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Influence of orlistat on gastric emptying rates of fats and solids in healthy subjects
GASTROENTEROLOGYVol. 114, No. 4
A740 AGA ABSTRACTS • G3054 GASTRIC EMPTYING OF LIQUIDS AND POSTPRANDIAL PANCREATOBILIARY SECRETION ARE TEMPORARILY IMPAIRED DURING ENDOTOXEMIA. JJ Cullen, S Titler, KS Ephgrave, MM Hinkhouse. Dept. of Surgery, University of Iowa College of Medicine & VAMC, Iowa City, IA.
Septic patients often develop delays in gastric emptying and become intolerant of enteral nutrition. Although endotoxemia has been shown to temporarily impair gastroduodenal motility (J Surg Res 58: 90, 1995), it is unknown what the effect of sepsis is on gastric emptying of liquids and pancreatobiliary output. AIMS: To determine the effect of endotoxin on postprandial pancreatobiliary secretion, antral motility and gastric emptying of liquids. METHODS: Six dogs underwent placement of duodenal perfusion and aspiration catheters, and gastric manometry catheters. Control studies of liquid gastric emptying, antral motility, output of bile acids and amylase were performed after ingestion of a 360-kcal mixed-nutrient liquid meal. Each dog was then given a single dose of E. coli lipopolysaccharide (200 pg/kg, iv) and the studies repeated for the next three days. RESULTS: Endotoxin slowed gastric emptying (GE) of liquids for two days but did not affect the postprandial antral motility index (MI) (Table). Postprandial output of bile acids and amylase were also decreased on postendotoxin day 1. CONCLUSIONS: Endotoxemia causes slowed gastric emptying and diminished pancreatobiliary secretions. Endotoxin decreases pancreatobiliary output by two possible mechanisms: 1) decreased nutrient flow into the duodenum or 2) decreased production of hormones that influence pancreatobiliary secretion. Enteral feedings may not be successful in the septic patient due to slowed gastric emptying or diarrhea from inadequate pancreatobiliary secretion. Postendotoxin Baseline# Day 1# Day 2# Day 3# Gastric emptying 48 ± 8 112 ± 8* 103 -+ 20* 89 _+ 19 (W,~,min) Antral Motility Index 756 ± 212 620 ± 200 492 ± 122 945 ± 782 (Ml/hr) Amylase secretion 12.8-+1.2 5.8±2.1" 10.2_+1.4 15.8_+2.0 (Uxl03/10 min) Bile acids output 135 ± 18 38 _+5* 47 ± 21 50 -+ 17 (U/10 min) # Means ± SEM, n --- 6, *P < 0.05 vs baseline. MI = motility index. Support: Veterans Affairs Merit Review grant. • G3055 DISTRIBUTION OF ENZYMES FOR RESYNTHKSIS OF L-ARGININE FROM L-CITRULLINE IN CANINE GASTROINTESTINAL TRACT: RELATIONSHIP TO NOS. E. E. Daniel. Y.-F. Wang, A. M. Salapatek, Y.-K. Mao, Hamilton, ON, Canada; M. Mori, Kumamoto, Japan. The purpose of this study was to determine the distributions of arginosuccinate synthetase (AS) and arginosuccinate lyase (AL), enzymes for resynthesis of L-arginine (L-ARG) from L-citruUine (L-CIT) in relation to the distribution of nNOS or NADPH-diaphorase (NADPH-d) for other NOS isozymes in selected gastrointestinal tissues from anesthetized animals. We used immunocytochemistry for AS, AL and nNOS and histochemistry for NADPH-d. AS and AL were present in neurones and nerve fibres in the myenteric plexus of the lower esophageal sphincter (LES), antrum, pylorus, ileum and colon. In ileum and colon, neurons and fibres of the submucous plexus were also stained as were nerve bundles in all circular muscle regions studied and longitudinal muscle of ileum and colon. LES muscle was also stained for both AS and AL as were many cells of circular and longitudinal muscle cells of the ileum and colon and cells resembling interstitial cells of Cajal in the deep muscular plexus of ileum and the submuscular plexus of colon and elsewhere. In many myenteric plexus and submucous plexus neurons, AS and nNOS were colocalized, but each was occasionally present alone. NADPH diaphorase activity (not nNOS) was present in LES, which also had AS and AL, and, to a lesser extent, in pyloric sphincter, which had neither AS nor AL. Other muscles lacked NADPH-d activity. In oval cells of the mucosa of all regions of the gastrointestinal tract there was also AS and AL activity. These cells were not endocrine cells, nerves nor