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Fedotozine and sensitivity to gastric distension: Effects of single and repeated doses
April 1995
•
Motility and Nerve-Gut Interactions
A679
INTESTINAL LAMINA PROPRIA MONONUCLEAR CELLS (LPMC): EFFECT ON INTESTINAL EPITHELIAL CELL FUNCTION. JK Roche, C Thompson, C Fiocchi, S Planchon. Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA; Case Western Reserve University School of Medicine, Cleveland, OH. Potentially injurious to the barrier function of intestinal epithelium is the resident population of mononuclear cells in the lamina propria. Although human LPMC show spontaneous and IL-2-induced cytotoxioity for certain in vitro target ceils, model systems have not been available to detect more subtle (nonlytic) effectS of LPMC upon the function of Figure 1 epithelium, the cell type(s) responsible, and the kineti°°1 ~ ,)J ics of release of lymphokines which may cause change in epithelial barrier function under these conditions. The current study took advantage of a unique 2-compartment system, recently described J0! 150:2363), and that permitS the integrity of a polarized, mature, human single cell-thick colonic epithelium to be studied upon exposure to factors or cells on Figure 2. O, mediaonly; a single (apical or basolateral) surface. [3, IFN~i' positive conHuman LPMC incubated on the basolateral side trol; v, apicalLPMC(I x nf epithelial monolayers caused a marked decrement lO*/mll; A, apieM LPMC (5 x lO*/rrd). in relative tissue resistance of colonic epithelium, when present at 5 x l & cells/ml, whether from histologically normal or ulcerative colitis-inyolved intestine (Fig. 1). Second, the barrier disfunction effect could be passed to fresh epithelial monolayers by cell-free supernatant taken from 72-hour cultures of unstimulated lamina propria mononuclear cells. Release of intefleuken-2 and -3 into media was maximum at 24 hours and decreased thereafter; and apical placement of LPMC revealed no changes compared with controls over the first two days (Fig. 2). Third, experiments using subsets of LPMC which were percol-gradient purified revealed that T lymphocytes ( > 95% pure) accounted for the decrease in relative tissue resistance in that, by themselves, they reduced epithelial resistance to the same extent as unfractionated LPMC. We conclude that productS secreted by human LPMC are potent modifiers of intestinal epithelial barrier function.
IMPACT OF PSYCHOSOCIAL F A c T o R s ON FUNCTIONAL BOWEL DISEASE (FBD) IN T H E ELDERLY. Y. Romero ICC. Fleming, J.M. Evans, N.J. Talley, A.R. Zinsmeister, S.F. Phillips. Gastroenterology Unit, Mayo Clinic, Rochester, MN. BACKGROUND: Investigators have long suspected a significant correlation between psychological dysfunction and complaints of constipation and Irritable Bowel Syndrome (IBS), however, findings have been mixed, groups studied may have been skewed by referral bias, and little has been done with regard to the elderly. AIMS: To determine if constipation, IBS, and colonic transit are associated with depression, lack of social support, specific psychological factors and/or personality traits in elderly subjects. METHODS: Age- and sex- stratified random sample of persons aged 65 and older (range 67-104 yrs), living in Olmsted Co., MN, were mailed a previously validated self-report measure, the Bowel Disease Questionnaire (BDQ), to which 74% responded (n= 1609). A subset of subjects without significant gastrointestinal symptoms (n=93), as well as subjects with functional constipation (n=52), and IBS (n=55), underwent a structured interview and physical examination, and colonic transit study, using radio opaque markers, to assess total and segmental colonic transit time. In addition, the following instruments were completed to assess social support, psychiatric illness, and psychoIogical and personality traits: Sickness Impact Profile (SIP), Social Support Questionnaire (SSQ), MMPI, SCL-90R, and the Yesavage Geriatric Depression Scale (YGDS). RESULTS: Univariately, YGDS, mean SIP, GSI-SCL, MMPI hypochondriasis and depression scales were associated with overall cnlonic transit time, adjusting for age and gender. Hypochondriasis, by MMPI, was useful in discriminating IBS from controls (p<0.001), and IBS from functional constipation (p<0.01). Given the score on the Hypochondriasis scale, the Depression scale was additionally useful to discriminate IBS from controls (p<0.01). Univariately, the Y G D S scale discriminated IBS from controls. The psychological and social inventory scores could not discriminate as accurately between functional constipation and controls. CONCLUSIONS: Psychosocial measures are associated with objective assessments of overall colonic transit as well as symptoms. The magnitude of hypochondriasis, as measured by the MMPI, was useful in discriminating between IBS, and control groups as well as functional constipation subjects. This was further improved when combined with analysis of the Depression scale. The degree of satisfaction with social support, or lack thereof, also correlated with symptoms of IBS.
