Polyethylene glycol without electrolytes for children with constipation and encopresis

3254

Table1: NF~B p65-positive LaminaPropriaCelIs/HPF(mean_+se) IBS-diarrhoea

IBS.alternatin 9

Post-Dysentery

_Control

t5.4+_5.5,1"

8.6±2.2_

13.6~3.2

10.5±5.1

Ginger Reduces Hyperglycemia-inducedGastric Dysrhythmiasand Nausea in Healthy Humans: Possible Mediation by Inhibiting the Action of Endogenous Prestaglandins Sutep Gonlachanvit, Yen H. Chen, William L. Hasler, Wei-Ming Sun, Chung Owyang, Univ of Michigan, Ann Arbor, MI

P<0.05v *alternating;v 1"controlsby ANOVA

BACKGROUND:Acute hyperglycemia (HGly) evokes gastric dysrhythmias via endogenous prostaglandin generation. Ginger reduces nausea and gastric dysrhythmias in experimental motion sickness. The ability of ginger to blunt the effects of hyperglycemia on slow wave activity and symptoms is unexplored. Furthermore, if ginger could be shown to prevent induction of dysrbythmiosafter administration of exogenousprostaglandin,this would suggest that any antiarrhythmic effect of ginger during hyperglycemia may stem from inhibition of the actions of endogenousprostaglandins.METHODS:7 healthy humans underwentelectrogastrography (EGG) during hyperglycemic clamping to 250 mg/dl after 1 gm gingerroot or placebo. EGG responses to 400/.,.g prostaglandin E2 were tested in 5 subjects after ginger or placebo. EGGs were recorded for 30 min basal, 30 min during hyperglycemia or after PGEz,and 60 rain after a 1000 kcal meal. Dominant frequencies (DF) and the % of DF in the brady (B) (< 2 cpm), normal (2-4.5 cpm), and tachygastric (T) (4.6.9 cpm) ranges were analyzed. RESULTS:There were no differences in basal or postprandial EGGsafter ginger vs placebo. Hyperglycemiaand PGE2reduced the % of normal 3 ¢pm activity (98_+2, 61_+19", 79_+9"-Baseline (B) PGE2)andevoked tachygastrias (2+-2, 38-+19', 13-+6" %T - R, HGly, PGE2),effects significantly reversed by ginger (% 3 cpm after ginger - 100, 76-+15" B, HGly, PGEz). Hyperglycemic clamping increased the DF, an effect suppressed by ginger. Nausea was reported by 4 of 7 subjects during hyperglycemiaand 2 of 5 subjects after PGE2.Ginger suppressednauseain 75% of subjects during hyperglycemicclamping and in 50% of subjects after PGE2.('p< .05) CONCLUSIONS:Acute hyperglycemiaevokes gastric dysrhythmias and nauseawhich are blunted by ginger. The ability of ginger to preventinduction of dysrhythmias and nauseaby exogenousPGE2suggeststhat its antiarrhythmic effects during hyperglycemia may stem from blockadeof the actions of endogenouslyproduced prostagtandinsrather than inhibition of prostaglandinrelease.Thesefindings suggestnovel mechanismsfortha antiemetic effects of the traditional Chinese herbal remedy ginger.

