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Notes: Background: Adaptation to gastric damage from nonsteroidal anti-inflammatory drugs (NSAID) has been observed during ongoing dosage in rats and humans. However, this does not always occur, and our previous data suggest that NSAID half-life may be a determining factor. Aim: To investigate whether adaptation occurs during 1 week of naproxen administration in humans. Subjects: Thirteen healthy volunteers were studied at baseline, and after me or seven daily doses of naproxen 750 mg. Gastric microbleeding was measured 4 h after naproxen in gastric washings collected during a 30-min period. Serum thromboxane B concentrations were also assayed, as a marker of cyclo-oxygenase inhibition. Results: Mean blood loss after placebo was 0.60, μL/10 min (95% CI: 0.21–0.98). This rose to 2.15 (0.73–3.57) and 1.75 (0.74–2.76) μL/10 min after one and seven daily doses of naproxen, respectively (P 〈 0.05 vs. baseline: day 1 vs. 7 not significant). Thromboxane B concentrations were 〈 10% of control at both day 1 and 7 of dosing. Conclusion: In accord with our findings in rats, adaptation to this moderately long acting NSAID in humans was not apparent. We conclude that any adaptation to naproxen is unlikely to be clinically important.

Notes: The aim of this study was to investigate the protective action of a new compound, ranitidine bismuth citrate, in the prevention of aspirin-induced acute mucosal injury to the upper gastrointestinal tract of healthy human volunteers. In a double-blind randomized three-way cross-over study 24 male volunteers received placebo, 900 mg aspirin or 900 mg aspirin and 800 mg ranitidine bismuth citrate at 12-h intervals for nine doses with a 2-week wash-out period between each treatment. The median (interquartile range) number of erosions seen at endoscopy when ranitidine bismuth citrate was given with aspirin (1 [0–4]) was significantly lower than aspirin alone (24 [16–32]) (P 〈 0.001) and not significantly different from either baseline or placebo (0 [0–2]). These findings were similarly reflected in the effects on microbleeding following the ninth dose: 12.1 (7.1–21.0) μL/10 min following aspirin alone compared to levels with placebo of 1.2 (0.4–2.9), and with aspirin and ranitidine bismuth citrate of 1.6 (0.8–2.6) (P 〈 0.005). Ranitidine bismuth citrate conferred substantial protection from aspirin-induced injury to the gastric and duodenal mucosa as determined by both endoscopic assessment and microbleeding rates, reducing injury to placebo levels.

Notes: Background: Local delivery of therapeutic agents to the stomach may be a useful strategy in the treatment of Helicobacter pylori infection. We aimed to see whether the intragastric distribution and gastric retention of a therapeutic agent could be improved, either by giving omeprazole or by dosing after a meal.Methods: Twelve healthy volunteers took part in this double-blind placebo-controlled crossover study comparing the effects of omeprazole 20 mg twice daily for 5 days with placebo, and the fasted with the fed state, on the gastric emptying and intragastric distribution of a soluble scintigraphic marker contained in a drug capsule.Results: Dosing after food profoundly prolonged gastric residence of the drug label, prolonging mean time to 50% emptying (T50) from 0.5 ± 0.1 h in the fasted state to 2.0 ± 0.2 h when given after food. Food also improved intragastric distribution by increasing delivery to the body and fundus. Omeprazole enhanced the effect of food, prolonging T50 to 2.9 ± 0.3 h, but had no effect in fasted subjects.Conclusions: Dosing after food markedly improves the aspects of local drug delivery to the stomach investigated in this study, and omeprazole enhances this effect. Post-prandial dosing may, therefore, be useful for improving delivery of some anti-Helicobacter agents.

Notes: Aim: To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane.Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B2 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay.Results: Dialysate thromboxane B, levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95 % CI:0.79–1.43 ng/ml) on placebo, by 29% (95% CI: 11–40%) to 0.75 ng/ml(0.56–1.01 ng/ml) (P= 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E, was 1.47 ng/ml (0.97–2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leultotriene B, was 0.45 ng/ml(0.34–0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95 % by plain aspirin 300 mg, and by 82 % by enteric coated aspirin 300 mg, respectively (P 〈 0.01). These results show that 29 % of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4, is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers.Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.

Notes: The ability of ranitidine to protect the human gastric mucosa against aspirin-induced damage was investigated by timed measurements of blood loss collected by gastric washing. Ranitidine (150 mg) 1 h or 5 h before 900 mg aspirin (5 doses of each) over 48 h reduced subsequent mean bleeding from 7.7 μi/10 min to 2.6 μl/10 min or 3.4 μl/10 min, respectively. Both regimens were antisecretory at the time of aspirin administration, as judged by a rise in the pH of the aspirated washings. The prolonged protection against aspirin-induced bleeding achieved with twice daily dosing with ranitidine has dinical potential in the management of patients taking anti-inflammatory drugs.

