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Effects of cisapride treatment on gastric myoelectric activity and emptying in dysmotility-like dyspepsia (DLD-NUD)
A640
•
AGA ABSTRACTS
GASTROENTEROLOGY,Vol. 108, No. 4
BALLOON DEFECATION AS A PREDICTOR OF OUTCOME IN CHILDREN WITH CHRONIC CONSTIPATION AND ENCOPRESIS. Loenin2-Baucke. Department of Pediatrins, The University of Iowa, Iowa cay, IA A model to test the coordinated function of the rectum, anal sphincters, and spinal reflexes is the rectal balloon defecation test. To evaluate if balloon defecation might predict recovery in children with chronic constipation and fecal soiling (CE), we evaluated the ability to defecate a 100 ml water-filled rectal balloon within 5 minutes in 139 CE > 5 years of age. 17 healthy children > 5 years of age were able to defecate the balloon. Treatment consisted of milk of magnesia, high fiber diet, and bowel training techniques, including biofeedback treatment in 48 patients. Follow-up occurred during a clinic visit or by mailed questionnaire 12 months alter treatment began, rating the last month. CE were rated as recovered if they had > 3 bowel movements/week, < 2 soilings/manth and were off medication for one month. 65 CE (47%) were able to defecate the balloon (def+) and 74 (53%) were unable to do so (def-). Severe constipation defined by the presence era palpable abdominal mass was present in 29% def÷ and 55% def- (p < 0.01). Primary oncopresis, stool withholding, abdominal pain, stool frequency, soiling frequency, and fecal impaetion of the rectum were similarly distributed in det% and clef-. Follow-up results in def+ and clef- are shown in the table, *p < 0.03. 12 me F/up def+ def-
Reoovered
Laxatives
51%, 34%
34% 43%
Stool Freq/Wk 6+4 7+-4
Soil Freq/Wk 1+2 2+_-3
Rectal Sensation
Crit. Volume
Anismus
23+9 163+75, 49.*/~ 26_T17 223_~99 78%
Abilityto defecate the balloon was significantly related to recovery (odd ratio 2.18, 95% confidence limits 1.08 - 4.4). Afterwards, no additional variables met the 0.1 significance level for entry into the model: presence of severe constipation (p > 0.29), anismus (p > 0.36), threshold volume for rectal sensation ( p > 0.73), critical volume (p > 0.27), and volume to induce rectal contractility of> 10 nun Hg (p > 0.28). CE with the ability to defecate the balloon were twice as likelyto recover.
• DEMONSTRATION O F LONG-LASTING BLOCKADE OF E X P E R I M E N T A L ILEUS IN RATS BY AN O P I O I D K-AGONIST. Y. Lopez, R.K. Rao, and F. Porreca. Department of Pharmacology, University of Arizona, Tucson, AZ 85724 Opioid K-, but not/~ or ~, agonists block acetic-acid induced inhibition of gastric emptying (GE) and gastrointestinal transit (GIT)(experimental ileus, Gastroenterology 104: 724, 1993). Development of a long-lasting opioid K agonist may be of therapeutic value. Here, the opioid K receptor mediated effect has been characterized further and possible identification of a long-lasting opioid r receptor action has been studied using [~-FNA (an opioid K agonist/~t antagonist). Methods: Peritonitis was induced by i.p. acetic acid (0.5 % 10 ml/kg). A test meal (1.5 ml of whole milk/5~Cr)was given by gavage 35 min after acid. GE and GIT were assessed 15 min after the meal. Bremazocine and U69,593 were given 5 rain after, while 13-FNA was given 24, 48 and 72 hr prior to, the acid. The possibility of tolerance was studied by injecting rats, twice daily for 3 days, with bremaz0cine (3 mg/kg); testing occurred on day 4 by challenge with the test agonist given 5 min after the acid. In antagonist experiments (-)UPHIT (an irreversible opioid K1 antagonist was given at :24 hr). Results: l.p. acetic acid produced approximately 57% inhibition of either GE or GIT. Bremazocine and U69,593 produced a significant and dose-related inhibition of the peritonitis effect. When tested after 24 (but not 48 or 72) hr after administration I~-FNA also inhibited the peritonitis actions: (-)UPHIT pretreatment blocked the actions of U69,593, but not of bremazocine. Tolerance could be shown with repeated administration of bremazocine and bremazocine-tolerant rats demonstrated cross-tolerance to U69,593 and 13FNA. Conclusion: These data suggest that (a) activation of 1< receptors reverse the inhibition of GE and GIT in this model of experimental ileus, (b) that significant differences in efficacy may be identified (bremazocine > U69,593 > ~-FNA); and (c) that the identification of a long-lasting opioid t~ agonist is possible. The latter may lead to the development of novel treatment for surgically-induced ilens.
