Time Intragastric pH Research Articles

A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection.

Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.

Evaluation of a long-acting injectable formulation of omeprazole in healthy dogs.

BackgroundTo evaluate the efficacy of a single intramuscular adminsitration of long‐acting omeprazole (LA‐OMEP) in increasing gastric pH in dogs.HypothesisWe hypothesized that LA‐OMEP would meet in healthy dogs the clinical goals defined for human patients for treatment of gastroduodenal ulceration.AnimalsNine healthy research dogs.MethodsProspective experimental study. Dogs were given a 4 mg/kg intramuscular injection of LA‐OMEP. Intragastric pH was continuously recorded on treatment days 0 to 7. Daily mean pH and mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were determined.ResultsThe mean onset of action for the LA‐OMEP was 98.11 min (SD 46.39). The mean number of days the dogs' pH met established goals for MPT pH ≥3 was 5.5 days (range, 3‐7) and 5.25 days for MPT pH ≥4 (range, 3‐7). Long‐acting omeprazole met the human clinical goals pH ≥3 for 72 hours in 8/8 of the dogs and MPT pH ≥4 for 96 hours in 7/8 of dogs.Conclusions and Clinical ImportanceThe LA‐OMEP formulation produced gastric acid suppression in healthy dogs for an average of 5 days and up to 7 days, after a single intramuscular injection. No major adverse effects were observed.

A prospective, randomized, masked, placebo-controlled crossover study for the effect of 10 mg omeprazole capsules on gastric pH in healthy dogs.

BackgroundEnteric‐coated omeprazole capsules are commonly used as a gastric acid suppressant in dogs. However, the efficacy of this formulation has not been evaluated for clinical use in dogs.Hypothesis/ObjectivesTo evaluate the efficacy of a 10 mg PO omeprazole capsule (TriviumVet) undergoing FDA approval to increase gastric pH in dogs. We hypothesized that encapsulated omeprazole would significantly increase the gastric pH compared to placebo and reach pH goals extrapolated from people for the treatment of esophagitis and duodenal ulceration.AnimalsSix healthy research dogs.MethodsRandomized, blinded, 2‐way crossover study. Dogs were PO administered omeprazole at 0.5 to 1.0 mg/kg or placebo (empty gelatin capsules) twice‐daily for 5 days. The intragastric pH was recorded on days 2 to 5 of treatment. Mean pH and the mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were compared between and within treatment groups.ResultsDogs treated with omeprazole had a significantly higher MPT ± SD intragastric pH ≥3 (91.2% ± 11.0%), ≥4 (86.9% ± 13.7%) and mean ± SD pH (5.4 ± 0.8) than dogs treated with placebo (19.7% ± 15.5%, 28.3 ± 20.7, and 2.4 ± 1.0, respectively) (P < .001 for all).Conclusions and Clinical ImportanceThe 10 mg enteric‐coated omeprazole capsule PO administered evaluated in this study is an effective gastric acid suppressant in healthy dogs.

Comparative analysis of the effect of PO administered acid suppressants on gastric pH in healthy cats.

