Effect of omeprazole on regional and temporal variations in intragastric acidity.

BACKGROUND: Conventional techniques for measuring gastric acidity have demonstrated the decrease in gastric acidity produced by proton pump inhibitors (PPI); however, such techniques do not detect transient or localized pH changes which may modify the intragastric environment without affecting the therapeutic efficacy of PPIs. AIM: To investigate local and temporal variations in intragastric pH and to test the hypothesis that omeprazole produces prolonged, generalized gastric anacidity (pH >6). METHODS: A single-blind study was conducted with triple-point 24-hour gastric pH-metry on days 7, 14 and 21 in 14 healthy, Helicobacter pylori-negative volunteers (7 M; 20-46 years) who received placebo for 7 days, followed by omeprazole 20 mg daily for 14 days. RESULTS: Omeprazole increased the median 24-hour pH significantly in the distal corpus (placebo: 1.3 (95% CI 1.1 to 1.6); omeprazole week 1: 4.0 (2.6-5.0); omeprazole week 2: 4.0 (2.8-4.6)) and at all other gastric recording sites (p < 0.01). At both corpus sites, nocturnal pH was lower and mealtime pH was higher than the non-meal daytime pH during placebo and both omeprazole administration periods; in the antrum, however, the major difference noted was that meal-time pH was higher than non-meal daytime pH. Antral pH was lower during meals and higher at night than proximal corpus pH. During placebo, gastric pH >6.0 was observed at 1 site only for 1.7% (median; 95% CI 0.4-3.3%), at 2 sites simultaneously for 0.24% (0.0-1.0%) and at 3 sites for 0.0% (0.0-0.28%), respectively, of the recording periods; during the second week of omeprazole, the equivalent results were 7.7% (1.4-14.0%), 4.9% (0.21-15.7%) and 4.7% (0.0-9.9%), respectively. CONCLUSIONS: Omeprazole, 20 mg daily, does not produce gastric anacidity despite significant increases in median 24-hour pH values. The time-, meal- and site-related variations in gastric pH observed under normal physiological conditions are seen to persist, with prolonged periods of low pH throughout the stomach and preservation of the normal, meal-related rise and nocturnal fall in gastric pH during omeprazole administration.

The effect of ammonia on omeprazole-induced reduction of gastric acidity in subjects with Helicobacter pylori infection.

OBJECTIVE: Omeprazole produces a higher intragastric pH during Helicobacter pylori (H. pylori) infection than after cure. We tested the hypothesis that this difference is due to the production of ammonia by H. pylori. METHODS: Gastric acidity and acid output (AO) were measured overnight in 12 subjects, with and without omeprazole, before and 1 and 6 months after cure of H. pylori infection. Gastric ammonia ([NH3]), total bile acid ([TBA]) and protein concentrations and plasma omeprazole levels were measured. RESULTS: During omeprazole, median AO were 0.0 mmol/h before, 0.86 mmol/h (p = 0.003 vs before cure) at 1 month, and 0.34 mmol/h (p = 0.02) at 6 months after cure; median NH3 output was 0.17 mmol/h before, 0.03 mmol/h (p = 0.002) at 1 month, and 0.02 mmol/h (p = 0.005) at 6 months after cure. AO and NH3 output were similar 1 and 6 months after cure. When corrected for [NH3], AO and gastric pH curves were similar before and after cure. Omeprazole plasma levels increased after cure and gastric [TBA] were unchanged. CONCLUSIONS: The higher pH observed before cure of H. pylori during omeprazole administration is attributable, in large part, to ammonia production. Other acid-neutralizing substances and changes in acid secretion may also be important, but duodenogastric reflux and omeprazole pharmacokinetics are not involved.

The effect of intra-gastric acidity and flora on the concentration of N-nitroso compounds in the stomach.

