Randomised clinical trial: sustained response to PPI treatment of symptoms resembling functional dyspepsia and irritable bowel syndrome in patients suffering from an overlap with erosive gastro-oesophageal reflux disease.

BACKGROUND: Gastro-oesophageal reflux disease (GERD), functional dyspepsia (FD) and irritable bowel syndrome (IBS) are highly prevalent gastrointestinal conditions with accumulating evidence of overlap in patients. Despite availability of a vast body of research related to individual disorders, major pharmacological breakthrough in treatment of the overlap condition is still lacking. AIM: To assess sustainability of GERD healing and whether known beneficial effects of proton pump inhibitor treatment on GERD also extend to symptoms suggestive of FD and IBS. METHODS: A total of 626 patients with reflux oesophagitis were treated with pantoprazole for up to 16 weeks depending on healing of GERD, followed by an observational phase of up to 6 months without treatment. Rates of patients suffering from GERD, FD or IBS were assessed at baseline, and at last visits of treatment and observational phase. RESULTS: Rates of patients with reflux oesophagitis and concomitantly with reflux symptoms, FD or IBS were each significantly lower after pantoprazole treatment (P < 0.0001). While rates of patients with reflux signs or symptoms increased again during observational phase, rates of FD and IBS were maintained at the low level after cessation of medication (P < 0.0001). CONCLUSIONS: Pantoprazole is efficacious in the treatment of patients suffering from signs and symptoms suggesting an overlap of GERD, FD and/or IBS, providing a sustained response post-treatment in FD and IBS symptom categories. Mechanisms underlying the beneficial effects of improvement in reflux oesophagitis on symptoms suggestive of FD or IBS still need to be determined.

Pharmacodynamic effects of 3-day intravenous treatment with pantoprazole or ranitidine after 10 days of oral ranitidine.

Tachyphylaxis (drug tolerance) is an undesirable condition in drug therapy with histamine-2-receptor antagonists (H2RAs). The concept of overcoming tachyphylaxsis via intravenous (i.v.) administration of proton-pump inhibitors (PPIs) or H2RAs is of significant interest to physicians. In the present study, 32 healthy Helicobacter pylori negative male volunteers were evaluated for the ability of i.v. pantoprazole or i.v. ranitidine to overcome oral ranitidine tachyphylaxis. After 10 days of oral treatment with enteric-coated 300-mg ranitidine tablets once daily in the evening, two groups of 16 volunteers each were randomized to receive either i.v. pantoprazole or i.v. ranitidine for up to 72 h. The primary variable was defined as the increase in 24-h gastric pH median after 1 day of i.v. treatment; the secondary variable was median percentage of time that 24-h gastric pH was <4, as calculated by Hodges-Lehman shift estimators. After 10 days of oral ranitidine treatment, tachyphylaxis was present in all volunteers. Within 1 day of continuous i.v. pantoprazole or i.v. ranitidine administration, 24-h median gastric pH increased from pH 1.45 to pH 3.50 (241%) and from pH 1.50 to pH 2.35 (157%), respectively. I.v. pantoprazole was found to be significantly more effective (p<0.05) than i.v. ranitidine in increasing the 24-h gastric pH after oral ranitidine tachyphylaxis.

Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients.

