PubMed Health⌕ Search

Biomedical subjects

J Rask-Madsen

Publications and source records attributed to J Rask-Madsen.

At least 73 records · Page 4Linked to original sources
PubMed1988

Prostaglandin E2 is a mediator of 5-hydroxytryptamine induced water and electrolyte secretion in the human jejunum.

Studies in the rat jejunum in vivo have shown that 5-hydroxytryptamine (5-HT) causes secretion of fluid and luminal release of prostaglandin (PG) E2. These effects can be blocked by indomethacin and ketanserin, which suggests that PGE2 may be an important intermediate in the transduction mechanism leading to 5-HT induced fluid secretion. To test this hypothesis in man 'steady state' perfusions (9 ml/min) were done in eight healthy volunteers using the triple lumen technique. The proximal jejunum was perfused with Ringer's solution which contained 51Cr-EDTA as a non-absorbable marker. Before and after the administration of indomethacin (1.0 mg/kg iv) the effects of exogenous 5-HT (10 micrograms/kg/min iv) on jejunal net transport of fluid and electrolytes and jejunal flow rate (JFR) of PGE2 were measured in 15-min periods for 2 x 60 minutes after a 60 minute control period. 5-HT reversed fluid and electrolyte absorption into profuse secretion (p less than 0.01, Duncan's multiple range test) and significantly increased JFR of PGE2 (p less than 0.01). Indomethacin partly restored fluid and electrolyte absorption (p less than 0.01) and inhibited JFR of PGE2 (p less than 0.05). These results provide further evidence in favour of the theory that PGs are involved in 5-HT induced intestinal fluid secretion.

Adult↗
PubMed1988

Source of endogenous arachidonate and 5-lipoxygenase products in human neutrophils stimulated by bradykinin and A23187.

The lipoxygenase products of arachidonic acid (AA) metabolism, 5-hydroxyeicosatetraenoic acid (5-HETE) and leucotriene B4 (LTB4), are considered to have an important pathophysiological role in inflammatory bowel disease by stimulating the inflammatory response and by contributing to the diarrhoea. The present studies were designed to investigate the effect of the physiological stimulants bradykinin (BK) and 5-hydroxytryptamine (5-HT), in addition to the influence of the calcium ionophore A23187, on the source of AA release and 5-lipoxygenation in human neutrophils (PMNs) in vitro. This was done to elucidate the specificity of the mechanism by which PMNs respond to physiological, extracellular Ca2+ dependent agonists. The results of the study indicate that stimulation of 1-14C-AA-prelabelled PMNs with BK liberates AA mainly from phosphatidylinositol, while A23187 causes release of AA from phosphatidylcholine, phosphatidylethanolamine, and possibly phosphatidylserine. Furthermore BK (10(-9)-10(-6)M) dose-dependently stimulated the formation of 5-HETE and LTB4, reaching a maximum at 10(-7)M, while 5-HT (10(-8)-10(-4)M) released only negligible amounts of eicosanoids, similar to those observed in control experiments. Stimulation with A23187 (10(-5)M) caused a high release of both 5-HETE and LTB4. These results offer evidence that BK, but not 5-HT, initiates formation of lipoxygenase products by binding to specific receptors on the external surface of PMNs, whereas A23187 accelerates 5-lipoxygenation through mechanisms which do not involve a cell surface receptor.

Arachidonate 5-Lipoxygenase↗
PubMed1988

Longterm olsalazine treatment: pharmacokinetics, tolerance and effects on local eicosanoid formation in ulcerative colitis and Crohn's colitis.

To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.

Adolescent↗
PubMed1988

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.

Adult↗
PubMed1987

Enprostil and ranitidine in prevention of duodenal ulcer relapse: one year double blind comparative trial.

One hundred and forty two patients with duodenal ulcer who after a short term study had relief of pain and healed ulcers proved endoscopically were allocated at random to double blind maintenance treatment with enprostil (a synthetic dehydroprostaglandin E2) 35 micrograms or ranitidine 150 mg at bedtime for up to 12 months. Patients were monitored every third month and examined by endoscopy at three, six, and 12 months, or more often if warranted. The cumulative relapse rates in the enprostil group at three, six, and 12 months were 37% (25/67), 56% (37/66), and 62% (41/66), respectively. The corresponding rates in the ranitidine group were 8% (6/71), 19% (13/69), and 29% (20/69). These differences were highly significant and further enhanced by life table analysis adjusting for withdrawals and by an "intention to treat" analysis in which absence of proof of non-recurrence was counted as failure, more patients in the enprostil group having been withdrawn because of adverse events or recorded as non-compliant with the protocol. Enprostil 35 micrograms at bedtime cannot be recommended for preventing relapse of duodenal ulcer. Furthermore, the results challenge the clinical relevance of using so called "cytoprotection" for preventing recurrence.