EFFECTS OF THE MACROLIDE LY274301 ON FASTING AND POSTPRANDIAL MOTOR ACTIVITY IN THE CANINE ANTRUM AND SMALL INTESTINE. John Lof, Oongliang Jin, Eamorm M.M. Qulgley, Internal Medicine and Surgery, University of Nebraska Medical Center, Omaha, NE LY274301 is a maerolide motilin agonist with potent in vitro effects on gastrointestinal smooth muscle. Oar aim was to evaluate the in vivo effects of this agent on motor patterns of the antrum, duodenum and jejunum. METHODS: Serosal strain gauges were implanted at 10cm intervals on the antrum, duodenum and proximal jejunum in six adult mixed-breed dogs. Separate studies of fasting and postprandial motor activity were performed on each animal at 2-weekly intervals over a 3 month study period. For fasting recordings vehicle or LY274301 (in doses of 0.01, 0.05, 0. lor 0.5mg/kg) was administered intravenously on completion of two complete cyales of the migrating motor complex (MMC). Recordings were continued thereafter for a further 4 hours. For postprandial recordings, animals were fed a standard meal on completion of one MMC cycle; 40 minutes later, vechicle or LY274301 (in doses of 0.05 or 0.5mg/kg) was administered IV, and recordings continued for a further 4 hours. For fasting studies, the'effects on overall motor pattems, interval (period) between MMCs and motility indices were compared. For postprandial recordings, motility indices were compared at 40 minute intervals: from 40 minutes prior to meal administration to 2 hours following drug administration. RESULTS: At doses of 0.05mg/kg and above IV LY274301 consistently induced an immediate burst of phasic contractile activity in the antrum and duodenum. This was followed by a premature phase III burst in all studies performed with 0.05mg/kg (MMC period, baseline vs post-drug 126±15.9 vs 39:7±6.2, p<.05). At doses of 0.1 and 0.5mg/kg an intense phase II-type activity followed and continued in all recordings for the duration of the study. At these two doses normal MMC cycling did not return; resumption of MMC cycling occured in 86%, 88% and 100% of recordings following 0.5, 0. lmg/kg and ,)chicle, respectively. Comparison Of motility indices demonstrated a dose-dependent increase in motility index, which was maximal in the first 20 minutes following drug administration. For the fed studies, LY274301 in a dose of 0.5mg/kg produced a significant increase in intensity of the fed pattern over the first 40 minutes in both the duodenum and jejunum (motility index, time interval -40 to 0 vs 0 to 40 vs 40 to 80 vs 80 to 120mins post-drug: 20.3±7.2 vs 42.1±5.3 vs 26.7±4.7 vs 22.2±7.7; p<.002 0 to 40 vs all other intervals). Premature "phase III" type activity was not observed in the postprandial recordings. CONCLUSIONS: LY274301 is a potent stimulant of foregnt motor aetivity in vivo. Both the magnitude and the nature of these effects are dosedependent, and should be further explored, especially in relation to functional correlates. (Supported by a grant from Eli Lilly and Company)
• EFFECTS OF CISAPRIDE TREATMENT ON GASTRIC MYOELECTRIC ACTIVITY AND EMPTYING IN DYSMOT I LITY-LI KE DYSPEPSIA (DLD-NUD) K. Lorens, F. Thor, S. Plebankiewicz, S.J. Konturek, Inst. Physiol. Univ. Sch. Med., Krakow, Poland. Chronic dyspepsia [NUD) can be defined as a constellation of symptoms of the upper abdomen which could be classified to different subgroups. Symptoms of dyspepsia with abdominal pain, nausea (vomitinEl~ bloating etc are characteristic to the dysmotility llke dyspepsia (DLD}. Prokinetics are recommended in this type of dyspepsia. The alm of this study was td investiE~te efficacy of cisapride treatment in DLD-NUD defined patients on symptoms, gastric myoeleotric activity and emptyin E rate. I0 patients with DLD-NUD {8 males, mean age 34 yrs