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: D9612L00107; ClinicalTrials.gov Identifier NCT00428701. MAIN OUTCOME MEASURES: The primary efficacy variable was the linear-interpolated percentage of time intragastric pH was > or =4 during 24-48 hours. Secondary efficacy variables included the interpolated percentage of time intragastric pH was > or =4 during 0-24, 0-48, and 48-72 hours, the percentage of gastric aspirates collected with pH > or =4 during 0-24, 24-48, 0-48, and 48-72 hours, and time to stable pH > or =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 > or =4 was 88.8%, 80.7%, and 83.5% for 24-48, 0-24, and 0-48 hours, respectively. For 0-72 hours, > or =78% of gastric aspirates had pH > or =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.

Intravenous esomeprazole 40 mg vs. intravenous lansoprazole 30 mg for controlling intragastric acidity in healthy adults.

BACKGROUND: Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral therapy is not appropriate. AIM: To compare IV esomeprazole and IV lansoprazole for the control of intragastric pH. METHODS: In this open-label crossover study, healthy, Helicobacter pylori-negative adults were randomized to one of two treatment sequences, each consisting of two 5-day dosing periods of IV esomeprazole 40 mg or IV lansoprazole 30 mg. Twenty-four-hour intragastric pH monitoring was conducted on days 1 and 5 of each dosing period. RESULTS: On days 1 and 5, intragastric pH was >4.0 significantly longer with esomeprazole than lansoprazole (least-squares means: day 1, 40.0% vs. 33.6%; day 5, 61.9% vs. 45.4%; both P < 0.0001). During the first 4 h of pH monitoring, intragastric pH was >4.0 significantly longer on days 1 and 5 with esomeprazole than lansoprazole (P < 0.0001). Kaplan-Meier estimates of median hours to stable pH >4.0 were 4.92 for esomeprazole and 5.75 for lansoprazole (P = 0.0014 for test on Gehan scores). CONCLUSION: In healthy adults, IV esomeprazole 40 mg controlled intragastric acidity faster and more effectively than IV lansoprazole 30 mg.

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

AIM: To assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis. METHODS: 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). RESULTS: 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). CONCLUSION: A positive relationship between intragastric acid control and erosive oesophagitis healing was demonstrated.

Intragastric acid suppression and pharmacokinetics of twice-daily esomeprazole: a randomized, three-way crossover study.

BACKGROUND: Patients with refractory gastro-oesophageal reflux disease, extra-oesophageal reflux symptoms, Barrett's oesophagus, or Zollinger-Ellison syndrome may require greater acid suppression than that obtained with once-daily esomeprazole. AIM: To assess gastric acid suppression (determined by intragastric pH) and pharmacokinetics of twice-daily vs. once-daily esomeprazole. METHODS: In a randomized, double-blind, three-way crossover study, healthy subjects received esomeprazole 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for five consecutive days. Twenty-four-hour continuous ambulatory intragastric pH was recorded on day 5. RESULTS: Esomeprazole 40 mg twice daily provided a mean of 19.2 h with intragastric pH > 4.0 (80.1% of a 24-h time period; 95% confidence interval 74.5-85.7%) vs. 14.2 h with 40 mg once daily (59.2%; 95% CI 53.7-64.7%) and 17.5 h with 20 mg twice daily (73.0%; 95% confidence interval 67.4-78.5%) in 25 subjects. Intragastric pH was maintained >4.0 for a similar percentage of time during active and sleeping periods for all doses. CONCLUSIONS: Esomeprazole 40 mg twice daily provides significantly greater acid suppression (number of hours in a 24-h period with pH > 4.0) than once-daily dosing and may be a reasonable consideration for patients requiring greater acid suppression for acid-related disease.

Esomeprazole administered through a nasogastric tube provides bioavailability similar to oral dosing.

AIM: To determine if nasogastric tube administration of the enteric-coated pellets from an opened esomeprazole capsule provides bioavailability similar to oral dosing with the intact capsule. METHODS: A randomized, single-centre, open-label, two-period crossover pharmacokinetic study consisting of two 5-day dosing periods separated by a 7- to 14-day washout period was conducted. Healthy subjects between the ages of 18 and 50 years received esomeprazole 40 mg once daily either orally as an intact capsule, or as a suspension of the enteric-coated pellets from an opened capsule in water through a nasogastric tube. RESULTS: In 47 evaluable subjects, the 90% confidence intervals were 0.87-1.08 and 0.93-1.25 for the geometric mean of the ratio of nasogastric tube administration relative to administration of the intact capsule for the area under the plasma concentration-time curve and for maximum plasma concentration, respectively, on day 1, demonstrating bioequivalence. Oral and nasogastric administration also demonstrated similar bioavailabilities on day 5. Esomeprazole was well tolerated regardless of the mode of administration. CONCLUSIONS: Nasogastric tube administration of the enteric-coated pellets from an opened esomeprazole 40 mg capsule provides bioavailability similar to oral dosing. Administration of the contents of an opened esomeprazole 40 mg capsule in water through a nasogastric tube is a practical alternative for patients with feeding tubes who require effective gastric acid suppression, but cannot swallow an oral preparation.

