating luminally active hydrogen potassium ATPase. Recovery of acid production after treatment with a proton pump inhibitor is driven by new pump synthesis, activation of existing cytoplasmic pumps, or reversal of proton pump inhibition. The authors measured the time course of the inhibition and recovery of acid secretion in healthy volunteers following intravenous administration of pantoprazole to determine the rate of proton pump activation under maximally stimulated conditions. Gastric acid production was measured in 27 Helicobacter pylori negative healthy volunteers (mean age = 31 ± 7 years; 17 men, 10 women) who received single doses of intravenous pantoprazole (20, 40, 80, or 120 mg) in the presence of a continuous intravenous infusion of 1 ug/kg/h of pentagastrin. From the time profile of acid secretion, the authors described the rate of change of acid output using an irreversible pharmacodynamic response model represented by the equation dR/dt = −k ṁ R ṁ Cpanto + Ln2/PPR ṁ (Ro‐R) and correlated the parameter values with demographic factors and gastric acid measurements. Mean stimulated acid output secretion was 21.6 ± 18.4 mEq/h (range: 1.6–90.5) prior to the administration of pantoprazole and remained steady for 25 hours after placebo administration. Intravenous pantoprazole inhibited acid output in a dose‐response fashion, with maximal inhibition (99.9%) occurring after an 80 mg dose. Mean proton pump recovery time was 37.1 ± 21.0 hours (range: 6.7–75), and recovery was independent of the dose of pantoprazole. There was no association noted between proton pump recovery time and gender, age, race, body weight, or pantoprazole dose. However, there was an inverse correlation between acid output during baseline stimulation and recovery of acid secretion. Mean proton pump recovery time in stimulated normal human volunteers was 37.1 ± 21.0 hours, with a range of 6.7 to 75 hours. The authors hypothesize that there may be a normal homeostatic mechanism that maintains acid secretory capability within a normal range by altering the rate of proton pump activation dependent on the individual's parietal cell mass. Abnormalities of this process may be responsible for the development of acid peptic disease in susceptible individuals.

In addition to numerous basolateral K+-channels that recycle K + imported by the Na+-K +-ATPase, parietal cells are thought to possess an apical K+-channel that is active only during acid secretion.The apical K+-channel could facilitate movement of cytoplasmic K ÷ into the gastric lumen and this K* would then be recycled by the H*-K*-ATPase during acid secretion.Here we show that the stomach possesses 2 inwardly rectifying K+-channels (Kir) that localize to the apical surface of parietal cells in the rat stomach.Methods: Nested primers were designed using rat brain Kit4.1 (GenBank X86818) and Kit5.1 (GenBank AF249676) nucleotide sequences, and RT-PCR was performed using rat stomach RNA.Purified PCR products cloned into a pCR 2.1-TOPO TA cloning vector were sequenced and subjected to BLAST analysis to verify that the amplification products corresponded to Kir channels.Frozen sections from the resting rat stomach were stained with anti-rat brain Kit4.1 antibody (kindly provided by Drs.Graham Wilkin and Chris Knott, Gila 30: 362, 2000) and anti-H+-K+-ATPase antibody (kindly provided by Dr. Adam Smolka).Results: KIN.1 and Kit5.1 mRNAs are expressed at low levels in the rat stomach.Antibody staining shows that Kir4.1 localizes at two sites.First, some cells in the neck region stain strongly with anti-Kir4.1 antibody, perhaps representing the presence of Kir4.1 in a type of stem cell precursor.Second, anti-Kir4.1 antibody localizes to the apical surface of parietal cells but does not co-localize with the H+-K+-ATPase.Instead, the signal is isolated to a domain that forms a thin continuous band along the apical surface.Conclusions: These finding show that Kir4.1 and KirS.1 mRNAs are expressed by rat stomach and that Kir4.1 (protein) is localized to the apical surface of parietal cells.Our results suggest that parietal cells have heteromeric Kir channels consisting of Kir4.1/Kir5.1.We postulate that Kir4.1/Kir5.1 moves cytoplasmic K + to the lumen during acid secretion and that this heteromeric channel is important for the regulation of gastric acid secretion.

Oral pantoprazole (PANTO) effectively controls gastric acid output (AO) in Zollinger-Ellinson syndrome (ZES) and idiopathic hypersecretion (IH)

An automated high-performance liquid chromatographic method with electrochemical detection is described for the determination of indoramin, a new antihypertensive drug. The procedure involves a single extraction of the drug from alkaline plasma with chlorobutane. The chlorobutane extract is evaporated to dryness, reconstituted in methanol and injected into the chromatograph. Separation is achieved using a CN-bonded silica column and an isocratic elution with 0.01 M sodium phosphate in 50% acetonitrile. Detection is at 0.95 V applied potential on a glassy carbon electrode versus an Ag/AgCl electrode. Electrochemical methods that depend on a high oxidation potential suffer from rapid electrode passivation by significant amounts of impurities extracted from plasma. Therefore, the instrumentation includes a valve-switching unit to divert most of the impurities away from the electrode compartment; thus, maintaining sensitivity during the automated analysis of a large number of samples. An RSD of 5-15% was obtained in the concentration range of 0.5-100 ng/mL plasma. The limit of detection is 0.5 ng/mL. The method has been successfully used for the determination of indoramin in plasma samples from human subjects given a 50-mg oral dose of the drug.

A highly specific and sensitive method using automated high-performance liquid chromatography with electrochemical detection (HPLC-ED) and a method using gas chromatography-mass spectrometry (GC-MS) have been developed for the quantitative determination of promethazine in plasma. The lowest detectable concentration by HPLC-ED is 0.1 ng/ml of plasma and by GC-MS 0.5 ng/ml of plasma. The HPLC-ED method incorporates a valve switching unit to prevent all of the electroactive impurities from entering the electrode compartment, thus maintaining the sensitivity of the detector for the analyses of large numbers of samples. The GC-MS method incorporates the highly specific selected-ion monitoring technique. Plasmas derived from healthy subjects each given a single 50-mg oral dose of promethazine were analyzed by both HPLC-ED and GC-MS. The two methods compare favorably with a correlation coefficient of 0.92 and a slope of 1.059. While both methods are suitable for studying single-dose pharmacokinetics of promethazine, the automated HPLC-ED method has a decided advantage in being more sensitive and suitable for unattended overnight analyses of the large number of samples encountered in pharmacokinetic studies. The specificity of the HPLC-ED method is demonstrated by comparison to the GC-MS analysis of biological samples.