• COLONIC FERMENTATION AND PROXIMAL GASTRIC TONE: "A COLONIC BRAKE"? A Ro0ert ae, S Bruley des Varannes a, C Cherbut b, C Roz~ d, JP Galmiche a. aFcnctions Digestives et Nutrition, blNRA, 44035 Nantes, CExplorations Fonctionnelles, 35033 Rennes, dlNSERM U410, Bichat, 75870 Paris-FRANCE.
FEDOTOZINE AND SENSITIVITY TO GASTRIC DISTENSION: EFFECTS OF SINGLE AND REPEATED DOSES. A. Ropert*, S. Bruley des Varannes*, C. de Meynard**, B. Fraitag**, J.P. Galmiche*. Fonctions Digestives et Nutrition, CHU Nord, Nantes*; Institut de Recherche Jouveinal, Fresnes, France ** Gastric hypersensitivity to mechanical distension was evidenced in functional dyspepsia. In healthy subjects, fedotozine (F), a synthetic ligand for peripheral K receptors was shown to increase discomfort threshold to gastric balloon distension [1 ]. The present work aimed at studying the duration of this effect after single and repeated administrations. Methods : 12 healthy volunteers (20-31 years) were randomized in a double-blind placebo (P) controlled trial, after written informed consent and according to the principles of the Declaration of Helsinski. The onset and duration of the effect were studied after single administration (F 30rag or P) in parallel groups, and after repeated administration according to a cross-over design (2 periods of 7 days : F 30rag / P t.i.d.). On the first day (D(}) and at the end of each period (D~ and D~6), isovolumic gastric distensions (2 min duration, 100 ml stepwise increments) were performed with an electronic barostat just before treatment (To) and 1, 2 and 8 hours after (T~,T~, Ts). Efficacy criteria were volume at pain threshold (VPT) as well as pressure (PPT), mean gastric compliance, circumference and tension at pain threshold. Time course of response was analysed for each parameter. Results : l) After a single dose, the time course of pressure at pain threshold differed between the 2 groups (p = 0.04) : with F, after T0 pressure reaching a maximum at T~ then decreasing at T 2 before increasing again at T 8 (I3.7 _+ 2.0, 16.5 _+ 4.6, 13.8 _+ 2.9 and 15.7 -.+. 1.7 mmHg respectively), whereas with P it decreased immediately (14.3 _+ 0.5, 13.2 _+ 1.6, 13.0 _+2.0 and 12.8 _+ 2.9 mmHg respectively). The pattern of VPT was essentially similar to that of PPT (except for a decrease at T 8 with F) but this difference in profile between groups did not reach significance. Changes in tension were similar to those in pressure and were nearly significant (p = 0.07). Compliance did not change significantly. 2) After repeated administration, all values at Dl6 were higher than those at Do and D8 whatever the treatment. Conclusions : Our results 1) confirm that a single administration of 30 mg of fedotozine induces an increase in gastric tolerance to distension and that this effect concerns gastric visceral sensitivity but not mechanical accommodation to distension, 2) are consistent with a 30 mg t.i.d, regimen in clinical studies, and 3) show that repetition of measurements induces a marked effect of experience which limits the interest of this technique in cross-over design studies. This research was funded by Institut de Recherche Jouveinal, Fresnes, France. ill : B. Coffin et al., Gastroenterology, 102 : A437, 1992.
