SummaryBackgroundOesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.MethodsThe Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77.FindingsBetween March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2–9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01–1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98–1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01–1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14–2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.InterpretationHigh-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus.FundingCancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

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.

The currently available drugs for the treatment of systemic fungal infections are amphotericin B. flucytosine. miconazole and ketoconazole.Amphotericin B has to be given intravenously in the treatment of deep mycoses. The dose is gradually increased following a small initial dose. though this may delay the attail/menl of therapeutic concentrations. Amphotericin B. serum concentrations are proportiol/al to dose but only up to doses of 50mg. The serum pharmacokinetics fit a 3-compartment model. while cerebrospinal fluid pharmacokinetics fit a 2-compartment model. The precise identities of these compartments have not been determined. In the serum there is a relatively rapid initial half-life of 1 to 2 days. and a slower elimination phase of 15 days. Amphotericin B penetrates poorly into other body tissues. and concentrations are usually well below those in serum. This may partly be due to its high protein binding. The routes of amphotericin B elimination in man are unknown. Amphotericin B invariably causes doserelated renal damage. but this does not markedly alter its pharmacokinetics; mannitol infusions do not reduce this nephrotoxicity. Concurrent gentamicin administration and sodium depletion may enhance amphotericin B nephrotoxicity.Flucytosine may be given orally or intravenously. It has a high (greater than 80%) oral bioavailability. but this is lower in patients with renal failure. Flucytosine absorption is delayed in renal failure and by antacids. The serum pharmacokinetics fit a I-compartment model. and the apparent volume of distribution approximates to body water. Flucytosine has low protein binding and good tissue penetration. There is minimal metabolism in man; conversion to 5-fluorouracil may be the basis of flucytosine toxicity. Since flucytosine is largely eliminated by renal excretion. serum concentrations are markedly increased in the presence of renal impairment. The renal clearance of flucytosine closely parallels creatinine clearance. and in renal failure the half-life is considerably prolonged. Toxicity can be avoided by therapeutic monitoring of serum concentrations and reducing the dose when renal functiol/ is impaired.Miconazole is poorly absorbed from the gut; therefore intravenous administration is required for treatment of systemic fungal infections. Its serum pharmacokinetics fit a 3-compartment model with a short initial half-life of less than 1 hour. an intermediate half-life of 2 hours. and a terminal half-life of 20 hours. Despite this long terminal half-life. miconazole has to be given every 8 hours. It has a high apparent volume of distribution and is highly bound to plasma proteins. Adequate penetration only occurs into certain body tissues. Pen-

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