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Biomedical subjects

J Rask-Madsen

Publications and source records attributed to J Rask-Madsen.

At least 91 records · Page 5Linked to original sources
PubMed1986

Effects of topical 5-aminosalicylic acid and prednisolone on prostaglandin E2 and leukotriene B4 levels determined by equilibrium in vivo dialysis of rectum in relapsing ulcerative colitis.

To determine the influence of inflammation and topical treatment with 5-aminosalicylic acid or prednisolone on arachidonic acid metabolism in vivo, we carried out a double-blind controlled study on the release of prostaglandin E2 and leukotriene B4 to the rectal lumen in 24 consecutive patients with proven distally located ulcerative colitis. Before and at days 15 and 29 a dialysis bag was placed in the emptied rectum for 4 h prior to assessing clinical, endoscopic, and histologic disease activity. A single enema was given daily at bedtime (1 g 5-aminosalicylic acid or 25 mg prednisolone) until complete remission or for a maximum of 4 wk. Clinical and endoscopic remission was obtained in 16 (7 on 5-aminosalicylic acid) and 11 (3 on 5-aminosalicylic acid) patients, respectively. Luminal concentrations of prostaglandin E2 and leukotriene B4 were positively correlated to disease activity and significantly decreased among the prednisolone-treated patients. In both treatment groups a decrease toward normal levels occurred in patients responding to therapy. In retrospect, the pretreatment prostaglandin E2 and leukotriene B4 levels were significantly higher in patients not responding to therapy than in those improving during treatment. In conclusion, luminal prostaglandin E2 and leukotriene B4 levels may prove more useful predictors of the outcome of treatment in relapsing ulcerative colitis than clinical indices of disease activity.

Adult↗
PubMed1986

Effect of azodisal sodium and sulphasalazine on ileostomy output of fluid and PGE2 and PGF2 alpha in subjects with a permanent ileostomy.

Azodisal sodium is a highly effective means of oral delivery of 5-amino-salicylic acid to the colonic mucosa. Administration of this drug to patients intolerant of sulphasalazine, however, occasionally results in liquid stools. In preliminary experiments, which comprised 10 healthy volunteers treated with colectomy for ulcerative colitis, ileostomy fluid output increased (p less than 0.001) during oral intake of azodisal sodium (1 g/day). In a double blind, placebo controlled crossover study, comprising eight similar volunteers, ileostomy fluid output increased (p less than 0.05) in a dose related manner during intake of azodisal sodium (1 g/day vs 2 g/day) compared with placebo or sulphasalazine (2 g/day). Concentrations of prostaglandin (PG)F2 alpha in free ileal water determined by equilibrium in vivo dialysis of ileostomy contents decreased (p less than 0.05) during intake of azodisal sodium (2 g/day), whereas concentrations of PGE2 and the output of PGE2, PGF2 alpha, and 'PGE2 + PGF2 alpha' remained unchanged. Thus increased formation of PGs is apparently not the cause of increased ileostomy fluid output associated with azodisalicylate intake.

Adult↗
PubMed1986

Prostaglandin E2 formation by the gall bladder in experimental cholecystitis.

Both experimental cholecystitis and luminal distension inhibit fluid absorption and stimulate motor activity in the gall bladder. These functional alterations are mimicked by exogenous prostaglandins (PGs) and inhibited by potent cyclooxygenase inhibitors, but direct evidence of a primary role of endogenous PGs is not available. Therefore, experiments in the cat were carried out in which the effects of lyso-phosphatidylcholine (lysoPC; 0.5-2.0 mmol/l), implantation of cholesterol stones, and raised intraluminal pressure in the gall bladder lumen were assessed. The gall bladder was perfused in vivo at a constant rate by a buffer solution. PGE2 was determined in the effluent by a radioimmunological method validated by gas chromatography-mass spectrometry. PGE2 output was markedly (p less than 0.01) raised (13.9 +/- 2.6 vs 1.1 +/- 0.5 ng/h; n = 10) during lysoPC perfusions and this response was inhibited by 66% (p less than 0.02) after indomethacin administration (2 mg/kg iv). A significant (p less than 0.05) increase in PGE2 output occurred six weeks after implantation of gall stones (3.7 +/- 1.5 ng/h; n = 6) and in response to distension of the normal gall bladder wall (3.6 +/- 1.2 ng/h; n = 6). These findings support the theory that PGs play an important pathophysiologic role in biliary tract disease.

