Alosetron, a 5HT3-receptor antagonist, is effective in the treatment of female irritable bowel syndrome patients

ASl2 AGA ABSTRACTS • G3336 ALOSETRON, A 5HT3-RECEPTOR ANTAGONIST, IS EFFECTIVE IN THE TREATMENT OF FEMALE IRRITABLE BOWEL SYNDROME PATIENTS. AR Northcutt (1), M Camilleri (2), EA Mayer (3), DA Drossman (4), GE Dukes (1), RSB Ehsanullah (1), LR Hamm (1), JP Harding (1), AT Heath (1), L Jacques (1), S Wolfe (i) S Kong(1), D McSorley (1), AW Mangel (1). Glaxo Wellcome, Research Triangle Park, NC (1); Mayo Foundation, Rochester, MN (2); CURE, UCLA School of Medicine, Los Angeles, CA (3); University of North Carolina School of Medicine, Chapel Hill, NC (4). Background: Semtonergic pathways modulate visceral sensory and colonic motor processes which may play a role in the pathogenesis of irritable bowel syndrome (IBS). We, therefore, sought to eval'uate the potent and selective 5HT3-receptor antagonist, alosetron, in the treatment of non-constipated IBS patients. Mct h0d.s: Three hundred and seventy patients with IBS were recruited from 5 countries and randomly assigned in a double-blind fashion to 12 weeks of treatment with one of the following regimens: alosetron 1,2,4,8 mg BID or placebo BID. During the screening~ treatment and follow-up periods, patients reported symptoms of pain and bowel function daily via an electronic touchtone telephone based system(l). During the treatment period, patients also reported weekly whether they had obtained adequate relief of their IBS-related abdominal pain and discomfort during the previous week. In patients completing the 12-week treatment period, a resvonder was prospectively defined as a patient who reported adequate reliet~ for at least 6 weeks; otherwise the patient was a nonresponder. Results: The proportion of female responders (reporting adequate relief) with alosetron 1 mg BID (60%) or 2 mg BID (59%) was significantly greater than the proportion of female responders reporting adequate relief with placebo (33%, p<0.05). Alosetron also significantly improved stool urgency, frequency and consistency in females. There was no evidence of improvement over placebo in the proportion of male patients reporting adequate relief of IBS-related pain/discomfort with any dose of alosetron examined. In males treated with alosetron only stool consistency showed improvement over placebo. The only adverse event of note was constipation that was reported by 20% (lmg BID) to 29% (8mg BID) of patients treated with alosetron. Conclusion: Alosetron is effective and well tolerated in relieving abdominal pain and improving stool frequency, consistency and urgency in female IBS patients. [1] Harding JP, et al. Use of a novel electronic data collection system in multicenter studies of irritable bowel syndrome. Alimen. Pharm. Ther. 1997, 11:6, 1073-1076. Supported by Glaxo Wellcome Inc. • G3337 INTRACISTERNAL OR MICROINJECTION OF TRH INTO DMN DOES NOT ACTIVATE NON-ADRENERGIC, NON-CHOLINERGIC INHIBITORY (NANC) NEURONS OF THE RAT STOMACH. T. Nozu, H.E. Raybould, N. Morrow, T. Garrick and Y. Tachr. CURE: Dig. Dis. Res. Ctr., VA Med. Ctr., Dept. of Medicine and Brain Res. Inst., UCLA. Los Angeles, CA. BACKGROUND: Medullary TRH is well established to activate neurons in the dorsal motor nucleus of the vagus (DMN) leading to stimulation of gastric vagal outflows and enteric cholinergic neurons. The vagus nerves also contain preganglionic fibers that activate NANC inhibitory enteric neurons. Demonstration of vagal dependent activation of NANC enteric neurons was mainly achieved by high frequency electrical vagal stimulation and little is known about the central coding which activates NANC neurons. AIM:To examine whether central TRH stimulates as well NANC neurons as shown by gastric relaxation under cholinergic and adrenergic blockade and moreover, test the effects of vasoactive intestinal polypeptide (VIP), which is involved in gastric relaxation induced by NANC neurons on intraluminal gastric pressure. METHODS: In SD male fasted rats (250 g), anesthetized with urethane, intraluminal gastric pressure was measured by a fluid-filled catheter positioned into the corpus and secured by pylorus ligation and pressure transducer. The areas of the response (cmH20-sec) corresponding to changes in gastric pressure induced by TRH or VIP were calculated. RESULTS: Consecutive intracisternal (ic) injections of TRH (30, 300, 3000 ng at approximately 50 rain intervals) increased gastric pressure dose dependently (Table 1). TRH-induced pressure response was no longer observed in presence of intraperitoneal pretreatment with atropine (2 mg/kg) and bretylium (25 mg/kg, Table 1). Atropine plus bretylium also suppressed the amplitude of phasic contractions (cmH20) in basal state (vehicle: 1.58 ± 0.34 vs atropine plus bretylium: 0.8 ± 0.09, P < 0.05, n=5 and 6 respectively). Table 1: Effects of consecutive ic injections of TRH on intragastric pressure [Area of the response (cmH20-sec), mean_.+SE, number o f rats in parenthesis]. Table 1: Effects of consecutiveic injections of TRH on intragastric pressure [Area of the response (cmH20*sec), mean ± SE, number of rats in parenthesis]. Vehicle TRH (nffrat, ic) (ic) 30 300 3000 Vehicle (n=5) 43 ± 27 4879 ± 1009" 6174± 289* 6400-1030" A+B (n=6) -3.5 ± 2.8 38.1 ± 34.7# 14.6 ± 11.2# 20.2 ± 14.4# *: P < 0.05 vs vehicle (ip) + vehicle (ic), #: P < 0.05 vs respective vehicle (ip) group, (ANOVA) A: atropine, B: bretylium. Treatment (ip)

