A possible secondary case of pneumococcal meningitis.

Although institutional outbreaks of pneumococcal infection have been reported, secondary cases of pneumococcal meningitis do not seem to have been described. We report two cases of pneumococcal meningitis involving the same serotype occurring in individuals with direct contact.

Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial.

The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentaenoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore--stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.

Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial.

OBJECTIVE: To investigate the possible therapeutic role of omeprazole, a powerful proton pump inhibitor, in unselected patients presenting with upper gastrointestinal bleeding. DESIGN: Double blind placebo controlled parallel group study. Active treatment was omeprazole 80 mg intravenously immediately, then three doses of 40 mg intravenously at eight hourly intervals, then 40 mg orally at 12 hourly intervals. Treatment was started within 12 hours of admission and given for four days or until surgery, discharge, or death. SETTING: The medical wards of University and City Hospitals, Nottingham. SUBJECTS: 1147 consecutive patients aged 18 years or more admitted over 40 months with acute upper gastrointestinal bleeding. MAIN OUTCOME MEASURES: Mortality from all causes; rate of rebleeding, transfusion requirements, and operation rate; effect of treatment on endoscopic appearances at initial endoscopy. RESULTS: Of 1147 patients included in the intention to treat analysis, 569 received placebo and 578 omeprazole. No significant differences were found between the placebo and omeprazole groups for rates of transfusion (302 (53%) placebo v 298 (52%) omeprazole), rebleeding (100 (18%) v 85 (15%)), operation (63 (11%) v 62 (11%)), and death (30 (5.3%) v 40 (6.9%)). However, there was an unexpected but significant reduction in endoscopic signs of upper gastrointestinal bleeding in patients treated with omeprazole compared with those treated with placebo (236 (45%) placebo v 176 (33%) omeprazole; p less than 0.0001). CONCLUSIONS: Omeprazole failed to reduce mortality, rebleeding, or transfusion requirements, although the reduction in endoscopic signs of bleeding suggests that inhibition of acid may be capable of influencing intragastric bleeding. Our data do not justify the routine use of acid inhibiting drugs in the management of haematemesis and melaena.

Separation of the impairment of haemostasis by aspirin from mucosal injury in the human stomach.

1. An increasing body of data suggests that the antihaemostatic as well as the ulcerogenic actions of aspirin and other non-steroidal anti-inflammatory drugs may be operative when patients present with haematemesis and melaena. 2. We therefore developed methods to allow separate evaluation of the erosive and anti-haemostatic actions of aspirin in the human gastric mucosa. Volunteer subjects took 300 mg of aspirin daily in the morning or 600 mg of aspirin four times a day for 5 days under blinded randomized conditions. Changes in spontaneous gastric microbleeding, endoscopic signs of injury, spontaneous bleeding per gastric erosion, biopsy-induced bleeding and eicosanoids were studied. 3. Both doses of aspirin significantly inhibited gastric mucosal synthesis of prostaglandin E2 and reduced the serum thromboxane concentration. Erosions developed and regressed rapidly; compared with baseline 300 mg of aspirin daily in the morning caused substantial numbers of gastric erosions to develop (mean 5.3, 95% confidence limits 2.7-10.2) but this was significantly less than that caused by 600 mg of aspirin four times a day (10.9, 7.2-16.5, P less than 0.05). The presence of erosions was associated with enhanced spontaneous bleeding, but only during aspirin administration. 4. Aspirin significantly increased bleeding induced by mucosal biopsy and was associated with significant enhancements in the rate of bleeding per gastric erosion. Bleeding rate per erosion but not biopsy-induced bleeding showed a significant dose-related increase with 600 mg of aspirin four times a day. Enteric coating reduced endoscopic signs of injury, but did not affect the impaired haemostasis caused by aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of roxatidine and ranitidine for the acute treatment of duodenal ulcer.

Roxatidine acetate is a new histamine H2-antagonist of about twice the potency of ranitidine on a weight-for-weight basis. Two hundred and thirty-two patients participated in a double-blind randomized trial of duodenal ulcer healing comparing 300 mg ranitidine nocte with 150 mg roxatidine nocte. Endoscopy was repeated fortnightly to 4 weeks in each of four participating centres. Usual exclusion criteria applied but NSAID users were allowed. There were no important demographic differences between treatment recipients. Three analyses were used: protocol (dropouts and violators not included), intention-to-treat I (dropouts considered failures), and intention-to-treat II (dropouts considered failures, but violators outcome included). Healing rates differed markedly (but not significantly) with each analysis. After 2 weeks of treatment ulcers had healed in 51% versus 45% using the intention to treat I analysis with roxatidine and ranitidine, respectively; by the protocol analysis the healing proportions were 60% and 55%. These differences between treatments were not significant. After 4 weeks of treatment healing rates ranged from 71% to 83% on roxatidine and between 69% and 84% on ranitidine depending on the analysis. Differential healing proportions of smokers and non-smokers were non-significant (83% vs. 79%). Both drugs were well tolerated and adverse events were similar with each agent. Roxatidine should prove as effective as ranitidine for acute duodenal ulcer treatment.

