A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism.

BACKGROUND: Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of PPIs. AIM: To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. METHODS: CYP2C19*2, *3, *4, *5 and *17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2 *2/*17 and 1 *2/*2 were included in a randomized investigator-blinded cross-over study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-h pH-monitoring was performed on days 0, 1 and 5 of oral dosing. RESULTS: A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid-inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid-inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at day 1 and 5. CONCLUSIONS: Esomeprazole provides acid-inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype.

Systematic review: Rebound acid hypersecretion after therapy with proton pump inhibitors.

BACKGROUND: The occurrence and the clinical relevance of rebound acid hypersecretion after discontinuation of proton pump inhibitors is unclear. AIM: To perform a systematic review of rebound acid hypersecretion after discontinuation of proton pump inhibitors. METHODS: PubMed, Embase and Central were searched up to October 2005 with indexed terms. RESULTS: Eight studies were included, sample size was 6-32. The studies used both basal and stimulated acid output as parameters to study rebound acid hypersecretion and assessed these at different time points and with variable methods. Five studies (including four randomized studies) did not find any evidence for rebound acid hypersecretion after proton pump inhibitor therapy. Of the remaining three studies, the duration of proton pump inhibitor therapy was the longest and two of these studies were the only to assess Helicobacter pylori status of their study subjects. These two studies suggested that rebound acid hypersecretion may occur in H. pylori-negatives after 8 weeks of proton pump inhibitors. CONCLUSIONS: Studies that have investigated rebound acid hypersecretion after cessation of proton pump inhibitor treatment are heterogenic in design, methods and outcome. There is some evidence from uncontrolled trials for an increased capacity to secrete acid in H. pylori-negative subjects after 8 weeks of treatment. There is no strong evidence for a clinically relevant increased acid production after withdrawal of proton pump inhibitor therapy.

Pharmacodynamics and kinetics of omeprazole MUPS 20 mg and pantoprazole 40 mg during repeated oral administration in Helicobacter pylori-negative subjects.

BACKGROUND: Omeprazole has become available in a tablet formulation, a Multiple Unit Pellet System (MUPS) containing a large number of small individually enteric-coated micropellets. AIM: To compare the acid-inhibitory effect of omeprazole MUPS 20 mg with pantoprazole 40 mg and to describe the pharmacokinetics of both drugs following administration on day 1 and day 6. METHODS: Randomized, two-way crossover study. Sixteen Helicobacter pylori-negative healthy subjects, whose gastric acidity fell below pH 4 for 70% of a 24-h baseline period were included. Intragastric pH was measured continuously. RESULTS: On day 1 both drugs significantly raised median 24-h gastric pH compared to baseline. Median pH and percentages of time above pH 3 and 4 on day 1 and day 6 of administration were not significantly different, with the exception of median daytime pH on day 6, which was significantly higher with omeprazole (4.65 vs. 4.05). AUC and Cmax of omeprazole were significantly increased on day 6. AUC and Cmax of pantoprazole were not significantly increased. CONCLUSIONS: No significant difference in acid-inhibitory effect on day 1. On day 6 median daytime pH was significantly higher with omeprazole MUPS, but the percentages of time spent above pH 3 and 4 were not significantly different. The significant increase in bioavailability of omeprazole may contribute to the increased effect on day 6.

Are there indications for intravenous acid-inhibition in the prevention and treatment of upper GI bleeding?

Administration of acid-inhibiting drugs in the prevention of stress ulcer bleeding is based on the hypothesis that pepsin activity is pH-dependent. In the treatment of peptic ulcer bleeding, acid-inhibition is based on the hypothesis that clot formation and clot lysis depend on intraluminal pH. Medications used in the prophylaxis of stress ulcer bleeding comprise antacids, sucralfate, H2-receptor antagonists and proton pump inhibitors (PPIs). Two studies show that prophylaxis with ranitidine is more effective than prophylaxis with sucralfate. PPIs give a more predictable and sustained pH control during prolonged dosing than ranitidine. Two trials show that patients who receive omeprazole run a significantly lower risk of bleeding than patients receiving ranitidine. The optimal initial treatment for bleeding peptic ulcers in patients with active bleeding or non-bleeding visible vessel is endoscopic therapy. Among patients with non-bleeding visible vessels or adherent clots who do not undergo endoscopic therapy, acid-inhibition with PPIs may significantly reduce rebleeding rate and need for surgery. After endoscopic therapy acid-inhibition with PPIs may have a beneficial effect on hemostasis. One direct comparative trial showed no significant difference in clinical outcomes between patients whether treated with high-dose or low-dose PPI. The use of multiple medications to treat concurrent conditions in ICU patients or bleeding peptic ulcer patients increases the risks of clinically important metabolic drug interactions. More recently developed PPIs are less dependent on CYP2C19 and probably have a lower potential for metabolic drug interactions. For both indications the optimal dose PPI has to be established.

