Effects of octreotide treatment on early TNF-alpha production and localization in experimental chronic colitis.

BACKGROUND: Colitis induced by trinitrobenzene sulphonic acid (TNB) is a model of Th1 disease, mainly explored from the third day of induction. It has recently been shown that octreotide and other somatostatin analogues can modify inflammatory/immune processes by acting on cytokines. AIM: To examine TNFalpha production and the effect of preventive treatment with octreotide, during the early phase of TNB-colitis. METHODS: Thirty milligrams TNB with 50% ethanol was instilled into the colon of male Wistar rats. Treated groups received octreotide (2x10 microg x day/rat) or dexamethasone (1x2 mg x day/kg), subcutaneously, with the first injection before TNB. Eight and 80 h later, the colon was excised and processed for histology, TNFalpha immunohistochemistry, quantification of cytokine release ex vivo and tissue-inducible NO synthase (iNOS) activity. RESULTS: Maximal TNFalpha production was observed at the 8th hour, associated with intense immunostaining of the external muscle layer. Octreotide treatment decreased TNFalpha expression (staining and activity) and iNOS activity. At the 80th hour, submucosal macrophages were positive for TNFalpha and colonic production of IL1beta and interferon gamma was increased; all these effects were reduced by octreotide treatment. CONCLUSIONS: TNFalpha was expressed early by resident muscle cells, before staining of infiltrated immune cells and increased production of interferon gamma. TNFalpha regulation by octreotide suggests that this drug might exert anti-inflammatory properties via smooth muscle cells.

Technetium Tc 99m hexamethyl propylene amine oxine leukocyte scintigraphy in patients with ulcerative colitis: correlation with clinical, biologic, endoscopic, and pathologic intensity, and local release of interleukin 8.

BACKGROUND: Technetium Tc 99m hexamethyl propylene amine oxine (99mTc-HMPAO) has been used to radiolabel leukocytes with promising results for its clinical use in inflammatory bowel disease. During active ulcerative colitis, colonoscopy is indicated to determine the extent and the intensity of the disease for proper management. The aim of this prospective study was to determine whether 99mTc-HMPAO-labeled leukocyte scintigraphy can give information similar to that obtained with colonoscopy during acute attacks of ulcerative colitis. METHODS: Thirty-three consecutive patients with 50 acute episodes of ulcerative colitis underwent 99mTc-HMPAO scintigraphy and colonoscopy with biopsies. Scintigraphic determination of disease extent and intensity were compared with those obtained by colonoscopy with biopsies and clinicobiologic markers. RESULTS: The scintigraphic index of disease intensity was correlated with endoscopic index, Truelove index, biologic markers, and local release of interleukin-8. The extent measured by scintigraphy was well correlated to the endoscopic and histologic extent. CONCLUSIONS: 99mTc-HMPAO scintigraphy accurately determines the extent and the intensity of acute ulcerative colitis lesions. This noninvasive method can specify the extent and the intensity of an acute attack in patients with previously known ulcerative colitis.

Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis.

OBJECTIVE: The inflammatory component of most human inflammatory chronic diseases implicates the production of proinflammatory cytokines. Tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL1beta) seem to play an important role in ulcerative colitis (UC) in relevant experimental models. Moreover, antiTNF therapy seems promising experimentally and clinically. However, these cytokines, and TNFalpha more particularly, are hardly seen in vivo in such patients. The mediators of choice, correlated with disease activities or drug efficacy, remain unclear. To characterize in vivo the network of colonic cytokines in patients with UC, and the contribution of the various cytokines to disease activity we performed this study, using the colonic perfusion method. METHODS: A 20-cm colon length was perfused. Perfusate samples were collected for cytokine determination by enzyme-linked immnoassays. Nineteen perfusions were performed in mild to moderate UC, including two successive perfusions in four patients. Six healthy control patients and four having Crohn's disease (CD) with rectal involvement were studied. Endoscopic score, leukocyte scintigraphy, and systemic markers of inflammation were simultaneously quantified. RESULTS: Large amounts of IL1beta, TNFalpha, IL6, and IL8 were produced in UC patients with a highly significant correlation between TNFalpha, IL1beta and IL8 two by two. Multivariate factorial analysis indicated that IL1beta showed the best correlation with disease activity. Locally produced IL6 was strongly associated with circulating platelet counts. Moreover, production of inflammatory cytokines was associated with similar variations of disease activity in the four patients with two successive perfusions performed. The level of inflammatory cytokines in CD was lower than in UC; TNFalpha, IL1beta, and IL6 were not found in any control patients. CONCLUSION: UC appears to be a chronic inflammatory disease characterized by high production of all four proinflammatory cytokines (IL1beta, TNFalpha, IL6, and IL8). These results suggest that colonic perfusion may be a suitable method to evaluate the local anticytokine properties of new drugs, in correlation with disease activity and systemic markers of inflammation.

