Ronald Fogel

Eluxadoline Benefits Patients With Irritable Bowel Syndrome With Diarrhea in a Phase 2 Study

BACKGROUND & AIMS Simultaneous agonism of the μ-opioid receptor and antagonism of the δ-opioid receptor can reduce abdominal pain and diarrhea in patients with irritable bowel syndrome with diarrhea (IBS-D) without constipating side effects. We evaluated the efficacy and safety of a minimally absorbed, μ-opioid receptor agonist and δ-opioid receptor antagonist (eluxadoline) in a phase 2 study in patients with IBS-D. METHODS We randomly assigned 807 patients to groups that received oral placebo twice daily or 5, 25, 100, or 200 mg oral eluxadoline for 12 weeks. The primary end point was clinical response at week 4, defined by a mean reduction in daily pain score from baseline of ≥ 30%, and of at least 2 points on 0-10 scale, as well as a stool consistency score of 3 or 4 on the Bristol Stool Scale (1-7) for at least 66% of daily diary entries during that week. RESULTS Significantly more patients receiving 25 mg (12.0%) or 200 mg (13.8%) eluxadoline met the primary end point of clinical response than patients given placebo (5.7%; P < .05). Patients receiving eluxadoline at 100 mg and 200 mg also had greater improvements in bowel movement frequency and urgency, global symptoms, quality of life, and adequate relief assessments (P < .05). Additionally, patients receiving 100 mg (28.0%) or 200 mg (28.5%) eluxadoline were significantly more likely than those receiving placebo (13.8%; P < .005) to meet the US Food and Drug Administration response end point during the full 12 weeks of the study. Eluxadoline was well tolerated with a low incidence of constipation. CONCLUSIONS In a phase 2 study of the mixed μ-opioid receptor agonist/δ-opioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D.

Multicenter trial of octreotide in patients with refractory acquired immunodeficiency syndrome-associated diarrhea

BACKGROUND/AIMS Diarrhea is a significant problem in patients with acquired immunodeficiency syndrome (AIDS). The aim of this study was to determine octreotide effectiveness in refractory AIDS-associated diarrhea. METHODS In a 3-week protocol, 129 patients with a stool weight of > 500 g/day despite standard antidiarrheal therapy were randomized to receive octreotide or placebo (3:2 ratio). Octreotide dose was increased 100 micrograms weekly to a maximum of 300 micrograms three times a day based on weekly 72-hour stool collections. Subsequently, patients received open-label octreotide at doses of up to 500 micrograms three times a day. RESULTS A 30% decrease in stool weight defined response. After 3 weeks, 48% of octreotide- and 39% of placebo-treated patients had responded (P = 0.43). At 300 micrograms three times a day, 50% of octreotide- and 30.1% of placebo-treated patients responded (P = 0.12). At a baseline stool weight of 1000-2000 g/day, 57% of octreotide- and 25% of placebo-treated patients responded (P = 0.06). Response rates based on CD4 counts, diarrhea duration, body weight, human immunodeficiency virus risk factor, and presence or absence of pathogens showed no benefit of octreotide. Adverse events were more frequent in the octreotide-treated group. CONCLUSION In the doses studied, octreotide was not more effective than placebo in patients with refractory AIDS-associated diarrhea. This lack of effectiveness may be attributable to inadequate sample size, doses, and duration of study treatment.

Neurons in the vagal complex of the rat respond to mechanical and chemical stimulation of the GI tract

Perfusing the duodenum with acid solutions dramatically reduces gastric motility and acid secretion. We propose that the presence of acid in the proximal small intestine initiates a vagovagal reflex that excites inhibitory neurons in the nucleus of the solitary tract (NST) and reduces the activity of the neurons in the dorsal motor nucleus of the vagus nerve (DMNV). However, results from several investigations suggest that the relevant circuit may not be as simple as we had believed. The present study was designed to address this dilemma by employing intracellular and extracellular recording and intracellular labeling techniques to provide direct information on the activity of neurons in the NST and DMNV during and after intestinal exposure to acid solutions. The results obtained prove that NST and DMNV neurons respond to HCl in the duodenum. In some instances, these neurons were very stimulus specific, although the majority of the cells in our sample (47% of NST neurons and 86% of DMNV neurons) also responded to distension of the stomach and/or duodenum. It is important to note, however, that many of the more broadly responsive neurons in the dorsal vagal complex were able to distinguish between mechanical and chemical stimulation of the gastrointestinal (GI) tract. Most of the NST neurons that responded to duodenal perfusion with HCl were excited by this stimulus. Conversely, activity of most of the DMNV neurons decreased after the onset of the HCl stimulus. These findings verify the existence of a vagovagal reflex pathway initiated by duodenal perfusion with acid. Presumably, this reflex would decrease gastric motility and acid secretion, reducing the amount of acid that enters the duodenum and ultimately protecting the intestinal mucosa.

