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The efficacy of an oral alpha galactosidase in complex carbohydrate digestion: A randomized crossover study
A308
AGA ABSTRACTS
DIFFERENT DIFFUSION KINETIKCS OF BILE ACIDS IN RABBIT JEJUNUM AND ILEUM: EFFECT OF INTESTINAL MUCOSAL PERMEABILITY. Montagnani M.1, Aldini R.2, Roda A. ~, Polimeni C. ~, F.Stagni', E. Roda~ 'Cattedra di Gastroenterologia, 21stitutodi Scienze Chimiche, 3Dipartimento di Scienze Farmaceutiche, Universita di Bologna, Bologna, Italy. Ileal bile acid (BA) transport is an active, Na+ coupled mechanism, considered a determinant step in the entero-hepatic circulation (EHC) of BA. Passive diffusion, on the contrary, occurs along the whole intestine, and little is known about possible differences in the diffusion rates of BA in different intestinal segments. In the present investigation, jejunal and ileal tracts of rabbit intestine (30 cm) were separately perfused with different BA and the blood was collected from the mesentedc vessels draining from the perfUsed intestine: Taurocholic (TCA), tauroursodeoxycholic (TUDCA), glycoursodeoxycholic (GUDCA) and ursodeoxycholic (UDCA) acid were separately infused at various doses (0.25-10mM) and a dose-response curve was thus obtained for each BA in the jejunum and ileum. UDCA perfusions were carried out at different flow rates in order to evaluate the effect of luminal stirring in both the intestinal tracts, Cholesterol to phospholipid ratio was evaluated in brush border membrane vesicles (BBMV) obtained from jejunum and terminal ileum~ TCA and TUDCA showed active transport rates in the ileum, a n d actually no transport in the jejunum; GUDCA showed both active transport and passive diffusion in the ileum; the latter component of the transportwas present in the jejunum. UDCA absorption was passive in both the intestinal tracts. Passive diffusion was in the following order: UDCA ileum > UDCA jejunum > GUDCA ileum > GUDCA jejunum. A higher cholesterol to phospholipid ratio was found in BBMV from the ileal tract, respect to jejunum. Active transport occurs only in the ileal tract, while passive diffusion of both free and glycine conjugated BA is present in both intestinal segments. Since the liquid resistance to BA luminal diffusion is similar in ileum and jejunum, the higher passive diffusion for UDCA and GUDCA in the ileum is due to a lower mucosal resistance to BA passive diffusion, possibly due to the higher cholesterol to phospholipid ratio in the ileal brush border membranes.
• ROLE OF REACTIVE OXYGEN METABOLITES IN TUMOR NECROSIS FACTORg-INDUCED LEUKOCYTE ADHESION TO RAT MESENTERIC VENULAR ENDOTHELII/M Y. Merita. L.S. Miller, U. Rangan, S. Kondo, M.G. Clemens, G.B. Bulkley. Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD We investigated the role of reactive oxygen metabolites as potential mediators ofcytokine-sfim-!ated neutrophil adhesion to rat mesenteric venules in vivo, using intravital microscopy and fixed whole-mount preparations of mesentery. In the intravital microscopic study intraperitoneal injection o f TNFc~ into male Sprague-Dawley rats significantly increased leukocyte rolling (from 32+6 to 65±10 cells/rain), adhesion (from 3±1 to 21:~5 cells/150pm vessel) and emigration (from 4±1 to 22±4 cells/field at lpg/kg at 4h) in a dose and time dependent manner. Intravenous admini.qtration of anti-ICAM-I attenuated this leukocyte adhesion 36% (p
GASTROENTEROLOGY, Vol. 1 0 8 , No. 4