AIM: To compare the efficacy and tolerability of pantoprazole 20 mg once daily (o.d.) with misoprostol 200 microg twice daily (b.i.d.), administered for 6 months to rheumatic patients who required long-term therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and who were at increased risk of developing gastrointestinal lesions. METHODS: This randomized, double-blind, multicenter, parallel group comparison study was performed with rheumatic patients (n = 515) who were likely to take NSAIDs continuously for at least 6 months. Patients were 55 years or older, at risk to develop gastrointestinal lesions, had less than five erosions/petechiae in the stomach and duodenum, no ulcers, no reflux esophagitis (endoscopy-proven), and gastrointestinal symptoms of at most moderate intensity. A minimum daily dose was defined for NSAIDs (COX-2 inhibitors were not available at the time). Patients were randomized to take either pantoprazole 20 mg o.d. (n = 257) or misoprostol 200 microg b.i.d. (n = 258) for 6 months while continuing NSAID therapy. Endoscopy was performed at baseline, 3, and 6 months. RESULTS: Pantoprazole was superior to misoprostol (p < 0.001) with regard to 'therapeutic failure' (occurrence of a peptic ulcer, ten or more erosions/petechiae in the stomach/duodenum, reflux esophagitis, severe gastrointestinal symptoms, and/or 'likely' or 'definitely' related adverse event leading to study termination). Estimated remission rates at 3 and 6 months (Kaplan-Meier life-table analysis) were, respectively, 93 and 89% (pantoprazole) and 79 and 70% (misoprostol). Pantoprazole was superior to misoprostol (p = 0.005) with regard to 'endoscopic failure' (occurrence of a peptic ulcer, ten or more erosions/petechiae in the stomach/duodenum, or reflux esophagitis) after 6 months. Estimated remission rates at 3 and 6 months were, respectively, 98 and 95% (pantoprazole) and 95 and 86% (misoprostol). Patients discontinuing the study early due to adverse events 'likely' or 'definitely' related to the study drug accounted for 13/257 (5%) in the pantoprazole and 33/258 (13%) in the misoprostol treatment groups. CONCLUSION: Pantoprazole 20 mg o.d. is superior to misoprostol 200 microg b.i.d. in the prevention of NSAID-induced gastrointestinal lesions and symptoms in patients on continuous long-term treatment with NSAIDs due to rheumatic diseases and at risk to develop such lesions or symptoms.

Pantoprazole therapy in the long-term management of severe acid peptic disease: clinical efficacy, safety, serum gastrin, gastric histology, and endocrine cell studies.

OBJECTIVE: Pantoprazole is the third proton pump inhibitor to become available. When this study was started, there were few data on its long-term use. Our aim was to investigate this aspect and, because powerful inhibitors of acid secretion can cause hypergastrinemia and, in experimental animals, enterochromaffin-like cell hyperplasia, we also monitored serum gastrin and endocrine cell histology. METHODS: One hundred fifty patients refractory to H2-receptor antagonists, running an aggressive course or with complications, were entered into a 5-yr treatment program. We performed serial endoscopy, checked for adverse events, and laboratory values. We also monitored serum gastrin, gastric endocrine cell histology, and antral and corpus gastritis. RESULTS: This report presents results from up to 3 yr of treatment. Cumulative healing on 40-80 mg of pantoprazole was 82% at 4 wk and 92% by 12 wk. Most patients became asymptomatic within 4 wk. Remission on maintenance treatment with 40 mg (n = 111) was 85% at 12 months and 78% at 24 months. Treatment was safe; only four patients had adverse events definitely related to pantoprazole. Elevations in gastrin were modest and there were no significant changes in gastric endocrine cells. The number of enterochromaffin-like cells tended to decrease. CONCLUSION: Pantoprazole is effective, safe, and does not seem to be associated with large increases in serum gastrin or alterations in gastric endocrine cells.

[Monotherapy of Parkinson's disease with budipine. A double blind comparison with amantadine]. / Monotherapie der Parkinsonschen Erkrankung mit Budipin. Ein randomisierter Doppelblindvergleich mit Amantadin.

In a randomised double blind parallel-group study in three centers budipine, a diphenylpiperidin derivate, was compared to amantadine with respect to efficacy and safety in the monotherapy of mild to moderate Parkinson's disease (PD). From 53 patients of either sex 27 patients were randomised to 3 x 20 mg/d budipine and 26 patients to 3 x 100 mg/d amantadine. The duration of treatment was 4 weeks in 1 center (21 patients) and 12 weeks in the other 2 centers (32 patients). Safety was measured by vital signs, ECG, adverse event recording and clinical laboratory. Both drugs caused a clinically relevant and statistically significant (p < 0.001) improvement of Parkinsonian symptoms according to the Webster-Rating-Scale (WRS) as compared to pretreatment values. With respect to the total WRS score sum there was no difference between the groups (p > 0.05; n.s.), while budipine showed a significantly (p < 0.05) better effect on the main symptom tremor after 12 weeks. During amantadine treatment more adverse events were observed than after budipine intake. Two patients left the study prematurely, one in the amantadine group due to psychiatric adverse events and one in the budipine group because of insufficient efficacy.

