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Anal endosonography: Are morphometric measurements of the anal sphinkter reproducible?
April 1 9 9 5
R E G I O N SELECTIVE DRUG DELIVERY T O THE COLON Hebden JM, Wilson CG, Spiller RC, Perkins AC, Gilchrist PJ, Binns J, Miller CJ. Queens Medical Centre, Nottingham; University of Strathclyde; & Scherer DDS, Strathclyde, UK. Targeting specific regions of the colon may have therapeutic advantages. The aim of this study was to target the proximal and distal colon using a novel drug delivery system (PulsincapWM), whose timed release depends on hydration and subsequent ejection of a hydrogel plug. 11 l-Indium labelled resin within the capsule permitted detection of position by gamma scintigraphy. Method. 11 healthy volunteers attended fasted on 2 study days (A&B). On study day A, following ingestion and gastric emptying of a 5hr release PulsineapTM, standard 200kcal breakfast, 600kcal lunch, and 1000keal evening meals were consumed. On study day B, subjects were dosed at 2200h with the 15hr release PulsincapTM, and adhered to an identical meal pattern the following day. Serial scintiscans were taken at 1/2 hourly intervals.. Results. (Mean+/-SEM). Key: Small intestine (SI); ascending colon (AC); transverse colon (TC); descending colon (DC). The 5hr Pulsincaps released successfully (10/I l) at 5.4+/-0.2hrs. At 6 hours post dose, the majority of the 5hr device tracer lay in the proximal colon: St(2); AC(4); TC(4); DC(I). Scintigraphic release was evident in only 2/11 of the 15hr Pulsincaps. Surprisinoly, at 15 hours post dose the 15hr release devices were only minimally more caudal than the 5hr Pulsincaps at 6hrs: SI(0); AC(6); TC( 1); DC(2); excreted(2). Summary. Proximal colonic targeting was successful using the 5hr PulsincapTM. By contrast, the device given the evening before failed to reach the distal colon probably due to retarded colonic transit overnight. Although 5hr release was reliable, our data suggests that t5hrs is too long for predictable release using the current technology of the delivery system.
• ANAL ENDOSONOGRAPHY: ARE MORPHOMETRIC MEASUREMENTS OF THE ANAL SPHINKTER REPRODUCIBLE ? T.Heyer, P.Enck, B.Gantke, *ASchmitt, T.Frieling, D.H~ussinger. Heinrich Heine University, Departments of Gastroenterology and *Surgery, DUsseldorf, Germany Anal endosonography (AES) is an imaging technique for the anal sphincter system and offers analysis of its muscular integrity. It is generally assumed that measurement of the thickness of muscle layers is provided by AES; however, reproducibility of such measurements have not yet been investigated. Methods: Study 1: In ten healthy volunteers (age 22-24 years, 3:7 females:males) AES was performed independently by two experienced investigators (II:TH;12:AS)with two different ultrasound machines (Kretz, IRW 170 AKJB, 7,5 MHz (U1); Bruel & Kjaer, 18148 Scanner, 7 MHz (U2)), and thickness of the muscle layers of the internal (IAS) and external (EAS) anal sphinkter was assessed in the position of the intermediate dorsal anal canal in a randomized cross-over fashion. Study 2: In a similar design, AES was performed in nine healthy volunteers (age 22-46 years, 3:6) by two investigators (II:TH;12:BG) using a stativ and a single ultrasound machine (Kretz, IRW 170 AK/B, 7,5 MHz) in three standardized positions (proximal / intermediate / distal anal canal) and the sphincter layers assessed in the left, right and dorsal segment. All data were compared by bivariate correlations. Results: Study 1: Both the same investigator with different ultrasound and different investigators with the same ultrasound failed to obtain reproducible results in regard to IAS and EAS muscle layer (4 correlations: U1(11-12); U2(11-12); I1(U1-U2); 12(U1-U2) for IAS and EAS, respectively, all with p>0,05). Study 2.' Standardisation of the probe position did not improve the agreement (2 x 9 bivariate correlations 01-12) for 3 positions and 3 directions for IAS and EAS, respectively, all with p>0,05 ). Conclusion: At present, AES may allow to determine muscle integrity but cannot provide reliable morphometric data. This finding could offer an explanation for previously conflicting observations of associations between anal morphometry and function. (Supported by grant DFG En 50110).