components of blood vessels and may be lymphocytes. These results suggest that resynthesis of L-ARG from the NOS product, L-CIT, occurs in many enteric nerves usually but not always in cells with a NOS and in some muscles, some with a NOS (LES) and some without a NOS (ileum and colon muscularis extema). However, besides the LES, only the pyloric sphincter among studied tissues had NOS (NADPH-d) activity. Financial support for this study by MRC, Canada • G3056 ESOPHAGEAL MOTILITY OF PATIENTS WITH DIFFERENT GRADES OF ESOPHAGEAL INVOLVEMENT BY CHAGAS' DISEASE. Roberto O. Dantas, Neifi H.S. Deghaide, Eduardo A. Donadi. Faculdade de Medicina de Ribeir~o Preto, USP, Ribeir~o Preto, SP, Brazil. Although almost all patients with Chagas' disease have some grade of esophageal denervation, in most of them it is of minor intensity and causes no clinical problem. Our aim in this study was to evaluate the esophageal motility of these patients. We studied 106 patients with a positive serologic
test for Trypanosoma cruzi, aged 20-82 years (median: 48), divided into four groups: Group I: patients without dysphagia and with normal esophageal radiologic examination (n=48); Group II: patients without dysphagia and with abnormal esophageal radiologic examination (n=l 1); Group III: patients with dysphagia and normal esophageal radiologic examination (n=13); Group IV: patients with dysphagia and abnormal esophageal radiologic examination (n=34). Forty healthy volunteers aged 21-70 years (median: 39) were the control group. We used the manometric method, with an 8 lumen catheter and continuous perfusion. We measured the lower (LES) and upper (UES) esophageal sphincter pressure by the rapid pull-through method. The esophageal contractions were measured at 5, 10 and 15 cm proximal to the LES, with one side hole measuring LES relaxation. Ten swallows of a 5ml bolus of water alternated with ten dry swallows were performed by each subject. Statistical analysis was done by ANOVA, Duncan and KruskalWallis tests, with the level of significance set at p<0.05. The amplitude of contractions was lower in the chagasic groups than in the control, and lower in group IV than in group I. At 15cm from LES the duration of contractions was longer in group IV than in the other groups. At 10cm and 5cm, with wet swallows, the duration was longer in group IV than in group 1. The velocity of contractions from 15cm to 10cm above LES was greater in groups III and IV than in groups 1, II and control. LES pressure was lower in group I (25.2 ± 2.0 mmHg) than in controls (31.2-+ 1.9 mmHg). UES pressure was higher in groups I and II than in groups 1V and control. Complete LES relaxation was less frequent in patients than in controls, with a decreasing trend from group I to IV. There was an increase in failed contraction in Chagas' disease patients, and those with abnormal esophageal radiologic examination (groups II and IV) showed the highest number. Nonperistaltic contractions were more frequent in patients than in controls, with an increasing trend from group I to group IV. We conclude that in Chagas' disease: 1. Patients with a more important esophagopathy have an increased number of nonperistaltic contractions and incomplete LES relaxation, and longer duration of contractions; 2. The proportion of failed contractions is higher among patients with abnormal radiologic esophageal examination; 3. The complaint of dysphagia is associated with an increase in contraction velocity in the middle part of the esophagus. • G3057 INFLUENCE OF ORLISTAT ON GASTRIC EMPTYING RATES OF FATS AND SOLIDS IN HEALTHY SUBJECTS. L.De~en. D.Matzinger, H.Maecke, H.Lengsfeld, C.Beglinger. Div. of Gastroenterology and Department of Nuclear Medicine, University Hospital, CH-4031 Basel, Switzerland and Hoffmann-LaRoche, CH-4002 Basel, Switzerland. Baekeround. Individual labeling of solids (with 111 In*resin pellets) and of fat (with-99mTc-thyocyanate) provides a tool to simultaneously characterize the distinctive gastric emptying rates of both meal components. Orlistat, a potent and specific inhibitor of gastrointestinal lipases, is a drug developed for weight reduction by inducing