Wood creosote prevented both increase and decrease in proximal colonic motility induced by psychological stress in rats. T1255 TD-5108 Pharmacokinetics and Bowel Function in Health and Constipation M. Louai Manini, Shekman L. Wong, Michael R. Goldberg, Seth R. Sweetser, Sanna McKinzie, Duane D. Burton, Yu-Ping Li, Michael Camilleri Background: TD-5108 is a potent, selective, high intrinsic activity agonist at serotonin 5- HT 4 receptors; it dose-dependently accelerates gastric, small bowel and colonic transit (Neurogastroenterol Motil 20(Suppl. 2):6, 2008). Aim: To assess TD-5108 pharmacokinetics (PK) in patients with chronic constipation (CC), qualified by modified Rome III criteria, and healthy controls, and acute effects on bowel function. Methods: 60 healthy volunteers were randomly assigned, double-blind, to placebo, 5, 15, 30 or 50 mg TD-5108. After a single dose and multiple doses for 6 consecutive days, we measured PK. We also compared PK and bowel function (frequency, time to first BM, form by Bristol stool form scale) after 15 mg TD-5108 in 11 CC patients and 11 healthy controls. Blood samples were collected for up to 48 hours post-dose for assay of TD-5108 and its primary active metabolite, THRX- 830449, which has similar pharmacological properties to that of the parent. All plasma samples were analyzed using a validated liquid chromatography-tandem mass spectrometry method for TD-5108 and THRX-830449. Pharmacokinetic parameters (AUC, C max ,t ½ , etc) for TD-5108 and its metabolite, THRX-830449, were determined by non-compartmental methods. Results: In the dose response study in healthy controls, there were dose-dependent increases in concentrations of TD-5108 and metabolite, and modest accumulation of both following multiple doses, consistent with their terminal t 1/2 values: for TD-5108 (t 1/2 =10- 13 hours; about 2-fold accumulation for AUC and C max ) and THRX-830449 (t 1/2 =20-30 hours; about 2-fold accumulation for C max and 3-fold for AUC). Increases in C max and AUC with dose were greater than proportional to the increase in dose following single and multiple administrations. After administration of 15 mg oral TD-5108 in CC patients and healthy controls, PK parameters for both TD-5108 and THRX-830449 [T max (hr), C max (ng/mL), AUC 0-24 (ng.hr/mL), AUC 0- ∞ (ng.hr/mL) and t 1/2 (hr)] were not significantly different. Bowel function (table) after 15 mg TD-5108 was also similar in CC and controls, although the percentage of complete spontaneous bowel movements was less in patients. Conclusions: TD-5108 PK and acute effects on bowel function are similar in CC and healthy controls. The acute effect on bowel function confirms the significant effects on gastrointestinal and colonic transit previously reported. T1256 Aloe Vera - a Promising Treatment Option for Patients with Irritable Bowel Syndrome (IBS) Stine Störsrud, Irina Midenfjord, Anette Lindh, Gisela Ringstrom, Pia Agerforz, Pernilla Jerlstad, Magnus Simren Introduction: Few effective treatment options exist for patients with irritable bowel syndrome (IBS). Alternative treatment options are often used, but blinded, randomized, controlled studies are lacking. In a subset of IBS patients, oral treatment with aloe vera juice has tended to improve IBS symptoms, and many patients state that they use aloe vera products in order to reduce their symptoms. Aim: The aim of the present study was to investigate the effect of aloe vera in IBS patients in a randomised, double blind, placebo controlled study. Methods: After a two week screening period 68 patients with IBS according to the Rome III criteria (mean age 44 (19-69) years, 51 women) were randomised to receive aloe vera (250mg; effervescent tablet; Aloe Life®) or matching placebo bid for four weeks. IBS Severity Scoring System (IBS-SSS) was completed on a weekly basis and the patients were asked if they had had adequate relief of their IBS symptoms during the preceding week. The patients also underwent examination of the oroanal transit time (OATT) and completed the Hospital Anxiety and Depression (HAD) scale before and after the treatment. Results: The overall severity of IBS symptoms was reduced in the aloe vera group (IBS-SSS total score: 314±83 vs. 257±107; p=0.003) but not in the placebo group (276±88 vs. 253±100; NS) (difference between the groups: p=0.10). The reduction in pain severity was larger in the aloe vera group than in the placebo group (p=0.03), and tendencies in the same direction were seen for other IBS symptoms. A higher proportion of responders (defined as a reduction in IBS- SSS ≥50 points) were seen in the aloe vera group (58%) versus placebo (29%) (p=0.09), and the proportion of subjects who reported adequate relief at least 50% of the weeks during the treatment period tended to be larger in the aloe vera vs. placebo group (32% vs 15%; p=0.12). OATT, depression or anxiety was not affected by the treatment. Aloe vera was well tolerated and no serious adverse events or laboratory abnormalities were observed. All patients except five (four in the placebo group and one in the aloe vera group) completed the study period. Conclusion: Aloe vera seems to be a promising treatment option for patients with IBS. Larger randomised, controlled studies are needed to confirm these results and to elucidate potential mechanisms behind this positive effect. A-533 AGA Abstracts T1257 Pharmacogenetic Predictors of Gastroparesis Treatment with Domperidone Henry P. Parkman, Michael Jacobs, Anurag K. Mishra, Jessica A. Hurdle, John Gaughan, Evgeny Krynetskiy Domperidone, a dopamine-2 receptor antagonist, is a potentially useful alternative to metoclo- pramide for treatment of gastroparesis due to less frequent side effects. Genomic analysis has potential to customize drug therapy by identifying patients likely to respond to treatment while decreasing adverse events. Genetic polymorphisms in genes encoding drug-metaboliz- ing enzymes (CYP1A2, CYP2D6), drug transport (MDR1), and targets of domperidone (DRD2 and myocardial ion channels) may be responsible for the effectiveness and/or side effects of domperidone. The aim of this study is to determine if clinical, demographic, and pharmaco- genetic parameters of patients receiving domperidone are useful in predicting response to treatment or adverse reactions. This will help develop appropriate genotyping assays for rational selection of patients and dose prior to beginning of domperidone therapy. Methods: 47 patients treated with domperidone under an IRB approved FDA investigational new drug application participated. Non-genetic parameters including age, gender, weight, daily dose, and therapeutic outcome (effectiveness and side effects) were recorded. Patients provided salivary samples using the Oragene DNA Self-Collection Kit (DNA Genotek, Ottawa, Ontario). DNA was extracted from salivary specimens, purified, and preserved. We genotyped these patients using 12 single nucleotide polymorphisms (SNPs) in 6 candidate genes (ABCB1, CYP2D6, DRD2, KCNE1, KCNH2, KCNQ1). Statistical analyses were performed for association between genotype and dose, effectiveness, and side effects of domperidone. Results: DNA was successfully obtained from saliva in all 47 patients. Neither sex nor age were significantly associated with daily dose or side effects. Importantly, there was statistically significant association between age and effectiveness of domperidone therapy (p=0.0055). The strongest predictor of the efficacious dose was a polymorphism in MDR1 gene (p=0.033). Genetic polymorphism in KCNH2 was associated with effectiveness of domperidone treatment (p= 0.044). Polymorphism in KCNH2 was weakly associated with the efficacious dose though this did not reach statistical significance (p=0.083). Conclusions: In this study of patients with gastroparesis treated with domperidone, DNA obtained from saliva was successfully used for pharmacogenomic analysis to identify patient characteristics for whom domperidone therapy was beneficial: polymorphisms in the drug transport MDR1 gene and the potassium channel KCNH2 gene. This information will be useful to prospectively assess patients prior to beginning domperidone and to select a dose that will maximize efficacy and minimize toxicity. T1258 Comparative Effectiveness of a Probiotic vs An Antibiotic in the Treatment of Patients with Intestinal Bacterial Overgrowth (SIBO) and Chronic Abdominal Functional Distension Luis O. Soifer, Angel D. Peralta, Guillermo Dima, Horacio R. Besasso INTRODUCTION: Patients with SIBO are usually treated with different antibiotics. Certain probiotics have proved to be clinically effective in patients with abdominal distension. AIM: To compare the short-term clinical effectiveness of metronidazol vs. probiotic in patients with SIBO and functional chronic abdominal distension. SUBJECTS AND METHOD: Randomized prospective pilot study. The study population consisted of 50 patients with chronic abdominal distension (Rome III criteria) and diagnosis of SIBO was made using lactose H2 breath test. Patients were consecutively randomized to receive either metronidazol or probiotic. The metronidazol group consisted of 25 subjects (23 women) aged 49±19 years, who received metronidazol 500 mg bid for 5 days. The probiotic group consisted of 25 subjects (20 women) aged 58±19 years. The probiotic administered to the latter group contained Lactobacillus casei (3.3x10/7U.F.C.), Lactobacillus plantarum (3.3x10/7U.F.C.), Streptococcus faecalis (3.3x10/ 7U.F.C.) and Bifidobacterium Brevis (1.0x10/6U.F.C.)5ml bid for 5 days. Both groups went on the same diet, which consisted in reduced consumption of alcohol, legumes, dairy products and leafy green vegetables. Response to treatment was assessed by an independent questioner 15 days post treatment. A five-level overall response questionnaire was used. Responses included “much better”, “better”, “the same”, “worse”, and “much worse”. Better and much better were considered positive responses. RESULTS: Of the 25 subjects receiving metronidazol, 13 (52%) referred improvement after this treatment. In the probiotic group, 20/25 (82%) subjects reported clinical improvement. Pearson Chi2 test revealed statistically significant differences with the use of the probiotic (p=0.036). All the study patients com- pleted treatment. No adverse events leading to treatment discontinuation were observed. CONCLUSIONS: Based on this pilot study results, we can suggest that the probiotic herein used has a higher effectiveness than metronidazol in the early clinical response of patients with chronic abdominal distension and SIBO. NOTE: This study was undertaken without any support or grant from the pharmaceutical industry. T1259 PAC-QOL Results from 3 Identical Randomized Placebo-Controlled Trials with Prucalopride in Patients with Severe Chronic Constipation Jan F. Tack, Dominique Dubois, Rene Kerstens, Greet Beyens, Lieve Vandeplassche, Jannie Ausma Objective: To determine the effect of prucalopride on health related Quality of Life (QOL) in patients with severe chronic constipation. Methods: In 3 phase III randomized, placebo- controlled trials, disease-related QOL was assessed at baseline, weeks 4 and 12, with the validated Patient Assessment of Constipation-Quality of Life (PAC-QOL) self-report question- naire. PAC-QOL assesses patient's physical discomfort, psychosocial discomfort, worries and concerns, and satisfaction. A 0.5 point change has been recommended as the minimum important difference for the overall PAC-QOL score (Marquis et al. Scand J Gastroenterol, 2005). Results: The proportion of patients with an improvement of ≥1 point in the scores of the overall PAC-QOL scale and the four subscales were statistically significantly higher in the PRU 2 and 4 mg groups than in the placebo group at weeks 4 and 12 (except for the psychosocial discomfort subscale score in the prucalopride 4 mg group at week 12). At AGA Abstracts