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Summary Background: Omeprazole has been marketed in France since 1989, for the healing of peptic ulcers, erosive reflux oesophagitis, and the Zollinger–Ellison syndrome. However, the drug has been associated with serious adverse reactions, including haemolytic anaemia and acute interstitial nephritis. More recently, an autoimmune syndrome induced by omeprazole has been described. Objective: We present here a clinical history and an in vitro test of cytotoxicity linking leukopenia to omeprazole. Results: A 37-year-old woman was hospitalized in the intensive care unit of our hospital with acute pulmonary insufficiency secondary to pneumonia. 72 h after starting omeprazole treatment, a decrease in leucocyte count was observed. The leukopenia was maximal on day 22: total white cell count was 2·1×109/l, and neutrophil count was less than 0·75×109/l. In order to find the cause of this leukopenia, an in vitro cytotoxicity test was performed. The test was positive only when patient neutrophils and patient serum were in the presence of omeprazole. This cytotoxicity seems to be complement-dependent, as in the presence of heated serum, the omeprazole toxic effect was substantially reduced. Conclusion: This case report suggests that the leukopenia was associated with omeprazole.

Summary Background: Treatment of anaemia in renal-insufficient patients relies on the use of an erythropoiesis-stimulating agent (ESA). This study aimed to compare the impact of two different strategies of ESA prescribing on variation in haemoglobin (Hb) concentration in end-stage renal disease (ESRD) patients. Methods: Patients with ESRD, on haemodialysis, and who had received ESA for >3 months were recruited. Different parameters were analysed: demographics, Hb level the last day of the year before dialysis, the most recent weekly ESA dose, risk factors for resistance and cost. Each institution continued its local practice for achieving the desired Hb level: increasing the ESA dose to overcome resistance in one centre and defining an upper ESA-dose limit in the other. Results: A total of 185 patients were recruited. No significant differences in the biological parameters were found between the two populations. In both centres, Hb levels were comparable and mean levels exceeded 11 g/dL, despite the higher ESA doses given in one centre to achieve this target. This finding also held true for the subgroups with greater than or equal to two resistance factors. These two strategies led to large between-centre differences in treatment costs. Conclusion: The ESA-use strategy difference probably indicates that erythropoietin-resistance was not overcome with increased dosing. The Hb concentrations remained stable even when ESA doses were increased. On current evidence, the cheaper ESA-dose limitation strategy is preferable but randomized controlled studies, including comparisons of alternative ESA formulations are necessary.

Summary New treatments for relapse of acute myeloid leukaemia (AML), include gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody. We describe a second case of GO-induced sinusoidal obstructive syndrome (SOS) effectively treated with defibrotide (DF). No stem-cell transplantation was involved. On day 23 after the first GO dose, a patient presented with ascites, weight gain, liver enlargement and pain in the right upper quadrant. Sudden hepatic cytolysis (transaminases at six times the normal range: grade 3) and cholestasis [alkaline phosphatase ALP and gamma-glutamyltransferase (GGT) respectively at four and eight times the normal range: grade 2] were observed but there was no evidence of increase serum bilirubin. Treatment with DF (Prociclide®, Crinos; 10 mg/kg/day, or 200 mg, q.i.d.) improved the hepatic abnormality within a few days (serum transaminases decreased from 312 to 103 IU/L for aspartate aminotransferase (AST) and from 141 to 80 IU/L for alanine aminotransferase (ALT) within 3 days ALP increased from 253 to 383 IU/L and gamma-GT from 238 to 417 IU/L 4 days after administration of DF. The clinical and biological features of our case suggest a direct involvement of GO in causing SOS, even when used as monotherapy, without allogenic stem-cell transplantation. Low dose DF (10 mg/kg/day) given early during the development of SOS associated with GO was effective. Unfortunately, in our case the patient eventually died of multi-organ failure probably because of failure of GO.

Summary Objective: To develop a model based on mean residence time for better understanding the effect of grapefruit juice on the metabolism of nifedipine (NIF). Material and methods: Sixteen healthy volunteers from an urban population were included. For each trial, the subjects drank water, fresh grapefruit juice or bottled grapefruit juice. Thirty minutes later, the subjects took a 10 mg capsule of NIF, orally. Plasma concentration of NIF was measured and the kinetic parameters were calculated with a non-compartmental model. Results: Grapefruit juice increased the bioavailability of NIF, but did not significantly reduce the drug's metabolism as shown by the approximately constant metabolite to parent drug AUC ratio (P = 0·948). There was no significant increase in the amount of non-metabolized drug absorbed during first-pass: 0·12 and 0·16 (P = 0·470) without and with grapefruit juices respectively. There was an increase in the relative bioavailability (P = 0·039) and the apparent volume of distribution (Vdm) (P =0·025) of dehydronifedipine with grapefruit co-administration. A second peak was also observed in the NIF plasma-concentration profile when the drug is co-administered with grapefruit juice. Therefore, the most likely explanation for the double peak phenomenon is a delay in gastric emptying (+32 min with grapefruit juice) caused by the pH of grapefruit juice. Conclusion: This study shows that grapefruit juice interferes with the metabolism of NIF by inhibiting NIF metabolism and slowing down the rate of gastric emptying. This study also confirms that the metabolic inhibition is not a first pass effect, but is a secondary oxidative step.

Objective Aspirin administered orally is one of most widely self-prescribed drugs to treat headaches or other pains. The aim of this study was to evaluate whether the influence of different beverages may be used to help in the ingestion of an aspirin tablet on the pharmacokinetic parameters of this drug. Method This study was undertaken in five healthy volunteers. Seven beverages were tested: water, tea, coffee, orange juice, milk, beer and 40 degrees distilled alcohol. After plasma extraction, aspirin and salicylic acid were measured by HPLC with UV detection. The main pharmacokinetic parameters were determined by the compartimental method and drug disposition profiles by the Wagner-Nelson modified method. Results Elimination was not modified by any of the beverages but absorption was affected. Two opposing effects were observed: 40 degrees alcohol seemed to increase AUC and Cmax. Milk and beer seemed to decrease these parameters. With 40 degrees alcohol and tea, the amount absorbed and the disposition rate were higher. For milk and orange juice, the amount absorbed was lower and the disposition rate was unaffected. For beer, both the amount absorbed and the disposition rate increased. For coffee, both the amount absorbed and disposition rate were not significantly modified. Conclusion The bioavailability of salicylates on the healthy volunteers in this study was significantly affected by concomitant administration of 40 degrees alcohol (spirit), beer and milk. The beverages seem to interfere with aspirin absorption and the drug disposition profile was modified.

Clozapine is an antipsychotic drug with few extra-pyramidal motor side-effects, used to treat schizophrenia which is resistant to classical neuroleptic therapy. This report shows that norclozapine but not clozapine-N-oxide has the same D2 receptor affinity as clozapine. Assay results suggest a bimodal distribution which may be explained by CYP1A2 polymorphism. Extensive metabolizers could produce other active metabolites, probably other hydroxy-clozapine derivatives.