3252 Antidepressants For Functional Gastrointestinal SymptomsAnd Syndromes:A MetaAnalysis Ray E. Clouse, Chandra Prakash, Ryan J. Anderson, Patrick J. Lustman', Washington Unlv, St. Louis, MO BACKGROUND: Antidepressant (AD) treatment trials have been reported for a variety of functional gastrointestinalsymptoms and syndromes,and mechanismof action is not conspicuously different from disorder to disorder. An aggregateestimate of effect across disorders is not available.METHODS:MEDLINEand psyclNFOdatabaseswere searchedfor AD treatment trials (->6 treated subjects) of functional gastrointestinaldisorders (FGIDs)in adults. Outcomes were categorizedas primary, global (or syndromatic), pain, and translt-syrnptom depending on available measures. Controlled trials (CTs) were subjectedto meta-analyticalprocedures; uncontrolled reports (URs) were used to determine open-labeltreatment response rates and extract other clinical observations. RESULTS:Twenty-one reports were identified from 1970 to 1999 (14 CTs; 7 URs); 11 involved patients with IBS, 5 functional esophagealsymptoms (including chest pain), 4 functional dyspepsia or variants, and 1 abdominal pain. A total of 849 patients were treated in the CTs and 326 patients in the URs. Nineteen reports involved tricyclic ADs and 4 utilized other contemporary agents (2 used both). Including all CTs in the analysis, aggregatep valuesfor treatment effect were highly significant for primary, global, and pain outcome measures (p
3255 BiofoNllesk Training Exercise in Treating Patients with Chronic Gastric Motility O i e s ~ : Possible Predictors for the Outcome Haiti Rashad,Teresa Cuffs, Unlv of TennesseeHealth Science Ctr, Memphis, TN; Patricia Cowings, William Toscano, National Aeronautics and Space Admin, Moffat Field, CA; Thomas L. Abell, Univ of Arkansas for Medical Science, Little Rock, AR Introduction: Chronicnauseaand vomiting remainsa significant clinical problem; many patients are refractory to treatment, and there is a lack of available medications. Autogenic Feedback Training Exercise (AFTE) is a physiological conditioning procedure developed by NASA for space motion sickness. Previousstudies suggestedthat this technique can be usedto alleviate some of those symptoms. However, prediction of who might respond to this therapy was not investigated.Therefore, in this study we investigatedthe effect of AFTE on patients with severe GI symptoms, many of which are related to motion sickness. Patients: 9 as controls and 26 patients (15 pts whose symptoms improved >30% and 11 ptns whose symptoms improved <30%). All pts with symptoms of nausea, bloating, abdominal pain, anorexia and early satiety weretreated with AFTEand their symptoms were scored as 3 = severe,2 = moderate, 1 =mild, O=none. Methods: All pts received up to 12 sessions of AFTE. Each session was of 30 minutes divided into 5 cycles of 3 minutes of relaxation followed by 3 minutes of stimulation. Results: A significant drop (p
3253 A Comparison of CP-331,684, a ~-adronergic Receptor Aoonist, Dicystomine and Placebo on Gallbladder and Colonic Motility in Man. Lesley A. Houghton, Dawn O'Brien, Peter J. Whorwell, Univ Hosp of South Manchester, Manchester United Kingdom; Linda Shaw, Jonathan Rachman, Pfizer Cent Research, Sandwich United Kingdom ~-adrenergic receptors (~3-AR) are expressed in human adipose tissue and ~3-AR agonists which increasemetabolic rate, are currently under investigationfor their potential anti-obssity and anti-diabetic properties. ~-AR mRNA is also expressed in the human gastrointestinal tract, particularly the colon and gallbladder, and there is pre-clinical evidenceto suggest that ~-AR agonists suppress motility. It was the aim of this study to assess the effects of CP331,684, a new/~-AR agonist and dicyclomine on human colonic and gallbladder motility. 24 healthy male volunteers (aged 19-37 yrs) participated in a double-blind, double-dummy, randomised, placebo-controlled,three-way crossover study in which they received either a single oral dose of CP-331,684 (300mg), dicyclomine (20mg) or placebo control. 90 rain post-dose, colonic motility was recorded for 30 rain fasting and then for a further 60 min post-meal using a 5-channel (5cm apart) solid state catheter introduced to a depth of 35cm by flexible sigmoidoscopy in the unprepared colon. Gallbladder volume was measured by ultrasound 45 min (fasting) and 180 rain (fed) post-dose, from which the maximum postmeal ejection fraction (EF) was calculatedas the difference betweengallbladdervolumes preto post-meal,expressedas a percentageof the pre-mealvolume.To provide a pharmacological marker of CP-331,684 activity, plasmafree fatty acid (FFA) concentration was measuredpreand 115 min post-dose (this should increase with ~-AR ogonism because of lipolysis). Results As expected plasma FFA concentration was greater after CP-331,684 (change pre to post-dose: 424umol/l(313,536)umoi/I, mean (95%CI)) compared with dicyclomine (62 umol/l(29,95)umol/I) and placebo (83umol/l(60,106)umol/I)(p
3256 Polyethylene Glycol without Electrolytes for Children with Constipation and Encopresis. Vera A. Loaning-Baucke,Univ of Iowa, Iowa City, IA BACKGROUND/OBJECTIVES:Children with functional constipation and encopresis benefit from behavior modification and long-term daily laxatives. In this study, we determine the acceptability, efficacy, and treatment dose of a new polyethylene glycol laxative without electrolytes (PEG). METHODS: Observational study of 28 children with constipation and encopresis treated with PEG. Children were rated as improved (defined as ->3 bowel movements (BMs)/wk and 75% reduction in soiling, but not more than 1 soil/wk) or treatment failure at 3, 6 and o~10 months later. Outcome was compared to 21 children treated with milk of magnesia (MOM) during the same time period. RESULTS:Four (14%) on PEG were treatment failures and were started during the first 3 months on additional daily senna and 6 (29%) on MOM refused to take MOM, 5-8 months later. These 10 children were rated as treatment failures from the time of occurrence. As seen in the table, at 3-, 6- and ~lO-month follow-up, significant improvement was seen in the PEG and MOM groups, due to increase in BMs and decrease in soiling (*p
A-64.2