artificial malabsorption through prevention of intestinal fat hydrolysis. While free fatty acids in the duodenum activate a negative feedback response, it is unknown whether undigested duodenal fat is able to retard gastric emptying. The aim of the study was to investigate the effect of orlistat on gastric emptying rates of both fat and solids in healthy male subjects using a double-blind, placebo-controlled design. Methods: 8 subjects were studied on 2 different days in random order at least 7 days apart. Each subject received either 120 mg orlistat or placebo together with a standardized meal. The meal consisted of hamburger served with 1 mCi 99mTc-thyocyanate labeled butter, french fries, scrambled eggs with 0.1 mCi llqn-resin pellets and toast. On each occasion, gastric emptying (GE), was quantified by scintigraphy (Cunningham et al., J Nucl Med 1991 ;32:878-881). Stool fat excretion was quantified to document the efficacy of orlistat. Results: Data are given as mean ± SEM. GE liquid fat
GE solids
lag (min) rate (%/min) tl/2 (rain) lag (min) rate (%/min) tl/2 (min)
Orlistat 120 mg 25 _+3 0.504 _+0.027 103 ± 8 64 ± 11 0.252 ± 0.023 203 ± 17
Placebo 30_+4 0.461 _+0.016 112_+8 50_+7 0.249 _+0.022 179 -+ 15
Summary. 1. Hydrolysis of dietary triglycerides was largely prevented by orlistat as shown by stool fat analysis and individual side effects (steatorrhea and oily leakage in several subjects). The drug did, however, not significantly affect GE. 2. GE rates of liquid fat was faster than of solids (p<0.03) both with placebo and with orlistat. We conclude that GE rates of liquid fat and solids differ substantially, but both are not affected by orlistat. Supported in part by Hoffmann-LaRoche and by a grant of the Swiss National Science Foundation #32-40604.94 • G3058 FATIGUE AND THE IRRITABLE BOWEL SYNDROME. V6ronique De Gucht, Benjamin Fischler, Catholic University of Leuven, Faculty of Medicine, Leuven, Belgium. Fatigue has been recognized as one of the most frequent complaints in IBS. The aims of the present study are to examine: 1) the different dimensions of fatigue in IBS controlling for neuroticism, somatization and job stress; 2) the
A740 AGA ABSTRACTS • G3054 GASTRIC EMPTYING OF LIQUIDS AND POSTPRANDIAL PANCREATOBILIARY SECRETION ARE TEMPORARILY IMPAIRED DURING ENDOTOXEMIA. JJ Cullen, S Titler, KS Ephgrave, MM Hinkhouse. Dept. of Surgery, University of Iowa College of Medicine & VAMC, Iowa City, IA.
Septic patients often develop delays in gastric emptying and become intolerant of enteral nutrition. Although endotoxemia has been shown to temporarily impair gastroduodenal motility (J Surg Res 58: 90, 1995), it is unknown what the effect of sepsis is on gastric emptying of liquids and pancreatobiliary output. AIMS: To determine the effect of endotoxin on postprandial pancreatobiliary secretion, antral motility and gastric emptying of liquids. METHODS: Six dogs underwent placement of duodenal perfusion and aspiration catheters, and gastric manometry catheters. Control studies of liquid gastric emptying, antral motility, output of bile acids and amylase were performed after ingestion of a 360-kcal mixed-nutrient liquid meal. Each dog was then given a single dose of E. coli lipopolysaccharide (200 pg/kg, iv) and the studies repeated for the next three days. RESULTS: Endotoxin slowed gastric emptying (GE) of liquids for two days but did not affect the postprandial antral motility index (MI) (Table). Postprandial output of bile acids and amylase were also decreased on postendotoxin day 1. CONCLUSIONS: Endotoxemia causes slowed gastric emptying and diminished pancreatobiliary secretions. Endotoxin decreases pancreatobiliary output by two possible mechanisms: 1) decreased nutrient flow into the duodenum or 2) decreased production of hormones that influence pancreatobiliary secretion. Enteral feedings may not be successful in the septic patient due to slowed gastric emptying or diarrhea from inadequate pancreatobiliary secretion. Postendotoxin Baseline# Day 1# Day 2# Day 3# Gastric emptying 48 ± 8 112 ± 8* 103 -+ 20* 89 _+ 19 (W,~,min) Antral Motility Index 756 ± 212 620 ± 200 492 ± 122 945 ± 782 (Ml/hr) Amylase secretion 12.8-+1.2 5.8±2.1" 10.2_+1.4 15.8_+2.0 (Uxl03/10 min) Bile acids output 135 ± 18 38 _+5* 47 ± 21 50 -+ 17 (U/10 min) # Means ± SEM, n --- 6, *P < 0.05 vs baseline. MI = motility index. Support: Veterans Affairs Merit Review grant. • G3055 DISTRIBUTION OF ENZYMES FOR RESYNTHKSIS OF L-ARGININE FROM L-CITRULLINE IN CANINE GASTROINTESTINAL TRACT: RELATIONSHIP TO NOS. E. E. Daniel. Y.