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Biomedical subjects

K Bukhave

Publications and source records attributed to K Bukhave.

At least 55 records · Page 3Linked to original sources
PubMed1988

Decomposition of wheat bran and ispaghula husk in the stomach and the small intestine of healthy men.

Decomposition of dietary fibers in the stomach and small bowel was studied in 13 healthy male volunteers. Liquid control meals were compared with test meals, which in addition contained a source of fiber (wheat bran or ispaghula husk) in random order. Aspirations were collected from the stomach, the proximal jejunum, the mid gut and the terminal ileum. Radiolabeled polyethylene glycol-4000 was used as nonabsorbable water-phase marker, and the formation of free arabinose was used to quantify the hydrolysis of dietary fibers. Ingested fibers, aspirates and urine specimens were analyzed for monosaccharides, either free or fiber-bound, by gas-liquid chromatography. Both types of fiber were hydrolyzed in the stomach, but not in the small bowel. Of ispaghula husk, 1-6% was hydrolyzed, as was 5-8% of wheat bran. Intestinal absorption of free arabinose was 85-93%, but excretion of arabinose in the urine was not greater than after control meals. For further evaluation of gastric hydrolysis six additional healthy male volunteers were studied by serial aspirations from the antral part of the stomach. Hydrolysis was instantaneous for both fibers, and was significantly more pronounced for wheat bran than for ispaghula husk.

Adult↗
PubMed1988

Use of colonic eicosanoid concentrations as predictors of relapse in ulcerative colitis: double blind placebo controlled study on sulphasalazine maintenance treatment.

To establish whether concentrations of eicosanoids determined by equilibrium in vivo dialysis of faeces and equilibrium in vivo dialysis of rectum might predict a relapse in ulcerative colitis, 23 patients with completely inactive disease, maintained on sulphasalazine, stopped treatment and entered a prospective study. Concentrations of prostaglandin E2 were determined by radioimmunoassay on purified faecal and rectal dialysates at entry, at two weeks, and at two, six, and 12 months. If the above concentrations exceeded control concentrations (0.5 ng/ml and 1.0 ng/ml in faecal and rectal fluid, respectively) at any study day, the patient was allocated at random to double blind treatment with sulphasalazine 2 g/day, or placebo for six months. A relapse, defined as recurrence of symptoms accompanied by endoscopic inflammation occurred in none of six and in four of five patients allocated to sulphasalazine and placebo, respectively (p less than 0.05). In no case a normal rectal prostaglandin E2 concentration was associated with a relapse in the short term, but only two of 12 patients observed passively remained in remission. In retrospect, leukotriene B4 was a less sensitive predictor of relapse than prostaglandin E2. We conclude that raised concentrations of prostaglandin E2 in rectal dialysis fluid identify patients with a substantial risk of relapse.

Adolescent↗
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

Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid.

The possible effect of sulfasalazine, 5-aminosalicylic acid, and acetyl-5-aminosalicylic acid on endogenous arachidonic acid release and metabolism was studied in human polymorphonuclear leukocytes (PMNs). A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr). After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry. Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both sulfasalazine and 5-aminosalicylic acid. The acetylated derivative of 5-aminosalicylic acid was ineffective. The present data suggest that inhibition of arachidonic acid lipoxygenation may be an essential action of sulfasalazine and its active metabolite, 5-aminosalicylic acid. Interference with lipoxygenase enzymes, rather than a steroid-like inhibition of arachidonic acid release from intracellular phospholipids, seems to be the mode of action.

Aminosalicylic Acids↗
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↗
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↗
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

Arachidonic acid metabolism in human neutrophils: lack of effect of cyclosporine A.

The metabolism of arachidonic acid (AA) in human neutrophils was studied by incorporation of 1-14C-AA, removal of excess 1-14C-AA, and stimulation of radiolabelled cells with A23187. Radiolabelled lipids were quantitated by extraction, thin-layer chromatography, autoradiography, and laser densitometry. Following 5 h of incubation with 1-14C-AA, the maximum amount of radioactivity was located in triglycerides, 70%, and phospholipids, 30%. Activation of the cells with calcium ionophore A23187 led to release of free AA, 58%, whereas AA-metabolites revealed mainly lipoxygenase (arachidonate 5 lipoxygenase, E.C. 1. 13. 11. 34) activity, 5-HETE 13%, LTB4 5%, with only small amounts of cyclooxygenase (prostaglandin synthase, E.C. 1. 14. 99. 1) metabolites, HHT 2%. Intra-assay coefficient of variation for release of metabolites was approximately 15%. A potent immunosuppressive agent, cyclosporine A (CS-A) was shown to be without any effect in AA-release and metabolism. This method is applicable to studies of both basic cell function in human disease and to further immunopharmacological investigations.

Arachidonic Acid↗
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↗
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↗