BMs/wk _PEG MOM Soilings/wk _PEG MOM % improved PEG MOM

Initial

_3-me FlU

6-me F/U

col0-moFlU

3+5 34--'4

10i-6" 7±3*

9+6* 7±3*

7+4* 7±3*

1~18 9~10

~3" 0,5_+2'

1±3" 1±2"

2~3" 0.1±0.2"1

0 0

78* 95*

72* 72*

64* 71"

3259 Early Effect of Tegaserod Predicts Continued Efficacy in Treatment of Constipation Predominant Irritable Bowel Syndrome Stefan Mueller-Lissner, Park-Klinik Weissensea, Humboldt Univ, Berlin Germany; Martin Lefkowltz, Yingqi Shi, Novartis Pharmaceuticals Corp, East Hanover, NJ; Bdgitte Nault, Novartis Pharma AG, Basel Switzerland; Joan Heggland, Kathie Glebas, Novarfis Pharmaceuticals Corp, East Hanover, NJ; Peter C. Rueegg, Novartis Pharma AG, Basel Switzerland BACKGROUND/OBJECTIVES:The current recommendation for the duration of treatment trials in functional GI disorders is 12 weeks. For clinical practice, however, it would be desirable to know as early as possible whether a patient responds to therapy. Tegaserod is a 5HT4 receptor partial agonist effective in the treatment of constipation predominant irritable bowel syndrome (C-IBS). A review of phase III studies was performed to assess the predictive value of early response for continued efficacy over time. METHODS:Three placebo controlled studies of 16 weeks duration (4 weeks baseline, 12 weeks double-blind) were conducted in a total of 3199 C-IBS patients (92% teroale). Patients were selectedbased on Rome-I criteria. Efficacy was assessedweekly by diary; the main efficacy variable was the Subject's Global Assessment (SGA) of Relief which evaluated overall well being, abdominal pain and altered bowel habit. Responders were those who had ->50% of the time complete/considerable relief, or 100% complete/considerable/somewhat relief. Persistence of clinical effectiveness was calculated from the Month-1 responders who continued to respond at study endpoint. RESULTS: Overall 81% of the patients completed the 3 studies. In females at Month-1 a superiority of 14-16% over placebo was observed, and 74-78% of the responders at Month-1 remained responders at study endpoint. Only one fourth of non-rssponders at Month-1 became responders at endpoint. Responder and persistence rates for females are shown below. CONCLUSIONS:In female patients tegaserod 12 mg/d has a consistent and reproducible, clinically relevant effect in relieving IBS symptoms. Responders at Month-1 are very likely to continue responding to treatment. Supported by Novartis Pharma AG