-F. Wang, A. M. Salapatek, Y.-K. Mao, Hamilton, ON, Canada; M. Mori, Kumamoto, Japan. The purpose of this study was to determine the distributions of arginosuccinate synthetase (AS) and arginosuccinate lyase (AL), enzymes for resynthesis of L-arginine (L-ARG) from L-citruUine (L-CIT) in relation to the distribution of nNOS or NADPH-diaphorase (NADPH-d) for other NOS isozymes in selected gastrointestinal tissues from anesthetized animals. We used immunocytochemistry for AS, AL and nNOS and histochemistry for NADPH-d. AS and AL were present in neurones and nerve fibres in the myenteric plexus of the lower esophageal sphincter (LES), antrum, pylorus, ileum and colon. In ileum and colon, neurons and fibres of the submucous plexus were also stained as were nerve bundles in all circular muscle regions studied and longitudinal muscle of ileum and colon. LES muscle was also stained for both AS and AL as were many cells of circular and longitudinal muscle cells of the ileum and colon and cells resembling interstitial cells of Cajal in the deep muscular plexus of ileum and the submuscular plexus of colon and elsewhere. In many myenteric plexus and submucous plexus neurons, AS and nNOS were colocalized, but each was occasionally present alone. NADPH diaphorase activity (not nNOS) was present in LES, which also had AS and AL, and, to a lesser extent, in pyloric sphincter, which had neither AS nor AL. Other muscles lacked NADPH-d activity. In oval cells of the mucosa of all regions of the gastrointestinal tract there was also AS and AL activity. These cells were not endocrine cells, nerves nor components of blood vessels and may be lymphocytes. These results suggest that resynthesis of L-ARG from the NOS product, L-CIT, occurs in many enteric nerves usually but not always in cells with a NOS and in some muscles, some with a NOS (LES) and some without a NOS (ileum and colon muscularis extema). However, besides the LES, only the pyloric sphincter among studied tissues had NOS (NADPH-d) activity. Financial support for this study by MRC, Canada • G3056 ESOPHAGEAL MOTILITY OF PATIENTS WITH DIFFERENT GRADES OF ESOPHAGEAL INVOLVEMENT BY CHAGAS' DISEASE. Roberto O. Dantas, Neifi H.S. Deghaide, Eduardo A. Donadi. Faculdade de Medicina de Ribeir~o Preto, USP, Ribeir~o Preto, SP, Brazil. Although almost all patients with Chagas' disease have some grade of esophageal denervation, in most of them it is of minor intensity and causes no clinical problem. Our aim in this study was to evaluate the esophageal motility of these patients. We studied 106 patients with a positive serologic
test for Trypanosoma cruzi, aged 20-82 years (median: 48), divided into four groups: Group I: patients without dysphagia and with normal esophageal radiologic examination (n=48); Group II: patients without dysphagia and with abnormal esophageal radiologic examination (n=l 1); Group III: patients with dysphagia and normal esophageal radiologic examination (n=13); Group IV: patients with dysphagia and abnormal esophageal radiologic examination (n=34). Forty healthy volunteers aged 21-70 years (median: 39) were the control group. We used the manometric method, with an 8 lumen catheter and continuous perfusion. We measured the lower (LES) and upper (UES) esophageal sphincter pressure by the rapid pull-through method. The esophageal contractions were measured at 5, 10 and 15 cm proximal to the LES, with one side hole measuring LES relaxation. Ten swallows of a 5ml bolus of water alternated with ten dry swallows were performed by each subject. Statistical analysis was done by ANOVA, Duncan and KruskalWallis tests, with the level of significance set at p<0.05. The amplitude of contractions was lower in the chagasic groups than in the control, and lower in group IV than