L. S. Laursen

Omeprazole in the Long-Term Treatment of Gastro-oesophageal Reflux Disease: A Double-Blind Randomized Dose-Finding Study

BACKGROUND Omeprazole is effective in the treatment of reflux oesophagitis, and it is important to determine the lower dose limit with still appropriate clinical efficacy. METHODS Patients with endoscopic oesophagitis grade 1-4 (N = 220) were randomized to double-blind treatment with 20 mg or 40 mg omeprazole daily for 4-8 weeks. Those healed after this initial treatment phase were re-randomized to double-blind treatment with 20 mg omeprazole daily (n = 67), 10 mg omeprazole daily (n = 68), or placebo (n = 33) for 6 months. Remission was defined as the absence of any endoscopic sign of oesophagitis. RESULTS Healing rates were increased with 40 mg omeprazole, the therapeutic gain compared with the 20-mg dose being 15% after 4 and 8 weeks. The proportion of patients in remission after 6 months was 59% with 20 mg omeprazole, 35% with 10 mg omeprazole, and 0% with placebo. CONCLUSION Maintenance treatment with 10 mg omeprazole can prevent recurrence of oesophagitis in about one-third of patients with all grades of oesophagitis, and 20 mg omeprazole in about twice as many.

5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease

The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes (LTs) makes it a likely target for biochemical manipulation. The rationale for using 5-LO inhibitors for the treatment of inflammatory bowel disease (IBD) is based on the increased generation of LTs in the inflamed mucosa, LTB4 being the most potent chemotactic and chemokinetic metabolite of arachidonic acid. Furthermore, conventional drugs, such as corticosteroids, sulphasalazine, and 5-aminosalicylic acid, inhibit LT production and specific 5-LO inhibition accelerates healing in animal models of acute colitis. The compounds identified as 5-LO inhibitors can be divided into antioxidants, substrate-analogous, and a large miscellaneous group of inhibitors, where hydroxamic acids are potent and more selective inhibitors of 5-LO. The benzothiophene hydroxyurea, zileuton, is the first selective 5-LO inhibitor evaluated for the treatment of patients with IBD. An 800-mg oral dose of zileuton was shown to reduce LTB4, but not prostaglandin E2, concentrations by 75–85% in rectal dialysates from patients with active ulcerative colitis. The clinical efficacy of zileuton 800 mg b.i.d. has also been tested in a randomized, double-blind, placebo-controlled trial in similar patients. Zileuton significantly improved the symptom scores and the histology score, but not the sigmoidoscopy score, compared to pretreatment conditions and with response to placebo, the beneficial effects being most pronounced in patients not receiving concomitant sulphasalazine treatment. The mean inhibition of LTB4 in the target tissue of inflammation was 70%. The proof that any putative 5-LO inhibitor is blocking LT production is an important stage in assessing any such drug. The main disadvantage of existing new LT inhibitors relates to the high potency of LTs, and unless a higher level of inhibition can be achieved, endogenous LTs may still be present in sufficient amounts to produce their effects.

Efficacy of omeprazole in lower grades of gastro-oesophageal reflux disease.

Grade I oesophagitis is usually considered to be a less severe form of gastro-oesophageal reflux disease (GORD). However, with regard to symptom severity, patients without macroscopic mucosal lesions have been shown not to differ from those with more severe oesophagitis. A number of controlled trials on the efficacy of omeprazole in GORD have included patients with lower grades of the disease. The results show that the differences in efficacy between omeprazole and H2-receptor antagonists, which have been established for the treatment of erosive and ulcerative oesophagitis, also extend to patients with grade I oesophagitis (erythema and friability). In these studies, omeprazole provided more rapid symptom resolution and histological improvement than ranitidine. In one double-blind comparative trial, complete endoscopic normalization of the oesophageal mucosa was observed in 90% of patients with grade I oesophagitis within 4 weeks of treatment with omeprazole, 40 mg once daily, compared with 55% of those treated with ranitidine, 150 mg twice daily; at 8 weeks the mucosa in all patients in the omeprazole group had completely healed at endoscopy, while oesophagitis was still present in 21% of the patients receiving ranitidine. A separate 6-month, placebo-controlled maintenance study was performed in patients who had completed a short-term study and who had total relief from the major symptoms of GORD and complete healing of endoscopic oesophagitis. All patients given placebo had an endoscopic recurrence (i.e. endoscopic grade I or more) and this was associated with the return of symptoms in 75% of cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Colonic Prostaglandin E2 Levels and Olsalazine Metabolism in Relapsing Ulcerative Colitis: Implications for Controlled Trials in the Long Term

To examine the tolerance and pharmacokinetics of long-term olsalazine administration, increasing doses of the drug were given to 31 patients with ulcerative colitis. All patients were refractory to or intolerant of sulphasalazine. Complete azo-reduction occurred in most cases. Concentrations of 5-ASA, but not acetyl-5-ASA, in faecal dialysates increased dose-dependently. Estimates of efficacy were more favourable among those intolerant of sulphasalazine. Patients with high prostaglandin E2 levels determined by equilibrium in vivo dialysis of rectum were less likely to benefit from treatment. In conclusion, olsalazine is a highly effective means of delivering 5-ASA to the colonic mucosa. Long-term use of olsalazine in controlled trials may be considered safe, even in high doses.

Actions of sulphasalazine and analogues on mucosal eicosanoid formation and metabolism in patients with ulcerative colitis

Sulphasalazine is the most widely prescribed drug for ulcerative colitis. Following oral administration sulphasalazine practically unabsorbed reaches the colon where it is split by colonie bacteria to 5-aminosalicylic acid and sulphapyridine. Although there is no doubt that 5-aminosalicylic acid is the active ingredient of sulphasalazine in ulcerative colitis, indications of disease-modifying effects of the intact molecule exist in rheumatoid arthritis. A substantial amount of evidence has accumulated that sulphasalazine and its analogues exert their therapeutic benefit in patients with ulcerative colitis through modulation of the formation and metabolism of eicosanoids, in particular leukotrienes, but they may also reduce inflammation by acting as inhibitors of platelet activating factor, interleukins, intestinal mast cell- and basophil cell-stimulated histamine release, in addition to being effective scavengers of the active oxygen species, suppressors of buturate metabolism, and modulators of polymorphonuclear leukocyte and lymphocyte functions. Although the mode of action of sulphasalazine and its analogues in ulcerative colitis is still incompletely understood, basic and clinical research into these multiactive compounds have paved the road for new drug development. Until then, sulphasalazine remains an effective means for the oral delivery to the colonie mucosa of the anti-inflammatory actions provided by mesalazine.