M o t i l i t y and Nerve-Gut Interactions
A613
GASTROINTESTINAL SYMPTOMS AND PSYCHOLOGICAL DISTRESS IN WOMEN WITH AND WITHOUT A DIAGNOSIS OF IRRITABLE BOWEL SYNDROME. M.M. Heitkemper, M Jarrett, E.F. Bond. Department of Physiological Nursing, University of Washington, Seattle, Washington Last year we reported that women with diagnosed irritable bowel syndrome (IBS) demonstrated increased sympathetic nervous system activity (basal levels of urinary norepinephrine [NE], epinephrine [El) and hypothalamic-pituitary-adrenal arousal (urine cortisol) as compared to women with symptoms but not seeking health care (IBS-non-patients; IBS-NP) and asymptumatic (Control) women. This study was performed to determine: 1) group differences in gastrointestinal (GI) symptom intensity, bowel patterns, psychological distress (daily and global), psychopathology, and number of daily stressful events; 2) relationships among physiological arousal variables and GI symptoms. Women, ages 20-43, (IBS, n=23; IBS-NP, n=23; Control, n=26) were studied across two menstrual cycles. Women were interviewed, completed questionnaires (Symptom Checklist-90R, Mayo Clinic Bowel Disease Questionnaire), then for two cycles maintained a daily diary for rating and recording symptoms, mood state, and daily stressors. Morning urine samples were obtained on specified days across both cycles. Ovulation was determined by OvuQuick TM, At study end, women were interviewed with the Diagnostic Interview Schedule for DSM-III diagnoses. NE and E were quantified by HPLC and cortisol by RIA. Menstrual cycle was divided into 6 phases (follicular, late follicular, early luteal, mid-luteal, premenses, menses). ANOVA-RM was performed to determine group and cycle phase differences. Retrospectively, there were no significant differences in GI symptom reports between IBS and IBS-NP groups. Daily reports of abdominal pain, bloating, intestinal gas, constipation, and diarrhea were significantly (p
• BLOCKADE EMPTYING P.Hildebrand, GI Unit and Switzerland
OF GRP RECEPTORS POTENTLY INHIBITS GASTRIC AND GALLBLADDER CONTRACTION IN MAN. F.P.Peng, S.Ketterer, R.Berthold, Y.Serrano, C.Beglinger. Dept of Research, University Hospital, CH-4031 Basel,
Gastrin-releasing peptide (GRP), a human analogue of bombesin, has been identified in the gastrointestinal tract. Within the gut, GRP is largely restricted to nerves and the peptide is not released into the circulation. Its precise role in physiologic and pathophysiologic conditions has not been determined. The availability of BIM26226, a potent and specific GRP receptor antagonist, opens the way to define physiologic functions of GRP in vivo in man. In this study, we have therefore investigated the effects of BIM26226 on gastric emptying and gallbladder contraction in 8 healthy male subjects. Methods: After oral intake of a liquid meal (250 ml EnsureTM), gastric emptying and gallbladder contraction were quantified over 3 hours using a duodenal intubation with double-marker (PEG4000/phenol red) perfusion technique and ultrasonography, respectively. On two different days and in random order, an infusion of either saline or BIM26226 (500 pg/kg per h) was administered throughout the experiment. In two additional experiments, gallbladder contraction was induced by intraduodenal (id) perfusion of EnsureT M (3 ml/min) with or without intravenous BIM26226 (500 pg/kg per h). Plasma CCK was taken for measurements by RIA. Results: Data are mean + SEM; emptying data were analyzed by power exponential fit; differences between treatments were tested by the Mann-Whitney U test. * indicates p<0.05. Gastric emptyin 9 Gallbladder contraction (id) Saline BIM26226 Saline BIM26226 tl/2 (min) 77 + 9 >120" 35 _+4 68 + 8* % remaining 26 _+14 62 + 7* 9 _+1 27 _+5* at the end 'Gallbladder ( )ntraction after oral food int ke was nearly abolished, bL only reduced after intraduodenal meal application; we interpret these results as inhibition of gastric emptying. Plasma CCK release during intraduodenal meal was not altered by BIM26226, whereas the increase after the oral meal was slower probably due to delayed gastric emptying. Conclusion: Blockade of GRP receptors in humans dramatically inhibits gastric emptying of a liquid meal and inhibits meal-stimulated gallbladder contraction in man. Circulating CCK, an important regulator of gallbladder contraction, seems not to be involved in this mechanism. We suggest that GRP is an important regulator of gastrointestinal motor functions in humans. Supported by grants of the Swiss National Science Foundation (32-31336.9) and the Henri Beaufour Institute, Washington D.C.