Adult↗
PubMed1987

Review: clinical trials in peptic ulcer disease--problems of methodology and interpretation.

This review focuses on the methodology and interpretation of drug trials in peptic ulcer disease. The problems of planning and conduct that are discussed include the ethics of using placebo, eligibility criteria, estimations of sample size, stopping rules, randomization, blinding, and efficacy criteria, that is, ulcer healing and pain relief in the short term and prevention of relapse and complications in the long term. Statistical topics covered include confidence intervals, evaluation of survival type data, post-stratification, and sub-group analysis. The difference between clinical and statistical significance is discussed, major problems being overemphasis on P-value, type II errors, and post hoc power determinations. Explanatory and pragmatic questions are based on compliance-to-protocol and intention-to-treat cohorts, respectively, and involve problems of compliance testing, evaluation of withdrawals, and the use of fixed-dose regimens. The rather slow process for clinical trials to gain acceptance is described, and it is proposed to rely on disease-related and behavioural barriers, lack of knowledge of the inherent limitations of methodology, and overemphasis on the subject of peptic ulcer healing, in addition to some concern at the relevance of assessing long-term drug intervention by repeated endoscopies rather than by studying symptoms and the incidence of complications. We foresee an increased impact of clinical trials on ulcer research and therapeutic decision making, provided physicians are able to develop the proper methodology to answer the relevant questions.

Anti-Ulcer Agents↗
PubMed1987

Does vitamin E supplementation modulate in vivo arachidonate metabolism in human inflammation?

To determine whether supplementation with the physiological radical scavenger, vitamin E, would modulate arachidonate metabolism in human inflammation, we performed equilibrium dialysis of rectum in eight patients with active ulcerative colitis confined to the rectum. The patients, all off drug treatment, were supplemented with 1920 IU/day of alpha-tocopherol and had rectal dialysis done at entry and after three and 14 days. Luminal concentrations of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), determined by radioimmunoassay in purified dialysates, were significantly raised compared to healthy controls. Supplements caused no change in these levels either at day 4 or 15, although serum-tocopherol showed a 3-fold increase. Also disease activity was unaffected. This failure of vitamin E supplementation to suppress the mucosal release of PGE2 and LTB4 in active inflammation does not encourage controlled trials on the effect of oral vitamin E in ulcerative colitis.

Adult↗
PubMed1987

In vivo effects of orally administered prednisolone on prostaglandin and leucotriene production in ulcerative colitis.

It has been proposed that anti-inflammatory actions of corticosteroids rely on promotion of a natural peptide phospholipase A2 inhibitor, lipocortin, but in vivo effects on arachidonic acid metabolism have not been shown. Equilibrium dialysis of the rectum in patients with ulcerative colitis was used to determine whether cyclooxygenase and lipoxygenase products released from the inflamed rectal mucosa could be differentially inhibited by systemic treatment with prednisolone and indomethacin, respectively. In 10 patients with severe disease luminal concentrations of prostaglandin E2, prostaglandin F2 alpha, and leucotriene B4 were markedly raised (p less than 0.05) on comparison with 10 healthy controls, and they decreased significantly (p less than 0.05) within 72 hours after administration of prednisolone 1.5 mg/kg/day orally. In contrast prostaglandin, but not leucotriene B4 concentrations decreased (p less than 0.05) within 72 hours after administration of indomethacin 150 mg/day in another 10 patients with distal disease. These prompt reductions in concentrations of arachidonic acid metabolites more likely are caused by direct drug actions, rather than being secondary to decreased tissue damage. The data accord with the theory explaining anti-inflammatory effects of corticosteroids through lipocortin activity and support the belief that leucotrienes are more important than prostaglandins as mediators of inflammation in ulcerative colitis.

Adult↗
PubMed1987

5-Aminosalicylic acid in the treatment of Crohn's disease. A 16-week double-blind, placebo-controlled, multicentre study with Pentasa.

The response to 5-aminosalicylic acid (5-ASA) in mild and moderately active Crohn's disease localized in the small bowel was studied in a randomized, double-blind, placebo-controlled trial in four centres. Sixty-seven patients were included, of whom 30 were treated with 1500 mg slow-release 5-ASA/day (Pentasa) for a scheduled period of 16 weeks. In the 5-ASA group 40% of the patients improved, versus 30% of the placebo-treated group ('intent to treat' basis; p greater than 0.1). Four of the patients treated with 5-ASA left the study owing to disease deterioration, versus 10 of the placebo-treated patients (p greater than 0.2). Seventeen patients were secondarily excluded, and the remaining 50 patients (23 receiving 5-ASA) were reevaluated in greater detail. No statistically significant differences in outcome were shown. Three patients (one given 5-ASA) were withdrawn from the study because of presumed side effects, but no serious adverse reactions were recorded. The present results indicate that 5-ASA, at least in the dosage used, is not superior to placebo. Nevertheless, trends towards a beneficial effect in Crohn's disease in the small bowel justify further clinical trials with a larger dosage of 5-ASA.