Pharmacodynamic modeling of the acid inhibitory effect of ranitidine in patients in an intensive care unit during prolonged dosing: characterization of tolerance.

OBJECTIVE: To characterize the relationship between the pharmacokinetics and the acid inhibitory effect of ranitidine during prolonged dosing on the basis of a physiologic indirect-response model. METHODS: Multiple doses of ranitidine were administered to 18 patients in an intensive care unit in an open randomized trial. All patients received an initial intravenous dose of 50 mg ranitidine; after 12 hours repeated injections (50 mg every 6 hours) or a primed continuous infusion (50 mg plus 0.125 mg/kg/h) was administered. Intragastric pH was monitored continuously for at least 42 hours. RESULTS: After the initial injection a time lag was observed between the increase of plasma concentration and the increase of pH. With the indirect-response model the rate of onset of effect (kout) could be estimated adequately by relating the inhibitory effect on acid secretion to the concentration according to a sigmoid Emax model. For administration of a single dose, estimated pharmacodynamic parameters were 4.5 +/- 0.9 h(-1) for kout, 1.4 +/- 0.1 for baseline pH, 0.051 +/- 0.012 mg/L for 50% inhibition constant, and 7.0 +/- 1.5 for Hill factor (mean +/- SEM; n = 18). Tolerance developed during subsequent dosing that could be described as a linear increase (beta) of 50% inhibition constant with time (beta = 0.0030 and 0.0045 mg/L/h for repeated and continuous administration, respectively). CONCLUSIONS: The developed physiologic indirect-response model may be used to quantify the pharmacokinetic-pharmacodynamic relationship of ranitidine during single and multiple dosing. During prolonged intravenous dosing, tolerance developed within 42 hours and could be characterized on the basis of the developed indirect-response model.

Post-prandial intragastric and duodenal acidity are increased in patients with chronic pancreatitis.

OBJECTIVES: Patients with chronic pancreatitis and exocrine insufficiency have lower intraduodenal pH compared to controls. It has been assumed that abnormal low intraduodenal pH in these patients not only results from impaired pancreatic bicarbonate secretion but also from an increased gastric acid load to the duodenum. METHODS: We have tested this hypothesis by combined intragastric and intraduodenal 24 h pH monitoring in nine chronic pancreatitis patients with exocrine pancreatic insufficiency and nine healthy control subjects during standardized test conditions. Postprandial gastrin and cholecystokinin release were also determined. RESULTS: Median 24-h intraduodenal pH (5.90 vs. 6.00) and intragastric pH (1.60 vs. 1.70) were not significantly different between patients and controls. However, in the 2-h postprandial periods intraduodenal pH was below five for a significantly higher percentage of time in chronic pancreatitis patients compared to controls (lunch: 14.5% vs. 0.17%, P=0.011; dinner: 24.1% vs. 5.75%, P=0.05). The post-dinner intragastric pH was below three for a significantly higher percentage of time in chronic pancreatitis patients vs. controls (72.2 vs. 48.9%, P=0.04). Postprandial gastrin release was not significantly different between the two groups. Postprandial secretion of cholecystokinin (CCK), as enterogastrone, was significantly (P < 0.01) reduced in chronic pancreatitis patients (78 +/- 13 pmol/L, 120 min) compared to controls (155 +/- 14 pmol/L, 120 min). CONCLUSIONS: Median intraduodenal and intragastric pH are not significantly decreased in patients with chronic pancreatitis and exocrine insufficiency but the postprandial time with an acidic pH in the duodenum (pH < 5) and in the stomach (pH < 3) is significantly (P

Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis.