BACKGROUND: Correa's hypothesis proposes that gastric carcinogenesis is due to atrophic gastritis and hypochlorhydria which permit gastric bacterial colonization, the reduction of dietary nitrates to nitrites and the formation of potentially carcinogenic N-nitroso compounds (NOCs). OBJECTIVE: To test the hypothesis that omeprazole-induced hypochlorhydria is associated with increased intra-gastric concentrations of nitrate-reducing bacteria (NRB), nitrites and NOCs. DESIGN: Single-blind study in healthy volunteers. PARTICIPANTS: Fourteen healthy subjects (seven female, mean age 24 years), free of Helicobacter pylori infection, received a one-week course of placebo followed by a two-week course of omeprazole, 20 mg daily. METHODS: Fasted gastric samples, aspirated using a sterile double-lumen nasogastric tube at the end of the 1 st week (placebo) and the 2nd and 3rd weeks (omeprazole), were cultured aerobically and anaerobically; gastric pH and intra-gastric concentrations of nitrates, nitrites and NOCs were also determined. RESULTS: After weeks 1, 2 and 3, the intra-gastric concentrations of nitrate-reducing bacteria exceeded 10(5) colony-forming units (c.f.u.)/ml in 3, 7 and 9 subjects, respectively (P > 0.05). A gastric pH greater than 4.0 was associated with increased NRB (P < 0.05); however, neither increased gastric pH nor increased NRB, alone or in combination, was associated with increased intra-gastric concentrations of nitrites or NOCs (P > 0.05). CONCLUSIONS: A two-week increase in gastric pH in healthy, H. pylori-negative subjects was associated with increased intra-gastric concentrations of nitrate-reducing bacteria but not of nitrites or N-nitroso compounds. These data suggest that reduced gastric acid secretion is not a necessary precursor to the formation of carcinogenic N-nitroso compounds and that other mechanisms should be invoked to explain gastric carcinogenesis.

High concentrations of ammonia, but not volatile amines, in gastric juice of subjects with Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori (H. pylori) produces large amounts of ammonia. Based on higher readings obtained with an ammonia-sensitive electrode when compared to a specific enzymatic assay, it has been claimed that H. pylori also produces potentially toxic volatile amines. METHOD: We measured ammonia concentrations (NH3) in gastric aspirates from 11 H. pylori positive subjects (22-40 y, 6 M), using an ammonia electrode sensitive to ammonia and amines, and an enzymatic assay specific for ammonia. Continuous aspiration was performed overnight and 220 aspirates were analyzed before and 6 weeks after cure of H. pylori. Gastric samples were diluted 1:3 (before cure) and 1:1 (after cure) according to dilution curves constructed prior to the assays. RESULTS: Median (95% CI) NH3 detected by the electrode/enzymatic assay were 4.34 mM[4.12-4.61]/4.50 mM [4.28-4.68] (p > .05) before cure and 0.54 mM[0.42-0.60]/0.73 mM[0.71-0.81] after cure (p > .05). Intra-class correlation coefficient between the two methods was 0.91 before cure and 0.90 after cure (p < .001). Without dilution, the enzymatic assay was linear for NH3 from 0.01 to 1 mM and saturated at 2.5 mM; the electrode was linear for NH3 from 0.01 to 20 mM. When appropriate dilutions were performed, the enzymatic assay was accurate for NH3 greater than 2.5 mM. CONCLUSION: In subjects with H. pylori infection there is a high NH3 in gastric juice; production of volatile amines appears to be negligible in vivo. An ammonia-sensitive electrode and a specific enzymatic assay are both suitable methods for determining NH3 in the gastric juice of subjects with H. pylori infection.

Efficacy of omeprazole one year after cure of Helicobacter pylori infection in duodenal ulcer patients.

OBJECTIVE: We have previously shown that, in duodenal ulcer patients, pH control by omeprazole is less pronounced after cure of Helicobacter pylori infection. The present study was designed to test the hypothesis that this response to omeprazole persists 1 yr after cure of H. pylori infection. METHODS: In 12 duodenal ulcer patients, intragastric acidity was measured with a glass electrode during treatment with omeprazole (20 mg) once daily before, and 4-6 wk and 1 yr after, cure of H. pylori infection. H. pylori infection was assessed by [13C]urea breath test, culture, histology (Warthin Starry stain), and rapid urease test. RESULTS: Cure of H. pylori infection resulted in a lowered pH during omeprazole treatment. This effect persisted after 1 yr. Median 24-h gastric pH before H. pylori treatment was 5.6; 4-6 wk after cure of the infection it was 2.9 (p = 0.003), and 1 yr after cure of the infection it remained unchanged (pH = 2.5; p = 0.5). Accordingly, twice as much time was spent above pH 3 and pH 4 before H. pylori treatment than 1 or 12 months after cure (percent of time > or = pH 3: 82.7 vs. 49.7 vs. 43.1; percent of time > or = pH 4: 72.7 vs. 38.3 vs. 26.4). CONCLUSION: In duodenal ulcer patients, cure of H. pylori infection resulted in a marked rapid and persistent decrease of the pH increasing effect of omeprazole. Therefore, H. pylori is a determinant of the pH achieved in response to omeprazole treatment in duodenal ulcer patients.