Pantoprazole 20 mg is an effective maintenance therapy for patients with gastro-oesophageal reflux disease.

OBJECTIVES: To compare the efficacy of 20 mg with 40 mg pantoprazole in maintaining symptomatic and endoscopic remission in patients with gastro-oesophageal reflux disease (GORD). STUDY DESIGN: Patients (18-84 years old; n = 433) with healed GORD II or III were included in this prospective multi-centre, randomized, parallel, double-blind study. Pantoprazole was administered once daily for up to 1 year as either a 20 mg or 40 mg enteric-coated tablet to 221 and 212 patients, respectively. Symptoms of GORD were assessed every 3 months. Endoscopy was performed at entry, after 6 and 12 months, or when symptoms of GORD were perceived on at least three consecutive days. The primary efficacy parameter was the time until endoscopically proven relapse of GORD occurred (stage I or greater); the secondary parameters included tolerability, safety, and time until symptomatic relapse occurred. RESULTS: In the 20 mg treatment group, 87% and 75% of patients were in endoscopic remission after 6 and 12 months, respectively; the corresponding rates in the 40 mg treatment group were 91% and 78%. In both treatment groups, GORD stage I accounted for about 50% of endoscopic relapses. The symptomatic remission rates in the 20 mg group were estimated as 85% and 77% after 6 and 12 months, respectively; the corresponding values in the 40 mg group were 87% and 76%. No correlation was seen either between the endoscopically proven relapse and perception of symptoms, or between the severity of the pre-treatment stage of GORD and the maintenance dose of pantoprazole. Both doses were well tolerated. CONCLUSIONS: Both the 20 mg and 40 mg doses of pantoprazole are safe and effective in maintaining patients with healed reflux oesophagitis in remission. Moreover, for the majority of patients, the 20 mg dose provides adequate long-term therapeutic efficacy at a minimal drug exposure and lower costs.

Relative efficacies of gastric proton pump inhibitors: their clinical and pharmacological basis.

The present review will verify by intra-study rank orders, and their comparison between studies, that the different gastric proton pump inhibitors (PPIs) display similar dose-response relationships with similar potencies and efficacies on a milligram basis, i.e., at the same milligram doses. This is in line with their basic pharmacology which suggests that, primarily, the serum AUCs of the free pro-drugs and their chemical activation half lives at pH 1 relative to their serum elimination half lives determine the efficacies of PPIs. According to the literature, these drug characteristics are similar for all PPIs. Although PPIs have been introduced into the therapy of acute peptic ulcer disease at different daily, oral doses of 20 mg (omeprazole and rabeprazole), 30 mg (lansoprazole) and 40 mg (pantoprazole), the data suggest that the optimal dose of lansoprazole, omeprazole and pantoprazole, with respect to the acute treatment of peptic ulcers and moderate to severe gastroesophageal reflux disease (GERD), is about 30-40 mg daily. The data base of rabeprazole appears to be too small at present to make any definite statement. Lower daily doses of the PPIs of about 15-20 mg are sufficient in less severe cases of GERD and in maintenance therapy. It appears that different dose recommendations were based on different strategies to balance optimal drug dosage and safety, rather than on real differences in milligram-related efficacies.

Efficacy and safety of pantoprazole in patients with gastroesophageal reflux disease using an intravenous-oral regimen. Austrian Intravenous Pantoprazole Study Group.