3257 Tegasered, a 5HT4 Receptor Partial Agonist, Devoid of Significant Electrocardiographic Effects Peter C. Rueegg, Cornelia Dunoer Baldauf, Silke Appel Dingemanse, Novartis Pharma AG, Basel Switzerland; Martin Lefkowltz, Novartis Pharmaceuticals Corp, East Hanover, NJ; Joel Morganroth, Univ of Pennsylvania, Philadelphia, PA BACKGROUND:Select gastro-prokinetic agents are known to affect cardiac repolarization (QTc interval) which may be associated with fatal arrhythmias such as torsades de pointes. The selective 5HT4 receptor partial agonist, tegaserod, is a new promotile agent developed for the treatment of irritable bowel syndrome (IBS). It is the first agent of a new class of compounds, the aminoguanidine indoles. METHODS: In a combined analysis of the electrocardiographic data of 3 clinical studies the cardiac safety profile of tegaserod was investigated. Patients with IBS were treated with tegaserod 4-12 mg/d (n = 1679) or placebo (n = 837) for 12 weeks, and standard 12-lead ECGs were recorded at baseline, Day 1, Weeks 4 and 12. A total of 11535 ECGswere analyzed centrally by an experiencedcardiologist unaware of the treatment assignment using a high resolution analysis system. RESULTS: The frequency of patients with prolongations of the OTc interval was the same for the tegaserod and the placebo treatment groups, as was the frequency of overall ECG abnormalities. The findings in the subgroup of elderly patients were similar. Newly occurring or worsening T- and U-wave abnormalities were similar in the 2 groups. No ventricular tachycardia was observed. In addition, healthy volunteer studies with tegaserod plasma concentrations of up to 100 times those expectedat therapeutic doses for IBS, did not show any prolongation of the OTc duration nor a correlation between tegaserod plasma concentrations and the OTc interval duration. Tegaserod did not effect Ik, in vitro. CONCLUSIONS:These data confirm that tegaserod at therapeutic doses has a more favorable cardiac safety profile than older gastro-prokinstic agents. Supported by Novartis Pharma AG.

Study 13301 I]351 13358

Before treatment After treatment

257+/-18

139+/-23

316+/-61

20.8+/-5

37.6+/-4

273+/-15"

111+/-4

253+•-25

25.6+/-'P

41.6+/-4#

76.2 73.5 78.4

Background: Visceral hypersensitivity is believed to contribute to symptoms in functional gastrointestinal disorders. Selective serotonin reuptake inhibltors [SSRIs] are used to treat these disorders, but little is known regarding their effect on visceral sensation or clinical symptoms. Our aims were to determine the effec~ of the SSRI sertraline [SERT] on symptoms induced by gastric distension in healthy humans. Methods: In a randomized, double-blind, crossover trial, 10 non-depressed healthy subjects (age 28 _+ 6 yrs, 6 female) received 50 mg/day of sertraline (t~ = 26 hr) or identical placebo [PLC] for 2 weeks each, separated by a 2-weak washout period. On the last day of each treatment, visceral sensory testing was performed with a barostat. Fullness, pain and nausea were rated (VAS 0-10) and volume was recorded during ascending, intermittent, 60-second isobaric gastric distensions (2-30 mm Hg above minimal distending pressure [MDP]). Thresholds for first sensation and pain were determined by a tracking method (double random staircase). Somatic pain tolerance was tested by ice water immersion of the dominant hand. Adherence to treatment was assessed by pill count. Results: Pill counts were exact in 75% of treatments, 1 dose was missed in 15%, and 1 extra dose was taken in 10%, reflecting excellent adherenceto treatment. Symptom scores as a function of distending pressure did not differ between SERT and PLC (fullness P=O.7; pain P=0.8; nausea P=0.4), as illustrated by mean scores at 22 mm Hg above MDP (fullness 4.0 _+ 1.1 vs 4.4 _+ 0.8; pain 3.3 _+ 0.8 vs 2.9 _+ 0.7; nausea 2.1 _+ 0.9 vs 2.1 _+ 0.9). Gastric compliance also did not differ with SERT vs PLC (P= 0.15), as illustrated by volumes at 22 mm Hg above MDP (650 +- 31 vs 690 _+ 27 mL). Mean thresholds for first sensation with SERT and PLC were 4.5 _ 0.6 vs 7.0 +_ 1.2 mm Hg above MDP (P= 0.09), and mean thresholds for pain were 14.6 -+ 2.2 vs 15.2 -+ 1.8 mm Hg above MDP (P=O.8). Median times for tolerance of hand immersion in ice water for SERT vs PLC were 27 [1999] vs 29 [20-180] seconds (P =0.7). Conclusion: In this study of healthy humans, a 2-week treatment with the SSRI sertraline had no effect on symptoms induced by gastric barostat distension, gastric compliance, or somatic pain tolerance. However, these findigs do not rule out the possibilities that SSRIs might blunt visceral sensation in healthy subjects with higher doses or longer treatment, or that SSRIs might affect visceral sensation or clinical symptoms in patients with functional gastrointestinal disorders.

