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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.

A suspension of benzoylmetronidazole (6.4% w/v) was given orally at a dose of 15-25 ml, equivalent to 0.6-1 g metronidazole, once a day for three days to 11 children with giardiasis. Blood samples were collected after the first and third doses for analysis of plasma metronidazole and its main oxidative metabolite by high performance liquid chromatography. Peak metronidazole concentrations were 22.60 +/- 8.52 mg/l (mean +/- S.D.) after the first dose, and 30.22 +/- 10.06 mg/l after the third dose, occurring at 3.6 +/- 1.4 and 4.4 +/- 2.9 hours post-dose, respectively. Peak concentrations of the metabolite were 4.26 +/- 1.94 mg/l after the first dose and 7.96 +/- 3.63 mg/l after the third dose, occurring 7.2 +/- 1.6 and 9.1 +/- 3.3 h post-dose, respectively. Calculation of plasma metronidazole half-life and clearance values was not possible. This study shows that oral administration of metronidazole as its benzoyl ester slows the rate of metronidazole absorption, followed by sustained plasma concentrations and a prolonged elimination phase. Giardiasis does not appear to prevent metronidazole absorption. Concurrent giardiasis is unlikely to influence metronidazole therapy for systemic anaerobic infections.

The plasma concentrations of ranitidine after oral and intravenous administration have been measured in 10 healthy young adults, nine cirrhotic patients, and eight healthy elderly people. In the first of these bioavailability was 51 +/- 4% and half life 161 +/- 11 minutes after oral and 124 +/- 5 minutes after intravenous administration. In the cirrhotics bioavailability was increased to 70 +/- 7%, clearance was reduced, and there was a modest increase in half life. In the elderly bioavailability was similar to that in young adults, clearance was markedly reduced, and half life was prolonged to 241 +/- 7 minutes after oral and 194 +/- 11 minutes after intravenous administration. It is predicted that blood levels in cirrhotics and the elderly would be 50 to 60% higher than in healthy young adults after repeated oral administration of similar doses.

A case is reported of a patient with known haemoglobin H disease who was found to have angioid streaks and retinal detachment. Angioid streaks have not previously been reported in cases of alpha-thalassaemia, and the question whether this is a chance association or otherwise is discussed.

The serum concentrations of miconazole were measured in 11 healthy adult females for 72 hours following a single 1200 mg vaginal pessary. The mean peak serum miconazole concentration was 10.4 micrograms/l and the mean elimination half life was 56.8 h. The mean area under the serum concentration time curve was 967 micrograms/l.h. The calculated mean systemic bioavailability of the vaginal pessary was 1.4%. There was large intersubject variation in serum miconazole pharmacokinetics. This formulation may provide effective single dose treatment for vaginal candidosis.

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.

Thirty-two patients with duodenal ulceration took trimipramine 50 mg or placebo. Fifteen patients on each treatment completed the study. Endoscopy at four weeks showed ulcer healing in seven (46%) patients on trimipramine, compared with only two (15%) on placebo (P less than 0.05). However, by eight weeks there were eight (53%) patients in both groups with healed ulcers. There were no significant differences between the two groups in ulcer symptoms. Drowsiness was reported by eight patients on trimipramine compared with only one on placebo. Trimipramine 50 mg appears to increase the rate of ulcer healing in the short term. Side-effects at the dose used may limit its long-term usefulness.

Ketoconazole, a synthetic imidazole antifungal, is effective for superficial fungal infections, genital candidosis and chronic mucocutaneous candidosis, and has been used in immunocompromised patients and advanced prostatic carcinoma. Absorption of ketoconazole is variable after oral administration, with large variability in peak serum concentrations. Antacids reduce, and food or dilute hydrochloric acid increase, absorption. Renal failure and bone marrow transplantation are associated with reduced absorption. Ketoconazole is not absorbed systemically after topical administration, and minimally absorbed from the vagina. Distribution of ketoconazole varies according to the tissue sampled, the underlying disease and the dose and duration of treatment. Ketoconazole does not cross the intact blood-brain barrier, and crosses to only a limited extent in fungal meningitis. Urinary concentrations of ketoconazole are usually low, but vaginal and vaginal tissue concentrations correlate with those in serum. Seminal fluid concentrations are inadequate for treatment of epididymitis. Ketoconazole is 83.7% plasma protein (mainly albumin) bound, and 15.3% is erythrocyte bound, resulting in only 1% of free drug. Animal studies indicate strong binding to the cytochrome P-450 mono-oxygenase complex. Extensive metabolism to inactive metabolites occurs, the products being mainly excreted in the faeces. Saturable hepatic first-pass metabolism is probable. The half-life of ketoconazole is dose-dependent, increases during long term treatment, suggesting auto-inhibition of metabolism. The kinetics after oral administration fit a 2-compartment model. Drug interactions of theoretical, if not practical, significance include warfarin, chlordiazepoxide, methylprednisolone, cyclosporin and drugs known to induce microsomal enzymes. In each case, some dosage adjustment for ketoconazole, or the interacting drug, may be required.

Cimetidine 200 mg three times daily and 400 mg at night was given to 10 subjects for four weeks. Apparent liver blood flow was measured by indocyanine green clearance and microsomal enzyme activity by antipyrine clearance, before and after cimetidine. There was no reduction in indocyanine green clearance but antipyrine clearance, as expected, was significantly reduced by 15% at four weeks. Chronic cimetidine treatment does not reduce apparent liver blood flow and is therefore unlikely to be of use in the treatment of portal hypertension. The cimetidine associated hepatic enzyme inhibition appears to persist with prolonged treatment. Therefore patients on chronic cimetidine remain vulnerable to certain drug interactions.

A case of recurrent leg ulceration associated with alpha-thalassaemia (haemoglobin H disease) is reported. It is suggested that leg ulcers occurring in the thalassaemic syndromes may be due to structural changes in the affected red cells which result in increased cell rigidity, decreased deformability and consequent diminished blood flow in capillary beds that are subjected to venous stasis.

The hypothesis that an increased rate of oxidative metabolism may be an initiator or promoter of hepatocellular carcinoma was tested in vivo. Elimination of antipyrine (phenazone) was used as an index of the activity of microsomal mixed function oxidative enzymes. Plasma antipyrine kinetics were examined in 10 patients with hepatocellular carcinoma and in 10 normal Sudanese adults. The half life, volume of distribution and clearance of antipyrine in patients were 18.8 +/- 7.9 hours (mean +/- SD), 33.8 +/- 7.7 litres and 23.7 +/- 10.1 ml/min, respectively; and in normal adults were 20.3 +/- 8.8 hours, 40.1 +/- 10.4 litres and 25.7 +/- 12.0 ml/min, respectively. These differences were not significant. Antipyrine plasma clearance when corrected for weight was similar in the two groups. This study suggests that in a population at risk for hepatocellular carcinoma, the overall activity of mixed function oxidative enzymes is not an important determinant in selectively increasing this risk.

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.