Adolescent↗
PubMed1987

The role of eicosanoids in the gastrointestinal tract.

Exploring the role of eicosanoids in the gastrointestinal tract entails fundamental problems of methodology and interpretation. Most important are the difficulties inherent in the choice of an experimental design which prevents non-specific stimulation of eicosanoid formation, because any perturbation of cell membranes will initiate eicosanoid synthesis. In addition to cyclic nucleotides, prostaglandins may serve as intracellular mediators for the stimulus of secretion coupling via intracellular free calcium in the gastrointestinal epithelial cells. By contrast, the effects of supraphysiological doses of prostaglandins parallel those of cyclic AMP-dependent secretagogues such as VIP, which increases calcium through activation of the mucosal adenylatecyclase. The question of whether patients develop gastric or duodenal ulcers as a result of a prostaglandin deficiency remains open. The synthetic prostaglandin analogues available commercially for anti-ulcer therapy appear to be unable to accelerate the healing of peptic ulcers unless they are administered in anti-secretory doses, and are unlikely to have a substantial effect on patients with bleeding from ulcerative lesions in the gastro-duodenal mucosa. Prostaglandins of the E type mediate, at least partly, the diarrhoea associated with a large number of clinical conditions and various pharmacological agents. Several types of secretory diarrhoea respond to drugs that inhibit prostaglandin biosynthesis. Whether eicosanoids are mediators, or merely epiphenomena, of inflammation in ulcerative colitis and Crohn's disease remains unclear. Improved knowledge of their functional role of eicosanoids has nevertheless allowed a reinterpretation of the rationale behind current therapy. Uncontrolled formation of eicosanoids may not only be the source of diarrhoea in colonic inflammation, but may also be critical for cell proliferation and the development of dysplasia in long-standing disease.

Diarrhea↗
PubMed1986

Enprostil and ranitidine in duodenal ulcer healing: double blind comparative trial.

One hundred and eighty patients with endoscopically proved duodenal ulcers were allocated at random to double blind treatment with the synthetic dehydroprostaglandin E2 enprostil 35 micrograms twice daily or ranitidine 150 mg twice daily for up to six weeks. Patients completed the study if ulcer healing and pain relief had occurred at two or four weeks. A total of 163 patients completed the trial. The duration of treatment was longer in the enprostil group (p less than 0.005) and the cumulative healing rates at two, four, and six weeks were 51%, 74%, and 85%, respectively. In the ranitidine group the corresponding figures were 65% (p less than 0.04), 89% (p less than 0.02), and 99% (p less than 0.002). More patients treated with ranitidine reported relief of pain (p less than 0.004 at weeks 5 and 6). The observed superiority of ranitidine 150 mg twice daily over enprostil 35 micrograms twice daily questions the clinical relevance of using so called "cytoprotection" as treatment for duodenal ulcer disease in the short term.

Adolescent↗
PubMed1986

Significance of calcium for the prostaglandin E2-mediated secretory response to 5-hydroxytryptamine in the small intestine of the rat in vivo.

5-Hydroxytryptamine (5-HT) has been claimed to mediate intestinal secretion in morphine withdrawal diarrhea through stimulation of local prostaglandin formation without involving cyclic adenosine monophosphate. Therefore, experiments were performed to study (a) the effects of exogenous 5-HT and the cyclic adenosine monophosphate-dependent secretagogue, vasoactive intestinal polypeptide, on intestinal prostaglandin E2 (PGE2) formation and (b) the involvement of calcium in the secretory response to close intraarterial infusion of 5-HT, PGE2, or vasoactive intestinal polypeptide in tied-off loops of rat jejunum in vivo. 5-Hydroxytryptamine and vasoactive intestinal polypeptide reversed fluid absorption to net secretion (p less than 0.01), but only 5-HT caused an increase in luminal PGE2 output (p less than 0.01). Indomethacin and d,l-verapamil prevented only the secretory effect of 5-HT. Exogenous PGE2 (1.6-160 ng/min) reversed absorption to secretion (p less than 0.01) in a dose-dependent manner, irrespective of whether the rats were pretreated with indomethacin or not. Racemic and l-verapamil, but not d-verapamil, markedly reduced (p less than 0.01) the secretory effect of physiologically low doses of PGE2 (1.6 and 16 ng/min), whereas high doses of PGE2 (160 ng/min), which caused a significant increase in mucosal cyclic adenosine monophosphate (p less than 0.005), were not inhibited by verapamil. These data suggest that PGE2 may be an important intermediate in the transduction mechanism leading to 5-HT-induced intestinal secretion, and that physiologic doses of PGE2 may act by facilitating calcium entry, rather than by increasing intracellular calcium through activation of the adenylate cyclase.

Animals↗