One-week low-dose triple therapy for Helicobacter pylori is sufficient for relief from symptoms and healing of duodenal ulcers.

AIM: To test the hypothesis that 1-week low-dose triple therapy for H. pylori is sufficient for relief from dyspeptic symptoms and healing of duodenal ulcers. METHODS: Fifty-nine out-patients with duodenal ulcers and positive rapid urease test participated in this randomized, double-blind, two-centre study. All patients were treated for 1 week with omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. In a double-blind fashion, patients were then randomly treated for another 3 weeks with either omeprazole 20 mg once daily or an identical-looking placebo. Patients were investigated endoscopically before treatment for H. pylori, after 2 weeks and after 4 weeks. H. pylori infection was assessed by a 13C-urea breath test at the time of enrollment and 4 weeks after cessation of any study medication. RESULTS: Fifty-two patients were included in the 'all patients treated' analysis of efficacy. The overall H. pylori cure rate was 96% (95% CI = 87-100%), with no difference between the treatment groups. After 2 weeks duodenal ulcer healing was confirmed in 91% (95% CI = 80-100%) of patients treated with omeprazole and in 76% (95% CI = 60-91%) in the placebo group (P = 0.14). After 4 weeks all ulcers had healed. Relief from dyspeptic symptoms and adverse events (13.8 and 16.7%) did not differ between the treatment groups. CONCLUSIONS: One-week low-dose triple therapy consisting of omeprazole, clarithromycin and metronidazole is a highly effective and well-tolerated approach to the cure of H. pylori infection in patients with a duodenal ulcer. Our data suggest that continuation of antisecretory drug therapy beyond anti-H. pylori therapy is actually excessive regarding relief from dyspeptic symptoms and healing of duodenal ulcers.

Intragastric pH during treatment with omeprazole: role of Helicobacter pylori and H. pylori-associated gastritis.

BACKGROUND: Omeprazole treatment produces lower intragastric pH values 4 weeks after cure of Helicobacter pylori infection than before. We therefore investigated the effect of healing H. pylori-associated gastritis on intragastric pH in the presence and in the absence of omeprazole therapy. METHODS: Before and on day 8 of omeprazole, 20 mg once daily, 24-h intragastric pH-recordings were performed in 14 subjects with H. pylori infection and repeated 4 and 52 weeks after cure of infection. Gastritis severity in corpus and antrum was graded by using a modified Sydney system. RESULTS: In the absence of omeprazole administration, median 24-h pH values before cure did not differ from those 4 and 52 weeks after cure. On day 8 of omeprazole administration, 24-h pH values were much higher before cure (median, 5.15; 95% confidence interval (CI), 4.3-6.0) than 4 weeks (3.6; 2.1-4.4; P < 0.001) and 52 weeks after cure (3.0; 2.1-4.4; P < 0.001). The activity of corpus and antral gastritis was not associated with the magnitude of H+ change induced by omeprazole. CONCLUSION: The increased pH produced by omeprazole during H. pylori infection is likely to be due to neutralizing substances produced by H. pylori and not to H. pylori-induced gastritis.

Eradication of Helicobacter pylori using one-week triple therapies combining omeprazole with two antimicrobials: the MACH I Study.

BACKGROUND: Eradication of Helicobacter pylori provides potential cure in the majority of patients with peptic ulcer disease, and eradication rates of more than 90% have been reported, using omeprazole in combination with two antimicrobials. The choice of antimicrobials, dose regimen and duration of treatment have varied between studies, however, and an optimal treatment still has to be established. MATERIALS AND METHODS: We conducted an international, randomized, double-blind, placebo-controlled study involving more than 100 patients in each of six treatment groups in 43 hospital gastrointestinal units in Canada, Germany, Ireland, Sweden, and the United Kingdom. Patients (n = 787) with proved duodenal ulcer disease were randomized to treatment twice daily for 1 week with omeprazole, 20 mg (O), plus either placebo (P) or combinations of two of the following antimicrobials: amoxicillin, 1 gm (A), clarithromycin, 250 or 500 mg (C250, C500), or metronidazole, 400 mg (M). Eradication of H. pylori was evaluated by 13C-UBT, performed before and 4 weeks after treatment cessation. RESULTS: The eradication rates for the all-patients-treated analysis were 96%, OAC500; 95%, OMC250; 90%, OMC500; 84%, OAC250; 79%, OAM; and 1%, OP. OAC500 and OMC250 achieved eradication rates with lower 95% confidence interval limits exceeding 90%. All regimens were well-tolerated, 96% of patients complied with their dose regimen, and 2.3% of the patients discontinued treatment owing to adverse events. CONCLUSIONS: Omeprazole triple therapies given twice daily for 1 week produce high eradication rates, are well-tolerated, and are associated with high patient compliance. The two most effective therapies were those combining omeprazole, 20 mg, with either amoxicillin, 1 gm, plus clarithromycin, 500 mg, or metronidazole, 400 mg, plus clarithromycin, 250 mg, all given twice daily.

Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice.

BACKGROUND & AIMS: The mechanism by which antimicrobial therapy against Helicobacter pylori is enhanced by acid suppression is unknown. The aim of this study was to investigate the effect of omeprazole on gastric juice, plasma, and saliva concentrations of metronidazole, amoxicillin, and clarithromycin. METHODS: Single doses of antibiotic were administered intravenously to 24 healthy men (each antibiotic to 8 subjects) while taking placebo or omeprazole. Antibiotic concentrations were measured in gastric juice, plasma, and saliva. The pharmacokinetic parameters gastric clearance and gastric transfer fraction were calculated for each antibiotic. RESULTS: In the omeprazole group compared with the placebo group, mean maximum antibiotic gastric juice concentrations (in milligram per liter) of metronidazole decreased from 33.6 to 8.3 (P = 0.0001), whereas those of clarithromycin were unchanged, and those of amoxicillin increased from 0.13 to 0.68 (P = 0.02). Omeprazole increased salivary concentrations of metronidazole (P = 0.02) but had no effect on clarithromycin concentrations (no amoxicillin was detectable in saliva). CONCLUSIONS: Omeprazole decreases the intragastric concentrations of metronidazole by reducing acid secretion and increases intragastric concentrations of amoxicillin partly by reducing gastric juice volume. Novel pharmacokinetic parameters have been described that provide an insight into the mechanisms underlying drug transfer across the blood-stomach barrier.

Omeprazole-amoxycillin versus omeprazole-amoxycillin-clarithromycin in the eradication of Helicobacter pylori.

AIM: To assess the effect of adding clarithromycin to the combination of omeprazole and amoxycillin for the eradication of H. pylori infection. PATIENTS AND METHODS: In an open, randomized, three-centre study 120 patients (69 men, mean age 47 years, caucasians 74%) with symptoms of dyspepsia had normal gastroscopic examination and a positive urease test. They underwent a 13C-urea breath test and received, for 14 days, either omeprazole 40 mg b.d. plus amoxycillin 750 mg b.d., or the same regimen plus clarithromycin 250 mg b.d. Compliance was assessed by returned tablet counts. H. pylori clearance at the end of treatment and eradication 4 weeks after finishing treatment were assessed by 13C-urea breath test. RESULTS: Results are expressed according to 'all patients treated analysis', excluding patients who did not receive treatment and patients who had no final 13C-urea breath test assessment. In the groups treated with omeprazole-amoxycillin or omeprazole-amoxycillin-clarithromycin good compliance (> or = 90%) was observed in 85% vs. 76% (N.S.) of patients but 25% vs. 34% (N.S.) experienced at least one adverse event. Adverse events were minor, and no patient reported a metallic taste. Four weeks after finishing treatment eradication rates were 26% (95% CI: 15-37%) vs. 93% (95% CI: 86-99%) (P < 0.001). CONCLUSION: These results show that dual therapy with omeprazole plus amoxycillin achieves an unacceptably low H. pylori eradication rate. Addition of clarithromycin at low dosage (250 mg b.d.) proved to be useful, achieving a high eradication rate without increasing side-effects.

Pharmacokinetic and pharmacodynamic interactions between omeprazole and amoxycillin in Helicobacter pylori-positive healthy subjects.