The benefits of a pharmacy-based, active therapeutic drug monitoring (TDM) service (ATM) on outcomes were examined in a prospective study at four hospitals. ATM involved pharmacokinetic dosage optimization at the start of treatment, subsequent Bayesian adaptive control, and frequent patient evaluation. Cost-effectiveness was calculated based on real costs. The ATM group comprised 105 patients and 127 patients with nonguided TDM who were followed up as controls. Forty-eight of the ATM and 62 of the nonguided TDM patients had an infection on admission. Peak concentrations in ATM patients were significantly higher (10.6+/-2.9 mg/L; nonguided TDM, 7.6+/-2.2 mg/L; p < 0.01). Trough levels in the ATM group were significantly lower (p < 0.01). There was a trend toward lower mortality in the ATM group (nine of 105 versus 18 of 127; p = 0.26) that was significant for patients with an infection on admission (one of the 48 ATM patients died versus nine of the 62 nonguided TDM patients; p = 0.023). ATM reduced the length of hospital stay for all patients in the study (20.0+/-1.4 days; nonguided TDM, 26.3+/-2.9 days; p = 0.045) and for patients admitted with an infection (12.6+/-0.8 days; nonguided TDM, 18.0+/-1.4; p < 0.001). The incidence of nephrotoxicity was reduced from 13.4% (nonguided TDM) to 2.9% (p < 0.01). With ATM, total costs were lower for all patients (Dutch guilders [DFL], 13,125+/-9,267; nonguided TDM, DFL 16,862+/-17,721; p < 0.05) and for patients admitted with an infection (DFL 8,883+/-3,778; nonguided TDM, DFL 11,743+/-7,437; p < 0.01). Goal-oriented, model-based dosing of aminoglycosides resulted in higher antibiotic efficacy, shorter hospitalization, and reduced incidence of nephrotoxicity. By combining efficacy with savings, ATM offered a significant alternative to usual care.

[Intravenous gastric acid inhibition for stress ulcers and bleeding peptic ulcers]. / Intraveneuze remming van de maagzuursecretie bij stressulcera en bloedende peptische ulcera.

Intravenous acid inhibition is used in the prevention of upper gastrointestinal bleeding in intensive care unit patients and in the treatment of peptic ulcer bleeding. The strongest risk factors for upper gastrointestinal bleeding are mechanical ventilation for more than 48 hours and coagulopathy. However, a subgroup of critically ill patients without these risk factors may still be at risk of upper gastrointestinal bleeding. Stress ulcer prophylaxis with sucralfate is not effective. Patients who receive intravenous ranitidine (50 mg every 8 hours) run a significantly lower risk of gastrointestinal bleeding. In one study stress ulcer prophylaxis with oral omeprazole was more effective than prophylaxis with intravenous ranitidine. Endoscopic therapy is the cornerstone in modern therapy of peptic ulcer bleeding. Addition of acid inhibition may be effective in preventing clot lysis. H2-receptor antagonists do not influence the natural history of peptic ulcer bleeding. In addition to endoscopic therapy acid inhibition with proton pump inhibitors like omeprazole is more effective than acid inhibition with H2-receptor antagonists. However, the optimal dose and way of administration of omeprazole are not known.

Acid-inhibitory effects of omeprazole and lansoprazole in Helicobacter pylori-negative healthy subjects.