PROTECTIVE EFFECT OF RO 24-4736 AGAINST RAT COLONIC MUCOSAL PERMEABILITY INDUCED BY ISCHEMIA-REPERFUSION (I/R) AND L-Na-NITRO-ARGININE METHYL ESTER (L-NAME). E. Morikawa and S.N. Murthy. Krancer Center for IBD Research, Hahnemann University, Philadelphia, Pa. Previous studies have shown that mucosal permeability in the intestine is deranged in animals after I/R. In a recent study we showed that during I/R, inhibition of nitric oxide (NO) synthesis by L-NAME causes exaggerated increases in colonic mucosal permeability in the rat. I/R in the intestine is also associated with increased PAF levels which may alter mucosal functional integrity of the intestine. In this study, a discrete rat model of colonic I/R which features increased mucoaal permeability was used to evaluate whether Ro 24-4736 (5-(3-[4-(2chlorophenyl)-9-methyl-6H-thieno[3,2-f] [ 1,2,4]-triazal01[4,3-a][ 1,4] diazepin-2-yl]-2-propynyl]phenanthrydin-6(5H)-one) affords protection against functional damage induced by I/R + L-NAME. Altered mucosal permeability in the colon was induced by infusing 1 umole/min of LNAME over 2 hours of ischemia and 60 minutes of reperfusion. Ro 24; 4736 was given p.o (7 and 20 mg/kg) 2 hours prior to surgery. F I T C dextran (71.2 kd, 100 mg/kg) was given i.v. one hour prior to the induction of ischemia. Colonic mucosal permeability was determined by measuring FITC-dextran (71.2 kd) output in the colonic perfusate (0.5% PEG 4000 in saline, 2 ml/hr) every 30 minutes. RESULTS: Colonic luminal nitrite was significantly inhibited (90%) by L-NAME and there was a corresponding increase in mucosal FITC output by 7x and 2.6x, respectively, after 30 and 60 min reperfusion compared to I/R alone (I/R alone 30 min after reperfusion = 3.8 +/- 0.6 ug FITC/30. min; I/R + L-NAME same time = 26.9 +/- 3.6 ug FITC/30 min). Low dose of p.o. Ro 24-4736 did not affect FITC output (30 after reperfusion = 26.4 +/- 10.1 ug FITC/30 min). However, high dose of p.o. Ro 24-4736 inhibited FITC output by 73% and 41%, respectively, at 30 and 60 min after reperfusion compared to placebo. Luminal nitrite output continued tO be inhibited in spite of significant reversal of permeability. Thesestudies suggest that Ro 24-4736 provides a direct protective effect against I/R +L-NAME-induced colonic mucosal permeability in the rat and further support a role for PAF as a mediator of abnormal mucosal permeability in the rat colon.
THE EFFICACY OF AN ORAL A L P H A GALACTOSIDASE IN COMPLEX CARBOHYDRATE DIGESTION: A RANDOMIZED CROSSOVER STUDY. RG Mosley, M Lloyd, L Davis, M Reichelderfer. Dept. of Medicine, U n i v e r s i t y of Wisconsin, Madison, WI. An oral ~-galactosidase (Beano, AKPharma, Pleasantville, NJ) has been marketed a s a n agent that promotes the digestion of dietary complex carbohydrates, thereby reducing symptoms of carbohydrate malabsorption. We evaluated the efficacy of this compound in a placebocontrolled trial. METHODS: We s t u d i e d ten subjects using a d o u b l e - b l i n d , randomized, crossover design. Following overnight fasting, test meals (red k i d n e y beans with a carbohydrate content of 50g) were consumed with either Beano (6 drops) or placebo added. Subjects were r e t e s t e d with the crossover combination one w e e k later, Carbohydrate absorption and malabsorption were m e a s u r e d by 4 hour serum glucose curves and 8 hour serial breath hydrogen determinations respectively. Symptom surveys were completed at 8 and 48 hours after the meals. R E S U L T S : Interpretations of breath hydrogen studies were complicated by high baseline vaIues for some subjects. Accordingly, individual means of breath hydrogen determinations at hours 2 t h r o u g h 4 (the nadir values) were assigned as modified baselines for subjects during both treatment and placebo evaluations. Cumulative b r e a t h hydrogen production over hours 5 through 8 was significantly reduced (P=0.0001), as were individual hydrogens at hours 6 and 7 (but not 5 or 8), following treated meals (p=0.040,0.022). There were no differences in mean serum glucose determinations. While the surveys showed no difference between Beano and p l a c e b o at 8 h r s (p=0.83), there was a tendency for treated meals to be accompanied by reduced symptom scores when assessed after 48 hrs (p=0.16). CONCLUSIONS: Administration of this oral ~-galactosidase reduces the malabsorption of bean carbohydrate though the benefits of the product on symptom reduction m a y be a p p r e c i a t e d only after considerable delay.
