Ambulatory assessment of colonic motility using the electromagnetic capsule tracking system: Effect of opioids.

BACKGROUND: Opioid treatment often causes debilitating constipation. However, it is not well described how opioids affect colonic motility and whether opioid-induced constipation is due to either a decrease of powerful peristaltic contractions or "uncoordinated" peristalsis. The present study aims to investigate the effect of oxycodone on parameters of colonic motility and to determine whether motility is normalized by the opioid antagonist naloxegol. METHODS: In two randomized, double-blind crossover trials, oxycodone or placebo was administered to 25 healthy males (Trial A), while another 24 healthy males were administered oxycodone with naloxegol or placebo (Trial B). Colonic motility was assessed by tracking the progression of an electromagnetic capsule throughout the large intestine. Segmental colonic transit times and capsule movements were calculated using displacement distance and velocity. KEY RESULTS: In Trial A, colonic transit time increased during oxycodone treatment compared with placebo (39 vs 18 hours, P < .01). Displacement during long fast antegrade movements was shorter during oxycodone treatment than with placebo (10 vs 20 cm, P = .03). In Trial B, colonic transit time was faster during oxycodone + naloxegol than during oxycodone + placebo (40 vs 55 hours, P = .049), mainly caused by an increase of the percentwise fraction of distance covered by fast movements in the left colon (P = .001). CONCLUSION & INFERENCES: Oxycodone treatment impaired colonic motility, manifested as increased transit time, specifically decreased long fast antegrade movements, and addition of naloxegol improved motility dynamics. In humans, the increased transit time during opioid treatment is caused by a decrease in long fast movements rather than uncoordinated peristalsis.

Assessment of the antidiarrhoeal properties of the aqueous extract and its soluble fractions of Chebulae Fructus (Terminalia chebula fruits).

Context Chebulae Fructus is used as an herbal remedy for diarrhoea in traditional Chinese medicine. However, there is no scientific evidence to support its antidiarrhoeal activity. Objective This study evaluates the antidiarrhoeal properties of Chebulae Fructus aqueous extract (CFAE) and determines the active fraction. Materials and methods The antidiarrhoeal effect of CFAE (200-800 mg/kg) was investigated by determining the wet dropping, intestinal transit in BALB/c mice and enteropooling in Wister rats. The protective effects of the CFAE on the intestinal and liver were tested by histopathological analyses. The antidiarrhoeal fraction was determined by castor oil-induced diarrhoea and its main constituents were identified by HPLC-ESI-MS. Results The extract at doses of 200, 400 and 800 mg/kg reduced the diarrhoea by 9.1, 40.0 and 58.2% and inhibited intestinal transit by 18.3, 24.1 and 35.7%, respectively. Additionally, the CFAE (200, 400 and 800 mg/kg) decreased the volume of enteropooling by 47.1, 58.8 and 64.7%, respectively. Mice treated with castor oil presented morphological alterations in the small intestine and the liver. However, the lesions of mice treated with CFAE were alleviated. Moreover, the ethyl acetate fraction was the active fraction of CFAE, the fraction (41.7, 83.4 and 166.8 mg/kg) reduced the diarrhoea by 9.1, 38.2 and 54.5%, respectively. The major components of the ethyl acetate fraction were tannins, including gallic acid, 3, 4, 6-tri-O-galloyl-ß-d-Glc, corilagin and ellagic acid according to the HPLC-ESI-MS analysis. Conclusion The CFAE possessed antidiarrhoeal property and the ethyl acetate fraction was its main active fraction.

An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability.