Animals↗
PubMed1986

Symptomatic recurrence of healed duodenal and prepyloric ulcers after treatment with ranitidine or high-dose antacid. A 1-year follow-up study.

Eighty-seven patients with duodenal (n = 49) or prepyloric (n = 38) ulcers healed with ranitidine (n = 44) or a high-dose liquid antacid (n = 43) completed a 1-year double-blind comparative study of symptomatic relapse without treatment. Both duodenal ulcers and prepyloric ulcers tended to remain true to their type of recurrence. Age, sex, history of ulcer disease, duration of initial treatment, and smoking habits were all without influence on the relapse rates. The subgroup of patients with a duodenal ulcer who had healed on either treatment regimen had a symptomatic relapse significantly more frequently than those with prepyloric ulcer (64% +/- 13 versus 34% +/- 15; p less than 0.025), but the estimated probabilities of relapse were unaffected (p greater than 0.05) by the initial type of medication (ranitidine group, 56% +/- 15; antacid group, 51% +/- 15). Thus the present study could not confirm the hypothesis that patients treated with H2-receptor antagonists tend to relapse earlier than those treated with antacids during the following year without treatment.

Antacids↗
PubMed1986

Prostaglandins and clinical experience in peptic ulcer disease.

Synthetic prostaglandin analogues of the E series offer a new approach to the medical treatment of peptic ulcer disease by combining antisecretory with cytoprotective properties, such as protection of the gastric mucosa against damage induced by aspirin. Controlled trials of prostaglandin analogues in peptic ulcer healing have failed to demonstrate any superiority to conventional treatment. Any beneficial effect is explicable by acid inhibition, and diarrhoea is a major and dose-limiting side effect. Non-antisecretory doses that are still said to be cytoprotective do not accelerate ulcer healing. Also, the prostaglandin analogues seem ineffective in the treatment of peptic ulcer haemorrhage. Thus the clinical relevance of cytoprotection by synthetic prostaglandins has not been established. Although antisecretory doses of some analogues may prove to be yet another approach to drug treatment, the present results do not forecast a new breakthrough in the management of peptic ulcer disease.

Duodenal Ulcer↗
PubMed1986

Eicosanoids and their role in the pathogenesis of diarrhoeal diseases.

Eicosanoids are unsaturated fatty acid compounds derived from 20-carbon 'essential' fatty acids, the most important being arachidonate. Both cyclooxygenase and lipoxygenase products of arachidonate are abundant in the human gut and their biological effects include modulation of fluid and electrolyte secretion, motor activity, mucosal blood flow, and cytoprotection, in addition to chemotaxis and immune response in inflammation. In health, these lipid mediators reinforce or synergize normal homeostatic mechanisms that could proceed in their absence. Receptors for control of intestinal secretion can be divided into two major classes, one of which triggers the production of cyclic AMP and another, which initiates phospholipid breakdown and arachidonate release. An intimate connection appears to exist between phospholipid metabolism, cytosolic Ca2+ levels, electrogenic anion secretion, Na+ pump rate, electroneutral Na+/H+ exchange activity, and intracellular pH. Ca2+-dependent secretagogues affect fluid and electrolyte transport in the small and the large bowel by increasing Ca2+ entry and Ca2+ mobilization through stimulation of eicosanoid formation, prostaglandins of the E type being the most important. Secretory diarrhoea may be thought of, therefore, as cellular Ca2+ intoxication. Uncontrolled formation of eicosanoids, perhaps with a changed spectrum of arachidonate metabolites, may not only be the source of diarrhoea associated with mucosal inflammation, but may also be critical for cell proliferation resulting in abnormal cell differentiation, which seems to be the link between long-standing inflammatory bowel disease and the increased risk of colonic neoplasia. A better understanding of the pathophysiological role of eicosanoids in diarrhoeal disease has allowed reinterpretation of the rationale behind current therapy.