Effects of lanreotide, a somatostatin analogue, on postprandial gastric functions and biliopancreatic secretions in humans.

AIMS: Lanreotide is a novel synthetic somatostatin analogue. A long-acting formulation of lanreotide has been shown to be effective for the treatment of gastroentero-pancreatic hormone-producing tumours but effects on postprandial digestive and absorptive functions remain obscure. The aim of the present study was to evaluate the effects of intravenous lanreotide on gastric and biliopancreatic secretions in man as well as the absorption of nutrients and the duodeno-caecal transit time after ingestion of an homogenized meal (500 kcal, 55% carbohydrates, 15% proteins, 30% lipids). METHODS: Eight healthy male volunteers were studied on two occasions within a 2 weeks interval, using a perfusion method. They received in single-blind and random order continuous i.v. infusion of either placebo or lanreotide (100 micrograms h-t after a bolus of 100 micrograms 15 min before the beginning of the study). RESULTS: Lanreotide significantly decreased gastric acid secretion (90%) for the initial 3 h period. Gastric emptying was not significantly modified by lanreotide infusion. Compared with placebo, lanreotide almost completely abolished both bile salts and lipase responses to the meal. It largely increased the duodeno-caecal transit time and decreased significantly the duodenal absorption of carbohydrates and triglycerides. CONCLUSIONS: Since lanreotide has powerful effects on gastrointestinal functions, it could be useful in the prevention or in the treatment of pancreatic and bowel fistulas as well as short bowel syndrome.

Could oral erythromycin optimize high energy continuous enteral nutrition?

BACKGROUND: Intravenous erythromycin has previously been reported to stimulate gastric emptying, to inhibit gastric acid secretion and to stimulate pancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers. AIM: The aim of this study was to evaluate the effects of oral erythromycin (160 mg/h) on gastrointestinal function under these conditions in seven healthy subjects. METHOD: This randomized double-blind cross-over study measured the gastric emptying rate of nutrients, gastric acid secretion, gastric pH, jejunal flow rate as well as biliopancreatic secretion and duodeno-caecal transit time during a 19.9 kJ/min continuous infusion of a nutrient solution (4.18 kJ/mL) in the antrum over a 6-h period by a perfusion method. RESULTS: The nutrition was well tolerated except by one subject with placebo perfusion. During the 6-period, total gastric volume and gastric volume of nutrient decreased during erythromycin administration by 22 +/- 8 and 22 +/- 6%, respectively. Gastric acid secretion was not modified by erythromycin. Lipase and bile salt outputs were significantly higher with erythromycin. The duodeno-caecal transit time was not statistically different with drug and placebo (169 +/- 15 and 146 +/- 19 min, respectively). CONCLUSION: During continuous gastric infusion of a liquid diet, the effect of oral erythromycin on gastric emptying could be useful to optimize cyclic enteral nutrition or to enhance the tolerance of enteral nutrition.

Intraluminal excretion of PAF, lysoPAF, and acetylhydrolase in patients with ulcerative colitis.