BACKGROUND: Omeprazole with amoxycillin has been used to treat Helicobacter pylori infection. It was speculated that omeprazole-induced hypoacidity enhances the antibacterial activity of amoxycillin. Limited information exists about intragastric pH and bioavailability of amoxycillin during combination therapy. No data are available about possible effects of the antibiotic on the pharmacokinetics and pharmacodynamics of omeprazole. METHODS: The study was performed in a three-way cross-over double-blind design. After a run-in period on placebo with a baseline intragastric pH-metry, 24 H. pylori-positive healthy subjects were randomly dosed with amoxycillin 750 mg b.d. + placebo, amoxycillin 750 mg b.d. + omeprazole 40 mg b.d. and omeprazole 40 mg b.d. + placebo for 5 days. On the last day of each regimen intragastric pH-metries were performed, and blood samples taken for omeprazole and amoxycillin serum profiles. RESULTS: Amoxycillin monotherapy had no acid-inhibiting effect. Median pH during combined dosing was significantly lower, compared to omeprazole monotherapy (P < 0.01). Mean serum concentrations of omeprazole and amoxycillin given alone or in combination were not different. CONCLUSIONS: High-dose omeprazole does not alter the pharmacokinetics of amoxycillin. The significantly lower intragastric pH during combination therapy might be due to the H. pylori-suppressive effect of this treatment.

Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer.

BACKGROUND & AIMS: Omeprazole is less effective in healthy subjects than in patients with duodenal ulcers. The aim of this study was to determine whether Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcers. METHODS: In 16 patients with duodenal ulcers, baseline intragastric acidity was measured before and 4-6 weeks after the cure of H. pylori infection. In 17 patients with duodenal ulcers, 24-hour pH metry was performed during treatment with 20 mg omeprazole once daily before as well as after eradication of H. pylori. Intragastric acidity was measured using a glass electrode placed 5 cm below the cardia. H. pylori infection was assessed by [13C] urea breath test, culture, histology, and rapid urease test. RESULTS: H. pylori eradication resulted in marked decrease of the pH-increasing effect of omeprazole (24-hour median gastric pH, 5.5 vs. 3.0; P<0.002) that was most pronounced during nighttime (median gastric pH, 6.4 vs. 2.1; P=0.001). On the other hand, baseline intragastric pH remained unchanged after eradication (median gastric pH, 1.0 vs. 1.1; P=0.5). CONCLUSIONS: In patients with duodenal ulcers treated with omeprazole, intragastric pH depends significantly on the presence or absence of H. pylori, whereas baseline pH remained unchanged after H. pylori eradication.

Gastrointestinal transit of amoxicillin modified-release tablets and a placebo tablet including pharmacokinetic assessments of amoxicillin.

BACKGROUND: We have investigated the gastrointestinal transit time of, the influence of food intake on, the disintegration of, and the pharmacokinetics of amoxicillin in a modified-release form. METHODS: Radiolabelled modified-release tablets of amoxicillin and placebo tablets were administered, in an open three-way, randomized, crossover design, as single doses during omeprazole treatment, to six male healthy subjects during fasting and non-fasting conditions. Radioscintigraphic images and plasma samples were obtained. RESULTS: The estimated mean (and range) gastric emptying time of the modified-release tablet after drug administration was 0.3 h (0.1-1.0 h) during fasting conditions, 4.3 h (1.7-5.0 h) after a light breakfast, and 4.9 h (1.9-18.0 h) after a heavy breakfast. The small-intestinal transit time during fasting conditions was 4.7 h (2.9-6.9 h) and was not significantly changed after light or heavy breakfast intake. The relative bioavailability of the modified-release tablet was 55%, compared with a commercially available amoxicillin immediate-release tablet. CONCLUSION: The modified-release tablet of amoxicillin administered postprandially apparently increases the amoxicillin release time in the stomach. The relevance of its use for anti-H. pylori treatment can be questioned.

Effect of curing Helicobacter pylori infection on intragastric pH during treatment with omeprazole.

It has been shown that omeprazole treatment produces higher intragastric pH values in Helicobacter pylori positive subjects than in H pylori negative subjects. This study aimed to investigate the effect of curing H pylori on the intragastric pH in both the presence and absence of omeprazole therapy. Twenty four hour intragastric pH recordings were performed before and after a one week course of omeprazole (20 mg once daily) in 18 H pylori positive subjects and were repeated after the infection had been cured. In the absence of omeprazole, the total 24 hour pH values before cure did not differ from those afterwards. During omeprazole treatment the 24 hour pH values were much higher before (median (95% CI) 5.4: 4.3, 6.0), than after cure of infection (3.6: 2.1, 4.4; p < 0.001). The omeprazole induced fall in H+ activity before cure of H pylori did not, however, differ from that afterwards. It is concluded that the apparently greater antisecretory effect of omeprazole during H pylori infection may be a result of the production of acid neutralising compounds by the H pylori. Although a direct interaction between H pylori and omeprazole cannot be excluded, it seems unlikely.

Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole.

To test the hypothesis that Helicobacter pylori infection is associated with a decreased intragastric acidity during omeprazole therapy, ambulatory 24 hour dual point gastric pH recordings were performed in 18 H pylori positive and 14 H pylori negative subjects. There was a four to six week washout period between the two pH recordings made in each subject after one week courses of placebo or omeprazole, 20 mg daily. During placebo, median 24 hour pH values were not different in the corpus (H pylori positive = 1.5, negative = 1.4; p = 0.9) or antrum (H pylori positive = 1.3, negative = 1.2; p = 0.1). However, during omeprazole treatment, median 24 hour pH values were higher in H pylori positive subjects, both in the corpus (H pylori positive = 5.5, negative = 4.0; p = 0.001) and antrum (H pylori positive = 5.5, negative = 3.5; p = 0.0004). During placebo treatment, the only difference between the two groups was a higher later nocturnal pH in the antrum in the H pylori positive group. During omeprazole treatment, gastric pH was higher both in the corpus and in the antrum in the H pylori positive group for all periods, except for mealtime in the corpus. These data indicate that omeprazole produces a greater decrease in gastric acidity in subjects with H pylori infection than in those who are H pylori negative. It is not, however, known whether there is a causal relationship between H pylori infection and increased omeprazole efficacy.

Effect of omeprazole on intragastric bacterial counts, nitrates, nitrites, and N-nitroso compounds.

Previous studies have suggested that profound inhibition of gastric acid secretion may increase exposure to potentially carcinogenic N-nitroso compounds. The aim of this study was to find out if the proton pump inhibitor omeprazole (20 mg daily) is associated with increased concentrations of potentially carcinogenic N-nitroso compounds in gastric juice. The volume of gastric contents, number of bacteria, and concentrations of nitrates, nitrites, and N-nitroso compounds was determined in gastric aspirates obtained after an overnight fast in 14 healthy volunteers (7M:7F) after one week of treatment with placebo, and one and two weeks' treatment with omeprazole. Median bacterial concentrations were 1.0 x 10(4) (range 5.0 x 10(3)-5.0 x 10(6)) colony forming units (CFU)/ml after one weeks' treatment with placebo and increased significantly to 4.0 x 10(5) (0-3.3 x 10(7)) CFU/ml after two weeks' treatment with omeprazole (p < 0.05). A similar increase was seen in the concentration of nitrate reducing bacteria. There was no difference in the volume of gastric aspirates after treatment with omeprazole when compared with placebo (65 (29-155) ml v 42 (19-194) ml). The concentration of N-nitroso compounds was 0.13 (0-1.0) mumol/l after two weeks of omeprazole, which was not significantly different from that seen with placebo (0.15 (0-0.61) mumol/l). There was also no increase in the concentrations of nitrates or nitrites. It is concluded that omeprazole (20 mg once daily) for two weeks in healthy volunteers is associated with gastric bacterial proliferation but does not increase concentrations of N-nitroso compounds.

Purine metabolic pathways in rat hindlimb perfusion model during ischemia and reperfusion.

The perfused rat hindlimb preparation was used with a blood cell-free perfusate to investigate alterations in the purine nucleotide metabolism, flow rate, perfusion pressure, and venous excretion in response to ischemia and ischemia followed by reperfusion in skeletal muscle. The development of a physical hindrance during postischemic reperfusion, indicated by an increase in reperfusion pressure and a decrease in flow rate, coincided with a 90% decrease in phosphocreatine and a 50-70% reduction in total adenine nucleotide pool. The reflow impairment could not be explained by blood cell plugging of the capillaries. Washout of several metabolites was demonstrated during reperfusion. Hypoxanthine accumulated intracellularly during ischemia, and a substantial amount of uric acid was excreted into the venous effluent during reperfusion. The experimental data were fitted into a computer simulation model of the purine pathways. The model indicated that AMP deaminase was the predominant enzymatic pathway for the AMP degradation. It was demonstrated that ATP preferably accumulated as inosine-5'-monophosphate during ischemia and that xanthine oxidase was undetectable in skeletal muscle tissue homogenates. However, vascular endothelial cell xanthine oxidase activity responsible for a free radical-induced reperfusion injury could not be excluded.