INTRODUCTION: Gastrointestinal adverse effects contribute significantly to drug attrition as well as reduced patient compliance. Determination of gastrointestinal liability early in a compound's preclinical development would be a valuable tool. We evaluated the non-invasive faecal pellet method in the rat, assessed the feasibility of adding the endpoint to other study types and investigated correlation with the charcoal meal method. METHODS: Han Wistar rats, pair housed in metabolism cages, received a single dose of vehicle, atropine, bethanechol, loperamide or metoclopramide. The number, weight and appearance of pellets produced were assessed over 10 h and at 24 h post-dose. The endpoint was also added to a modified Irwin screen (testing atropine, theophylline, clonidine, amphetamine, baclofen or quinine) and a whole body plethysmography study (testing theophylline or bethanechol). Pellets were collected from home cages out to 4 h post-dose (Irwin) or following a 45 minutes plethysmography session. To assess correlation with stomach emptying and intestinal transit charcoal meal data was generated where published data was not available. RESULTS: Atropine decreased, while bethanechol and metoclopramide increased the number and weight of faecal pellets produced. Atropine produced darker, harder pellets and bethanechol lighter, softer pellets. Loperamide reduced pellet production at later time points only. Theophylline increased (Irwin and plethysmography) and atropine (Irwin) decreased pellet number and weight. Effects were maximal at the T(max) and detected in all study environments. Primary data generation was not affected by pellet collection. Pellet findings were generally comparable to charcoal meal transit data, with compounds showing an inhibition (atropine, loperamide, amphetamine, baclofen, clonidine, quinine) or stimulation (bethanechol) in both models. DISCUSSION: We have demonstrated that the faecal pellet method can detect expected reference compound induced changes in pellet transit. The technique is a useful non-invasive 'add-on' to other study types allowing gastrointestinal effects to be flagged earlier in preclinical development.

Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT4 receptors.

OBJECTIVES: The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)(4) receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold. METHODS: Three compounds were tested for affinity at the 5-HT(4) receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test. KEY FINDINGS: The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT(4) receptor and was a full agonist at relaxing human colon circular muscle with efficacy closest to 5-HT. Compounds 1 and 2 were partial agonists in this assay with lower efficacies; compound 2 was a full agonist in the guinea-pig ileum assay whereas compound 3 was a partial agonist. Compounds 1 and 2 also showed activity in the mouse gut transit assay while compound 3 had no activity. CONCLUSIONS: Of the compounds tested, compound 3 was the most promising 5-HT(4) receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity.

Assessment of gastrointestinal propulsive activity using three different models of peristalsis in vivo in the mouse.

The protocols described in this unit are designed to assess the acute effects of drugs on the propulsive activity of the gastrointestinal muscles in the conscious mouse. These protocols are currently applied to investigate the pharmacological activity of novel compounds undergoing preclinical development and to obtain predictive data needed to advance drugs into clinical trials. Moreover, these methods could be useful in evaluating the functional toxicity by environmental or alimentary pollutants, like xenobiotics and naturally occurring toxins endowed with noxious activity in the control of physiologic peristalsis. The three models detailed-the measurement of gastric emptying, ileal transit, and colonic propulsion-are substantially non-invasive and do not require analgesic pretreatments or the induction of general anesthesia. In contrast to an in vitro approach, these in vivo studies provide a unified understanding of drug effects on gut functionality, in particular when the central nervous system, the extrinsic nerves, or the (neuro)endocrine system is targeted by the test drugs.

Prucalopride.

Prucalopride, a first-in-class dihydrobenzofuran-carboxamide derivative, is a potent, selective and specific serotonin 5-HT(4) receptor agonist with enterokinetic properties. Over a 12-week treatment period, prucalopride 2 and 4 mg once daily significantly improved bowel habit assessments (based on patient diary data) relative to placebo in three large, randomized, double-blind, multicentre trials in patients (aged 17-95 years) with severe chronic constipation, the majority of whom were women who experienced inadequate relief with previous therapies. There was no additional benefit with the 4 mg/day over the 2 mg/day dosage of prucalopride. Patient assessments of constipation symptoms and severity, treatment efficacy, satisfaction with bowel habit and treatment, and health-related quality of life were also significantly improved with prucalopride compared with placebo. The improvement in patient satisfaction with bowel habit and treatment was maintained for up to 24 months in open-label, multicentre, long-term follow-up studies. Prucalopride therapy was generally well tolerated; most adverse events in the 12-week studies were transient and of mild to moderate severity. In terms of cardiovascular tolerability, the incidence of QT interval prolongation with prucalopride at dosages of 2 and 4 mg/day was low and similar to that with placebo. Moreover, prucalopride at dosages up to 20 mg/day (10-fold higher than the recommended therapeutic dosage) had no clinically relevant effects on cardiovascular parameters in healthy volunteers.

Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release, and pharmacokinetics.

Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MMM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MMM studies.