PAF-acether (PAF) is a phospholipid synthesized by numerous inflammatory cells. PAF can produce several pathological changes in various organs, especially in the colon. In animals PAF causes colonic ulceration and inflammation, which are similar to the anatomic lesions seen in human ulcerative colitis. The aim of this study was to measure in vivo colonic production of PAF in active ulcerative colitis using a modified colonic perfusion method. Ten patients with active ulcerative colitis and six control patients were investigated. A colonic segment was continuously perfused with a buffer and the liquid was recovered 20 cm distally, after a 45-min period of equilibration, at 20-min intervals. PAF, lysoPAF, and acetylhydrolase were measured in the colonic samples. PAF and lysoPAF outputs were significantly higher in patients with active ulcerative colitis compared to controls patients. There was a significant correlation between colonic PAF output and, respectively, macroscopic mucosal lesions and myeloperoxidase colonic output. We thus conclude: (1) the colonic perfusion method allows in vivo study of the metabolism of PAF during ulcerative colitis and could also be used to study the efficiency of PAF antagonists in UC; and (2) colonic production of PAF is increased during ulcerative colitis and correlated to local injury and inflammation. Whether or not PAF plays a role in the pathogenesis of ulcerative colitis remains open for further investigations.

Effects of erythromycin on gastric emptying, duodeno-caecal transit time, gastric and biliopancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers.

OBJECTIVE: Erythromycin, a macrolide antibiotic, has been reported to increase gastric emptying. The aim of this study was to evaluate the effects of intravenous erythromycin (150 mg/h) on gastric emptying, small intestinal transit time, gastric and biliopancreatic secretions during gastric infusion of a liquid diet in healthy volunteers. DESIGN: A randomized double-blind crossover study (erythromycin versus placebo). METHODS: Gastric emptying rates of nutrients, gastric acid secretion, gastric pH, jejunal flow rates, as well as biliopancreatic secretions and duodeno-caecal transit time, were evaluated during a continuous infusion at 4.5 kcal/min of a nutrient solution (1 kcal/ml) in the antrum, over a 6 h period, by a perfusion method. RESULTS: During the 6 h period, total gastric volume and gastric acid secretion decreased during erythromycin administration of 37 and 22%, respectively (area under the curves). Lipase outputs were significantly higher with erythromycin than placebo. Bile salt output was not significantly different between erythromycin and placebo. Duodeno-caecal transit time increased significantly during erythromycin infusion compared with placebo (191 +/- 12 versus 159 +/- 17 min; P < 0.05). CONCLUSION: During continuous gastric infusion of a liquid diet, intravenous erythromycin has a powerful effect on gastrointestinal function. The motor and secretory effects may enhance the tolerance and the efficiency of enteral nutrition in humans.

Gastrointestinal and biliopancreatic response to continuous nasogastric feeding in man: effect of increasing nutrient infusion rate.

Nasogastric feeding is a safe and inexpensive procedure used in various conditions to provide artificial nutritional support. However, the effects of increasing energy load of nutrients during continuous enteral nutrition on gastric physiology, biliopancreatic secretions and intestinal absorption of nutrients are unknown. A nutrient solution (1 kcal/ml, 15% proteins, 30% lipids, 55% carbohydrates) was randomly infused at three rates, 1.5, 3.0 and 4.5 ml/min, into the gastric antrum in 6 volunteers over a 6 h period. Gastric emptying, gastric and biliopancreatic secretion, and intestinal absorption were studied using a perfusion technique. Gastric emptying rate reached the infusion rate during continuous enteral nutrition at 1.5 and 3.0 ml/min although a steady state was not reached at 4.5 ml/min. During feeding at 1.5, 3.0 and 4.5 ml/min, the median gastric pH values were 1.9, 2.3 and 3.0 respectively and the total gastric volumes at the sixth hour were 78 +/- 13, 226 +/- 43 and 539 +/- 101 ml respectively. There was a significant increase in biliary and pancreatic secretion between 1.5 and 3.0 ml/min but not between 3.0 and 4.5 ml/min. Gastric emptying became the limiting factor in lipid and in carbohydrate absorption. Our study shows that, in healthy volunteers, the maximal infusion rate of a nutrient solution infused into the stomach should be approximately 3 ml/min to avoid complications such as nausea, vomiting, regurgitation and pulmonary inhalation.

Does lansoprazole influence postprandial digestive function?

