Alosetron versus traditional pharmacotherapy in clinical practice: effects on resource use,health-related quality of life,safety and symptom improvement in women with severe diarrhea-predominant irritable bowel syndrome

Objective: Severe diarrhea-predominant irritable bowel syndrome (IBS-D) is associated with decreased health-related quality of life (HRQOL) and increased health care costs. Treatment recommendations for IBS-D often start with traditional pharmacotherapy (TP), with escalation to alosetron, rifaximin or eluxadoline if there is no success. There has been no previous head-to-head clinical trial comparing IBS-D treatment outcome for alosetron versus TP. This study, GSK protocol S3B30020, evaluated resource use, work productivity, health-related quality of life and global symptom response in women with IBS-D who were treated with alosetron or TP.

Methods: A total of 1956 patients who met criteria for severe IBS-D were randomized to treatment with alosetron 1?mg twice daily (BID) or only TP for up to 24 weeks. Work productivity and resource use were evaluated by standard questionnaires, HRQOL by the IBSQOL instrument and IBS symptoms by the Global Improvement Scale (GIS).

Results: Compared to only TP, alosetron-treated patients reported: (1) fewer clinic/office visits for any health problem (p?=?.0181) or for IBS-D (p?=?.0004); (2) reduced use of over-the-counter medications for IBS-D (p < .0001); (3) fewer days of lost work productivity (p < .0001); (4) decreased restriction of social and outdoor activities (p < .0001); and (5) greater global improvement in IBS-D symptoms (p < .0001). Alosetron treatment improved HRQOL scores for all domains (p < .0001). Incidence of adverse events during alosetron use was not remarkable and was similar to that previously reported.

Conclusions: Alosetron 1?mg BID significantly reduced health care utilization and lost productivity, and significantly improved global IBS symptoms, HRQOL, and participation in outdoor and social activities compared with treatment response to TP.     

Radioimmunoassay of motilin

A radioimmunoassay method of motilin was developed in our laboratory and was validated in dogs with a platinum monopolar electrode in the duodenum. We confirmed that a bolus infusion of 0.3 M tris-buffer solution or 0.1 N HCl solution in the duodenum produces a significant rise in plasma immunoreactive motilin (IRM) concentrations. This coincided with a marked increase in the percentage of spike potentials on slow waves of the duodenum, similar to phase III of interdigestive myoelectric-activity (MA). A possible relationship between plasma IRM and interdigestive MA of canine duodenum was studied. It was found that cyclic changes occurred in the fasting plasma IRM concentrations in dogs. While the peak motilin concentration was always observed in phase III, the lowest concentration of motilin was found in phase I of interdigestive MA in the duodenum. In dogs with the electrodes in the duodenum and jejunum, the peak IRM concentration did not correlate with phase III of interdigestive MA in the jejunum. A dose of synthetic porcine motilin, 0.06 g/kg/hr, which produced the plasma IRM concentration comparable to the peak fasting motilin concentration, could induce an identical phase III in the duodenum. These observations indicate that there is a relationship between cyclic changes in plasma IRM concentrations and interdigestive MA of the duodenum. It is suggested further that motilin is a hormone which may play an important role in inducing phase III of interdigestive MA in the duodenum.This work was supported by the Gastrointestinal Research Fund at The Genesee Hospital.     