BACKGROUND: Omeprazole 20 mg once daily (o.d.) and lansoprazole 30 mg o.d. have similar acid-inhibitory effects in healthy Helicobacter pylori-positive subjects. However, little is known about the acid-inhibitory effects of the o.d. and twice daily (b.d.) doses in H. pylori-negative subjects. AIM: To compare the decrease in gastric acidity of omeprazole 20 mg (o.d. and b.d.) with lansoprazole 30 mg (o.d. and b.d.) in healthy H. pylori-negative subjects on day 6-7 of dosing. METHODS: A randomized, investigator-blind, crossover study design was used. Intragastric pH was measured continuously with glass electrodes positioned in the gastric corpus. Sixteen H. pylori-negative subjects, whose intragastric acidity fell below pH 4 for 70% of a 24-h baseline period. were entered in the study. RESULTS: Both dosing regimens of omeprazole and lansoprazole significantly increased median gastric pH and percentages of time above pH 4 during the entire 24-h period, night- and daytime, compared to baseline. There were no significant differences in median gastric pH values or time above pH thresholds 3, 4 and 5 between the o.d. dosing regimens. During the night the percentage of time spent above pH 3 and 4 was significantly higher with omeprazole 20 mg b.d. than with lansoprazole 30 mg b.d. CONCLUSIONS: This comparative study demonstrates that daily doses of omeprazole 20 mg and lansoprazole 30 mg are equally effective in raising intragastric pH in H. pylori-negative subjects on day 6 of dosing. During the night, omeprazole 20 mg b.d. provides superior gastric acid suppression compared to lansoprazole 30 mg b.d.

Effect of omeprazole 40 mg once daily on intraduodenal and intragastric pH in H. pylori-negative healthy subjects.

There is a lack of information about the effect of omeprazole or other antisecretory drugs on intraduodenal pH. Aim of the study was to document the variation over time of intraduodenal pH during a 24-hr period and to simultaneously study the effect of omeprazole 40 mg once daily on intragastric and intraduodenal pH in healthy H. pylori-negative subjects. In a randomized, placebo-controlled study, eight subjects (five women, three men, mean age 22.7 years) received oral 40 mg omeprazole or placebo once daily for eight days. On day 7, intragastric and intraduodenal pH was measured continuously for 24 hr, using two miniature glass-membrane electrodes placed in the stomach (fundus) and in the distal third of the duodenum. The 24-hr median intraduodenal pH was 5.95 with placebo and 5.85 with omeprazole. Median intragastric pH was 1.68 without and 4.93 with omeprazole. During omeprazole therapy, intragastric pH fell below 4.0 in five of eight subjects. In the 2- and 3-hr postprandial periods, the percentage of time with pH < 5 was significantly reduced with omeprazole. In healthy subjects, 24-hr median and postprandial pH in the distal part of the duodenum was lower than previously thought. Omeprazole significantly reduced the percentage of time with pH < 5 postprandially. At night, intragastric pH fell below 4.0 with omeprazole 40 mg once daily. Omeprazole does not change 24-hr median intraduodenal pH significantly.

In vitro dissolution profiles of enteric-coated microsphere/microtablet pancreatin preparations at different pH values.

OBJECTIVES: Enteric-coated microsphere/microtablet pancreatin should stay intact in the stomach and dissolve promptly on entering the duodenum. Postprandial intraluminal pH in the distal duodenum is 5.75 and is lower in exocrine pancreatic insufficiency. The aim of the study was to measure in vitro dissolution times in buffer solutions with pH 4.0-6.0 for five currently available enteric-coated microsphere/microtablet pancreatin preparations. METHODS: The following preparations were tested: Creon, Creon Forte, Pancrease, Pancrease HL and Panzytrat. Two capsules were placed in the buffer solution at 37 degrees C in a USP dissolution testing apparatus. Buffer solutions with pH between 4.0 and 6.0 were used. Solutions were stirred at 125 r.p.m. and the rate of dissolution was monitored by taking 2-mL samples at regular intervals and measuring extinction at 280 nm. Measurements were repeated six times. RESULTS: All preparations failed to dissolve at pH 4.0. At pH 5.0 Pancrease HL showed 43% dissolution within 30 min, all other preparations 15% or less. Panzytrat and Pancrease HL showed more than 50% dissolution within 30 min at pH 5.2. Panzytrat, Pancrease HL and Creon Forte had more than 90% dissolution within 30 min at pH 5.6, and all preparations more than 90% dissolution within 30 min at pH 5.8 and higher. CONCLUSIONS: For the treatment of exocrine pancreatic insufficiency conventional strength enteric-coated microsphere/microtablet pancreatin preparations do not have an optimal dissolution profile. The newer, high lipase preparations such as Pancrease HL perform better, although still not optimally, at pH 5.4 and lower.

Gastro-oesophageal reflux disease in The Netherlands. Results of a multicentre pH study.