in group I. At 15cm from LES the duration of contractions was longer in group IV than in the other groups. At 10cm and 5cm, with wet swallows, the duration was longer in group IV than in group 1. The velocity of contractions from 15cm to 10cm above LES was greater in groups III and IV than in groups 1, II and control. LES pressure was lower in group I (25.2 ± 2.0 mmHg) than in controls (31.2-+ 1.9 mmHg). UES pressure was higher in groups I and II than in groups 1V and control. Complete LES relaxation was less frequent in patients than in controls, with a decreasing trend from group I to IV. There was an increase in failed contraction in Chagas' disease patients, and those with abnormal esophageal radiologic examination (groups II and IV) showed the highest number. Nonperistaltic contractions were more frequent in patients than in controls, with an increasing trend from group I to group IV. We conclude that in Chagas' disease: 1. Patients with a more important esophagopathy have an increased number of nonperistaltic contractions and incomplete LES relaxation, and longer duration of contractions; 2. The proportion of failed contractions is higher among patients with abnormal radiologic esophageal examination; 3. The complaint of dysphagia is associated with an increase in contraction velocity in the middle part of the esophagus. • G3057 INFLUENCE OF ORLISTAT ON GASTRIC EMPTYING RATES OF FATS AND SOLIDS IN HEALTHY SUBJECTS. L.De~en. D.Matzinger, H.Maecke, H.Lengsfeld, C.Beglinger. Div. of Gastroenterology and Department of Nuclear Medicine, University Hospital, CH-4031 Basel, Switzerland and Hoffmann-LaRoche, CH-4002 Basel, Switzerland. Baekeround. Individual labeling of solids (with 111 In*resin pellets) and of fat (with-99mTc-thyocyanate) provides a tool to simultaneously characterize the distinctive gastric emptying rates of both meal components. Orlistat, a potent and specific inhibitor of gastrointestinal lipases, is a drug developed for weight reduction by inducing artificial malabsorption through prevention of intestinal fat hydrolysis. While free fatty acids in the duodenum activate a negative feedback response, it is unknown whether undigested duodenal fat is able to retard gastric emptying. The aim of the study was to investigate the effect of orlistat on gastric emptying rates of both fat and solids in healthy male subjects using a double-blind, placebo-controlled design. Methods: 8 subjects were studied on 2 different days in random order at least 7 days apart. Each subject received either 120 mg orlistat or placebo together with a standardized meal. The meal consisted of hamburger served with 1 mCi 99mTc-thyocyanate labeled butter, french fries, scrambled eggs with 0.1 mCi llqn-resin pellets and toast. On each occasion, gastric emptying (GE), was quantified by scintigraphy (Cunningham et al., J Nucl Med 1991 ;32:878-881). Stool fat excretion was quantified to document the efficacy of orlistat. Results: Data are given as mean ± SEM. GE liquid fat
GE solids
lag (min) rate (%/min) tl/2 (rain) lag (min) rate (%/min) tl/2 (min)
Orlistat 120 mg 25 _+3 0.504 _+0.027 103 ± 8 64 ± 11 0.252 ± 0.023 203 ± 17
Placebo 30_+4 0.461 _+0.016 112_+8 50_+7 0.249 _+0.022 179 -+ 15
Summary. 1. Hydrolysis of dietary triglycerides was largely prevented by orlistat as shown by stool fat analysis and individual side effects (steatorrhea and oily leakage in several subjects). The drug did, however, not significantly affect GE. 2. GE rates of liquid fat was faster than of solids (p<0.03) both with placebo and with orlistat. We conclude that GE rates of liquid fat and solids differ substantially, but both are not affected by orlistat. Supported in part by Hoffmann-LaRoche and by a grant of the Swiss National Science Foundation #32-40604.94 • G3058 FATIGUE AND THE IRRITABLE BOWEL SYNDROME. V6ronique De Gucht, Benjamin Fischler, Catholic University of Leuven, Faculty of Medicine, Leuven, Belgium. Fatigue has been recognized as one of the most frequent complaints in IBS. The aims of the present study are to examine: 1) the different dimensions of fatigue in IBS controlling for neuroticism, somatization and job stress; 2) the