and 2 females, mean age 39 yrs) took part in the study. EGG in fasted subjects recorded for a period of 1 h and patients were fed with liquid mixed meal (500 ml, S00 kcal), fed pattern were recorded for a period of two h with use of Synectics system (Syneotics Sweden). Gastric antrai area was measured with sonography (Hitachi EUB-240) in fasted patients and every ten rain after meal. EGG and gastric emptyin E study were repeated after one and four weeks of cisapride treatment (S mE, tid). Symptom score (7 symptom scored from O-3l in group of patients with DLD before treatment was 11.8-+0.7, in the first week of treatment it wag improved to 4.0+8 and in forth 3.8-+0S. Symptoms like nausea and vomiting were slightly improved after cisapride from 3.4 to 2. In 30% of patients EGG was normal with lack of increase of amplitude of signal after food. IOX of patients showed taohyEastria before treatment and 707, dysrhythmias with frequency signal of 1-4 cpm. Slow gastric emptyin E without EGG changes was observed in 10% of patients which had wide antral area. Treatment with cisapride accelerated total emptyin E time from 72-+12 to $2-+9 min. However, there was no effect of treatment on tachygastria which persisted and oha/aged to tachyarhythmia or dysrhythmias s e e n even one month of treatment. Most stable findin E of treatment was increase of amplitude of EGG signal after food in treated patients. Cisapride is effective in treatment of all symptoms of DLD except nausea and vomitin E. M o n t h l y cisapride treatment accelerated gastric emptyin E but dysrhMthmiawas unchanged.
•
AGA ABSTRACTS
GASTROENTEROLOGY,Vol. 108, No. 4
BALLOON DEFECATION AS A PREDICTOR OF OUTCOME IN CHILDREN WITH CHRONIC CONSTIPATION AND ENCOPRESIS. Loenin2-Baucke. Department of Pediatrins, The University of Iowa, Iowa cay, IA A model to test the coordinated function of the rectum, anal sphincters, and spinal reflexes is the rectal balloon defecation test. To evaluate if balloon defecation might predict recovery in children with chronic constipation and fecal soiling (CE), we evaluated the ability to defecate a 100 ml water-filled rectal balloon within 5 minutes in 139 CE > 5 years of age. 17 healthy children > 5 years of age were able to defecate the balloon. Treatment consisted of milk of magnesia, high fiber diet, and bowel training techniques, including biofeedback treatment in 48 patients. Follow-up occurred during a clinic visit or by mailed questionnaire 12 months alter treatment began, rating the last month. CE were rated as recovered if they had > 3 bowel movements/week, < 2 soilings/manth and were off medication for one month. 65 CE (47%) were able to defecate the balloon (def+) and 74 (53%) were unable to do so (def-). Severe constipation defined by the presence era palpable abdominal mass was present in 29% def÷ and 55% def- (p < 0.01). Primary oncopresis, stool withholding, abdominal pain, stool frequency, soiling frequency, and fecal impaetion of the rectum were similarly distributed in det% and clef-. Follow-up results in def+ and clef- are shown in the table, *p < 0.03. 12 me F/up def+ def-
Reoovered
Laxatives
51%, 34%
34% 43%
Stool Freq/Wk 6+4 7+-4
Soil Freq/Wk 1+2 2+_-3
Rectal Sensation
Crit. Volume
Anismus
23+9 163+75, 49.*/~ 26_T17 223_~99 78%
Abilityto defecate the balloon was significantly related to recovery (odd ratio 2.18, 95% confidence limits 1.08 - 4.4). Afterwards, no additional variables met the 0.1 significance level for entry into the model: presence of severe constipation (p > 0.29), anismus (p > 0.36), threshold volume for rectal sensation ( p > 0.73), critical volume (p > 0.27), and volume to induce rectal contractility of> 10 nun Hg (p > 0.28). CE with the ability to defecate the balloon were twice as likelyto recover.