Information on the relationships between gastro-oesophageal reflux (GOR), reflux symptoms, hiatal hernia (HH) and oesophagitis, and the response to antisecretory treatment is lacking. In a multicentre study endoscopy, ambulatory 24-h pH monitoring and symptom assessment were carried out in 142 patients with symptomatic reflux disease before and during treatment with ranitidine. Using a randomized, double-blind design, patients took ranitidine 150 mg bid or 300 mg bid. Macroscopic oesophagitis (grade I or II) was found in 85 patients; the remaining 57 patients had normal oesophageal mucosa. A significant correlation was found between the presence of an HH and the presence of oesophagitis. Symptom scores were similar in patients with and without oesophagitis, and in patients with and without HH. Patients with oesophagitis had significantly greater oesophageal acid exposure during the night, and in the total 24-h period, but not during the day. Likewise, patients with HH had greater acid exposure during the night (p < 0.008). Both doses of ranitidine significantly decreased oesophageal acid exposure and the effect was independent of baseline acid exposure. Reflux symptoms cannot be used to differentiate between presence or absence of oesophagitis and/or HH. Reflux patients without oesophagitis have less night-time reflux. Ranitidine dose-dependently decreases oesophageal acid exposure, and the effect is independent of baseline reflux.

Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years.

BACKGROUND: Cystic fibrosis is usually diagnosed in childhood, but a number of patients are not diagnosed until adulthood. The aim of this study was to investigate whether patients diagnosed at an older age had a different genetic constitution, manifestations of disease, and prognosis from those diagnosed at an early age. METHODS: Clinical data and results of lung function tests and DNA analysis of 143 adult patients with cystic fibrosis were entered into a computerised database. Patients diagnosed before their 16th birthday (early diagnosis, ED) were compared with those diagnosed at 16 years of age or older (late diagnosis, LD). RESULTS: Mean age of diagnosis of the ED group was 4.6 years compared with 27.7 years for the LD group. Mean (SD) percentage predicted pulmonary function was better for the LD group than for the ED group: forced expiratory volume in one second (FEV1) 72.5 (31.1)% and 52.0 (24.8)%, and forced vital capacity (FVC) 89.8 (25.7)% and 71.9 (23.0)%, respectively. Colonisation with Pseudomonas aeruginosa was present in 70% of the ED group and 24% of the LD group. In the ED group 81% had pancreatic insufficiency compared with only 12% of the LD group. None of the LD group was homozygous for delta F508 compared with 58% of the ED group. In the LD group 72% were compound AF508 heterozygotes and 28% had two non-delta F508 mutations. CONCLUSIONS: Among this group of 143 adult patients with cystic fibrosis late diagnosis is caused mainly by delayed expression and mild progression of clinical symptoms. Late diagnosis is associated with milder pulmonary disease, less pancreatic insufficiency, and different cystic fibrosis mutations. Since mortality in cystic fibrosis depends on the progression of pulmonary disease, patients with a late diagnosis have a better prognosis than those diagnosed early.

Glass and antimony electrodes for long-term pH monitoring: a dynamic in vitro comparison.

OBJECTIVE: To compare the performance of combined glass microelectrodes with monocrystalline and polycrystalline antimony electrodes with external reference in a 24-h dynamic in vitro study. DESIGN AND METHODS: In an artificial stomach, the pH of the contents titrated from pH1-7 and back by NaOH and HCI was simultaneously measured at 37 degrees C with antimony and glass probes connected to three recording devices. The recorded data were compared with data monitored continuously by a laboratory pH measurement system. The sensitivity and drift of glass microelectrodes were also analysed in intensive-care unit patients during intragastric pH monitoring for up to 96 h. RESULTS: The sensitivities of antimony polycrystalline, monocrystalline and of glass electrodes were 54.6, 55.3, and 61.8 mV/pH, respectively. The hysteresis was 6.4, 7.2 and 2.75 mV for antimony polycrystalline, monocrystalline and for glass electrodes, respectively. The drift in 24 h was -0.1 pH for glass over the pH range 1-7, and +0.3 pH over pH 1-2.5, and +0.15 pH over pH 2.5-7 for both of the antimony electrodes. The response times of both antimony and glass electrodes were similar over the pH range 2.5-7. The difference in the percentages of time below pH 1.5 was significant: 28.2% for glass, 17.3% for antimony polycrystalline and 18.1% for monocrystalline electrodes, respectively (P < 0.05). However, the difference in the percentages of time below pH 4 was not significant. After 96 h intragastric pH monitoring in six intensive-care unit patients, the mean drift of glass electrodes was 0.15 pH (range, pH 0.1-0.2) and the mean change in sensitivity 1.2%. CONCLUSIONS: (1) Antimony electrodes may be acceptable for intra-oesophageal pH monitoring but are not suitable for intragastric use. (2) The use of glass microelectrodes is recommended for intragastric pH monitoring, particularly when extended monitoring over periods longer than 24 h is required.