BackgroundProton pump inhibitors (PPIs) are among the most commonly prescribed medications for esophagitis and upper gastrointestinal erosion and ulceration in cats. Newer PPIs such as lansoprazole and esomeprazole are believed to be effective in cats, but the effect of many of these PPIs on gastric pH in cats has not been explored.Hypothesis/ObjectivesTo evaluate the efficacy of PO esomeprazole, dexlansoprazole, and lansoprazole on intragastric pH in healthy cats. We hypothesized that esomeprazole and lansoprazole would provide superior acid suppression compared to dexlansoprazole and reach pH goals extrapolated from people for the treatment of esophagitis and duodenal ulceration.AnimalsTwelve healthy research cats.MethodsRandomized, 3‐way crossover study. Cats were given esomeprazole and lansoprazole at a dosage of 1 mg/kg PO q12h or dexlansoprazole at 6 mg/kg PO q12h. Intragastric pH was recorded at baseline and for 4 days of treatment. Mean pH and the mean percentage time (MPT) intragastric pH was ≥3 or ≥4 were compared among and within treatment groups.ResultsCats treated with lansoprazole had a lower MPT ± SD of intragastric pH ≥3 (8.8 ± 6.8%) and mean ± SD pH (1.6 ± 0.5) than did cats treated with dexlansoprazole (41.2 ± 34.6% and 3.11 ± 1.6, respectively) or esomeprazole (54 ± 33.8% and 4.1 ± 3.9, respectively;P ≤ .04). Esomeprazole was the only treatment that achieved the goals defined for people for the treatment of duodenal ulceration by Day 4 of treatment (MPT ± SD of intragastric pH ≥4 of 77.1 ± 29.2%).Conclusions and Clinical ImportanceOrally administered esomeprazole might be a superior acid suppressant in cats compared to PO lansoprazole or dexlansoprazole.

Pharmacokinetics and Acid Suppressant Efficacy of Esomeprazole after Intravenous, Oral, and Subcutaneous Administration to Healthy Beagle Dogs.

BackgroundEsomeprazole is an S‐enantiomer of omeprazole that has favorable pharmacokinetics and efficacious acid suppressant properties in humans. However, the pharmacokinetics and effects on intragastric pH of esomeprazole in dogs have not been reported.ObjectiveTo determine the pharmacokinetics of esomeprazole administered via various routes (PK study) and to investigate the effect of esomeprazole on intragastric pH with a Bravo pH monitoring system (PD study).AnimalsSeven adult male Beagle dogs and 5 adult male Beagle dogs were used for PK and PD study, respectively.MethodsBoth studies used an open, randomized, and crossover design. In the PK study, 7 dogs received intravenous (IV), subcutaneous (SC), and oral doses (PO) of esomeprazole (1 mg/kg). Each treatment period was separated by a washout period of at least 10 days. Esomeprazole plasma concentrations were measured by HPLC/MS/MS. In the efficacy study, intragastric pH was recorded without medication (baseline pH) and following IV, SC, and PO esomeprazole dosing regimens (1 mg/kg) in 5 dogs.ResultsThe bioavailability of esomeprazole administered as PO enteric‐coated granules and as SC injections was 71.4 and 106%, respectively. The half‐life was approximately 1 hour. Mean ± SD percent time intragastric pH was ≥3 and ≥4 was 58.9 ± 21.1% and 40.9 ± 17.3% for IV group, 75.8 ± 16.4% and 62.7 ± 17.7% for SC group, 88.2 ± 8.9% and 82.5 ± 7.7% for PO group, and 12.5 ± 3.6% and 3.7 ± 1.8% for baseline. The mean percent time with intragastric pH was ≥3 or ≥4 was significantly increased regardless of the dosing route (P < .05).ConclusionThe PK parameters for PO and SC esomeprazole administration were favorable, and esomeprazole significantly increased intragastric pH after IV, PO, and SC administration. IV and SC administration of esomeprazole might be useful when PO administration is not possible. No significant adverse effects were observed.

Intragastric acidity and omeprazole exposure during dosing with either PA32540 (enteric‐coated aspirin 325 mg + immediate‐release omeprazole 40 mg) or enteric‐coated aspirin 325 mg + enteric‐coated omeprazole 40 mg – a randomised, phase 1, crossover study