The effects of a potent proton pump inhibitor on postprandial digestive functions were compared with those of a placebo in a double-blind randomized crossover study. Six healthy male volunteers received 30 mg/day of lansoprazole or placebo for 7 days, with a wash-out period of 14 days. As compared to placebo, lansoprazole induced a marked decrease of mean +/- S.E.M. 3-h gastric acid secretion from 46.8 +/- 10.8 mmol to 10.9 +/- 2.5 mmol (P < 0.05), and a decrease of the volume of gastric contents emptying into the duodenum from 1043 +/- 139 ml to 660 +/- 87 ml (P < 0.05). However, gastric emptying remained unchanged with meal gastric emptying half times of 66 +/- 5 min and 67 +/- 13 min, respectively. During the 3-h postprandial period, duodenal lipase and chymotrypsin outputs were 366 +/- 123 KIU and 56 +/- 11 KIU with lansoprazole and 436 +/- 119 KIU and 49 +/- 8 KIU with placebo (N.S.). Bile acid outputs were 5.3 +/- 0.7 mmol and 6.0 +/- 1.0 mmol, respectively (N.S.) There was no change in kinetic profiles of biliary-pancreatic secretion. We conclude that potent inhibition of gastric secretion by chronic administration of a proton pump inhibitor at usual therapeutic dose alters neither meal gastric emptying nor postprandial biliary-pancreatic secretion.

Effect of ethanol on absorption of a nutrient solution in the upper human intestine.

The study compares the duodenal and jejunal absorption of an ethanol-containing nutrient solution (4% wt/vol, 4.06 kcal/min = 17.2 kJ/min, 1190 mosmol/kg) with the corresponding ethanol-free solution (2.64 kcal/min = 11.2 kJ/min, 160 mosmol/kg) and with another ethanol-free solution adapted in caloric load and osmolality (4.06 kcal/min = 17.2 kJ/min, 1160 mosmol/kg) by the addition of NaCl and glucose in eight healthy volunteers, using the intestinal perfusion technique. Ethanol added to a nutrient solution did not exert a significant effect on the net absorption of nutrients in the upper intestine. However, duodenal but not jejunal net water (p < 0.05) and sodium (p < 0.02) movements were significantly modified. Compared with the hyperosmolar ethanol-free solution, perfusion of ethanol induced in the duodenum a significantly lower (p < 0.001) net water and sodium secretion and higher absorption rates of total nitrogen and fatty acids (p < 0.001). The importance of the composition of control solutions in studies investigating the effects of ethanol in the gastrointestinal tract is emphasized.

Inhibitory effect of jejunal high caloric nutrient load on human biliopancreatic secretion. The role of atropine, naloxone and composition of nutrient solutions.

Our previous studies shown that a high caloric load in the jejunum decreases biliopancreatic output. However, the factors responsible for this inhibition have not yet been fully assessed. In this study, we have compared the effect of a high caloric load of either proteins or carbohydrates on stimulated pancreatic output and investigated the mechanism of this inhibition. The small intestine of 6 healthy volunteers was intubated 10 cm below the angle of Treitz, for 3 consecutive days, to infuse test solutions. After a 90 min period of stimulation, using a protein solution (0.6 kcal/min; solution A), one of the following 2 solutions was infused on for 90 min each day, in random order. In each instance, either a protein plus carbohydrate solution (3.5 kcal/min; solution B), or a protein solution (3.5 kcal/min; solution C) was administered. On the 3rd day, first solution A then solution B were infused with either IV atropine (17 mug/kg/h) in 3 subjects, or naloxone (40 mug/kg/hl) in 3 subjects. PEG 4000 was also added to solutions B and C and (14)C-PEG to solution A, as nonabsorbable markers. Intraluminal content was aspirated 25 cm below the infusion point and 50 cm distally to prevent unabsorbed nutrients from reaching the ileum. Solution B and C caused similar decreases in lipase, chymotrypsin and bile salt outputs. Neither atropine nor naloxone inhibited the jejunal-brake induced by solution B. However, naloxone, but not atropine, decreased the carbohydrate absorption rate of solution B. In conclusion, a high caloric load of proteins or carbohydrates infused into the human jejunum decreased the bilio-pancreatic output induced by a low caloric load of proteins. This mechanism is neither cholinergic nor opioid dependent. This effect, in relation to a jejunal brake, might explain functional pancreatic insufficiency after surgical procedures such as gastro-jejunostomy.

Effect of jejunal infusion of different caloric loads on pancreatic enzyme secretion and gastro-intestinal hormone response in man.