BACKGROUND/AIMS: To investigate the efficacy and safety of an intravenous-oral regimen using the gastric proton pump inhibitor pantoprazole. METHODOLOGY: Outpatients, with endoscopically diagnosed moderate or severe gastro-esophageal reflux disease (GERD stage II and III, respectively, Savary-Miller classification), were recruited from ten hospitals or private practice centers and enrolled into an open-labeled study (intention-to-treat population n=110, age 20-88 years; per-protocol population n=98). Patients were treated once daily with 40 mg pantoprazole which was administered as an intravenous injection for the initial 5-7 consecutive days, then as a tablet, for up to 8 weeks. The efficacy parameters were complete healing of lesions evaluated endoscopically after week 4 and 8, and relief from symptoms assessed after week 2 and 4. RESULTS: Complete healing was achieved in 85/98 (87%) and 93/98 (95%) per-protocol patients, after 4 and 8 weeks, respectively. The corresponding results for the intention-to-treat population were 85/110 (77%) and 93/110 (85%), respectively. After 2 weeks of treatment, heartburn, acid regurgitation, and pain on swallowing resolved in 97%, 98%, and 100% of the per-protocol patients, respectively. Faster healing was observed in non-smokers, those infected with Helicobacter pylori, and those with initial GERD stage II. The intravenous and oral administration phases were well tolerated. CONCLUSIONS: Pantoprazole (40 mg), applied as an intravenous-oral regimen to patients with GERD led to fast resolution of symptoms and high healing rates. For patients, temporarily unable to take oral medications, this regimen offers safe and reliable gastric acid suppression and allows the possibility of changing between the oral and intravenous administration without the need for dose adjustment.

Effects of pumaprazole (BY841), a novel reversible proton pump antagonist, and of omeprazole, on intragastric acidity before and after cure of Helicobacter pylori infection.

BACKGROUND: Omeprazole produces a higher intragastric pH in the presence of Helicobacter pylori infection than after cure. AIM: To investigate whether this effect also occurs with pumaprazole (BY841), a reversible proton pump antagonist which, in contrast to omeprazole, does not require activation in the acid compartment of the parietal cell. METHODS: In a randomized, crossover, double-blind study, 24-h intragastric pH was measured in 13 H. pylori-positive subjects before and after a 1-week course of omeprazole (20 mg o.d.) or of pumaprazole (100 mg b.d.). The studies were repeated after the infection was cured. RESULTS: In the absence of drug administration, the median 24-h pH values before cure (median 2.0, 90% CI: 1.2-3.2) did not differ from those after cure (median 1.5, 90% CI: 1.3-2.2; P = 0.115). The 24-h pH values were higher before cure of the infection than after during both pumaprazole (6.0, 4.8-6.7 vs. 4.3, 2.6-5.7; P = 0.002) and omeprazole (5.8, 4.0-6.2 vs. 3.6, 2.8-5; P = 0.004). Both before and after cure, there were no significant differences between the two drugs with respect to acid inhibition over the 24-h period. The median decrease in acid inhibition after cure of the infection (calculated as the difference in H+ activity in mmol/L) during pumaprazole (median 0.05, 90% CI: 6 x 10-4- 2.3) was no different from that during omeprazole (median 0.2, 90% CI: 3 x 10-3-1.5; P = 0.6). CONCLUSIONS: Both before and after cure of H. pylori infection, pumaprazole raised the intragastric pH over a 24-h period to a similar degree as omeprazole. H. pylori infection similarly augments the pH-increasing effect of both drugs. This effect is related to H. pylori infection and not to an increased activation of acid inhibitory agents in the parietal cell compartment.

Equipotent inhibition of gastric acid secretion by equal doses of oral or intravenous pantoprazole.

BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 system, and linear pharmacokinetics. The recommended oral dose for treatment of acid-related diseases is 40 mg. METHODS: Using a randomized, crossover study design we compared the ability of 40 mg oral and intravenous pantoprazole to elevate the intragastric pH in healthy volunteers (n = 20, 'per protocol'), during two treatment phases. The duration of each phase was 5 days. Pantoprazole 40 mg was administered once daily either as a tablet or as an intravenous injection. A 24 h pHmetry was used to record the intragastric pH on day 5 of each regimen; this was compared to the baseline curve obtained before each study period. The calculated 90% confidence intervals (90% CI) represent the mean difference in the intragastric pH, attained after intravenous or oral administration. The predefined equivalence range for the 90% CI was +/- 20% for the percentage time at which the gastric pH was at least pH 3 or 4 and +/- 1 unit for the median pH. RESULTS: Pantoprazole was well tolerated during both treatment phases. The mean of the 24 h median pH was 3.3 and 3.1 for the intravenous and oral treatments, respectively; the corresponding differences were 0.2 (90% CI: - 0.03 to 0.44). For the mean percentage time at which the pH was 3 or above, the respective calculated values were 57% and 51%, with a difference between the two administration routes of only 5.7% (90% CI: 1.8 to 9.6). At an intragastric pH of 4 or above, the mean percentage time was 420% and 38% following intravenous and oral treatment, respectively, with a difference between the treatment routes of only 4.4% (90% CI: 0.6 to 8.3). CONCLUSIONS: These results imply that the two formulations of pantoprazole can be assumed to be equipotent. Hence, the intravenous formulation of pantoprazole could be considered as an alternative route of administration.