Effectsof 5HT3antagoniston anorectalfunction. Threshold for stool perception (mmH9)

<0.001 0.003 <0.001

The Selective Serotonin Reuptake Inhibitor Sertraline Does Hot Affect Gastric Sensitivity Or Compliance In Healthy Humans Uri Ladabaum, David Glidden, UC San Francisco, San Francisco, CA

BACKGROUND:5HT3antagonists delay colonic transit and increase colonic wall compliance in diarrhea predominant IBS patients. However, the effects of 5HT3antagonists on anorectal function, which may contribute to the improvement of symptoms in patients with diarrhea predominant IBS or fecal incontinence have not been characterized. OBJECTIVE:To determine the ~ects of the selective 5HT3antagonist; alosetron, on anorectal function in healthy female volunteers. METHODS:5 healtyfemale subjects, aged 32-49 yrs, underwent anorectal manometry and computered barostat study before and after 1-2 weeks of alosatron administration (1 mg pc bid), using a perfused multiport manometric assembly and a polyethylene bag located between 8-16 cm from the anal verge. Perception in response to rectal distention was rated for stool sensation, fecal urgency, and pain. RESULTS: After alosetron treatment, rectal wall compliance was significantly increased (p
Squeeze pressure (mmHg)

20.1 (288) 31.7 (267) 26.2 (752)

3260

Effects of Selective 5HT3Antagoniston Anorectal Function in Normal Female Subjects. Sutep Gonlachanvit, Yen-Hsueh Chen, Wei-Ming Sun, William D. Chey, Univ of Michigan, Ann Arbor, MI

Restinganal sphincter pressure (mmH9)

35.7 (294) 45.4 (267) 40.5 (767)

Persistence rateI (%)

i ~

3258

Intrsbag volume at 40 mmHg (ml)

SGA responderrate: % (n) at Month.1 Tega 12 mg/d Placebo p-value

Threshold for severe urgency (mmHg)

3261 Acute Pancreatitis In Children With Idiopathic Vs Neuromuscular Scoliosis Post Surgical Repair Devendra I. Mehta, Alfred I duPont Hosp for Children/TJU, Wilmington, DE; Christopher Festa, Shdner's Children's Hospital/Temple University, Philadelphia, PA; Kirk Dabney, Mary Theroux, Freeman Miller, Alfred I duPont Hosp for Children, Wilmington, DE

Mean+/-SEM,* p
Background/Objectives:Acute pancreatitis has been shown to occur at high rates after spinal fusion surgery. Though the basis of this association is not known, poor nutritional status, use of seizure medications, and seen particularly in children with cerebral palsy at the time of surgery were postulated as risk factors. The clinical suspicion that the rate is higher in neuromuscular scoliosis, and cerebral palsy in particular, compared with idiopathic scoliosis

A-643