It has recently been demonstrated that the infusion of a high caloric load (3.3 kcal min-1 = 14.0 kJ min-1) into human upper jejunum inhibited pancreatic enzyme and bile salt secretion. The aim of the present study was to investigate whether this phenomenon was mediated by gastrointestinal hormones which interfere with pancreatic secretion. In six healthy volunteers, jejunal infusion of 1.3 kcal min-1 (5.5 kJ min-1) did not modify secretion of lipase and chymotrypsin to any significant extent compared with saline infusion, but the rate of 3.3 kcal min-1 (14.0 kJ min-1) resulted in an inhibition. Somatostatin and pancreatic polypeptide, which are known to inhibit exocrine pancreatic secretion, remained unchanged during jejunal nutrient infusion. The inhibition of pancreatic enzyme secretion was observed in temporal relationship with an increase of the stimulators of pancreatic exocrine secretion such as secretin, neurotensin, and CCK. The existence of an hitherto undefined inhibitor and a feedback mechanism is postulated.

Absorption of a nutrient solution in chronic alcoholics without nutrient deficiencies and liver cirrhosis.

Duodenal and jejunal absorption of a nutrient solution at two different caloric loads (1.32 and 3.96 kcal/min = 5.6 and 16.8 kJ/min) was compared in chronic alcoholics without malnutrition, liver cirrhosis, obvious small-bowel dysfunction, and exocrine pancreatic insufficiency and in an age-matched control group, by means of the intestinal perfusion technique. In chronic alcoholics duodenal net absorption of water (p < 0.025), sodium (p < 0.02), potassium (p < 0.005), total nitrogen (p < 0.02), carbohydrates (p < 0.05), and lipids (p < 0.05) was lower than in controls when both caloric loads were administered, but jejunal absorption rates were not decreased. Biliopancreatic secretion did not differ between alcoholics and controls. Higher serum protein leakage in alcoholics was indicated by an increased (p < 0.01) duodenal alpha 1-antitrypsin clearance under low caloric load infusion. It is concluded that the absorptive function of the duodenum is impaired in alcoholics, whereas the upper jejunum is not affected.

Fate of orally ingested enzymes in pancreatic insufficiency: comparison of two pancreatic enzyme preparations.

The effect on steatorrhoea of a pH-sensitive enteric-coated pancreatic preparation (Eurobiol 25,000) was compared with a conventional pancreatic enzyme preparation (Eurobiol) in six adult patients with exocrine pancreatic insufficiency. In addition, the fate of orally ingested pancreatic enzymes in the upper digestive tract was evaluated by measuring gastric and duodenal pH, amount of enzymes in the stomach, duodenal enzyme output, and fat absorption at the angle of Treitz for the 4 hours following a standard meal. When compared with placebo, Eurobiol and Eurobiol 25,000 reduced daily faecal fat excretion by 24% (not significant) and 43% (P less than 0.05), respectively. With the conventional preparation, enzyme output and fat absorption at the duodeno-jejunal flexure were significantly improved (P less than 0.05). Marked inter-individual differences in duodenal enzyme recovery (lipase 3% to 80%; chymotrypsin 26% to 100%) and, consequently, in the reduction of steatorrhoea (0% to 67%) were observed, with the gastric emptying rate emerging as a key determinant factor. With the enteric-coated preparation, enzyme output and fat absorption at the duodenojejunal flexure were not significantly improved. Discrepancy between the marked reduction of faecal fat excretion and the low duodenal enzyme recovery could indicate that enzyme delivery from microtablets occurs further down in the small bowel. Efficacy of enteric-coated preparations could be enhanced by adding unprotected enzymes, especially in patients with rapid gastric emptying.

Human jejunal secretion induced by prostaglandin E1: a dose-response study.