• DEMONSTRATION O F LONG-LASTING BLOCKADE OF E X P E R I M E N T A L ILEUS IN RATS BY AN O P I O I D K-AGONIST. Y. Lopez, R.K. Rao, and F. Porreca. Department of Pharmacology, University of Arizona, Tucson, AZ 85724 Opioid K-, but not/~ or ~, agonists block acetic-acid induced inhibition of gastric emptying (GE) and gastrointestinal transit (GIT)(experimental ileus, Gastroenterology 104: 724, 1993). Development of a long-lasting opioid K agonist may be of therapeutic value. Here, the opioid K receptor mediated effect has been characterized further and possible identification of a long-lasting opioid r receptor action has been studied using [~-FNA (an opioid K agonist/~t antagonist). Methods: Peritonitis was induced by i.p. acetic acid (0.5 % 10 ml/kg). A test meal (1.5 ml of whole milk/5~Cr)was given by gavage 35 min after acid. GE and GIT were assessed 15 min after the meal. Bremazocine and U69,593 were given 5 rain after, while 13-FNA was given 24, 48 and 72 hr prior to, the acid. The possibility of tolerance was studied by injecting rats, twice daily for 3 days, with bremaz0cine (3 mg/kg); testing occurred on day 4 by challenge with the test agonist given 5 min after the acid. In antagonist experiments (-)UPHIT (an irreversible opioid K1 antagonist was given at :24 hr). Results: l.p. acetic acid produced approximately 57% inhibition of either GE or GIT. Bremazocine and U69,593 produced a significant and dose-related inhibition of the peritonitis effect. When tested after 24 (but not 48 or 72) hr after administration I~-FNA also inhibited the peritonitis actions: (-)UPHIT pretreatment blocked the actions of U69,593, but not of bremazocine. Tolerance could be shown with repeated administration of bremazocine and bremazocine-tolerant rats demonstrated cross-tolerance to U69,593 and 13FNA. Conclusion: These data suggest that (a) activation of 1< receptors reverse the inhibition of GE and GIT in this model of experimental ileus, (b) that significant differences in efficacy may be identified (bremazocine > U69,593 > ~-FNA); and (c) that the identification of a long-lasting opioid t~ agonist is possible. The latter may lead to the development of novel treatment for surgically-induced ilens.
EFFECTS OF THE MACROLIDE LY274301 ON FASTING AND POSTPRANDIAL MOTOR ACTIVITY IN THE CANINE ANTRUM AND SMALL INTESTINE. John Lof, Oongliang Jin, Eamorm M.M. Qulgley, Internal Medicine and Surgery, University of Nebraska Medical Center, Omaha, NE LY274301 is a maerolide motilin agonist with potent in vitro effects on gastrointestinal smooth muscle. Oar aim was to evaluate the in vivo effects of this agent on motor patterns of the antrum, duodenum and jejunum. METHODS: Serosal strain gauges were implanted at 10cm intervals on the antrum, duodenum and proximal jejunum in six adult mixed-breed dogs. Separate studies of fasting and postprandial motor activity were performed on each animal at 2-weekly intervals over a 3 month study period. For fasting recordings vehicle or LY274301 (in doses of 0.01, 0.05, 0. lor 0.5mg/kg) was administered intravenously on completion of two complete cyales of the migrating motor complex (MMC). Recordings were continued thereafter for a further 4 hours. For postprandial recordings, animals were fed a standard meal on completion of one MMC cycle; 40 minutes later, vechicle or LY274301 (in doses of 0.05 or 0.5mg/kg) was administered IV, and recordings continued for a further 4 hours. For fasting studies, the'effects on overall motor pattems, interval (period) between MMCs and motility indices were compared. For postprandial recordings, motility indices were compared at 40 minute intervals: from 40 minutes prior to meal administration to 2 hours following drug administration. RESULTS: At doses of 0.05mg/kg and above IV LY274301 