GASTROENTEROLOGY Vol. 114, No. 4

Intra-arterial VIP (6 lag&g) decreased the gastric pressure significantly (vehicle: 0.5 ± 7.4 vs VIP: -2502 ± 660, n=5 for each group, P < 0.05) and this effect was attenuated but not abolished by atropine plus bretylium (vehicle: -0.7 ± 1.6 vs VIP: - 332 ± 94, n=5 for each group, P < 0.05). TRH (300 ng) microinjected unilaterally into the DMN stimulated the gastric contractility (vehicle + vehicle: -6.2_.+6.9, n=3 vs vehicle + TRH: 1783 ± 146, n=6, P < 0.05, ANOVA) and this effect was abolished by atropine plus bretylium (32.6 ± 23.4, n=6). TRH did not induce relaxation of the stomach. CONCLUSIONS: TRH is a selective activator of vagal cholinergic excitatory pathways within the stomach. NANC vagal dependent inhibitory neurons might be controlled by other neurotransmitter(s) in brain. G3338 PERIPHERAL U R O C O R T I N - AND CRE- INDUCED GASTRIC STASIS:

ROLE OF CRFz RECEPTOR SUBTYPE IN RATS. T, N0zu, V. Martfnez, J. River # and Y. Tachr. CURE: Dig. Dis. Res. Ctr., VA Med. Ctr., Dept. of Medicine and Brain Res. Inst., UCLA. Los Angeles, CA. and ~l'he Salk Ins. for Biological Studies, La Jolla, CA. Peripheral corticotropin-releasing factor (CRF) inhibits gastric emptying (GE) in rats. Urocortin, a new member of the CRF peptide family, possesses characteristics of an endogenous ligand for the type-2 CRF receptors (Nature 378:287, 1995) which are expressed in the periphery. AIM:(1) To characterize the biological activity of peripheral urocortin on GE and to compare its action with that of CRF, and (2) to examine the effect of peripheral CRF antagonists [astressin: a CRF type 1 and 2 receptor antagonist (PNRS 92:10575, 1995) and antalarmin: a selective CRF type 1 receptor antagonist (Endocrinology 137:5447, 1996)] on the actions of urocortin and CRF. METHODS: In SD male fasted conscious rats (250 g), GE (% in 20 min) of a phenol red methylcellulose solution was determined 30 min after intravenous (iv) rat CRF Or rat urocortin under short anesthesia. Astressin was injected iv immediately before or antalarmin was administered intraperitoneaUy (ip) 1 h before CRF or urocortin injection. RESULTS: Basal GE was 52.9 ± 1.8 (n=20). Urocortin (252, 504 and 840 pmol/kg, iv) inhibited GE by 56, 77 and 87% respectively (n=5-9) and CRF (252, 504 and 840 pmol/kg, iv) by 40, 54 and 52% respectively (n=4-6). Urocortin inhibited GE with 2.3 fold greater potency than CRF (urocortin EDso=224 pmol/kg, CRF EDso=526 pmol/kg). Astressin (1, 3, 10 lag) dose-dependently antagonized CRF (504 pmol/kg)-induced 56% inhibition of GE with full reversal at 3 lag while partly preventing urocortin (504 pmol/kg) action (Table 1).