Tegaserod does not alter fasting or meal-induced biliary tract motility

OBJECTIVE: Tegaserod is a 5-HT(4) receptor partial agonist that increases peristaltic activity of the intestinal tract. It is approved for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). IBS is a chronic gastrointestinal disorder of function that is reported to be associated with an increased incidence of abdominal surgery including cholecystectomy. The effect of tegaserod on nongut digestive organs, such as the gallbladder and biliary tract, has not been previously investigated. Therefore, this study aimed to evaluate the effects of tegaserod on gallbladder contractility and on functional status of the sphincter of Oddi during both the interdigestive and the digestive periods in healthy female subjects and in female patients with IBS-C. METHODS: During a 6-wk, double-blind, placebo-controlled crossover study, gallbladder contractility and concomitant change in luminal diameter of the common hepatic duct (CHD) and the common bile duct (CBD, both proximal and distal) in response to a standard liquid meal were quantified using real-time ultrasonography. Changes in luminal diameter of the CHD and the CBD were used as a surrogate marker for sphincter of Oddi function. Ultrasound measurements were conducted every 15 min from 45 min before, to 60 min after the test meal to observe the impact of tegaserod on gallbladder volume and any concomitant change in the diameters of the CHD and the CBD that developed in response to gallbladder contraction. The ultrasound measurements of gallbladder contractility, along with the CHD and the CBD diameters, were repeated after each of the two 2-wk periods of treatment with tegaserod or placebo. The recommended dose of tegaserod (6 mg b.i.d.) for IBS-C patients was used in healthy female subjects (n = 13) and female patients with IBS-C (n = 20). Twice this dose (12 mg b.i.d.) was also evaluated in an additional 20 female patients with IBS-C. Statistical evaluations were conducted using a two-sided analysis of variance (ANOVA). RESULTS: Gallbladder contractility variables including ejection fraction, ejection rate and ejection period, fasting and residual volume, and maximal emptying, were similar after 2 wk of treatment with tegaserod 6 mg b.i.d. and placebo in healthy female subjects and female patients with IBS-C. There were no significant changes in the luminal diameters of the CHD or the CBD after tegaserod compared to placebo in any cohort. Additionally, no significant dilation (> or =7 mm in diameter) of the CHD or CBD was observed during maximal gallbladder emptying. Similar results were also observed when tegaserod was given at 12 mg b.i.d. in patients with IBS-C. Tegaserod treatment had no significant effect on plasma CCK concentration in response to the test meal. No significant abdominal pain or unexpected adverse events were reported during the study. CONCLUSIONS: This study showed no significant pharmacodynamic effect of tegaserod on gallbladder contractility or on CBD and CHD diameters as a surrogate marker of sphincter of Oddi function during both the interdigestive (fasting) and the digestive (postprandial) periods in healthy female subjects and female patients with IBS-C.     

Routine droperidol pre-medication improves sedation for ERCP

BACKGROUND: Pre-medication with droperidol has been used to improve sedation during endoscopy, especially in patients with a history of alcohol or narcotic abuse. We studied whether routine use of droperidol pre-endoscopic retrograde cholangiopancreatography (ERCP) could improve patient and physician satisfaction with sedation. METHODS: Sixty-seven patients undergoing routine ERCP were enrolled in this double-blind placebo-controlled study. Patients were given either parenteral normal saline solution or 5 mg of droperidol 15 minutes before the procedure. After the ERCP, several parameters of procedural sedation were scored on an ordinal scale by the endoscopist, the endoscopy nurse, and the recovered patient. In addition, a follow-up telephone call was made to the patient after 24 hours. RESULTS: The mean procedural room time was similar in the two groups. Nearly 25% less meperidine and diazepam was used in the droperidol-treated patients, making the overall medication cost similar in both groups. The mean recovery room time was 113 minutes for the placebo group and 106 minutes for the droperidol group. Droperidol premedication significantly decreased post-procedure nausea and vomiting, reduced gagging at intubation, and decreased retching during the procedure. Droperidol also improved physician (p = 0.001), nurse (p = 0.001), and patient (p = 0.0001) impressions of overall sedation and decreased the need for physical restraint during the procedure. Droperidol significantly increased the number of patients with no memory of the procedure. CONCLUSION: Droperidol improved overall patient, physician, and nurse satisfaction with sedation during ERCP. It also reduced post-ERCP nausea and vomiting without increasing recovery time or medication cost. Droperidol is recommended for routine pre-ERCP sedation. (Gastrointest Endosc 2000;52:362-6).     

Gastric emptying characteristics of a novel (13)C-octanoate-labeled muffin meal

GOALS: Determine the gastric emptying characteristics of a novel, 350-kcal test meal consisting of two muffins, using scintigraphy and the 13C-octanoate breath test (OBT). STUDY: Healthy volunteers underwent three studies on separate days within a 1-week period. On day 1, we measured emptying of the 350-kcal muffin test meal labeled simultaneously with 99mTc sulfur colloid and 13C-octanoate. On day 2, reproducibility of the OBT using a single-labeled 350-kcal test meal was assessed. On day 3, the effect of erythromycin on the 350-kcal OBT was determined. RESULTS: The mean (+/-SD) half-emptying time (T1/2) as measured by scintigraphy was 104 +/- 24 minutes, versus 212 +/- 52 minutes by OBT. There was a strong correlation between T1/2 determined by scintigraphy and the breath test (r = 0.83). Multiple linear regression analysis identified a significant relationship between T1/2 determined by scintigraphy and the 90-and 180-minute breath samples. There was a strong correlation (r = 0.830, slope = 0.732 +/- 0.120 [SE], intercept = 26.4 +/- 12.7) between the T1/2 obtained using the regression equation and the actual T1/2 obtained by scintigraphy. The mean T1/2 (+/-SD) for replicate determinations using the OBT was 209 +/- 52 minutes, compared with 196 +/- 42 minutes on days 1 and 2, respectively (not significant, p = 0.28, paired Student t test). Treatment with erythromycin on day 3 produced a significant decrease in T1/2 (155 +/- 49 minutes, p = 0.002). CONCLUSIONS: The 350-kcal muffin meal OBT provides a convenient, nonscintigraphic way of measuring solid-phase gastric emptying. Multiple linear regression appears promising as a method of analyzing OBT data and may allow for an abbreviated breath test protocol.     