Myenteric plexus destruction alters morphology of rat intestine

BACKGROUND It has been shown previously that myenteric plexus destruction by benzalkonium chloride (BAC) increased villus height, crypt depth, and muscle thickness, suggesting that these neurons influence intestinal morphology. A nonspecific trophic effect of BAC, intraluminal stasis, and inflammation resulting from the chemical treatment could also be causes for these changes. Our goals were to (1) show that the morphological sequelae of BAC treatment are caused by myenteric plexus removal and not the factors listed above, and (2) determine whether segmental myenteric plexus removal alters morphology elsewhere in the small intestine. METHODS Six groups of rats were studied: control, chemical denervation (3 mmol/L BAC), surgical denervation, intraluminal stasis produced by partial obstruction, chemical inflammation (5% acetic acid), and surgical inflammation (serosa removal only). Tissue for histological study was taken from the treated segment, 15-20 cm proximal to the treated segment, and 5-10 cm distal to the treated segment 28 days after treatment. RESULTS Chemical and surgical denervation reduced the number of myenteric neurons by 94% and 98%, respectively. Denervation had a direct effect on morphology; it increased villus height, crypt depth, and muscle thickness in the treated and proximal segments, but only muscle thickness was increased in the distal segment. The other treatments had minimal morphological sequelae. CONCLUSIONS Segmental myenteric plexus removal alters the mucosa in the treated and proximal segments but influences muscle thickness throughout the intestine.

The Economic Impact of Irritable Bowel Syndrome in a Managed Care Setting

Goals To compare the healthcare resource consumption of patients who have irritable bowel syndrome (IBS) with an age-, gender-, and comorbidity-matched cohort of patients without IBS from a managed care perspective. Study Retrospective cohort analysis. Data were obtained electronically through the Henry Ford Health System corporate data warehouse. Patients with IBS were eligible if they had at least one primary diagnosis of irritable colon (ICD-9-CM 564.1). The control cohort was identified from an age, gender, and comorbidity population-matched (5:1) sample. The index date for the IBS and control cohorts was defined as the first initial diagnosis and first clinical encounter in 1998, respectively. The charges per patient by resource use type were collected for the 12 months before and after the index date. Results A total of 501 patients with IBS and 2505 controls fulfilled the inclusion and exclusion criteria (70% female, 58% between 40 and 65 years). The IBS cohort, before the IBS diagnosis, had significantly higher total charges (p < 0.001), drug charges (p < 0.001), and outpatient charges (p < 0.001) than the control cohort. During the postindex (postdiagnosis period), the patients with IBS had higher total charges (p < 0.006), outpatient charges (p < 0.022), and drug charges (p < 0.001) than the control population. The control cohort had higher procedure charges (p < 0.001) during both periods. Conclusions Patients with an IBS diagnosis represent a substantial cost to managed care before and after the diagnosis of IBS. Costs associated with these patients result mainly from non-IBS conditions. Further research is warranted to identify these patients earlier, and to prevent the economic burden associated with them.

Managing patients with acute, nonvariceal gastrointestinal hemorrhage: development and effectiveness of a clinical care pathway

OBJECTIVES:To develop a clinical care pathway for the management of patients with acute upper or lower nonvariceal GI hemorrhage (GIH) who do not require immediate surgical intervention. To test the effectiveness and safety of the pathway in improving the efficiency of care for patients with acute GIH.METHODS:A multidisciplinary team developed the evidence-based GIH clinical care pathway by consensus techniques. In a quasiexperimental design, pathway outcomes were measured prospectively during the first 8 months of pathway implementation, and compared to similar time periods in the 2 prior yr. Effectiveness measures were the number of patients <65 yr of age admitted for GIH and the hospital length of stay for all patients. Thirty-day safety outcomes were the rates of recurrent GIH, mortality, and readmission to hospital for any reason.RESULTS:Of 368 patients studied after pathway implementation, 81 (22%) were managed as outpatients. The number of admissions for pathway patients <65 yr of age was significantly lower compared to 691 prepathway patients (p < 0.002). Mean length of stay (±95% CI) for pathway inpatients was 3.5 (3.1, 3.9) days, compared to 5.3 (4.9, 5.7) and 4.6 (4.2, 5) days in the 2 prepathway yr, respectively (p < 0.001). Multivariable regression controlling for admission vital signs, comorbid conditions, age, and the etiology of GIH confirmed that admission after pathway implementation was an independent predictor of a reduced length of hospital stay. There were no significant between-year differences in the 30-day rates of recurrent GIH, mortality, or hospital readmission.CONCLUSION:A multidisciplinary clinical care pathway may improve the efficiency of caring for patients with acute upper or lower nonvariceal GIH. Decreasing the number of admissions for GIH and reducing the hospital length of stay can be achieved without increasing the number of adverse outcomes.