AGA ABSTRACTS
DIFFERENT DIFFUSION KINETIKCS OF BILE ACIDS IN RABBIT JEJUNUM AND ILEUM: EFFECT OF INTESTINAL MUCOSAL PERMEABILITY. Montagnani M.1, Aldini R.2, Roda A. ~, Polimeni C. ~, F.Stagni', E. Roda~ 'Cattedra di Gastroenterologia, 21stitutodi Scienze Chimiche, 3Dipartimento di Scienze Farmaceutiche, Universita di Bologna, Bologna, Italy. Ileal bile acid (BA) transport is an active, Na+ coupled mechanism, considered a determinant step in the entero-hepatic circulation (EHC) of BA. Passive diffusion, on the contrary, occurs along the whole intestine, and little is known about possible differences in the diffusion rates of BA in different intestinal segments. In the present investigation, jejunal and ileal tracts of rabbit intestine (30 cm) were separately perfused with different BA and the blood was collected from the mesentedc vessels draining from the perfUsed intestine: Taurocholic (TCA), tauroursodeoxycholic (TUDCA), glycoursodeoxycholic (GUDCA) and ursodeoxycholic (UDCA) acid were separately infused at various doses (0.25-10mM) and a dose-response curve was thus obtained for each BA in the jejunum and ileum. UDCA perfusions were carried out at different flow rates in order to evaluate the effect of luminal stirring in both the intestinal tracts, Cholesterol to phospholipid ratio was evaluated in brush border membrane vesicles (BBMV) obtained from jejunum and terminal ileum~ TCA and TUDCA showed active transport rates in the ileum, a n d actually no transport in the jejunum; GUDCA showed both active transport and passive diffusion in the ileum; the latter component of the transportwas present in the jejunum. UDCA absorption was passive in both the intestinal tracts. Passive diffusion was in the following order: UDCA ileum > UDCA jejunum > GUDCA ileum > GUDCA jejunum. A higher cholesterol to phospholipid ratio was found in BBMV from the ileal tract, respect to jejunum. Active transport occurs only in the ileal tract, while passive diffusion of both free and glycine conjugated BA is present in both intestinal segments. Since the liquid resistance to BA luminal diffusion is similar in ileum and jejunum, the higher passive diffusion for UDCA and GUDCA in the ileum is due to a lower mucosal resistance to BA passive diffusion, possibly due to the higher cholesterol to phospholipid ratio in the ileal brush border membranes.
• ROLE OF REACTIVE OXYGEN METABOLITES IN TUMOR NECROSIS FACTORg-INDUCED LEUKOCYTE ADHESION TO RAT MESENTERIC VENULAR ENDOTHELII/M Y. Merita. L.S. Miller, U. Rangan, S. Kondo, M.G. Clemens, G.B. Bulkley. Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD We investigated the role of reactive oxygen metabolites as potential mediators ofcytokine-sfim-!ated neutrophil adhesion to rat mesenteric venules in vivo, using intravital microscopy and fixed whole-mount preparations of mesentery. In the intravital microscopic study intraperitoneal injection o f TNFc~ into male Sprague-Dawley rats significantly increased leukocyte rolling (from 32+6 to 65±10 cells/rain), adhesion (from 3±1 to 21:~5 cells/150pm vessel) and emigration (from 4±1 to 22±4 cells/field at lpg/kg at 4h) in a dose and time dependent manner. Intravenous admini.qtration of anti-ICAM-I attenuated this leukocyte adhesion 36% (p
GASTROENTEROLOGY, Vol. 1 0 8 , No. 4
PROTECTIVE EFFECT OF RO 24-4736 AGAINST RAT COLONIC MUCOSAL PERMEABILITY INDUCED BY ISCHEMIA-REPERFUSION (I/R) AND L-Na-NITRO-ARGININE METHYL ESTER (L-NAME). E. Morikawa and S.N. Murthy. Krancer Center for IBD Research, Hahnemann University, Philadelphia, Pa. Previous studies have shown that mucosal permeability in the intestine is deranged in animals after I/R. In a recent study we showed that during I/R, inhibition of nitric oxide (NO) synthesis by L-NAME causes exaggerated increases in colonic mucosal permeability in the rat. I/R in the intestine is also associated with increased PAF levels which may