Aspirin therapy is associated with adverse upper gastrointestinal effects. PA32540 is a coordinated-delivery tablet containing enteric-coated aspirin (EC-ASA) 325mg and immediate-release (IR) omeprazole 40mg. Immediate-release omeprazole (located in outer layer of tablet) is available for instantaneous dissolution rapidly after ingestion, while dissolution of the EC-ASA core is delayed until pH >5.5. To compare the pharmacodynamic and pharmacokinetic effects of PA32540 (EC-ASA 325mg + IR-omeprazole 40mg) vs. enteric-coated (EC)-omeprazole 40mg. This single-centre, open-label, randomised, two-way crossover study in healthy volunteers compared 7days of once-daily dosing with PA32540 with 7days of once-daily EC-ASA 325mg + EC-omeprazole 40mg dosed concomitantly. The primary endpoint was per cent time intragastric pH >4 over 24h on Day 7. A key secondary endpoint was determination of the pharmacokinetics of omeprazole and salicylic acid. Twenty-six subjects (mean age 29years) were enrolled into the study. On Day 7, mean per cent time intragastric pH >4 was 50.6% for PA32540 and 57.6% for EC-omeprazole 40mg (P=0.004) and geometric least squares mean AUC0-24 for omeprazole was 1446h*ng/mL for PA32540 and 2558h*ng/mL for EC-omeprazole 40mg. Day 7 median Tmax of omeprazole was 0.5h for PA32540 and 1.25h for EC-omeprazole 40mg. Total exposure to omeprazole from PA32540 was 57% of that from EC-omeprazole for the same dose amount (40mg), while absolute difference in 24-h acid control was 7%. Omeprazole exposure and pH control with PA32540 appear similar to EC-omeprazole 20mg.

The effect of once daily omeprazole and succinic acid (VECAM) vs once daily omeprazole on 24‐h intragastric pH

Parietal cell H(+)/K(+) ATPase activation is essential for optimal proton pump inhibitor (PPI) activity. Succinic acid (SA) was shown to induce gastric acid secretion. VECAM is a combination of omeprazole (OMP) and SA. To compare the effect of once daily bedtime dosing of VECAM 40 and VECAM 20 without food vs OMP 20 mg administered before breakfast on gastric acidity. Open label, randomized, crossover study enrolling 36 healthy subjects comparing the study treatments at steady state for 24 h intragastric pH monitoring. The median percent time intragastric pH > 4 demonstrated that VECAM 40 was superior to VECAM 20 (65.7%vs 49.1%P < 0.0001) and OMP 20 mg (65.7%vs 47.6%P = 0.005) during 24 h. VECAM 40 was superior to VECAM 20 (52.8%vs 38.8%P = 0.0079) and OMP 20 mg (52.8%vs 27.2%P < 0.0001), and VECAM 20 was superior to OMP 20 mg (38.8 vs 27.2 P = 0.0069) during the nighttime. VECAM 20 and OMP 20 mg were comparable during 24 h. VECAM 40 and VECAM 20 were significantly better in maintaining intragastric pH > 4 during the nighttime than OMP 20 mg. Succinic acid eliminates the need for a subsequent meal for intragastric pH control by VECAM.

Comparator pH study to evaluate the single-dose pharmacodynamics of dual delayed-release dexlansoprazole 60 mg and delayed-release esomeprazole 40 mg

Background:This paper describes a Phase 1, single-center, randomized, open-label, two-period crossover study which compared the pharmacodynamic effects of single doses of dexlansoprazole modified-release 60 mg and esomeprazole 40 mg on 24-hour intragastric pH in healthy adult subjects.Methods:Forty-four subjects aged 20–54 years were randomized in a 1:1 ratio to two sequence groups defining the order in which they received dexlansoprazole and esomeprazole in periods 1 and 2. Primary pharmacodynamic end points over 24 hours postdose were percentage of time with intragastric pH > 4 and mean pH, and secondary pharmacodynamic end points were percentage of time intragastric pH > 4, and mean pH at 0–12 hours, and at >12–24 hours postdose. Each drug was given after an overnight fast and one hour before breakfast. Continuous pH recording began immediately before dosing through to 24 hours postdose.Results:At 0–24 hours postdose, the mean percentage of time with pH > 4 for dexlansoprazole and esomeprazole was 58% and 48%, respectively; the difference was statistically significant (P = 0.003). The average of mean pH values at 0–24 hours postdose for dexlansoprazole and esomeprazole were 4.3 and 3.7, respectively; the difference was statistically significant (P < 0.001). At >12–24 hours postdose, mean percentage of time with pH > 4 and average of mean pH were greater for dexlansoprazole (60% and 4.5, respectively) compared with esomeprazole (42% and 3.5, respectively); the difference was statistically significant (P < 0.001 for both intervals). At 0–12 hours postdose, the difference in dexlansoprazole and esomeprazole values for the pharmacodynamic end points was not statistically significant.Conclusion:For the entire 24-hour postdose period, predominantly resulting from the >12–24-hour postdose interval, the average intragastric pH following a single dose of dexlansoprazole 60 mg was higher compared with that observed following a single dose of esomeprazole 40 mg, and the difference was statistically significant.