!++1+ +
Ileal nutrients inhibit gastrojejunal motility and delay gastric emptying (the "ileal brake"). In humans, various amounts of nonabsorbed carbohydrates reach the proximal colon where bacterial fermentations produce short-chain fatty acids (SCFAs), Whether caeco-colonic fermentations may affect gastric motility, like a colonic brake, is not known. The aim of this study was to determine whether intra-colonic oligcsaccharides and the SCFAs they produce in the colon might change proximal gastric tone (PGT) in the healthy man. M e t h o d s . Changes in PGT (electronic barostat), and H2 concentrations in expelled air were simultaneously assessed: 1. In 6 healthy volunteers after ingestion of either t00 ml 20% lactulose or 100 ml saline, in randomised order on two separate days (study 1); 2~ In 7 other healthY volunteers, during the intraoolonic infusion (3 ml/min for 60 min) of either saline, 20% lactose, 54 mM SCFAs or 90 mM SCFAs (both SCFAs solutions pH=6, isotonized with NaCI, C2: 66%, C3: 24%, C4: 10%) over 2 consecutive days (study 2). Results (m+SD). Study 1: In all subjects, lactulose ingestion decreased PGT (peak amplitude, A = 239 _+ 19 ml) occurring 25 + 8 min after peak H2 concentration) whereas saline had no significant effect on PGT and H2. Study 2: PGT decreased in all subjects during the intracolonic infusions of 90 mM SCFAs, in 6/7 subjects during infusions of 54 mM SCFAs or lactose. The peak decrease in PGT was larger (a = 227 + 75 ml) and occurred earlier (latency 22 + 3 min) during 90 mM SCFAs than during lactose and 54 mM SCFAs (respectively A -- 141 + 68 and 146 + 42 ml, p<0.01, and 28 + 6 and 29 + 6 min, p<0.05, ANOVA). Conclusions. 1. Delivery of disaccharides or physiological amounts of SCFAs, their fermentation products, in the proximal colon relaxes the gastric fundus. 2. Proximal colon, alike the ileum, may play a role in the regulation of gastric motility, perhaps as a physiological brake.
•
Motility and Nerve-Gut Interactions
A679
INTESTINAL LAMINA PROPRIA MONONUCLEAR CELLS (LPMC): EFFECT ON INTESTINAL EPITHELIAL CELL FUNCTION. JK Roche, C Thompson, C Fiocchi, S Planchon. Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA; Case Western Reserve University School of Medicine, Cleveland, OH. Potentially injurious to the barrier function of intestinal epithelium is the resident population of mononuclear cells in the lamina propria. Although human LPMC show spontaneous and IL-2-induced cytotoxioity for certain in vitro target ceils, model systems have not been available to detect more subtle (nonlytic) effectS of LPMC upon the function of Figure 1 epithelium, the cell type(s) responsible, and the kineti°°1 ~ ,)J ics of release of lymphokines which may cause change in epithelial barrier function under these conditions. The current study took advantage of a unique 2-compartment system, recently described J0! 150:2363), and that permitS the integrity of a polarized, mature, human single cell-thick colonic epithelium to be studied upon exposure to factors or cells on Figure 2. O, mediaonly; a single (apical or basolateral) surface. [3, IFN~i' positive conHuman LPMC incubated on the basolateral side trol; v, apicalLPMC(I x nf epithelial monolayers caused a marked decrement lO*/mll; A, apieM LPMC (5 x lO*/rrd). in relative tissue resistance of colonic epithelium, when present at 5 x l & cells/ml, whether from histologically normal or ulcerative colitis-inyolved intestine (Fig. 1). Second, the barrier disfunction effect could be passed to fresh epithelial monolayers by cell-free supernatant taken from 72-hour cultures of unstimulated lamina propria mononuclear cells. Release of intefleuken-2 and -3 into media was maximum at 24 hours and decreased thereafter; and apical placement of LPMC revealed no changes compared with controls over the first two days (Fig. 2). Third, experiments using subsets of LPMC which were percol-gradient purified revealed that T lymphocytes ( > 95% pure) accounted for the decrease in relative tissue resistance in that, by themselves, they reduced epithelial resistance to the same extent as unfractionated LPMC. We conclude that productS secreted by human LPMC are potent modifiers of intestinal epithelial barrier function.