Comparison of a high lipase pancreatic enzyme extract with a regular pancreatin preparation in adult cystic fibrosis patients.

BACKGROUND: Malabsorption due to exocrine pancreatic insufficiency is the main gastrointestinal problem in cystic fibrosis. Despite high doses of pancreatic enzyme supplements it is often not possible to normalize fat absorption. We compared a new high lipase pancreatic enzyme preparation (Pancrease-HL; Cilag, Brussels, Belgium), containing enteric coated microspheres with 25,000 U of lipase, 22,500 U of amylase and 1250 U of protease per capsule, with regular Pancrease capsules, containing 5000 U of lipase, 2900 U of amylase and 330 U of protease per capsule. METHODS: In a randomized double-blind crossover study, 13 cystic-fibrosis patients (6 male, 7 female, mean age 27.7 years) received either four capsules of Pancrease t.d.s. or one capsule of Pancrease-HL t.d.s. Patients took 20 mg omeprazole daily to raise intra-duodenal pH and thus optimize release of enzymes from the enteric coated microspheres. RESULTS: With four capsules of Pancrease t.d.s., mean fat excretion was 15.4% and mean nitrogen excretion was 19.9% vs. 15.5% fat and 19.9% nitrogen excretion with one capsule Pancrease-HL t.d.s. Fat and protein energy loss (as a percentage of total daily intake) was 18.3% with Pancrease and 18.2% with Pancrease-HL. The differences were not statistically significant. Pancrease-HL was well tolerated, with no difference in abdominal pain or general well-being scores. The number and average weight of stools passed remained the same. CONCLUSIONS: One capsule of Pancrease-HL appears to be equivalent to four capsules of regular Pancrease. Treatment with less capsules per day with the same efficacy may facilitate patient compliance.

Pattern of 72-hour intragastric acidity in a homogeneous group of intensive care unit patients.

To gain insight into the variation over time of gastric acidity in postoperative ICU patients, intragastric pH was prospectively studied in patients undergoing elective abdominal aortic reconstructive surgery during a 72-hr intra- and postoperative period. Intragastric pH was monitored continuously in 14 patients with combined glass electrodes. During the day of surgery (day 1), the median 24-hr pH for all patients was 6.25 (5.8-7.0, IQR). However, three of the 14 studied patients had a median 24-hr pH of 1.8. The median 24-hr pH throughout day 2 for all was 2.45 (1.6-4.7, P = 0.001). The median 24-hr pH on day 3 was 1.6 (1.5-2.1, P = 0.001). Median 8-hr pH values demonstrate a remarkable interpatient and intraindividual variation in the course of the postoperative period. A progressive lowering of the intragastric pH was observed in the first 40 hr. From the 40- to 48-hr interval until the end of the study, no further significant decrease was found. The intragastric pH was above 4, 74% of the time during day 1, 39% during day 2 (P = 0.006) and 16% during day 3 (P = 0.003). Percentage of time above 4 on day 2 was significantly higher than on day 3 (P = 0.04). In conclusion, since gastric acid and pepsin seem to play a role in stress ulceration, this study suggests some patients are at risk of stress ulceration from the beginning of surgery, but most patients become at risk of stress ulceration in the course of the postoperative period.

Comparison of two intravenous ranitidine regimens in a homogeneous population of intensive care unit patients.