Efficacy of Oral Famotidine and 2 Omeprazole Formulations for the Control of Intragastric pH in Dogs

Little is known about the efficacy of commonly used acid suppressants on intragastric pH in dogs. To compare the effect of oral famotidine, 2 formulations of omeprazole, and placebo on intragastric pH in dogs with a catheter-free, continuous pH monitoring system. Six healthy adult mixed-breed colony dogs. Utilizing a randomized, 4-way cross over, open-label study, dogs were administered famotidine PO (1.0-1.3 mg/kg q12h), omeprazole tablet (1.5-2.6 mg/kg q24h), omeprazole reformulated paste (RP) (Gastrogard, 1.5-2.6 mg/kg q24h), and placebo for 7 days followed by a 10-day washout period. Radiotelemetric pH capsules were placed with gastroscopy assistance to continuously record intragastric pH for 4 days (days 4-7 of dosing). The percentage of time that intragastric pH was ≥3 and ≥4 was compared among treatment groups using repeated measures of analysis of variance. Tukey's Studentized range test was used to determine which groups were different with α= 0.05. Mean ± SD percent time intragastric pH was ≥3 and ≥4 was 22 ± 8% and 14 ± 6% for famotidine, 63 ± 14% and 52 ± 17% for omeprazole tablet, 54 ± 17% and 44 ± 18% for omeprazole RP, and 6 ± 6% and 5 ± 5% for placebo. Both omeprazole formulations significantly increased intragastric pH compared with famotidine and placebo, but omeprazole tablet and RP was not significantly different from each other. Oral omeprazole tablet and RP provide superior gastric acid suppression to famotidine, and should therefore be considered more effective for the treatment of acid related disorders in dogs.

Effect of CYP2C19 genotypes on the pharmacokinetic/pharmacodynamic relationship of rabeprazole after a single oral dose in healthy Chinese volunteers

To explore the pharmacokinetic/pharmacodynamic relationship of rabeprazole and the role of CYP2C19 genotypes after a single oral dose in healthy Chinese volunteers by a population approach. Plasma concentration time profile data and intragastric pH values of 19 genotyped healthy male adults after a single oral dose of rabeprazole in an open label randomized fashion were used for this population analysis. Simulation technology was performed to examine the rabeprazole response in subjects with different CYP2C19 genotypes to further investigate the effect of acid inhibition. The pharmacokinetics of rabeprazole was characterized by a two-compartment model with first order absorption and with an absorption lag-time. The results show that clearance of rabeprazole was affected by CYP2C19 genotypes (average clearances of homEM, hetEM, and PM were 13.9, 11.5, and 8.74 L·h(-1) respectively). An effect compartment with a sigmoidal Emax model was considered more rational for analyzing the relationship between rabeprazole concentrations and intragastric pH values. Simulated results suggest that rabeprazole 20 mg once daily for PMs is sufficient, but might be administered more frequently for other genotypes in treating gastro-esophageal reflux disease. The CYP2C19 genotype played a considerable role in the pharmacokinetic characteristics of rabeprazole, and this might need to be taken into account for clinical use.