Pantoprazole 20 mg is effective for relief of symptoms and healing of lesions in mild reflux oesophagitis.

AIM: To investigate the efficacy of a low dose of pantoprazole, a gastric proton pump inhibitor, for the relief of symptoms and healing of lesions in mild gastro-oesophageal reflux disease (GERD), and to compare it with the efficacy of ranitidine. METHODS: Patients with endoscopically established GERD (Stage I, Savary-Miller classification) were enrolled into a randomized, double-blind, parallel-group and multicentre study (intention-to-treat n = 209, age range 19-82 years). They were treated once daily with oral pantoprazole 20 mg or ranitidine 300 mg, for up to 8 weeks. End-point parameters included relief of symptoms (heartburn, acid regurgitation, pain on swallowing) and the healing of GERD lesions. Relief from symptoms was assessed after 2 and 4 weeks, and endoscopically confirmed healing of lesions after 4 and 8 weeks. RESULTS: The proportion of patients reporting complete relief from symptoms after 2 weeks was greater in the pantoprazole than in the ranitidine group (69 vs. 48%, P < 0.01), with further improvements seen in the pantoprazole group after 4 weeks (80 vs. 65%, P < 0.05, Cochran-Mantel/Haenszel test). Healing of lesions was confirmed in 70/87 (80%) patients after 4 weeks (pantoprazole group), as compared with 55/86 (64%) patients (ranitidine group) (P < 0.05, per protocol population); after 8 weeks the respective results were 78/87 (90%) and 63/86 (73%) patients (P < 0.01). Both study medications were well tolerated. CONCLUSION: Low-dose pantoprazole (20 mg) is clinically superior to ranitidine (300 mg) in providing fast relief from symptoms and healing of lesions in patients with mild GERD.

Pharmacokinetics of pantoprazole in patients with end-stage renal failure.

BACKGROUND: Pantoprazole is a selective inhibitor of the gastric H+/K+-ATPase with a low potential to interact with the cytochrome P450 enzyme system. Since pantoprazole is metabolized in the liver to metabolites which are mainly cleared by the renal route, it was the aim of this study to investigate its pharmacokinetics in patients with end-stage renal failure undergoing regular haemodialysis. METHODS: Eight patients with end-stage renal failure (creatinine clearance < 5 ml/min, age 45-65 years) on regular haemodialysis (duration of haemodialysis 4-5 h, cuprophan-dialyser Hemoflow E3, surface 1.3 m2) were given single i.v. doses of 40 mg pantoprazole one day before haemodialysis (A) and on a haemodialysis day immediately before the start of the haemodialysis (B). Concentrations of pantoprazole and metabolite M2 were determined in plasma and urine over 24 h and in timed samples of the dialysis fluid by HPLC. The protein binding was determined using equilibrium dialysis. RESULTS: The pharmacokinetic characteristics of pantoprazole AUC, t(1/2), CL and V(d area) (geometric means) were 2.4 mgxh/l, 0.63 h, 0.227 l/h/kg and 0.206 l/kg on day A (without dialysis) and 2.3 mgxh/l, 0.8 h, 0.237 l/h/kg and 0.273 l/kg on day B (with dialysis), respectively. The protein binding was 96%. Pantoprazole was found in small amounts in the dialysis fluid (max. 2.1% of the dose) but not in the urine. Pantoprazole was well tolerated. In particular, there were no clinically relevant changes in blood count, electrolytes or liver enzymes. CONCLUSIONS: Haemodialysis has no influence on the pharmacokinetic characteristics of pantoprazole. Thus, pantoprazole is not dialysed to any relevant degree, and therefore no dose-adjustment is required for patients with end-stage renal failure undergoing regular haemodialysis treatment.