IMPACT OF PSYCHOSOCIAL F A c T o R s ON FUNCTIONAL BOWEL DISEASE (FBD) IN T H E ELDERLY. Y. Romero ICC. Fleming, J.M. Evans, N.J. Talley, A.R. Zinsmeister, S.F. Phillips. Gastroenterology Unit, Mayo Clinic, Rochester, MN. BACKGROUND: Investigators have long suspected a significant correlation between psychological dysfunction and complaints of constipation and Irritable Bowel Syndrome (IBS), however, findings have been mixed, groups studied may have been skewed by referral bias, and little has been done with regard to the elderly. AIMS: To determine if constipation, IBS, and colonic transit are associated with depression, lack of social support, specific psychological factors and/or personality traits in elderly subjects. METHODS: Age- and sex- stratified random sample of persons aged 65 and older (range 67-104 yrs), living in Olmsted Co., MN, were mailed a previously validated self-report measure, the Bowel Disease Questionnaire (BDQ), to which 74% responded (n= 1609). A subset of subjects without significant gastrointestinal symptoms (n=93), as well as subjects with functional constipation (n=52), and IBS (n=55), underwent a structured interview and physical examination, and colonic transit study, using radio opaque markers, to assess total and segmental colonic transit time. In addition, the following instruments were completed to assess social support, psychiatric illness, and psychoIogical and personality traits: Sickness Impact Profile (SIP), Social Support Questionnaire (SSQ), MMPI, SCL-90R, and the Yesavage Geriatric Depression Scale (YGDS). RESULTS: Univariately, YGDS, mean SIP, GSI-SCL, MMPI hypochondriasis and depression scales were associated with overall cnlonic transit time, adjusting for age and gender. Hypochondriasis, by MMPI, was useful in discriminating IBS from controls (p<0.001), and IBS from functional constipation (p<0.01). Given the score on the Hypochondriasis scale, the Depression scale was additionally useful to discriminate IBS from controls (p<0.01). Univariately, the Y G D S scale discriminated IBS from controls. The psychological and social inventory scores could not discriminate as accurately between functional constipation and controls. CONCLUSIONS: Psychosocial measures are associated with objective assessments of overall colonic transit as well as symptoms. The magnitude of hypochondriasis, as measured by the MMPI, was useful in discriminating between IBS, and control groups as well as functional constipation subjects. This was further improved when combined with analysis of the Depression scale. The degree of satisfaction with social support, or lack thereof, also correlated with symptoms of IBS.
• COLONIC FERMENTATION AND PROXIMAL GASTRIC TONE: "A COLONIC BRAKE"? A Ro0ert ae, S Bruley des Varannes a, C Cherbut b, C Roz~ d, JP Galmiche a. aFcnctions Digestives et Nutrition, blNRA, 44035 Nantes, CExplorations Fonctionnelles, 35033 Rennes, dlNSERM U410, Bichat, 75870 Paris-FRANCE.