BACKGROUND:

Table 1: Antagonismof iv CRF (504 pmol/kg)or urocortin (504 pmol/kg)-induced gastric ileus by astressin [% GE in 20 rain, mean + SE, numbers of rats in parentheses. *: P < 0.05 vs vehicle + vehicle; +: P < 0.05 vs vehicle + CRF or urocortin (ANOVA)]. Astressin 10 i.tg 20 ~.tg Vehicle 54.4±2.7(12) 57.7±1.4(6)÷ 47.0±3.6(7)+ CRF 23.9±4.3(6)* 40.5±0.9(5)* 56.0±5.3(6)+ 58.1±2.8(5)+ Urocortin 13.4±2.1(13)* 29.1±2.9(5)* 35.2_+2.8(6)** 35.1±4.7(5)*+ 25.7±3.2(5)**

Treatment

Vehicle

l I.tg

3 ttg

Urocortin (252 pmol/kg)-induced similar inhibition of GE (vehicle + vehicle: 61.0±4.2, n=10, vehicle + urocortin: 28.9±4.3, n=ll, P <0.05) as CRF (504 pmol/kg) was partly (44.1 _+5.6, n=7, P < 0.05 vs vehicle + vehicle, vehicle + urocortin) and completely (56.2 _.+4.7, n=8) abolished by astressin at 10 and 20 lag, respectively. Antalarmin (20 mg/kg, ip) modified neither basal GE (vehicle + vehicle: 53.8 ± 4.4, n=9, antalarmin + vehicle: 53.2 _+_2.4, n=10) nor CRF (504 pmol/kg) or urocortin (252 pmol/kg)-induced gastric stasis (CRF without or with antagonist: 32.5 ± 6.2, 38.0 ± 3.0, respectively, urocortin without or with antagonist: 30.4 ± 5.6, 24.6 ± 2.4, respectively, n=5 for each group). Antalarmin at such dose prevents stress-induced stimulation of colonic motor function (Gastroenterology in press). CONCLUSIONS: These results indicate that :(1) peripheral CRF inhibits GE through the activation of CRF2 receptor; and (2) peripheral urocortin is more potent than CRF and its action involves CRF2 receptor and/or additional specific urocortin receptors yet to be characterized. G3339 GASTRIC EMPTYING IN CHILDREN WITH EXTREME SHORT GUT SYNDROME. S. Ohwada, T. Ishii, J. Bueno, L. Sigurdsson, *M. Charron, **S. Kocoshis, G. Mazariegos, J. Reyes. Pediatric Transplant Surgery, *Radiology and **Gastroenterology of Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center. We have observed that children with short gut syndrome often show symptoms of delayed gastric emptying and gastroesophageal reflux. The purpose of this study is to evaluate gastric emptying in children with extreme short gut syndrome. Material and Methods: Children (6 female, 8 male) with extreme short gut syndrome referred to the Children's Hospital of Pittsburgh for small bowel transplantation (Tx) evaluation between 1994 and 1997 were examined. The mean length of remaining small bowel was 14.4 ± 12.4 cm. The original disease that led short gut syndrome were: intestinal atresia (n=7), volvulus (n=3), necrotizing enterocolitis (n=3), Hirschsprung's disease (n=I). Children with pseudo-obstruction (n=3) were also studied. The median age of the patients at the time of evaluation was 2.7 years (range 0.5-10 years). After more than 3 hrs NPO, the liquid radionuclide gastric emptying study was