Pantoprazole does not affect performance in traffic-related safety tests: a double-blind, randomised, placebo-controlled, crossover study in healthy volunteers.

UNLABELLED: OBJECTIVE AND STUDY PARTICIPANTS: The effects of pantoprazole, a potent inhibitor of gastric acid production, were evaluated in traffic-related performance tests in 18 healthy male and female volunteers, aged 18 to 60 years, in a randomised, placebo-controlled, double-blind, crossover study. METHODS: Oral pantoprazole (40mg) or a placebo tablet was taken once a day for two periods of 5 days each, with a washout period of 7 to 14 days. Drug tolerability was assessed by vital signs, clinical laboratory parameters and volunteers' own subjective appraisal of their mental condition. The computerised Viennese test system (WTS 90) was used to examine parameters related to traffic safety including visual orientation, concentration span, acoustic reaction time, multiple choice reaction, stress, tolerance, vigilance and motor coordination. The effects were tested one day before and then on the first and fifth days of each medication period. RESULTS: Results showed that in comparison with placebo, neither single nor multiple doses of pantoprazole led to clinically relevant differences in the performance of standardised, traffic-related safety tests. CONCLUSION: Pantoprazole did not appear to impede normal everyday activities, including car driving, and thus can be administered without special precautions in this regard.

Morning and evening administration of pantoprazole: a study to compare the effect on 24-hour intragastric pH.

OBJECTIVE: To determine whether the time of administration (morning vs. evening) of pantoprazole influences the effect of a 40 mg dose upon intragastric pH in healthy subjects. DESIGN: Randomized, double-blind, two-period crossover study to compare intragastric pH following treatment with pantoprazole, 40 mg once daily for 7 days, the drug being given as either a morning or an evening dose before meals. METHODS: Intragastric pH was measured for 24 h on three occasions. The baseline recording was made 2 days prior to the first treatment period and subsequent measurements were made on days 6 to 7 of each period. Adverse events were recorded and fasting laboratory variables measured. RESULTS: Twelve subjects were evaluable for efficacy. Increases in median pH over 24 h were observed in all subjects with both dosage regimens. There was a greater increase from baseline in 24-h median pH values following morning than evening administration of pantoprazole (P < 0.05). This difference was due to a greater effect on median daytime pH (07.00-19.00 h, P < 0.01) compared with that after evening administration. No adverse events were reported and there were no clinically significant changes in laboratory variables. CONCLUSION: The study supports the recommendation of a once-daily morning dosage regimen of pantoprazole 40 mg in the treatment of acid-related diseases.

Intragastric pH and serum gastrin during administration of different doses of pantoprazole in healthy subjects.

OBJECTIVE AND DESIGN: The effect of increasing doses of pantoprazole, a newly developed proton pump inhibitor, given at once daily doses of 40, 80 and 120 mg, on intragastric pH and serum gastrin profiles was studied in 15 healthy subjects in a randomized, double-blind, crossover study and compared to recordings without therapy. Measurements of intragastric pH and serum gastrin were performed on the 7th day of treatment by continuous pH recording and radioimmunoassay in blood samples obtained in 1-h intervals, respectively. RESULTS: Pantoprazole significantly increased gastric pH above basal at all pantoprazole doses studied: median 24-h pH rose from 1.2 without therapy to 3.4, 3.3 and 3.6 at 40, 80 and 120 mg daily, respectively. The corresponding integrated 24-h gastrin output was 1632, 2338 and 2248 pg/ml x 24 h compared to 575 pg/ml x 24 h without pantoprazole. There was no interindividual correlation between values of 24-h median pH and 24-h gastrin output at any pantoprazole dose studied. However, fasting gastrin levels closely correlated with 24-h gastrin output (r = 0.789; P < 0.0001). The acid inhibitory effect was significantly (P < 0.01) augmented in Helicobacter pylori positive subjects. CONCLUSION: It is concluded that pantoprazole is an effective inhibitor of gastric acid secretion. Increasing a single pantoprazole dose above 40 mg does not lead to increased median pH elevation. The individual extent of acid inhibition does not predict the magnitude of gastrin elevation. Acid inhibition appears more efficient in Helicobacter pylori positive subjects.