Stress Ulcer Prophylaxis in Medical ICU Patients: Annual Utilization in Relation to the Incidence of Endoscopically Proven Stress Ulceration

OBJECTIVE: To measure changes in the proportion of medical intensive care unit (MICU) patients prescribed pharmacologic stress ulcer prophylaxis therapy over a 4-year period in relation to the incidence of stress-related ulceration detected by endoscopy at our institution. DESIGN: Retrospective 4-year review of pharmacy and endoscopy databases. SETTING: A 35-bed MICU. PATIENTS: Patients (n = 2941) admitted to the MICU for longer than 24 hours, between January 1, 1993, and December 31, 1996, without acute gastrointestinal hemorrhage on admission. METHODS: Records were reviewed to identify patients prescribed pharmacologic stress ulcer prophylaxis (>24 h of sucralfate or a histamine2-receptor antagonist [H2RA]), and patients with evidence of stress ulceration during endoscopy. RESULTS: The number of patients per year receiving stress ulcer prophylaxis significantly (p < 0.001) decreased between 1993 and 1996: 1993, 492/693 (71%); 1994, 478/798 (60%); 1995, 295/670 (44%); 1996, 164/780 (21%). There was no difference between years in the median duration of stress ulcer prophylaxis therapy or the proportion of patients receiving sucralfate versus H2RA therapy. There was no difference (p = 0.91) between years in the annual incidence of definite or possible stress-related ulceration: 1993, 6/693 (0.87%); 1994, 5/798 (0.63%); 1995, 6/670 (0.90%); 1996, 5/780 (0.64%). CONCLUSIONS: The incidence of endoscopically proven stress-related ulceration has remained unchanged over the past 4 years in our MICU despite significantly fewer patients receiving pharmacologic stress ulcer prophylaxis therapy.

Vagal innervation of the rat duodenum

Electrophysiologic and anterograde tract tracing studies have demonstrated that the vagus nerve innervates the duodenum. These studies, however, have provided little information regarding the finer anatomic topography within the vagal complex. In this study, the retrograde neuronal tracers WGA-HRP or DiI, applied to the duodenum, were used to characterize the vagal afferent and efferent innervation of this portion of the gastrointestinal tract. This approach labeled a substantial number of motor neurons in both the medial and lateral columns of the dorsal motor nucleus of the vagus (DMNV). Vagal motor neurons innervating the duodenum were seen across the medial-lateral extent of the DMNV and between 600 microm rostral to obex and 1600 microm caudal to obex. The three branches of the vagus nerve contained efferent fibers to the duodenum. The gastric branch of the vagus nerve was the pathway that connected the majority of DMNV neurons with the duodenum. These neurons were located in the medial and middle thirds of the DMNV. The celiac branch to the duodenum was composed of axons from the majority of lateral column neurons but also contained axons from neurons in the medial column. The hepatic branch of the vagus nerve contained only a small number of cell axons. Some neurons were located medially whereas others were in the lateral third of the duodenum. Although central terminations of vagal primary afferents from the duodenum were not found in previous tract tracing studies, we observed a large number of terminals in the subpostremal/commissural region of the nucleus of the solitary tract. Similar to the motor fibers, most afferent fibers from the duodenum were located in the gastric branch of the vagus nerve, although the hepatic and celiac branches also contained afferent neurons. These results demonstrate that the vagal innervation of the duodenum is unique, being an amalgam of what would be expected following labeling of more proximal and distal portions of the GI tract. The uniqueness of the sensory and motor innervation to the duodenum has implications for hypotheses regarding the organization of vagovagal reflexes controlling gastrointestinal function.

Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis

Matrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.

Responsiveness of Endoscopic Indices of Disease Activity for Crohn’s Disease

Objectives:The Crohn’s Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn’s Disease (SES-CD) are commonly used to assess Crohn’s disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy.Methods:Paired video recordings (N=112) of colonoscopies (baseline and week 8–12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn’s disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt’s Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed.Results:Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates.Conclusions:Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.