Functional characterization of five constitutively activating thyrotrophin receptor mutations

OBJECTIVE: Gain of function mutations of the thyrotrophin receptor (TSHR) affect several functional characteristics, such as cAMP and inositol phosphate (IP) accumulation, cell surface expression and TSH affinity. In this study we compared five constitutively activating TSHR mutations, four receptors with a point mutation (S505N, L629F, I630L, V656F) and a nine amino acid (aa) deletion mutant (aa positions 613-621) for these functional parameters in parallel transfection experiments. METHODS: The wild-type TSHR (wt) and TSHRs containing the mutations S505N, L629F, I630L, V656F and the deletion 613-621 (all cloned in the expression vector pSVL) were transiently expressed in COS-7 cells in parallel experiments. Forty-eight hours after transfection the basal and stimulated cAMP and inositol phosphate accumulation as well as the cell surface expression (by FACS and ELISA), KD-values and TSHR down regulation by different stimuli were determined. RESULTS: In contrast to the very different values for specific constitutive activity (sca) (ranging from 7.5 to 100.3-fold wt) and very different levels of receptor cell surface expression (11-94% wt level) the basal cAMP accumulation determined in transfected COS-7 cells was surprisingly uniform (6.5-8.0 over wt basal). None of the point mutated receptors constitutively activates the phospholipase C cascade. In contrast the deletion 613-621 mutant showed constitutive activity for the IP pathway with a twofold increase in basal IP accumulation compared to the wild type TSHR. All investigated TSHR-mutants showed a TSH-stimulated receptor down-regulation, which seems to be independent of the phospholipase C pathway. CONCLUSIONS: The uniform basal cAMP values in spite of the large variation in specific constitutive activity values suggest that the COS-7 cell overexpression system used for the in vitro characterization is partly regulated. This regulation is most likely due to receptor down regulation. The TSHR deletion mutant (613-621) showed a constitutive activity for both the Galphas and the Galphaq/11 pathways. The TSH-mediated IP-stimulation by this mutant contrasts with its unresponsiveness to TSH for cAMP accumulation and therefore supports the model of different active conformations of the TSHR.     

Hyperglycemia alters perception of rectal distention and blunts the rectoanal inhibitory reflex in healthy volunteers

Acute hyperglycemia has been shown to alter gastrointestinal motility. The effects of hyperglycemia on rectal afferent neural and anal sphincter function were studied. Perception of rectal balloon distention, pressure-volume relationships, volumes necessary to induce reflex internal anal sphincter relaxation, resting anal sphincter pressure, and maximal anal sphincter squeeze pressure were measured under basal, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions in 9 healthy volunteers. Hyperglycemic clamping (258 ± 14 mg/dL) significantly blunted threshold perception and the urge to defecate in response to rectal distention without altering perception of maximally tolerated distention. In contrast, euglycemic, hyperinsulinemic clamping had no effect on perception of rectal distention. Rectal pressure-volume relationships after hyperglycemic clamping were unchanged compared with basal conditions. Hyperglycemic clamping caused a significant increase in the distention necessary to induce the rectoanal inhibitory reflex. This effect was not observed under euglycemic, hyperinsulinemic clamp conditions. Hyperglycemia did not significantly affect resting internal anal sphincter pressure or maximal external anal sphincter squeeze pressure. Acute hyperglycemia but not secondary hyperinsulinemia reduces sensation of rectal distention and blunts the onset of the rectoanal inhibitory reflex, suggesting effects both on visceral afferents projecting to the cortex and intrinsic afferents mediating local reflex activity.