Twenty-four-hour intragastric pH profiles and pharmacokinetics following single and repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole.

BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzyme system in man. Its effect on intragastric pH following single and repeated oral intake was investigated in comparison to omeprazole by continuous intragastric pH-metry at doses recommended for treatment of peptic ulcer disease. METHODS: Sixteen healthy male subjects underwent two dosing periods. From day 1 to day 7, they were given once daily by mouth 40 mg pantoprazole in one period and 20 mg omeprazole in the other period, according to a double-blind randomized crossover design. Twenty-four-hour intragastric pH was recorded and frequent blood samples for pharmacokinetic analysis were taken on day 1 and day 7. A placebo pH profile was obtained prior to each treatment period. RESULTS: Pantoprazole was significantly more effective than omeprazole with regard to increase in 24-h and daytime pH, following both single (median 24-h pH: 1.45 vs. 1.3, P < 0.05; median daytime pH: 1.6 vs. 1.3, P < 0.01) and repeated (median 24-h pH: 3.15 vs. 2.05, P < 0.01; median daytime pH: 3.8 vs. 2.65, P < 0.05) oral intake. As compared to the first dose, repeated administration of both drugs markedly increased the effect on intragastric pH. With pantoprazole, steady-state serum concentrations were obtained after the first dose, but not with omeprazole. Both drugs were well tolerated without relevant changes in vital signs of clinical laboratory parameters. CONCLUSION: Pantoprazole 40 mg is significantly more effective than omeprazole 20 mg in raising intragastric pH.

Pharmacokinetics of pantoprazole in man.

The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2 induction was confirmed using the specific probe caffeine. As sensitive probes for CYP3A enzyme induction, urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol were also unchanged.

Dose linearity of the pharmacokinetics of the new H+/K(+)-ATPase inhibitor pantoprazole after single intravenous administration.

Pantoprazole is a specific inhibitor of the H+/K(+)-ATPase of the gastric parietal cell. The dose-dependency of a range of pantoprazole pharmacokinetic characteristics was studied. Twelve healthy male subjects were given 10, 20, 40 and 80 mg pantoprazole intravenously according to a randomized, single blind, 4-period change-over scheme. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with the dose. Apparent volume of distribution (Vd area), clearance (Cl) and terminal half-life (t1/2) were independent of the dose. The dose-independent elimination of pantoprazole was attributed to the lack of interaction of the drug with cytochrome P450. In clinical practice, a good predictable response, as well as a low potential for interaction with other drugs might be expected.

Pharmacokinetics of pantoprazole in man.

The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(O,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination halflife of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2 induction was confirmed using the specific probe caffeine. As sensitive probes for CYP3A enzyme induction, urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol were also unchanged.

Comparative trial of pantoprazole and ranitidine in the treatment of reflux esophagitis. Results of a German multicenter study.

In 249 patients with acute symptomatic reflux esophagitis grade II and III (Savary-Miller classification), we compared the efficacy and safety of pantoprazole, a newly developed proton pump inhibitor given at a once-daily dose of 40 mg, with a standard dose of the H2 receptor antagonist ranitidine (150 mg b.i.d.) in a randomized, double-blind, multicenter study. Complete healing was achieved after 4 and 8 weeks of therapy (protocol-correct) in 69 and 82% (pantoprazole) and 57 and 67% (ranitidine), respectively (p = 0.054 at 4 weeks and p < 0.01 at 8 weeks). The predominant symptoms of gastroesophageal reflux, i.e., heartburn and acid eructation, were more effectively reduced in pantoprazole- than in ranitidine-treated patients. The frequency of adverse events was low and did not differ between the two treatment groups. We conclude that pantoprazole is superior to ranitidine in the acute treatment of reflux esophagitis.