Oral colon targeted delivery systems for treatment of inflammatory bowel diseases: synthesis, in vitro and in vivo assessment.

The aim of this study was to investigate the potential of prodrugs of some non-steroidal anti-inflammatory drugs (NSAIDs) as colon targeted delivery systems for treatment of inflammatory bowel diseases. Naproxen, sulindac and flurbiprofen (Fbp) were used. The carboxylic group of those drugs was conjugated onto the amino group of l-aspartic acid or the hydroxyl group of alpha- or beta-cyclodextrin (CyD). Prodrugs hydrolysis in buffers of pH range 1.2-7.2 and in rat gastrointestinal tract homogenates and the effect of oral pretreatment of rats with clindamycin on the hydrolysis of the prodrugs was examined. Additionally, the effect of oral administration of Fbp-beta-CyD prodrug on the experimentally induced colitis in rats was evaluated. The in vivo inflammatory response was assessed macroscopically, histologically and by measurement of reduced glutathione (GSH) levels in colon tissues. No significant hydrolysis of the proposed seven prodrugs in buffers having pH range of 1.2-7.2 was observed over 72h. Negligible % of drug released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs was detected in rat stomach contents, intestinal tissues and intestinal contents homogenates. On the other hand, Fbp-alpha-CyD and Fbp-beta-CyD prodrugs released about 60% Fbp within 4h in rat colon homogenate. Oral pretreatment of rats with clindamycin significantly reduced % Fbp released from Fbp-alpha-CyD or Fbp-beta-CyD prodrugs. Oral administration of Fbp-beta-CyD to rats after induction of colitis significantly attenuated the severity of the colonic injury and reduced the score of the macroscopic and microscopic damage. Additionally, there was a significant increase in the level of GSH. The present study provided an evidence that Fbp-beta-CyD prodrug may be beneficial in treatment of inflammatory bowel disease.

Evaluating and managing constipation in the elderly.

Constipation is common in the elderly because of age-related physiologic changes and polypharmacy. Secondary constipation is treated by correcting underlying pathology or reducing predisposing factors. Primary constipation is amenable to dietary adjustments, education and behavioral training, and laxatives when necessary.

Assessment of orocaecal transit time in different localization of Crohn's disease and its possible influence on clinical response to therapy.

BACKGROUND: A study on orocaecal transit time (OCTT) in patients with different localizations of Crohn's disease (CD) is not available. Because slow-release drug formulations are increasingly available for the treatment, there is a concrete risk that delayed OCTT may impair the efficacy of these formulations. AIMS: We investigated OCTT before and after therapy using lactulose H2-breath test and we studied whether OCTT can influence the clinical response to therapy with slow-release mesalazine formulations in adult CD patients.(2) PATIENTS AND METHODS: We studied 45 adult patients with non-obstructive CD and Crohn's Disease Activity Index (CDAI) <200 (29 men, 16 women; mean age 42 years, range 22-73 years). Twenty patients had ileocolonic, 16 colonic and 9 ileal localization of CD. The control group consisted of 20 healthy subjects (13 men, seven women; mean age 53 years, range 22-71 years). After OCTT assessment, 29 patients were treated with time-dependent mesalazine 3.6 g/day, while 16 patients were treated with pH-dependent mesalazine 3.6 g/day. If bacterial overgrowth was detected, the patients were also treated with rifaximin 800 mg/day for 7 days. RESULTS: OCTT was delayed (120 min, range 115-210 min) in 30 of the 45 CD patients (67%). Four patients (9%) showed bacterial overgrowth, while OCTT was regular (82.5 min, range 75-90 min) in 11 patients (24%). In the control group, the mean OCTT was 88.2 min (range 75-135 min); (P<0.01). OCTT was more prolonged in ileal localization (182.2 min, range 150-210 min), rather than in patients with ileocolonic (122 min, range 75-180 min) or colonic (106 min, range 75-150 min) localization of CD; (P<0.01). Thirty-nine patients showed normal OCTT after starting therapy (83 min, range 75-105 min), while OCTT remained slightly delayed in the remaining patients (110 min, range 105-115 min); (P<0.01). CDAI was <100 (mean value 83) in all patients with reduction of OCTT to normal value 4 months after starting therapy, while it was >140 (mean value 143) in patients with a slight reduction but not normalization of OCTT respectively (five patients with ileal and one with ileocolonic localization of CD) with a statistically significant correlation between OCTT and CDAI (P<0.01). CONCLUSIONS: This study shows clearly for the first time that OCTT is not only delayed in patients with active CD, but also that it is prolonged in ileal and ileocolonic rather than colonic localization of CD. Moreover we obtained these results using a simple, sensitive, non-invasive and repeatable method, namely, a lactulose hydrogen breath test.