R E G I O N SELECTIVE DRUG DELIVERY T O THE COLON Hebden JM, Wilson CG, Spiller RC, Perkins AC, Gilchrist PJ, Binns J, Miller CJ. Queens Medical Centre, Nottingham; University of Strathclyde; & Scherer DDS, Strathclyde, UK. Targeting specific regions of the colon may have therapeutic advantages. The aim of this study was to target the proximal and distal colon using a novel drug delivery system (PulsincapWM), whose timed release depends on hydration and subsequent ejection of a hydrogel plug. 11 l-Indium labelled resin within the capsule permitted detection of position by gamma scintigraphy. Method. 11 healthy volunteers attended fasted on 2 study days (A&B). On study day A, following ingestion and gastric emptying of a 5hr release PulsineapTM, standard 200kcal breakfast, 600kcal lunch, and 1000keal evening meals were consumed. On study day B, subjects were dosed at 2200h with the 15hr release PulsincapTM, and adhered to an identical meal pattern the following day. Serial scintiscans were taken at 1/2 hourly intervals.. Results. (Mean+/-SEM). Key: Small intestine (SI); ascending colon (AC); transverse colon (TC); descending colon (DC). The 5hr Pulsincaps released successfully (10/I l) at 5.4+/-0.2hrs. At 6 hours post dose, the majority of the 5hr device tracer lay in the proximal colon: St(2); AC(4); TC(4); DC(I). Scintigraphic release was evident in only 2/11 of the 15hr Pulsincaps. Surprisinoly, at 15 hours post dose the 15hr release devices were only minimally more caudal than the 5hr Pulsincaps at 6hrs: SI(0); AC(6); TC( 1); DC(2); excreted(2). Summary. Proximal colonic targeting was successful using the 5hr PulsincapTM. By contrast, the device given the evening before failed to reach the distal colon probably due to retarded colonic transit overnight. Although 5hr release was reliable, our data suggests that t5hrs is too long for predictable release using the current technology of the delivery system.
• ANAL ENDOSONOGRAPHY: ARE MORPHOMETRIC MEASUREMENTS OF THE ANAL SPHINKTER REPRODUCIBLE ? T.Heyer, P.Enck, B.Gantke, *ASchmitt, T.Frieling, D.H~ussinger. Heinrich Heine University, Departments of Gastroenterology and *Surgery, DUsseldorf, Germany Anal endosonography (AES) is an imaging technique for the anal sphincter system and offers analysis of its muscular integrity. It is generally assumed that measurement of the thickness of muscle layers is provided by AES; however, reproducibility of such measurements have not yet been investigated. Methods: Study 1: In ten healthy volunteers (age 22-24 years, 3:7 females:males) AES was performed independently by two experienced investigators (II:TH;12:AS)with two different ultrasound machines (Kretz, IRW 170 AKJB, 7,5 MHz (U1); Bruel & Kjaer, 18148 Scanner, 7 MHz (U2)), and thickness of the muscle layers of the internal (IAS) and external (EAS) anal sphinkter was assessed in the position of the intermediate dorsal anal canal in a randomized cross-over fashion. Study 2: In a similar design, AES was performed in nine healthy volunteers (age 22-46 years, 3:6) by two investigators (II:TH;12:BG) using a stativ and a single ultrasound machine (Kretz, IRW 170 AK/B, 7,5 MHz) in three standardized positions (proximal / intermediate / distal anal canal) and the sphincter layers assessed in the left, right and dorsal segment. All data were compared by bivariate correlations. Results: Study 1: Both the same investigator with different ultrasound and different investigators with the same ultrasound failed to obtain reproducible results in regard to IAS and EAS muscle layer (4 correlations: U1(11-12); U2(11-12); I1(U1-U2); 12(U1-U2) for IAS and EAS, respectively, all with p>0,05). Study 2.' Standardisation of the probe position did not improve the agreement (2 x 9 bivariate correlations 01-12) for 3 positions and 3 directions for IAS and EAS, respectively, all with p>0,05 ). Conclusion: At present, AES may allow to determine muscle integrity but cannot provide reliable morphometric data. This finding could offer an explanation for previously conflicting observations of associations between anal morphometry and function. (Supported by grant DFG En 50110).