Primed continuous infusion and repeated intravenous injections of ranitidine (daily dose 200 mg) were compared in a homogeneous population of post-operative intensive care unit patients in a randomized fashion. Intragastric pH was measured continuously for 72-96 h with combined glass electrodes positioned in the gastric corpus. Patients whose intragastric acidity fell below pH 4.0 for 70% of a 24-h period within 48 h after the operation (baseline period) were considered 'at risk' of developing stress-related lesions. From the 26 patients screened, 18 fulfilled this criterion. Nine received the continuous infusion regimen (50 mg bolus + 0.125 mg.kg/h) and nine received repeated boluses (50 mg ranitidine every 6 h). A consistent decrease of intragastric acidity was shown in each group by a rise in 24-h median pH from 1.4 (1.3-1.7; 26th-75th percentile) during the baseline period to 4.2 (1.9-5.4, P < 0.01) for the continuous infusion and from 1.55 (1.1-2.2) to 2.65 (2.1-3.5, P < 0.02) for the repeated boluses during the final 24 h of the therapy period. During that period intragastric pH was maintained above 4 for 52% of time by continuous infusion and for 40% of time for repeated boluses compared with 10.8% (P = 0.01) and 6.2% (P = 0.008) of time, respectively, in the baseline period. In conclusion, although no statistically significant differences between the two regimens could be detected, the continuous infusion regimen tended to show slightly better results in percentages of time that pH values were above 1 to 7, and in median 24-h pH values.

Pharmacokinetics of ranitidine in a homogeneous population of intensive care unit patients during intermittent and continuous administration.

The pharmacokinetics of ranitidine during two different modes of intravenous administration was studied in a homogeneous group of postoperative intensive care unit patients (n = 18). Patients at risk of developing stress-related lesions were randomized to receive repeated injections, 50 mg every 6 h (group A), or a continuous infusion, 50-mg bolus followed by 0.125 mg/kg/h (group B). Before treatment all patients received a single 50-mg ranitidine dose. Serum ranitidine concentrations were measured for 12 h after the single dose and during the treatment period, to calculate individual pharmacokinetic variables. From the single-dose study the calculated half-life, volume of distribution, and clearance were 3.14 +/- 0.61 h, 1.45 +/- 0.42 l/kg, and 0.40 +/- 0.14 l/kg/h for group A and 3.33 +/- 1.08 h, 1.16 +/- 0.20 l/kg, and 0.35 +/- 0.21 l/kg/h, for group B, respectively. Ranitidine pharmacokinetics after the single dose was comparable in the two groups. No statistically significant differences could be detected between the ranitidine pharmacokinetics after the first single dose and the multiple dose or continuous infusion.

Prevention of stress ulcer bleeding: a review.

The pathophysiology of stress ulcers is complex. There is either too much acid and pepsin or inadequate mucosal defenses. The incidence of upper GI bleeding due to stress ulcers in the ICU is 5-25% depending upon the minimum criterion of bleeding. For the individual patient the risk of bleeding is determined by his underlying condition and the number of risk factors. SAPS and APACHE II may assist in identifying those patients. Attainment of an increase in intragastric pH is effective and frequently necessary to prevent stress ulcer bleeding and reduces the incidence of overt bleeding. Based on presently available information the most suitable regime for prevention of stress ulcer bleeding is a continuous infusion or fixed bolus dosing of cimetidine or ranitidine. With respect to the side effects, ranitidine appears to be the more favorable of these two H2 blockers. The position of sucralfate in the prophylaxis has not yet been established.

Determination of urinary cystine for monitoring anticystinuric therapy.

Cystine is assayed in urine by a method adapted from the procedure of Haux and Natelson (Clin Chem 1970;16:366-369) and modifications of the method, which improved its specificity, are presented. Assay imprecision (CV) at four different cystine concentrations (range: 0.042-1.658 mmol/l) varied from 23.1% to 3.7%. Analytical recovery was 94.6 +/- 6.0%. D-Penicillamine, alpha-mercaptopropionylglycine, L-glutamine and metabolites, added to urine, had negligible effect on the results of the cystine assay. Samples were stable for 3 wk when stored at 4 degrees C or frozen. Cystine excretion (mmol/24 h) in apparently healthy persons ranged from 0.041 to 0.170 (mean +/- SD: 0.099 +/- 0.039). Cystine excretions are presented in patients treated with anticystinuric drugs.