Possible therapeutic use of loperamide for symptoms of lactose intolerance.

OBJECTIVES: To examine a potential practical therapeutic use of loperamide (Lo) to decrease the symptoms of lactose intolerance. SUBJECTS AND METHODS: Nineteen (eight men, 11 women) healthy lactose maldigesters (18 of 19 with symptoms) underwent a 25 g lactose challenge on five separate days. Breath hydrogen was measured, areas under the curve (AUC) were calculated for 4 h, and 4 and 12 h symptom scores were recorded. After establishing baseline measurements, test doses of 4 mg, 8 mg and 12 mg Lo were randomly administered without placebo in a double-blind manner. As well, each subject received seven lactase tablets, in a random, unblinded manner. RESULTS: The median AUC and mean oral cecal transit time followed dose response expectations; however, only lactase treatment achieved significance. Nevertheless, 8 mg Lo significantly improved symptom scores, which were statistically indistinguishable from those of lactase. Four subjects complained of delayed constipation and cramps with various doses of Lo. CONCLUSIONS: Lo monotherapy for lactose intolerance is not economical and may have some side effects. However, Lo may be studied further as an adjunctive treatment of lactose intolerance in an effort to reduce the need for complete lactose digestion. Such a manoeuvre may allow rapid colonic adaptation, which in turn may be beneficial for prophylaxis for a number of colonic diseases.

Assessment of orocaecal transit time in cats by the breath hydrogen method: the effects of sedation and a comparison of definitions.

Oro-caecal transit times (OCTTs) were assessed in 10 healthy adult cats by the lactulose breath hydrogen method with either no sedation (group A), or after the intramuscular administration of three sedative regimens: a combination of acetylpromazine at 0.1 mg kg-1 with buprenorphine at 10 micrograms kg-1 (group B), ketamine at 5 mg kg-1 with midazolam at 0.1 mg kg-1 (group C), or medetomidine at 50 micrograms kg-1 (group D). For each test, the OCTT was defined by four methods: a visual assessment, the first maintained 4 ppm increase in hydrogen production, and the first maintained 0.5 ml hr-1 increase in hydrogen production assessed by two cumulative sum methods. Depending on the definition, the median OCTTs of the cats were between 113 and 131.5 minutes in group A, 86.5 and 97.5 minutes in group B, 218 and 235.5 minutes in group C and 86.5 and 97.5 minutes in group D. By two of the definitions, the median OCTTs in group C were significantly longer than in group A (P < or = 0.037) and approached significance by the other two definitions. The use of sedatives significantly increased the inter-individual variability of the OCTTs, particularly in groups C and D. There were significant differences between the median OCTTs defined by the four different methods, but all the methods were very highly and significantly correlated (rs < or = 0.9503, P < 0.0001).

Quantitative, noninvasive assessment of antidiarrheal actions of codeine using an experimental model of diarrhea in man.

Enteric coating of a capsule has been used to deliver a bolus of radioisotope to the ileocecal region. This has allowed quantitative assessment of regional colonic transit in a group of healthy subjects whose proximal colonic transit was accelerated by lactulose 20 ml thrice daily. In this experimental model of diarrhea, codeine delayed transit from mouth to terminal ileum and also delayed transit through the ascending colon from 5.3 +/- 2.5 hr to 7.4 +/- 2.5 hr, N = 11, P < 0.05. Furthermore, codeine delayed whole colon transit, as assessed by geometric center analysis, which showed the delay to be most marked in the right colon with little effect noted in the left colon. In addition, codeine significantly reduced the number of retrograde movements observed and reduced the colonic response to eating. The antidiarrheal effect of codeine appears to be due to a combination of delayed mouth-cecum transit plus an additional delay in the ascending colon. This colonic delay may be partially explained by a reduction in postprandial propulsive movements that were seen in this model of diarrhea.