M o t i l i t y and Nerve-Gut Interactions
A613
GASTROINTESTINAL SYMPTOMS AND PSYCHOLOGICAL DISTRESS IN WOMEN WITH AND WITHOUT A DIAGNOSIS OF IRRITABLE BOWEL SYNDROME. M.M. Heitkemper, M Jarrett, E.F. Bond. Department of Physiological Nursing, University of Washington, Seattle, Washington Last year we reported that women with diagnosed irritable bowel syndrome (IBS) demonstrated increased sympathetic nervous system activity (basal levels of urinary norepinephrine [NE], epinephrine [El) and hypothalamic-pituitary-adrenal arousal (urine cortisol) as compared to women with symptoms but not seeking health care (IBS-non-patients; IBS-NP) and asymptumatic (Control) women. This study was performed to determine: 1) group differences in gastrointestinal (GI) symptom intensity, bowel patterns, psychological distress (daily and global), psychopathology, and number of daily stressful events; 2) relationships among physiological arousal variables and GI symptoms. Women, ages 20-43, (IBS, n=23; IBS-NP, n=23; Control, n=26) were studied across two menstrual cycles. Women were interviewed, completed questionnaires (Symptom Checklist-90R, Mayo Clinic Bowel Disease Questionnaire), then for two cycles maintained a daily diary for rating and recording symptoms, mood state, and daily stressors. Morning urine samples were obtained on specified days across both cycles. Ovulation was determined by OvuQuick TM, At study end, women were interviewed with the Diagnostic Interview Schedule for DSM-III diagnoses. NE and E were quantified by HPLC and cortisol by RIA. Menstrual cycle was divided into 6 phases (follicular, late follicular, early luteal, mid-luteal, premenses, menses). ANOVA-RM was performed to determine group and cycle phase differences. Retrospectively, there were no significant differences in GI symptom reports between IBS and IBS-NP groups. Daily reports of abdominal pain, bloating, intestinal gas, constipation, and diarrhea were significantly (p
• BLOCKADE EMPTYING P.Hildebrand, GI Unit and Switzerland
OF GRP RECEPTORS POTENTLY INHIBITS GASTRIC AND GALLBLADDER CONTRACTION IN MAN. F.P.Peng, S.Ketterer, R.Berthold, Y.Serrano, C.Beglinger. Dept of Research, University Hospital, CH-4031 Basel,
Gastrin-releasing peptide (GRP), a human analogue of bombesin, has been identified in the gastrointestinal tract. Within the gut, GRP is largely restricted to nerves and the peptide is not released into the circulation. Its precise role in physiologic and pathophysiologic conditions has not been determined. The availability of BIM26226, a potent and specific GRP receptor antagonist, opens the way to define physiologic functions of GRP in vivo in man. In this study, we have therefore investigated the effects of BIM26226 on gastric emptying and gallbladder contraction in 8 healthy male subjects. Methods: After oral intake of a liquid meal (250 ml EnsureTM), gastric emptying and gallbladder contraction were quantified over 3 hours using a duodenal intubation with double-marker (PEG4000/phenol red) perfusion technique and ultrasonography, respectively. On two different days and in random order, an infusion of either saline or BIM26226 (500 pg/kg per h) was administered throughout the experiment. In two additional experiments, gallbladder contraction was induced by intraduodenal (id) perfusion of EnsureT M (3 ml/min) with or without intravenous BIM26226 (500 pg/kg per h). Plasma CCK was taken for measurements by RIA. Results: Data are mean + SEM; emptying data were analyzed by power exponential fit; differences between treatments were tested by the Mann-Whitney U test. * indicates p<0.05. Gastric emptyin 9 Gallbladder contraction (id) Saline BIM26226 Saline BIM26226 tl/2 (min) 77 + 9 >120" 35 _+4 68 + 8* % remaining 26 _+14 62 + 7* 9 _+1 27 _+5* at the end 'Gallbladder ( )ntraction after oral food int ke was nearly abolished, bL only reduced after intraduodenal meal application; we interpret these results as inhibition of gastric emptying. Plasma CCK release during intraduodenal meal was not altered by BIM26226, whereas the increase after the oral meal was slower probably due to delayed gastric emptying. Conclusion: Blockade of GRP receptors in humans dramatically inhibits gastric emptying of a liquid meal and inhibits meal-stimulated gallbladder contraction in man. Circulating CCK, an important regulator of gallbladder contraction, seems not to be involved in this mechanism. We suggest that GRP is an important regulator of gastrointestinal motor functions in humans. Supported by grants of the Swiss National Science Foundation (32-31336.9) and the Henri Beaufour Institute, Washington D.C.