1. Intraluminally infused prostaglandins induce jejunal secretion of water and electrolytes in man, and a receptor-mediated process in the intestinal epithelial cells has been suggested to explain this secretion. In an attempt to obtain data under basal conditions for pharmacological studies, we tested the dose-response effect of PGE1 on jejunal hydroelectrolytic movements in 10 healthy volunteers. 2. Accordingly, a solution with or without PGE1 was infused via a four-lumen tube with a proximal occluding balloon and jejunal water and electrolyte transport were determined. The segment tested was 40 cm long. Seven randomized doses of PGE1 ranging from 0.01 to 1.3 micrograms kg-1 min-1 (2.83 to 364 pmol kg-1 min-1) were infused in an isotonic control saline solution. The secretion induced by PGE1 was evaluated in each subject as the difference between fluxes in response to the control saline solution and to PGE1. 3. Whatever the dose, PGE1 induced secretion of water, Na+, K+ and Cl- which was dose-dependent and saturable, with a mean Km of congruent to 6-8 pmol kg-1 min-1, suggesting that at the pharmacological doses used, enterocytes have a saturable membrane site similar to a single class of receptor for PGE1. 4. These findings may be of great importance if prostaglandins are administered as drugs or used as jejunal secretory agents in vivo when the antisecretory effect of another drug is studied.

Intestinal absorption of amiodarone in man.

The jejunal absorption rate of amiodarone and the influence of lipids on it were studied in human volunteers using the intestinal perfusion technique. A nutrient solution (Realmentyl, Sopharga Laboratories, France) with 300 mg of the drug was infused for 120 minutes at the ligament of Treitz. The segment tested was 25 cm long. Two caloric loads of the nutrient solution, 3.3 Kcal/min (solution A) and 1.3 Kcal/min (solution B), A containing total lipid and caloric load 2.5 times higher than B, were administered. Minor interindividual differences in amiodarone absorption rate were observed (20.2 to 31.7%) with solution A. Amiodarone absorption correlated with lipid absorption significantly. Since the maximal plasma concentrations of the drug and the area under the curve (AUC/24 hours) did not correlate with the amount of amiodarone absorbed, the wide fluctuations of amiodarone pharmacokinetics must mainly be due to amiodarone tissue distribution and metabolic pathway.

Effect of jejunal infusion of nutrients on gastrointestinal transit and hormonal response in man.

The effects of jejunal infusion of nutrients on gastric emptying and secretion, intestinal transit and hormone release were studied in human volunteers. Two caloric loads, 1.3 and 3.3 kcal/min, of a nutrient solution consisting of 18 percent protein, 27 percent lipids, and 55 percent carbohydrates were tested. These were first used in random order in 6 subjects to assess the effects on intestinal transit. For the study of gastric emptying, jejunal infusion was started 1 h after intragastric instillation of a 490 kcal, 400 ml, homogenized meal. Intestinal transit time and gastric emptying half-time increased with the rate of nutrient infusion into the jejunum. Postprandial gastric secretion was reduced. The two caloric loads induced significant rises of plasma cholecystokinin and gastric inhibitory polypeptide concentrations. Plasma motilin decreased in relation to the jejunal caloric load. The other peptides were essentially not affected by jejunal nutrient infusion in fasting subjects. We conclude that in man, gastric emptying rate, gastric secretion, and intestinal transit are regulated by the presence of nutrients in the jejunum.

Inhibitory effect of high caloric load of carbohydrates or lipids on human pancreatic secretions: a jejunal brake.

Effects of jejunal infusion of a saline solution, a protein meal, and a mixed protein and carbohydrate meal on biliopancreatic secretions were compared in six healthy volunteers. Protein infusion stimulated biliopancreatic secretions whereas carbohydrate infusion inhibited these secretions compared with saline infusion. The roles of lipid, carbohydrate, and caloric load on the inhibition of pancreatic secretions by jejunal infusion of nutrients was investigated in six other healthy volunteers. Carbohydrate, lipid, and the mixed meal inhibited pancreatic secretions whereas the carbohydrate solution was the only one that inhibited biliary secretion. These studies indicate that the mechanism of jejunal brake seems mainly related to the jejunal caloric load. In malabsorption or in the short bowel syndrome, a high caloric load or unabsorbed nutrients in the jejunum further inhibits pancreatic secretion, contributing to the loss of nutrients from the intestinal tract.

Evaluation of the gastric absorption and emptying of drugs under various pH conditions using a simple intubation method: application to diclofenac.

Sodium diclofenac (50 mg) together with [14 C]-PEG as a non-absorbable marker were dissolved in 400 ml of water (A), phosphate buffer pH 7.5 (B) or a homogenized meal (C). Each of these was ingested in random order by six volunteers on 3 consecutive days. Some gastric absorption of the drug was established with C but the plasma drug concentration-time profiles mainly reflected the process of gastric emptying.