Notes: Background:  A 15-fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people.Aim:  To quantify the risk of gastrointestinal bleeding associated with current exposure to non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and both drugs concurrently.Methods:  We conducted a case–control analysis of 11 261 cases with upper gastrointestinal bleeding and 53 156 controls matched by gender, age and general practice from computerized primary care data. We coupled this with self-controlled case series analysis.Results:  Both drugs were associated with a twofold increased risk of gastrointestinal bleeding (odds ratio =2.38, 95% confidence interval 2.08–2.72 for selective serotonin reuptake inhibitors and odds ratio = 2.15, 95% confidence interval 2.02–2.28 for non-steroidal anti-inflammatory drugs). This increased risk was marginally higher for concurrent prescription (odds ratio = 2.93, 95%confidence interval 2.25–3.82). The self-controlled analysis showed a greater incidence rate ratio for gastrointestinal bleeding with non-steroidal anti-inflammatory drugs (2.71, 95% confidence interval 2.51–2.91) and lower incidence rate ratio with selective serotonin reuptake inhibitors (1.71, 95% confidence interval 1.48–1.98). The incidence rate ratio when both drugs were combined was 3.25, 95% confidence interval 1.95–5.42. Estimates were similar after restricting to people over 80 years of age. Increased risk of gastrointestinal bleeding was not specifically related to class of non-steroidal anti-inflammatory drugs and was similar when we looked at tricyclic anti-depressants.Conclusions:  Our study suggests that the risk of gastrointestinal bleeding is not substantially increased when non-steroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors are prescribed together, compared with their use alone.

Notes: Aim : A double-blind, randomized study was designed to determine whether rabeprazole- and omeprazole-based triple therapy regimens are therapeutically equivalent in the eradication of Helicobacter pylori.Methods : Three hundred and forty-five patients with current or previously active peptic ulcer and a positive H. pylori urease test were randomly assigned to receive RCA, OCA, RCM or OCM twice daily for 7 days (R, rabeprazole 20 mg; O, omeprazole 20 mg; C, clarithromycin 500 mg; A, amoxicillin 1000 mg; M, metronidazole 400 mg). H. pylori eradication was documented by negative 13C-urea breath tests at 4 and 12 weeks, and was evaluated using a 2 × 2 factorial design with proton pump inhibitor and antibiotic as factors.Results : Overall eradication rates (per protocol/intention-to-treat) were 87%/77% and 85%/75% with rabeprazole and omeprazole, respectively (not significant). However, a statistical interaction between proton pump inhibitor and antibiotic was identified. RCA produced a somewhat higher eradication rate than OCA (94% vs. 84%; difference, 9.8%; 95% confidence interval, − 0.7% to + 20.4%), whereas RCM produced a lower eradication rate than OCM (79% vs. 86%; difference, 8.1%; 95% confidence interval, − 21.4% to + 5.1%). Ulcer healing rates were 〉 90% with H. pylori eradication. Each regimen was well tolerated.Conclusions : Rabeprazole- and omeprazole-based triple therapy regimens are therapeutically equivalent in the eradication of H. pylori and well tolerated. The statistical interaction observed between the proton pump inhibitor and supplementary antibiotic may be due to chance.

Notes: Aim: To use Prescribing Analysis and Costs data to investigate factors associated with differences in rates of nonsteroidal anti-inflammatory drug prescribing in Nottingham general practices. Results: Poisson regression analysis revealed that the Age, Sex and Temporary Resident Prescribing Unit Index was the largest identifiable influence; larger practice size and a higher index of deprivation were also significantly associated with lower prescribing, whilst the number of partners was associated with higher levels of prescribing. However, even after correcting for the influence of age, sex and temporary residents, there was an 5.9-fold variation in rates of prescribing. A similar Poisson regression analysis to identify factors associated with admission to hospital with ulcer bleeding in the elderly over the preceding 57 months identified the rate of nonsteroidal anti-inflammatory drug (NSAID) prescribing as the only significant influence. Conclusion: The data are compatible with 1 hospital admission per 2823 NSAID prescriptions (95% confidence intervals 2098–8110) and they emphasize the need for strategies to reduce levels of NSAID prescribing.

Notes: Non-steroidal anti-inflammatory drugs (NSAIDs) are the major recognized cause of iatrogenic disease, and may cause 100 000 deaths per annum through peptic ulcer complications. A number of risk factors can be identified that indicate patients at high risk. These patients can be managed by substitution of a COX-2 inhibitor or by prophylaxis with a proton pump inhibitor (PPI). Because risk factors that render patients at high risk of ulcer complications also act in the absence of NSAID use, PPI prophylaxis (or Helicobacter pylori eradication where H. pylori is the risk factor) have much to offer and controlled studies show that the incidence of recurrent peptic ulcer bleeding can be reduced substantially by PPI co-administration. Substitution of COX-2 inhibitors also has much to offer, arguably most in those without risk factors (although regulatory authorities do not accept this argument). Recent data show that PPI and COX-2 inhibitors can play complementary roles in the management of patients with moderate to severe dyspepsia and at high risk of ulcer complications.