W1100 Intragastric pH Holding Time of pH

Introduction We have previously proposed a linear relationship between the degree and duration of suppression of 24-h intragastric acidity and the healing rate of erosive esophagitis (EE) with the best predictor as per cent time pH ≥4. Poor response to PPI is an increasingly important concern. Simply reporting time pH Methods A meta-analysis was performed to provide 24-h intragastric pH values at steady state (day 5–8) in healthy volunteers and the EE healing rate at 4 or 8 weeks, by searching the English-language literature up to June 2009 in MEDLINE and EMBASE. For pH data, a weighted mean is only possible by using the sample size of each arm ((mean×n from each study)/Σ treated N). A regimen was excluded if Result 95 studies (411 arms) provided intragastric pH data and 109 studies (243 arms) provided EE healing data for 3 H2-RAs, 5 PPIs and placebo. The commonly reported pH parameter in the pH-EE model was mean per cent time pH Conclusion Any increase in the time intragastric pH is pH

The effect of time‐of‐day dosing on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR: evidence for dosing flexibility with a Dual Delayed Release proton pump inhibitor

Dexlansoprazole MR is a Dual Delayed Release proton pump inhibitor formulated to extend the duration of acid suppression. To evaluate the pharmacokinetics and pharmacodynamics of dexlansoprazole MR dosed before 4 different meal times. In this randomized, open-label, four-way crossover study, 48 healthy subjects received dexlansoprazole MR 60 mg once daily 30 min before breakfast, lunch, dinner or an evening snack. Pharmacokinetics of dexlansoprazole MR and intragastric pH were assessed over a 24-h postdose interval on day 5 for each regimen. Absorption was delayed when dexlansoprazole MR was administered before each regimen relative to breakfast; however, systemic exposures of dexlansoprazole at all regimens were bioequivalent. There were no statistically significant differences in mean 24-h intragastric pH between dosing before dinner or an evening snack vs. breakfast; however, there was a small (0.2), but statistically significant difference between lunch and breakfast. There was a statistically significant difference of 7 percentage points in the percentage of time intragastric pH was >4 for the snack regimen relative to the breakfast regimen, but there were no statistically significant differences between lunch or dinner compared with breakfast. Dexlansoprazole MR provides comparable acid control when administered at different times of the day.

PWE-078 Intragastric ph holding time of pH &lt;4 predicts low erosive esophagitis healing rate

<h3>Introduction</h3> We have previously proposed a linear relationship between the degree and duration of suppression of 24-h intragastric acidity and the healing rate of erosive esophagitis (EE) with the best predictor as per cent time pH ≥4. Poor response to PPI is an increasingly important concern. Simply reporting time pH &lt;4 may not reflect the extent of acid exposure because of the log scale of pH (1 unit pH change is a 10-fold change in [H+ ion] and a 100-fold increase if pH falls from 4 to 2). Indeed, in healthy volunteers ∼40% of the 24-h is pH ≤4 after 5 days esomeprazole 40 mg om and pH is &lt;2 for 42% of the time between midnight and 0700.1 We aimed to investigate the relationship of time pH &lt;4 in the 24-h and the EE healing rate at 4 and 8 weeks with antisecretory drugs, since time pH &lt;4 is the only widely available pH parameter. <h3>Methods</h3> A meta-analysis was performed to provide 24-h intragastric pH values at steady state (day 5–8) in healthy volunteers and the EE healing rate at 4 or 8 weeks, by searching the English-language literature up to June 2009 in MEDLINE and EMBASE. For pH data, a weighted mean is only possible by using the sample size of each arm ((mean×n from each study)/Σ treated N). A regimen was excluded if &lt;20 subjects provided pH data. For EE data, the pooled healing rate was calculated by weighting the sample size (random effect model) using StatsDirect®2.6.3. Here also a regimen was excluded if &lt;30 subjects per arm provided EE data. Standard linear regression was performed by SPSS® 17.0, with the pooled EE healing rate at 4 weeks or 8 weeks as the dependent variable and mean per cent time pH &lt;4 in 24-h of the corresponding treatment regimen as the independent variable. <h3>Result</h3> 95 studies (411 arms) provided intragastric pH data and 109 studies (243 arms) provided EE healing data for 3 H2-RAs, 5 PPIs and placebo. The commonly reported pH parameter in the pH-EE model was mean per cent time pH &lt;4, which was used in the model. At 4 weeks, the model for the EE (all grades) healing rate = 110.52−1.01* mean per cent time pH &lt;4 in 24 h (R=0.862, p&lt;0.001). At 8 weeks. The model for EE (all grades) healing rate=124.88−1.02* mean per cent time pH &lt;4 in 24 h (R=0.887, p&lt;0.001). <h3>Conclusion</h3> Any increase in the time intragastric pH is pH &lt;4 in the 24 h at steady state in healthy volunteers is associated with a decrease in the EE healing rate at 4 and 8 weeks. The per cent time that intragastric pH &lt;4 is a significant predictor for EE non-healing. Although, not usually reported, a better predictor is likely to be the time pH is &lt;3 or better pH &lt;2, especially during the night-time period.