consistently induced an immediate burst of phasic contractile activity in the antrum and duodenum. This was followed by a premature phase III burst in all studies performed with 0.05mg/kg (MMC period, baseline vs post-drug 126±15.9 vs 39:7±6.2, p<.05). At doses of 0.1 and 0.5mg/kg an intense phase II-type activity followed and continued in all recordings for the duration of the study. At these two doses normal MMC cycling did not return; resumption of MMC cycling occured in 86%, 88% and 100% of recordings following 0.5, 0. lmg/kg and ,)chicle, respectively. Comparison Of motility indices demonstrated a dose-dependent increase in motility index, which was maximal in the first 20 minutes following drug administration. For the fed studies, LY274301 in a dose of 0.5mg/kg produced a significant increase in intensity of the fed pattern over the first 40 minutes in both the duodenum and jejunum (motility index, time interval -40 to 0 vs 0 to 40 vs 40 to 80 vs 80 to 120mins post-drug: 20.3±7.2 vs 42.1±5.3 vs 26.7±4.7 vs 22.2±7.7; p<.002 0 to 40 vs all other intervals). Premature "phase III" type activity was not observed in the postprandial recordings. CONCLUSIONS: LY274301 is a potent stimulant of foregnt motor aetivity in vivo. Both the magnitude and the nature of these effects are dosedependent, and should be further explored, especially in relation to functional correlates. (Supported by a grant from Eli Lilly and Company)
• EFFECTS OF CISAPRIDE TREATMENT ON GASTRIC MYOELECTRIC ACTIVITY AND EMPTYING IN DYSMOT I LITY-LI KE DYSPEPSIA (DLD-NUD) K. Lorens, F. Thor, S. Plebankiewicz, S.J. Konturek, Inst. Physiol. Univ. Sch. Med., Krakow, Poland. Chronic dyspepsia [NUD) can be defined as a constellation of symptoms of the upper abdomen which could be classified to different subgroups. Symptoms of dyspepsia with abdominal pain, nausea (vomitinEl~ bloating etc are characteristic to the dysmotility llke dyspepsia (DLD}. Prokinetics are recommended in this type of dyspepsia. The alm of this study was td investiE~te efficacy of cisapride treatment in DLD-NUD defined patients on symptoms, gastric myoeleotric activity and emptyin E rate. I0 patients with DLD-NUD {8 males, mean age 34 yrs and 2 females, mean age 39 yrs) took part in the study. EGG in fasted subjects recorded for a period of 1 h and patients were fed with liquid mixed meal (500 ml, S00 kcal), fed pattern were recorded for a period of two h with use of Synectics system (Syneotics Sweden). Gastric antrai area was measured with sonography (Hitachi EUB-240) in fasted patients and every ten rain after meal. EGG and gastric emptyin E study were repeated after one and four weeks of cisapride treatment (S mE, tid). Symptom score (7 symptom scored from O-3l in group of patients with DLD before treatment was 11.8-+0.7, in the first week of treatment it wag improved to 4.0+8 and in forth 3.8-+0S. Symptoms like nausea and vomiting were slightly improved after cisapride from 3.4 to 2. In 30% of patients EGG was normal with lack of increase of amplitude of signal after food. IOX of patients showed taohyEastria before treatment and 707, dysrhythmias with frequency signal of 1-4 cpm. Slow gastric emptyin E without EGG changes was observed in 10% of patients which had wide antral area. Treatment with cisapride accelerated total emptyin E time from 72-+12 to $2-+9 min. However, there was no effect of treatment on tachygastria which persisted and oha/aged to tachyarhythmia or dysrhythmias s e e n even one month of treatment. Most stable findin E of treatment was increase of amplitude of EGG signal after food in treated patients. Cisapride is effective in treatment of all symptoms of DLD except nausea and vomitin E. M o n t h l y cisapride treatment accelerated gastric emptyin E but dysrhMthmiawas unchanged.