alter mucosal functional integrity of the intestine. In this study, a discrete rat model of colonic I/R which features increased mucoaal permeability was used to evaluate whether Ro 24-4736 (5-(3-[4-(2chlorophenyl)-9-methyl-6H-thieno[3,2-f] [ 1,2,4]-triazal01[4,3-a][ 1,4] diazepin-2-yl]-2-propynyl]phenanthrydin-6(5H)-one) affords protection against functional damage induced by I/R + L-NAME. Altered mucosal permeability in the colon was induced by infusing 1 umole/min of LNAME over 2 hours of ischemia and 60 minutes of reperfusion. Ro 24; 4736 was given p.o (7 and 20 mg/kg) 2 hours prior to surgery. F I T C dextran (71.2 kd, 100 mg/kg) was given i.v. one hour prior to the induction of ischemia. Colonic mucosal permeability was determined by measuring FITC-dextran (71.2 kd) output in the colonic perfusate (0.5% PEG 4000 in saline, 2 ml/hr) every 30 minutes. RESULTS: Colonic luminal nitrite was significantly inhibited (90%) by L-NAME and there was a corresponding increase in mucosal FITC output by 7x and 2.6x, respectively, after 30 and 60 min reperfusion compared to I/R alone (I/R alone 30 min after reperfusion = 3.8 +/- 0.6 ug FITC/30. min; I/R + L-NAME same time = 26.9 +/- 3.6 ug FITC/30 min). Low dose of p.o. Ro 24-4736 did not affect FITC output (30 after reperfusion = 26.4 +/- 10.1 ug FITC/30 min). However, high dose of p.o. Ro 24-4736 inhibited FITC output by 73% and 41%, respectively, at 30 and 60 min after reperfusion compared to placebo. Luminal nitrite output continued tO be inhibited in spite of significant reversal of permeability. Thesestudies suggest that Ro 24-4736 provides a direct protective effect against I/R +L-NAME-induced colonic mucosal permeability in the rat and further support a role for PAF as a mediator of abnormal mucosal permeability in the rat colon.
THE EFFICACY OF AN ORAL A L P H A GALACTOSIDASE IN COMPLEX CARBOHYDRATE DIGESTION: A RANDOMIZED CROSSOVER STUDY. RG Mosley, M Lloyd, L Davis, M Reichelderfer. Dept. of Medicine, U n i v e r s i t y of Wisconsin, Madison, WI. An oral ~-galactosidase (Beano, AKPharma, Pleasantville, NJ) has been marketed a s a n agent that promotes the digestion of dietary complex carbohydrates, thereby reducing symptoms of carbohydrate malabsorption. We evaluated the efficacy of this compound in a placebocontrolled trial. METHODS: We s t u d i e d ten subjects using a d o u b l e - b l i n d , randomized, crossover design. Following overnight fasting, test meals (red k i d n e y beans with a carbohydrate content of 50g) were consumed with either Beano (6 drops) or placebo added. Subjects were r e t e s t e d with the crossover combination one w e e k later, Carbohydrate absorption and malabsorption were m e a s u r e d by 4 hour serum glucose curves and 8 hour serial breath hydrogen determinations respectively. Symptom surveys were completed at 8 and 48 hours after the meals. R E S U L T S : Interpretations of breath hydrogen studies were complicated by high baseline vaIues for some subjects. Accordingly, individual means of breath hydrogen determinations at hours 2 t h r o u g h 4 (the nadir values) were assigned as modified baselines for subjects during both treatment and placebo evaluations. Cumulative b r e a t h hydrogen production over hours 5 through 8 was significantly reduced (P=0.0001), as were individual hydrogens at hours 6 and 7 (but not 5 or 8), following treated meals (p=0.040,0.022). There were no differences in mean serum glucose determinations. While the surveys showed no difference between Beano and p l a c e b o at 8 h r s (p=0.83), there was a tendency for treated meals to be accompanied by reduced symptom scores when assessed after 48 hrs (p=0.16). CONCLUSIONS: Administration of this oral ~-galactosidase reduces the malabsorption of bean carbohydrate though the benefits of the product on symptom reduction m a y be a p p r e c i a t e d only after considerable delay.