Omeprazole‐Mg 20.6 mg is superior to lansoprazole 15 mg for control of gastric acid: a comparison of over‐the‐counter doses of proton pump inhibitors

Over-the-counter (OTC) proton pump inhibitors (PPIs) relieve heartburn by decreasing the production of gastric acid, but may not do so with equal effectiveness. It is important for healthcare professionals to compare the ability of OTC PPIs to control gastric acid when recommending them for patients with frequent heartburn. To compare the effects of omeprazole-Mg 20.6 mg and lansoprazole 15 mg (OTC doses in the US) on 24-h steady state gastric acid suppression. This single-centre, randomized, double-blind clinical study compared the steady-state gastric acid control of omeprazole-Mg 20.6 mg vs. lansoprazole 15 mg, dosed before breakfast. Volunteers were enrolled in a 3-period, cross-over design (ABB, BAA) with 24-h gastric pH monitoring on dosing day 5. The primary efficacy variable was the percentage time intragastric pH was >4.0 over 24 h on day 5 of dosing. Forty subjects were enrolled; all completed the study. The mean (SE) percentage time pH was >4.0 was 45.7% (3.45%) for omeprazole-Mg 20.6 mg and 36.8% (3.45%) for lansoprazole 15 mg, an absolute difference of 8.9% (P < 0.0001), and a relative difference of 24.2%. Both drugs were well tolerated. Omeprazole-Mg 20.6 mg provided a statistically significantly (P < 0.0001) greater acid control than lansoprazole 15 mg.

Intravenous esomeprazole pharmacodynamics in critically ill patients

Objective:A widely held belief contends that food-induced proton pump activation is important for optimal proton pump inhibitor–induced inhibition of gastric acid secretion. This study was undertaken to assess intragastric acid control with intravenous (IV) esomeprazole in critically ill patients.Research design and methods:This open-label, single-arm, exploratory trial was conducted at five university or regional hospital intensive care units in the US. Adult patients admitted to an intensive care unit who required mechanical ventilation and had at least one additional risk factor for stress-induced ulcer received twice-daily IV esomeprazole 40 mg for 48 hours and could continue for another 24 hours if no prepyloric enteral feedings were planned.Clinical trial registration:Trial registration: ClinicalTrials.gov identifier: NCT00428701.Main outcome measures:The primary efficacy variable was the linear-interpolated percentage of time intragastric pH was ≥4 during 24–48 hours. Secondary efficacy variables included the interpolated percentage of time intragastric pH was ≥4 during 0–24, 0–48, and 48–72 hours, the percentage of gastric aspirates collected with pH ≥4 during 0–24, 24–48, 0–48, and 48–72 hours, and time to stable pH ≥4. Safety was assessed based on adverse events (AEs), physical examinations, vital signs, laboratory tests, and electrocardiograms.Results:Forty-five patients were enrolled (one was excluded because of previous partial gastrectomy). Interpolated mean percentage time pH ≥4 was 88.8%, 80.7%, and 83.5% for 24–48, 0–24, and 0–48 hours, respectively. For 0–72 hours, ≥78% of gastric aspirates had pH ≥4. Median time to stable pH was 1 hour (95% confidence interval: 0.67, 2.00). Treatment was well tolerated, with no evidence of gastrointestinal bleeding. A total of 75 AEs occurred in 34 patients, none considered treatment related.Conclusions:In this noncontrolled exploratory study, twice-daily IV esomeprazole 40 mg rapidly decreased intragastric acidity and effectively maintained pH ≥4 during 0–72 hours in fasting, critically ill, mechanically ventilated patients at high risk for stress ulcers.