Sedation for upper gastrointestinal endoscopy: results of a nationwide survey.

A postal questionnaire inquiring about routine sedation and premedication practice for upper gastrointestinal endoscopy was sent to 1048 doctors. Of 665 appropriate returns, 81% were from consultant physicians and surgeons. Most endoscopists (90%) reported using an intravenous benzodiazepine for at least three quarters of endoscopies and 54% of physicians and 69% of surgeons always did so. Midazolam was the intravenous sedative used by a third of all respondents and 13% also used an additional intravenous agent, usually pethidine. Over the previous two years a total of 119 respiratory arrests, 37 cardiac arrests, and 52 deaths were identified. Adverse outcomes were reported more frequently by consultant physicians, by those who 'titrated' the intravenous sedative, and by those who used an additional intravenous agent, but were reported equally frequently by endoscopists using midazolam and endoscopists using diazepam. There is an urgent need for a prospective study to identify the circumstances and risk factors associated with adverse outcomes related to endoscopy.

Abolition by omeprazole of aspirin induced gastric mucosal injury in man.

This study investigates whether aspirin injury to the human gastric mucosa can be prevented by profound acid suppression with omeprazole, in a randomised, double blind, crossover design according to latin square. It was concluded that profound acid suppression can prevent aspirin induced gastric mucosal injury in normal subjects. This approach may prevent the development of peptic ulcers and their complications in patients taking aspirin and other non-steroidal anti-inflammatory drugs.

Effect of ranitidine and indomethacin on nocturnal gastric acidity in normal subjects.

To assess the effect of indomethacin on gastric acidity and to identify a potential pharmacodynamic interaction between indomethacin and ranitidine, we measured nocturnal acidity on half-hourly aliquots of gastric contents from 10 volunteers on the seventh day of four dosing regimens given in a randomized double-blind manner. These were indomethacin (50 mg t.d.s.) and ranitidine (300 mg in the evening) together or alone with matching placebos. Median nocturnal acidity on placebo was 41.7 mmol/L (range 67.6-25.1 mmol/L) and was 39.8 mmol/L (63.1-24.0 mmol/L) on indomethacin (N.S.). During ranitidine dosing it was 0.4 mmol/L (21.3-0.0 mmol/L) without and 0.8 mmol/L (43.7-0.0 mmol/L) with concurrent indomethacin, representing 99 and 98% decreases in gastric acidity (P less than 0.01) compared with placebo. Indomethacin did not increase overnight gastric acidity and did not influence the suppression of acidity produced by ranitidine. It is unlikely that the ulcerogenic potential of indomethacin is explicable by an effect on gastric acidity.

Effect of reactive pharmacy intervention on quality of hospital prescribing.

OBJECTIVE: To evaluate the medical impact of reactive pharmacy intervention. DESIGN: Analysis of all interventions during 28 days by all 35 pharmacists in hospitals in Nottingham. SETTING: All (six) hospitals in the Nottingham health authority (a teaching district), representing 2530 mainly acute beds, 781 mental illness beds, and 633 mainly health care of the elderly beds. PATIENTS: Hospital inpatients and outpatients. INTERVENTIONS: Recording of every important intervention made by pharmacists to prescriptions for both inpatients and outpatients when they perceived inadequacies of drug prescription or administration, including characterisation of the problem, coding of outcome, recording of time taken to initiate and resolve intervention, and grade of prescribing doctor. The problems were independently assessed for their potential to cause medical harm. RESULTS: 769 Interventions (about 2.9% of prescriptions) were made, of which 60 concerned prescriptions rated as having a major potential for medical harm. The commonest problems concerned dosage, which was wrong in 280 prescriptions (102 for antibiotics) and not stated in 50 (one for antibiotics), especially those associated with a major potential for medical harm (32 prescriptions). These concerned sedatives; analgesics; cardiovascular drugs or diuretics; and iron, vitamin, or mineral preparations. Also common were overprolonged prescription of antibiotics (48 prescriptions), confusion of drug names (nine), and inadvertent coprescription of excessive quantities of aspirin or paracetamol in plain and compound preparations (seven). The pharmacist's recommendation was accepted in 639 instances (86%), and the prescription was altered in 575, leading to an appreciable (246 cases) or minor (231 cases) improvement. Interventions had little effect on costs; 427/646 had no effect and 130 produced savings less than 50p. Pharmacy intervention (730/769 interventions) occupied on average 41 minutes per pharmacist per week. CONCLUSIONS: Most reactive pharmacy interventions concerned prescribing errors with a limited potential for medical harm, but a small number of detected errors with a major potential for medical harm; cost savings were not appreciable.

Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine.

1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min-1 (95% confidence limits 0.3-0.8 microliters 10 min-1) to 2.8 microliters 10 min-1 (1.9-4.1 microliters 10 min-1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min-1 (1.9-6.1 microliters 10 min-1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min-1 (1.0-2.3 microliters 10 min-1) after 5 days and 1.6 (1.0-2.5 microliters 10 min-1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.

Use of microbleeding and an ultrathin endoscope to assess gastric mucosal protection by famotidine.

We have developed an ultrathin endoscope for repeated endoscopy in unsedated subjects and used it with assessment of bleeding rates to investigate aspirin-induced gastric mucosal injury and its prevention by famotidine. Compared with placebo, 900 mg of aspirin b.i.d. taken for 48 h caused significant endoscopic injury (median grade 3.5, interquartile range 2-4, modified Lanza scale, p less than 0.01), with an increase in mucosal bleeding from 2.0 (geometric mean; 95% confidence limits, 1.1-3.9) microliters/12 min, to 8.3 (2.4-28.8) microliters/12 min (p less than 0.05). Famotidine (20 mg b.i.d.) raised intragastric pH and reduced endoscopic antral injury (median 1.5, interquartile range 0.5-2, p less than 0.05) and bleeding [3.1 (1.2-8.3) microliters/12 min, p less than 0.01] to levels not significantly different from placebo [1 (0-1) and 2.0 (1.1-3.9) microliters/12 min, respectively]. By contrast, 2 mg of famotidine b.i.d. had no significant effect on intragastric pH endoscopic injury or bleeding rates. The two assessments of gastric mucosal injury correlated strongly (r = 0.71, p less than 0.01). The reduction in bleeding with famotidine tended to be higher, the greater the intragastric pH (r = 0.66, p = 0.057). Ultrathin endoscopy is a simple technique that validates gastric mucosal bleeding as a measure of acute gastric mucosal injury in humans. Acid suppression is an effective method of ameliorating this injury.

Failure of ethamsylate to reduce aspirin-induced gastric mucosal bleeding in humans.

1. We investigated the effect of the haemostatic agent ethamsylate on aspirin-induced gastric mucosal bleeding. 2. Eighteen healthy subjects were studied three times: at the end of 48 h periods of treatment with (a) placebo, (b) aspirin 600 mg four times daily, (9 doses) and (c) aspirin 600 mg four times daily with each dose preceded by ethamsylate 500 mg. 3. At the end of each treatment period gastric mucosal bleeding into timed gastric washings was quantified using the orthotolidine reaction. 4. Aspirin increased bleeding from a rate on placebo of 1.2 microliters 10 min-1 geometric mean (95% confidence limits) (0.7-1.8) microliters 10 min-1 to 20.0 (11.6-34.2) microliters 10 min-1, (P less than 0.01). The rate of bleeding after aspirin preceded by ethamsylate [14.1 (8.5-23.4) microliters 10 min-1] was not significantly different from that after aspirin alone. 5. We conclude that ethamsylate does not reduce acute aspirin-induced gastric mucosal bleeding in healthy humans.

Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin.

OBJECTIVE: To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding. DESIGN: Randomised crossover trial. SETTING: Academic department of therapeutics. SUBJECTS: Twenty healthy male volunteers aged 19-22. INTERVENTIONS: On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6. END POINT: Loss of blood over 10 minutes into gastric washings. MEASUREMENTS AND MAIN RESULTS: Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin. CONCLUSIONS: Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.

Devastating diarrhoea caused by azathioprine: management difficulty in inflammatory bowel disease.

Azathioprine toxicity complicated the management of four patients with inflammatory bowel disease. All patients received the drug as adjunctive therapy to steroids when responses to the latter were poor. After a variable sensitising period the patients developed severe diarrhoea and abdominal pain and this was believed at first to be a manifestation of their underlying diseases but rechallenge with azathioprine reproduced the problem. During three episodes described emergency admission to hospital and resuscitation with intravenous fluids was required. The cases illustrate the difficulty clinicians have in recognising drug induced effects which mimic the underlying disease. When a patient suspects a reaction to azathioprine we believe any rechallenge should only be undertaken in the controlled hospital environment.