Animals↗
PubMed1985

Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial.

We conducted a double-blind randomized study of 132 patients to determine whether the new, investigational proton-pump inhibitor, omeprazole (30 mg per day), would accelerate healing and pain relief, as compared with cimetidine (1 g per day), in patients with duodenal ulcer. After two weeks of treatment, which was completed by all patients, the healing rates were 73 per cent in the omeprazole group and 46 per cent in the cimetidine group (P less than 0.01). After four weeks of treatment, which was completed by 118 patients, the corresponding figures were 92 and 74 per cent (P less than 0.05). In the omeprazole group 55 per cent of the patients were free of pain after the first week, as compared with 40 per cent of those treated with cimetidine (P greater than 0.05). No major clinical or biochemical side effects of omeprazole or cimetidine were noted. A six-month follow-up study revealed no significant difference between the recurrence rates after omeprazole and after cimetidine treatment. In May 1984 clinical trials with omeprazole were temporarily suspended, since a study of long-term toxicity in rats had shown the development of gastric carcinoid tumors.

Adult↗
PubMed1985

Increased jejunal prostaglandin E2 concentrations in patients with acute cholera.

Supraphysiologic doses of prostaglandins (PGs) mimic the effect of cholera toxin and cAMP in the small intestine, but not all observations are explicable in terms of the theory that links PGs to cAMP. Because no data exist on endogenous PGs in human cholera we measured PGE2 concentrations in jejunal fluids and fasting intestinal flow rates of PGE2 during slow marker perfusion of proximal jejunum in nine patients with high purging cholera. Nine patients in the recovery phase of cholera or other watery diarrhoeas served as controls. In acute cholera PGE2 concentrations were significantly (p less than 0.001) raised (172-1435 (n = 9) vs 60-270 (n = 9) pg/ml) and negatively correlated (r = 0.71; p less than 0.05) to the time following onset of diarrhoea. Also fasting jejunal flow rates of PGE2 were significantly (p less than 0.005) increased (0.77-8.22 (n = 7) vs 0.21-0.92 (n = 6) ng/min), and positively correlated (r = 0.84; p less than 0.01) to stool output (2.9-9.5 ml/min). By extrapolation, at normal stool output fasting jejunal flow rates of PGE2 equalled those measured during convalescence. The results support the notion that PGs, in addition to cAMP, may play a pathophysiologic role in human cholera. As the ratio between the medians of the highest values measured during the acute phase of cholera and in late convalescence was at least 15, local intestinal PGE2 formation in full blown cholera should result in mucosal PGE2 concentrations above those required for a maximal secretory response. This observation might explain why conventional doses of aspirin and indomethacin had no significant antidiarrhoeal effect in clinical trials.

Acute Disease↗
PubMed1985

Comparison of ranitidine and high-dose antacid in the treatment of prepyloric or duodenal ulcer. A double-blind controlled trial.

One hundred and nineteen patients with endoscopically confirmed prepyloric (n = 59) or duodenal (n = 60) ulcer were stratified for ulcer location before entering a randomized double-blind trial comparing ranitidine (150 mg twice daily) and a potent liquid antacid (Novaluzid; 10 ml seven times daily, with a neutralizing capacity of 600 mmol H+). Fifty-four patients with prepyloric (26 receiving ranitidine) and 53 patients with duodenal ulcer (28 receiving ranitidine) completed the trial in accordance with the protocol. The 4 and 6 weeks' healing rates for prepyloric ulcers were 54%, 68%, and 61%, versus 69%, 79%, and 74% for the ranitidine, the antacid, and whole groups, respectively. For duodenal ulcers these figures were 89%, 84%, and 87%, versus 100%, 96%, and 98% for the ranitidine, antacid, and whole groups, respectively. Differences in healing rates between treatments were statistically insignificant within strata for ulcer type, but healing rates for prepyloric ulcers were significantly lower than for duodenal ulcers (p less than 0.002). A significant early pain relief was found in all groups, and side effects, including diarrhoea, were rare. In conclusion, these two ulcer treatment modalities appear to be equally effective in the short term. In addition, the data emphasize the need for proper stratification of prepyloric and duodenal ulcers in clinical trials of ulcer healing.