FEDOTOZINE AND SENSITIVITY TO GASTRIC DISTENSION: EFFECTS OF SINGLE AND REPEATED DOSES. A. Ropert*, S. Bruley des Varannes*, C. de Meynard**, B. Fraitag**, J.P. Galmiche*. Fonctions Digestives et Nutrition, CHU Nord, Nantes*; Institut de Recherche Jouveinal, Fresnes, France ** Gastric hypersensitivity to mechanical distension was evidenced in functional dyspepsia. In healthy subjects, fedotozine (F), a synthetic ligand for peripheral K receptors was shown to increase discomfort threshold to gastric balloon distension [1 ]. The present work aimed at studying the duration of this effect after single and repeated administrations. Methods : 12 healthy volunteers (20-31 years) were randomized in a double-blind placebo (P) controlled trial, after written informed consent and according to the principles of the Declaration of Helsinski. The onset and duration of the effect were studied after single administration (F 30rag or P) in parallel groups, and after repeated administration according to a cross-over design (2 periods of 7 days : F 30rag / P t.i.d.). On the first day (D(}) and at the end of each period (D~ and D~6), isovolumic gastric distensions (2 min duration, 100 ml stepwise increments) were performed with an electronic barostat just before treatment (To) and 1, 2 and 8 hours after (T~,T~, Ts). Efficacy criteria were volume at pain threshold (VPT) as well as pressure (PPT), mean gastric compliance, circumference and tension at pain threshold. Time course of response was analysed for each parameter. Results : l) After a single dose, the time course of pressure at pain threshold differed between the 2 groups (p = 0.04) : with F, after T0 pressure reaching a maximum at T~ then decreasing at T 2 before increasing again at T 8 (I3.7 _+ 2.0, 16.5 _+ 4.6, 13.8 _+ 2.9 and 15.7 -.+. 1.7 mmHg respectively), whereas with P it decreased immediately (14.3 _+ 0.5, 13.2 _+ 1.6, 13.0 _+2.0 and 12.8 _+ 2.9 mmHg respectively). The pattern of VPT was essentially similar to that of PPT (except for a decrease at T 8 with F) but this difference in profile between groups did not reach significance. Changes in tension were similar to those in pressure and were nearly significant (p = 0.07). Compliance did not change significantly. 2) After repeated administration, all values at Dl6 were higher than those at Do and D8 whatever the treatment. Conclusions : Our results 1) confirm that a single administration of 30 mg of fedotozine induces an increase in gastric tolerance to distension and that this effect concerns gastric visceral sensitivity but not mechanical accommodation to distension, 2) are consistent with a 30 mg t.i.d, regimen in clinical studies, and 3) show that repetition of measurements induces a marked effect of experience which limits the interest of this technique in cross-over design studies. This research was funded by Institut de Recherche Jouveinal, Fresnes, France. ill : B. Coffin et al., Gastroenterology, 102 : A437, 1992.
!++1+ +
Ileal nutrients inhibit gastrojejunal motility and delay gastric emptying (the "ileal brake"). In humans, various amounts of nonabsorbed carbohydrates reach the proximal colon where bacterial fermentations produce short-chain fatty acids (SCFAs), Whether caeco-colonic fermentations may affect gastric motility, like a colonic brake, is not known. The aim of this study was to determine whether intra-colonic oligcsaccharides and the SCFAs they produce in the colon might change proximal gastric tone (PGT) in the healthy man. M e t h o d s . Changes in PGT (electronic barostat), and H2 concentrations in expelled air were simultaneously assessed: 1. In 6 healthy volunteers after ingestion of either t00 ml 20% lactulose or 100 ml saline, in randomised order on two separate days (study 1); 2~ In 7 other healthY volunteers, during the intraoolonic infusion (3 ml/min for 60 min) of either saline, 20% lactose, 54 mM SCFAs or 90 mM SCFAs (both SCFAs solutions pH=6, isotonized with NaCI, C2: 66%, C3: 24%, C4: 10%) over 2 consecutive days (study 2). Results (m+SD). Study 1: In all subjects, lactulose ingestion decreased PGT (peak amplitude, A = 239 _+ 19 ml) occurring 25 + 8 min after peak H2 concentration) whereas saline had no significant effect on PGT and H2. Study 2: PGT decreased in all subjects during the intracolonic infusions of 90 mM SCFAs, in 6/7 subjects during infusions of 54 mM SCFAs or lactose. The peak decrease in PGT was larger (a = 227 + 75 ml) and occurred earlier (latency 22 + 3 min) during 90 mM SCFAs than during lactose and 54 mM SCFAs (respectively A -- 141 + 68 and 146 + 42 ml, p<0.01, and 28 + 6 and 29 + 6 min, p<0.05, ANOVA). Conclusions. 1. Delivery of disaccharides or physiological amounts of SCFAs, their fermentation products, in the proximal colon relaxes the gastric fundus. 2. Proximal colon, alike the ileum, may play a role in the regulation of gastric motility, perhaps as a physiological brake.