Addition of a H2 Receptor Antagonist to PPI Improves Acid Control and Decreases Nocturnal Acid Breakthrough

The addition of a bedtime H2 receptor antagonist (H2RA) to proton pump inhibitor (PPI) b.i.d. to inhibit nocturnal acid breakthrough (NAB) is controversial. H2RA tolerance has been documented suggesting limitations in its long-term effect. To compare the intragastric pH and NAB occurring with twice daily PPI with or without the addition of a H2RA. Multichannel intraluminal impedance-pH studies in 100 patients were reviewed. Fifty-eight patients (female 41; mean age, 54 y; range, 17 to 85) were studied on twice daily PPI. Forty-two patients (female 36; mean age, 53 y; range 20 to 85) were studied on a PPI b.i.d.+H2RA for at least 1 month at bedtime. The percentage time of intragastric pH<4 (upright, recumbent, and total) and NAB were compared between the groups. In the patients with PPI b.i.d. 64% had NAB, compared with only 17% of patients on PPI b.i.d. and H2RA q.h.s. (P<0.001). The percent time intragastric pH<4 for patients on PPI b.i.d. was significantly higher (P<0.01) compared with patients on PPI b.i.d.+H2RA q.h.s. during upright (29.1+/-3.0 vs. 18.3+/-2.9), recumbent (33.5+/-3.4 vs. 12.5+/-3.1), and entire period (31.5+/-2.8 vs. 18.0+/-3.0). The addition of a bedtime H2RA reduces the percentage time of the intragastric pH<4 and also NAB. H2RA should be considered as adjunct therapy in whom greater suppression of gastric acid control is considered desirable.

Pharmacokinetics and Pharmacodynamics of Lansoprazole in Children 13 to 24 Months Old With Gastroesophageal Reflux Disease

To evaluate the pharmacokinetics and pharmacodynamics of lansoprazole in children between 13 and 24 months of age with gastroesophageal reflux disease (GERD). From the population of 66 children with symptomatic GERD, erosive esophagitis (> or = grade 2) or esophageal pH < 4 for > 4.2% of the 24-h period who participated in a phase I/II, open-label, multicenter (11 sites) US study, a subanalysis of 8 toddlers between 13 and 24 months of age was performed. All children were treated, based on body weight, with lansoprazole 15 mg once daily for 8 to 12 weeks. If a child were still symptomatic after 2 weeks of treatment, then the dose of lansoprazole could be increased to twice daily at the discretion of the investigator. Pharmacokinetic parameters were assessed at day 5. Twenty-four-hour median intragastric pH and the percentage of time intragastric pH > 3 or > 4 were assessed at baseline and at day 5 of treatment. Symptom response was assessed by investigator interview and daily diary. Safety was monitored by physical examinations including vital signs, adverse event assessments and laboratory evaluations. Pharmacokinetic analysis of 5 children found a mean time to reach maximum concentration of 1.4 h, maximal plasma concentrations of 894 ng/mL, area under the concentration time curve of 1906 ng * h/mL and a half-life of 0.66 h. Significant (P < or = 0.027) increases from baseline to day 5 were observed in mean 24-h intragastric pH (2.76-3.52) and the percentages of time pH were > 3 (29.46%-55.36%) and pH was > 4 (16.96%-40.77%). Six of the 8 children had improvement in their overall GERD symptom severity on the basis of investigator assessment, and a reduction was seen in the percentage of days with moderate, severe or very severe GERD symptoms compared with baseline. The dosage of lansoprazole was increased in 3 of the 8 children. Median fasting serum gastrin level increased from 65.0 pg/mL at baseline to 136.5 pg/mL at the final visit. Treatment-related events were mild constipation (1 subject) and mild diarrhea (1 subject). Although larger studies are needed to confirm these results, lansoprazole displays pharmacokinetic and pharmacodynamic parameters in children between 13 and 24 months of age that are similar to those results observed in older children as well as adults.