Adult↗
PubMed1985

Ranitidine and high-dose antacid in reflux oesophagitis. A randomized, placebo-controlled trial.

The liquid antacid Novaluzid (10 ml seven times daily) was compared with ranitidine (150 mg twice daily) and with placebo in 57 patients with symptoms and endoscopic signs of oesophagitis and gastro-oesophageal reflux. A randomized three-period change-over design with the double-dummy technique was used. Each treatment period lasted 6 weeks. Only 37 patients (64.9%) completed the entire trial. In retrospect, five patients receiving placebo were withdrawn because of insufficient effect, six patients because of side effects while taking Novaluzid and two while taking ranitidine. The remaining seven dropouts/withdrawals were for reasons without evident relationship to the treatment given. Statistical analyses based both on the 37 completers and on the 43 patients who had at least two treatment periods showed that ranitidine and Novaluzid were superior to placebo with regard to pain score (p less than 0.005) but not with regard to regurgitation, dysphagia, histology, and appearance on endoscopy (p greater than 0.05). It was impossible to distinguish statistically between ranitidine and Novaluzid. In conclusion, ranitidine and high-dose antacids are of equal effectiveness in the short-term treatment of reflux oesophagitis, and both are superior to placebo with regard to symptomatic relief.

Adult↗
PubMed1984

Secretion rates of immunoglobulins, albumin, haptoglobin and complement factors C3 and C4 in the perfused jejunum and ileum of human Salmonella carriers.

Secretion rates of immunoglobulins and other proteins were assessed by luminal perfusion of jejunum and distal ileum, and the jejunal histology was evaluated in eight Danish chronic Salmonella typhi and paratyphi carriers compared to nine healthy controls who previously had suffered from typhoid or paratyphoid fever not followed by a carrier state. The median secretion rates for each protein investigated in the distal ileum as well as in the jejunum revealed no significant differences between the two groups. The secretion rate of secretory IgA was raised in both groups compared to previously investigated normal persons. The histological examination revealed no signs of inflammation or presence of bacteria. It was concluded that no primary humoral immune defect was revealed in the carriers.

Adult↗
PubMed1984

Effects of sulphasalazine and disodium azodisalicylate on colonic PGE2 concentrations determined by equilibrium in vivo dialysis of faeces in patients with ulcerative colitis and healthy controls.

The role of arachidonic acid metabolites and the mode of action of 5-aminosalicylic acid, the active moiety of sulphasalazine and disodium azodisalicylate, in ulcerative colitis remain obscure. Therefore, experiments were performed in which the effects of medication on immunoreactive prostaglandin (PG) E2 concentrations in free faecal water were assessed using the equilibrium in vivo dialysis of faeces. Colonic PGE2 concentrations in patients with active ulcerative colitis (n = 11) ranged from 2035-18,000 pg/ml to be compared with a range of 103-188 pg/ml in healthy volunteers (n = 10; p less than 0.001). In all healthy volunteers PGE2 concentrations decreased slightly (p less than 0.05) after disodium azodisalicylate intake 2 g/day, whereas low dose disodium azodisalicylate (0.25 g/day) caused no change. In patients with ulcerative colitis in complete clinical, sigmoidoscopic, and histologic remission withdrawal of sulphasalazine (2 g/day; n = 6) increased PGE2 concentrations to values above normal levels (p less than 0.05) which returned to pretrial values (p less than 0.05) on disodium azodisalicylate (2 g/day; n = 7). In conclusion, increased PGE2 in free faecal water indicates an abnormality in the colonic mucosa, even in the absence of conventional signs of inflammation. We could not confirm the hypothesis that sulphasalazine and 5-aminosalicylic acid exert their therapeutic effect through promotion of endogenous cytoprotective prostaglandins. In contrast, the observation that raised PGE2 concentrations were normalised by disodium azodisalicylate in patients with inactive ulcerative colitis suggests that subclinical disease activity was decreased by 5-aminosalicylic acid.

Adult↗
PubMed1984

Colonic secretion mediated by prostaglandin E2 and 5-hydroxytryptamine may contribute to diarrhea due to morphine withdrawal in the rat.

