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Background and aims: To evaluate the safety and efficacy of the intercellular adhesion molecule 1 (ICAM-1) antisense phosphorothioate oligonucleotide alicaforsen (ISIS 2302) in Crohn's disease. Methods: Active (Crohn's disease activity index (CDAI) 200-350), steroid dependent (prednisone 10-40 mg) Crohn's patients were randomised into three treatment groups: placebo versus ISIS 2302 (2 mg/kg intravenously three times a week) for two or four weeks. Patients were treated in months 1 and 3, with steroid withdrawal attempted by week 10. The primary end point (steroid free remission) was a CDAI <150 off steroids at the end of week 14. Results: A total of 299 patients were enrolled, with a mean baseline CDAI of 276 and steroid dose of 23 mg/day. Rates of steroid free remission were equivalent for the two and four week ISIS 2302 groups (20.2% and 21.2%) and the placebo group (18.8%). At week 14, steroid withdrawal was successful in more ISIS 2302 patients compared with placebo treated patients (78% v 64%; p=0.032). Steroid free remission was highly correlated with exposure (p=0.0064). Other clinical responses were correlated with exposure, with significant results versus placebo being observed in the highest area under the curve subgroup. CDAI scores decreased by 136 (112) at week 14 versus 52 (107) for placebo (p=0.027) and inflammatory bowel disease score questionnaire improved by 43 (31) versus 15 (36) for placebo (p=0.027). Conclusions: Although the primary outcomes failed to demonstrate efficacy, pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy for steroid dependent Crohn's disease.

A B S T R A C T It is generally recognized that glucocorticoid administration may diminish calcium absorption in vivo as well as the active transport of calcium by the intestine in vitro. Recent studies by others have emphasized the possibility of an alteration in the metabolism of vitamin D to 25-hydroxycholecalciferol in accounting for the steroid effects on calcium absorption. The results obtained in the present studies fail to support this hypothesis.The present studies confirm that the administration of cortisone or other glucocorticoids to the rat interferes with the active transport of calcium by duodenal gut sacs in vitro. This abnormality is not due to an alteration in the permeability of the intestine to calcium, and it cannot be corrected by the administration of either massive doses of vitamin D3 or modest doses of 25-hydroxycholecalciferol. Experiments concerned with the effects of cortisone on the level of the vitamin D-dependent duodenal calcium-binding protein, the amount of bioassayable vitamin D activity in the mucosa, and the distribution and metabolism of 'H-vitamin D3, did not provide evidence in favor of a hormone-related defect in either the localization of vitamin D or its metabolism to 25-hydroxycholecalciferol. Alterations in the transport of iron and D-galactose, not dependent on vitamin D, suggest that cortisone treatment may be responsible for more than a simple antagonism to the effects of vitamin D.The results of the present studies indicate that cortisone administration affects the cellular mechanisms mediating calcium transport in a manner that is opposite to the

Background: Esomeprazole, the S‐isomer of omeprazole, is the first proton pump inhibitor to be developed as an optical isomer. In patients with erosive oesophagitis, esomeprazole has produced significantly greater healing rates and improved symptom resolution vs. omeprazole. Aim: This study assesses the efficacy of esomeprazole for preventing relapse in patients with healed oesophagitis. Methods: In this 6‐month US multicentre randomized double‐blind placebo‐controlled trial, 375 Helicobacter pylori‐negative patients with endoscopically healed oesophagitis received esomeprazole 40 mg, 20 mg, 10 mg, or placebo once daily. The primary efficacy end‐point was maintenance of healing at 6 months. Secondary end‐points assessed changes in symptoms, and long‐term safety and tolerability. Results: Significantly (P < 0.001) more patients remained healed with esomeprazole 40 mg (87.9%), 20 mg (78.7%), or 10 mg (54.2%), than with placebo (29.1%). Relapse, when it occurred, was later with esomeprazole. Sustained resolution of heartburn was observed in the 40 mg and 20 mg groups; there was a high correlation between absence of heartburn and maintenance of healing. Adverse effects were mild, infrequent and not significantly different between groups. Conclusions: Esomeprazole is effective and well‐tolerated in the maintenance of healing of erosive oesophagitis. Esomeprazole 40 mg and 20 mg offer significant clinical benefit to patients.

A B S T R A C T The intestinal absorption of calcium is often depressed in patients with chronic renal insufficiency. Furthermore, the malabsorption of calcium and the osteodystrophy which occur in association with chronic renal disease are often "resistant" to vitamin D; the basis for this resistance remains uncertain however. Recent studies by others have emphasized the role of an abnormality in the metabolism of vitamin D in accounting for the alterations in the calcium absorption and the apparent vitamin D-resistance wh ch accompany the uremic syndrome.The present studies with an experimentally uremic animal model demonstrate a defect in the active transport of calcium by duodenal gut sacs in vitro. This abnormality is not due to the semistarvation associated with renal insufficiency and cannot be corrected by the administration of physiologic amounts of vitamin D:o; it is reversed by massive doses of the vitamin.Neither the metabolism of vitamin D3 nor the levels of calcium binding protein activity in the duodenal mucosa are affected by renal insufficiency under the conditions employed in the present studies. The results of the present studies strongly suggest that in addition to the recently proposed mechanism involving an interference with the metabolism of vitamin D renal insufficiency also affects the cellular mechanisms for calcium transport in a manner which, while opposite in direction to that of vitamin D, is independent of a direct interaction with the v tamin or its metabolites.