Relationship between intragastric acid control and healing status in the treatment of moderate to severe erosive oesophagitis

To assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis. In this proof-of-concept study, adults with endoscopically verified Los Angeles grade C or grade D erosive oesophagitis were randomly assigned to oral esomeprazole 10 or 40 mg once daily for 4 weeks. On day 5, patients underwent 24-h pH monitoring. At 4 weeks, erosive oesophagitis healing status was endoscopically assessed. Investigators scored gastro-oesophageal reflux disease symptoms on a 4-point scale [none to severe (0-3)] before and 4 weeks after treatment. The percentage of time intragastric pH was >4.0 and healing status were correlated and tested for significance using a Spearman rank correlation (r). 103 patients had evaluable data (mean age, 48.7 years; 65% men). Mean percentages of time with intragastric pH >4.0 on day 5 in patients with healed and unhealed erosive oesophagitis were 61% and 42%, respectively (P = 0.0002), indicating that erosive oesophagitis healing rates were positively related to the percentage of time intragastric pH was >4.0. Greater intragastric acid control correlated with lower final daytime and night-time heartburn and acid regurgitation symptom scores (r = -0.029, -0.029 and -0.021; P = 0.003, 0.003 and 0.032, respectively). A positive relationship between intragastric acid control and erosive oesophagitis healing was demonstrated.

Endothelin-1, Inducible Nitric Oxide Synthase and Macrophage Inflammatory Protein-1?? in the Pathogenesis of Stress Ulcer in Neurotraumatic Patients

To prospectively identify histologically and endoscopically the effect of omeprazole on the expression of endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS) and macrophage inflammatory protein-1alpha (MIP-1alpha) in the gastric mucosa of neurosurgical patients with stress ulcer. Twenty-five patients with severe acute intracranial lesions caused by trauma were enrolled in this study. A 40 mg intravenous bolus of omeprazole (OME) was given daily for 7 days. The intragastric pH was continuously recorded for 24 hours on day 1 and 8. Endoscopic evaluation of the gastric corpus, antrum, and duodenal bulb was performed in the ICU, within 24 hours after brain injury, and at follow-up on the 7th day after admission. Paired biopsies were obtained for histologic examinations and immunohistochemical analysis was performed using a LSAB method for MIP-1alpha, ET-1, and iNOS. There were 72% and 70% of gastroduodenal mucosal lesions at the initial and follow-up endoscopies, respectively. However, the severity of mucosal lesions showed significant improvement in most patients at follow-up (p < 0.05). Mean percentages of time intragastric pH were greater than or equal to 4.0 were 20 +/- 11% and 70 +/- 17% on day 1 and 8, respectively (p < 0.05). The incidences of ET-1, iNOS and MIP-1alpha expression were not significantly different between the patients before and after OME prophylaxis. Prophylactic OME is effective in reducing the severity of stress ulcerations in severe neurotraumatic patients. High incidence of tissue ET-1 expression combined with increased activity of iNOS and MIP-1alpha may be responsible for the gastric mucosal injury. We also show that OME fails to counter the enhancement in the mucosal expression of ET-1, iNOS, and MIP-1alpha caused by severe brain damage.

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

Attainment of intragastric pH < 6.0 may require high-dose continuously infused proton pump therapy. To assess the pharmacokinetic and pharmacodynamic dose-responses of continuous infusion regimens of lansoprazole. 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. 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. 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.