Prostaglandins and cyclic adenosine monophosphate have been claimed to play a major role in the morphine withdrawal syndrome, but intestinal secretion has not been ruled out as being responsible, at least in part, for the accompanying diarrhea. Therefore, experiments were performed in which the effect of naloxone-induced morphine withdrawal on jejunal and on colonic fluid transport was assessed in tied-off loops of rat intestine in vivo simultaneously with mucosal cyclic adenosine monophosphate levels or colonic luminal release of prostaglandin E2 or 5-hydroxytryptamine. Naloxone-induced withdrawal reversed fluid absorption to secretion without changing cyclic adenosine monophosphate levels, but markedly enhanced local prostaglandin E2 and 5-hydroxytryptamine release (p less than 0.01). Indomethacin and the 5-hydroxytryptamine receptor antagonist ketanserin prevented withdrawal-induced fluid secretion and the increase in prostaglandin E2 release without influencing the release of 5-hydroxytryptamine. In addition, the alpha 2-adrenergic receptor agonist clonidine promoted absorption during withdrawal, whereas atropine failed to influence fluid transport. These data suggest that naloxone-precipitated intestinal fluid secretion may contribute to diarrhea due to morphine withdrawal and that 5-hydroxytryptamine may play an important role in mediating this secretion through stimulation of local prostaglandin formation.

Animals↗
PubMed1984

Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis.

Azodisalicylate, a second generation drug of sulfasalazine, delivers twice the amount of 5-aminosalicylic acid to the colonic lumen on a molar basis when split by bacterial azoreductases. In 6 patients with inactive ulcerative colitis, the colonic metabolism of sulfasalazine and azodisalicylate was studied by equilibrium in vivo dialysis of feces to measure the therapeutically relevant concentrations of their metabolites (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) in free fecal water. After oral intake of sulfasalazine (2 g/day) the total luminal concentrations of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid determined by high-performance liquid chromatography were higher (median 14 mmol/L) than previously reported and almost doubled (median 25 mmol/L, p less than 0.05) when sulfasalazine was replaced by the same dose of azodisalicylate. In contrast, the corresponding serum concentrations were negligible. After administration of azodisalicylate to 12 healthy volunteers, a similar distribution of the metabolites was found. In nearly all cases, the concentrations of azodisalicylate in fecal dialysates were below the detection limit (6 mumol/L). We conclude, therefore, that oral azodisalicylate is a highly effective means of delivery of 5-aminosalicylic acid to the colonic mucosa. In addition, determination of the active metabolites in free fecal water seems important for the interpretation of results obtained in vitro concerning the mode of drug action.

Adult↗
PubMed1983

Comparison of radioimmunological determinations with gas chromatography mass spectrometry dosage. A study of PGE2 and PGF2alpha in gastrointestinal fluids.

The reliability of radioimmunoassays for determination of PGE2 and PGF2alpha in gastrointestinal fluids was checked by two gas chromatographic mass spectrometric methods. Analyses were performed on samples of gastric juice from dogs and man (healthy volunteers), jejunal fluids from patients with celiac disease, mucous discharge from a villous adenoma of rectum, and bathing solutions from the Ussing chamber containing human jejunal mucosa. The radioimmunoassays included extraction and Sephadex LH-20 chromatography as a preliminary purification before quantification was carried out. Gas chromatographic mass spectrometric analysis of PGE2 was performed by monitoring the molecular ion of the trimethylsilyl ether of PGB2 methyl ester, m/z 420 and m/z 424 for the protium and the deuterium form, respectively, while PGF2alpha was quantified as the triacetyl derivative of the methyl ester, using the ion pair (M-3x60) i.e. m/z 314 and m/z 318. Recovery of immunoreactive PGE2 relative to gas chromatographic mass spectrometric dosage was 85.5% + / - 6.5 (mean + / - SEM; n=13), while the amount of PGF2alpha in the same sample volume was at the borderline of sensitivity for the gas chromatographic mass spectrometric method used, with a recovery of 114% + / - 19 (mean + / - SEM; n=4).

Animals↗