Energetics of nutrition and polyamine-related tumor growth alterations in experimental cancer.

The aim of this study was to evaluate whether food intake modulates experimental tumour growth by acute alterations in the energy state and blood flow of the tumour, and if so whether such changes are related to alterations in the enzyme ornithinedecarboxylase (ODC) and DNA synthesis. Inbred mice (C57BL/J) bearing a syngeneic undifferentiated and rapidly growing tumour were used. The tumour levels of high energy phosphates were measured in vivo by 31-P-NMR spectroscopy and biochemically following tissue extraction. DNA synthesis was estimated by measuring the incorporation of bromodeoxy-uridine into tumour DNA. Difluoro-methylornithine (DFMO) was used to inhibit ODC-activity. Tumour blood flow was estimated by a 132Xe local clearance technique. Tumour progression was associated with a significant decrease in tumour tissue high energy phosphates. Acute starvation decreased DNA-synthesis and tumour energy charge as well as its PCr/Pi which were rapidly normalised during subsequent refeeding. These changes were related to similar alterations in tumour blood flow. The inorganic phosphate (Pi) resonance and the resonances in the phosphomonoester (PME) region were considerably increased in tumour tissue. Inhibition of ODC-activity by DFMO decreased DNA-synthesis, which was associated with a secondary increase in tumour high energy phosphates probably due to a lowered energy demand for tumour cell division. The results demonstrate that host undernutrition was translated into retarded tumour growth associated with a decrease in the energy state and blood flow of the tumour. The results have bearing for the evaluation and planning of all treatment protocols with potential influence on food intake in experimental tumour-bearing animals.

A study of the interaction between omeprazole and cyclosporine in renal transplant patients.

1. To determine any interaction between omeprazole and cyclosporine A (CsA) 10 male patients with 1-7 year renal transplants and stable renal function, participated in this randomised blind cross-over trial with omeprazole, 20 mg, and placebo treatment once daily for 2 consecutive weeks each. 2. Blood samples for measurement of trough concentrations of CsA were obtained twice a week during the 4 study weeks, and during the 2 weeks before and after the study. Unchanged CsA concentrations were measured by h.p.l.c. and using a monoclonal antibody r.i.a., and drug plus metabolites were measured by a polyclonal antibody f.p.i.a. In addition, one of the metabolites, M17, was assayed separately by h.p.l.c. 3. The mean whole blood trough CsA concentration during omeprazole treatment was 102 (95% confidence interval, 84-122) micrograms l-1 determined by h.p.l.c. and 81 (65-100) micrograms l-1 determined by r.i.a. Corresponding values during placebo treatment were 100 (79-127) micrograms l-1 and 95 (75-120) micrograms l-1. The ratios between omeprazole and placebo treatments were 1.01 (0.84-1.22) (h.p.l.c.) and 0.85 (0.67-1.08) (r.i.a.). Assuming that a change of < 30% in CsA blood concentrations is of no clinical significance, these results show that there was no clinically or statistically significant influence of omeprazole on CsA concentrations. Neither CsA concentrations determined by f.p.i.a. nor determination of M17 by h.p.l.c. indicated any effect of omeprazole on the metabolism of CsA. 4. It is concluded that omeprazole (20 mg daily) does not significantly interfere with CsA metabolism in stabilised renal transplant patients and may be used safely without extra monitoring of blood CsA concentrations.

A study of the interaction of omeprazole and warfarin in anticoagulated patients.

1. Thirty-five patients on continuous therapy with warfarin were given omeprazole 20 mg once daily and placebo each for 3 weeks according to a two-centre randomised double-blind cross-over design. 2. Blood samples were obtained once weekly during the run-in and follow-up periods as well as during the first 2 weeks of each treatment period, and twice during the last week of each treatment period. Plasma concentrations of R- and S-warfarin were measured by h.p.l.c. and the anticoagulant effect was assessed using the Trombotest. 3. Twenty-eight patients were evaluated. The mean plasma concentration of R-warfarin was increased by 9.5% during omeprazole treatment compared with placebo, while that of S-warfarin, the more active isomer, was unaffected. The coagulation time was not significantly changed (106 s during omeprazole and 98 s during placebo). Corresponding TT-values (Trombotest) were 8.8 and 9.9 (NS).