High prevalence of chronic gastrointestinal symptoms in a National Guard Unit of Persian Gulf veterans.

OBJECTIVES: To determine the prevalence and spectrum of GI complaints in a group of Persian Gulf veterans (PGV) and to compare these data to a group of veterans (controls) from the same unit who were not deployed to the Persian Gulf region. METHODS: A 68-item survey was distributed to 136 members of a single National Guard Unit. The survey asked the veterans to rate the frequency of GI symptoms before, during, and after the Persian Gulf war had concluded. The participants were also asked to rate frequency of 10 non-GI symptoms at the time of this survey. RESULTS: Fifty-seven PGV and 44 nondeployed veterans participated in the survey. Before the Persian Gulf war, both PGV and control groups reported low frequencies of GI symptoms. A majority of the PGV experienced GI symptoms during their deployment to the Gulf region, which persisted after their return to the United States. There were many significant differences observed between the two groups in frequency of both GI and non-GI symptoms. The greatest differences seen were for excessive gas, loose or greater than three stools per day, incomplete rectal evacuation, and abdominal pain. CONCLUSIONS: A high prevalence of chronic GI symptoms exists in this group of PGV and is significantly greater than a group of controls. The most prevalent chronic GI symptoms are those that have been associated with functional GI disorders. However, the abrupt onset and clustering in this group suggests that nonfunctional etiologies may be contributing factors.

Ca2+-mediated degradation of central nervous system (CNS) proteins: topographic and species variation.

Incubation of homogenates of rat, rabbit, and bovine spinal cord and of bovine brain white and gray matter in the presence of calcium (5 mM) produced an extensive degradation of the neurofilament triplet proteins (NFP; 200 K, 150 K, and 69 K). The breakdown products of the NFPs were identified by immunoblot. The glial fibrillary acidic protein (GFAP), microtubular proteins (MTP), and myelin proteins were also degraded. The 150 K NFP was more susceptible than the other NFPs. The extent of calcium-mediated degradation was slightly greater with rat spinal cord than the others. Bovine brain white matter had more activity than gray, which had no appreciable degradative activity. The breakdown was prevented by both EGTA and leupeptin but a similar concentration of MgCl2 (5 mM) had no effect. These results suggest that NFPs are degraded by a Ca2+-activated neutral proteinase in the central nervous system (CNS) of several species. The lesser activity in gray matter suggests that the enzyme is enriched in axons, myelin, and/or oligodendroglial cells.

Purification of a calcium-activated neutral proteinase from bovine brain.

A calcium-activated neutral proteinase (CANP) resolved into three components has been partially purified from bovine brain. The method of isolation has resulted in 22,000, 7,100, and 8,000-fold purification for CANP I, II and III respectively. All three fractions require Ca2+ for activation. The characterization of the purified CANP I has shown that it is activated by 250 microM Ca2+ and the enzyme loses its activity when incubated in the presence of Ca2+ without substrate. Mg2+ is ineffective. The enzyme degrades neurofilament triplet proteins, tubulin and casein efficiently. The myelin basic protein is hydrolyzed after longer incubation. Bovine serum albumin and histones are unaffected. The enzyme is active at pH 5.5 to 9.0 with optimum between pH 7.5 and 8.5. It has a Km of 1.8 X 10(-7) M for the 69,000 dalton neurofilament protein. The enzyme is inhibited by sulphydryl blocking reagents and also by EGTA, leupeptin and E-64c. The SDS-PAGE analysis of the enzyme fractions has shown a major band at 66-68,000 daltons and two minor bands at 60,000 and 48-50,000 daltons for CANP I; a major band at 48-50,000 daltons and a minor band at 30-32,000 daltons for CANP II and a predominant doublet at 30-32,000 daltons with a minor band at 48-50,000 daltons for CANP III. The degradation of neurofilament proteins suggests that the CANP(s) may be involved in the turnover of these proteins.