Gastrointestinal Transit Time Research Articles

A high-throughput method for predicting drug effects on gut transit time using larval zebrafish

IntroductionZebrafish are an attractive vertebrate model due to their small size, transparency through organogenesis, and high fecundity. The zebrafish gastrointestinal (GI) tract is similar to the mammalian GI tract in gene expression, nervous system control, and response to chemical challenges. GI intolerance is a common preclinical finding and can be a serious clinical safety concern. Mammalian GI liability tests are conducted at the expense of time, test article, and labor. We developed a high-throughput method to predict mammalian GI safety issues using larval zebrafish. MethodsFluorescent food is fed to larval zebrafish (7days post fertilization). After feeding, larvae are placed individually into wells of a 96-well plate and dosed with test compounds. Fluorescence is measured from the bottom of the wells repeatedly over the course of 24h and thus fecal accumulation is tracked over time. The area under the curve is compared between treated and vehicle-treated groups. ResultsDrugs with established clinical GI effects significantly impacted zebrafish GI transit time as measured by this method; tegaserod and metoclopramide accelerated transit time, while atropine and amitriptyline slowed transit time. This method is sensitive enough to reflect dose-level associated effects as demonstrated using atropine. Using a suite of 24 compounds with known (positive or negative) mammalian GI effects, we characterized this method as having a high positive predictive value. DiscussionHere we present an efficient assay for predicting mammalian GI transit liabilities using larval zebrafish. With this assay, an investigator can evaluate dozens of compounds in a single day using very little amount of each test article. As such, safe drug candidates can be prioritized for mammalian testing, which expedites the discovery process and provides 3Rs impact.

Regional gastrointestinal transit and pH studied in 215 healthy volunteers using the wireless motility capsule: influence of age, gender, study country and testing protocol.

The wireless motility capsule (WMC) offers the ability to investigate luminal gastrointestinal (GI) physiology in a minimally invasive manner. To investigate the effect of testing protocol, gender, age and study country on regional GI transit times and associated pH values using the WMC. Regional GI transit times and pH values were determined in 215 healthy volunteers from USA and Sweden studied using the WMC over a 6.5-year period. The effects of test protocol, gender, age and study country were examined. For GI transit times, testing protocol was associated with differences in gastric emptying time (GET; shorter with protocol 2 (motility capsule ingested immediately after meal) vs. protocol 1 (motility capsule immediately before): median difference: 52 min, P = 0.0063) and colonic transit time (CTT; longer with protocol 2: median 140 min, P = 0.0189), but had no overall effect on whole gut transit time. Females had longer GET (by median 17 min, P = 0.0307), and also longer CTT by (104 min, P = 0.0285) and whole gut transit time by (263 min, P = 0.0077). Increasing age was associated with shorter small bowel transit time (P = 0.002), and study country also influenced small bowel and CTTs. Whole gut and CTTs showed clustering of data at values separated by 24 h, suggesting that describing these measures as continuous variables is invalid. Testing protocol, gender and study country also significantly influenced pH values. Regional GI transit times and pH values, delineated using the wireless motility capsule (WMC), vary based on testing protocol, gender, age and country. Standardisation of testing is crucial for cross-referencing in clinical practice and future research.

Investigations of bisacodyl with modified β-cyclodextrins: Characterization, molecular modeling, and effect of PEG

Bisacodyl inclusion into hydroxypropyl-β-cyclodextrin and 2,6-di-O-methyl-β-cyclodextrin cavities was experimentally and theoretically investigated, and the effect of PEG 4000 on these inclusions was studied. Isothermal calorimetry titration curves indicated that the binary inclusion processes are enthalpy- and entropy-driven. The solid-state complexes were fully characterized by FT-IR, XRPD, DSC and SEM analyses. FT-IR, 1H NMR, and ROESY studies provided the most favorable encapsulation modes of binary complexes, and results were further confirmed by molecular docking and molecular dynamics studies. The presence of PEG 4000 slightly enhanced encapsulation efficiency, solubility and dissolution rates of the binary complexes. In vivo studies showed that complexes with CDs markedly accelerated gastrointestinal transit time compared with pure bisacodyl, whereas addition of PEG 4000 showed no further significant improvement of the bioavailability.

Regional Gastrointestinal Transit Times in Patients With Carcinoid Diarrhea: Assessment With the Novel 3D-Transit System.

Background/AimsThe paucity of knowledge regarding gastrointestinal motility in patients with neuroendocrine tumors and carcinoid diarrhea restricts targeted treatment. 3D-Transit is a novel, minimally invasive, ambulatory method for description of gastrointestinal motility. The system has not yet been evaluated in any group of patients. We aimed to test the performance of 3D-Transit in patients with carcinoid diarrhea and to compare the patients’ regional gastrointestinal transit times (GITT) and colonic motility patterns with those of healthy subjects.MethodsFifteen healthy volunteers and seven patients with neuroendocrine tumor and at least 3 bowel movements per day were investigated with 3D-Transit and standard radiopaque markers.ResultsTotal GITT assessed with 3D-Transit and radiopaque markers were well correlated (Spearman’s rho = 0.64, P = 0.002). Median total GITT was 12.5 (range: 8.5–47.2) hours in patients versus 25.1 (range: 13.1–142.3) hours in healthy (P = 0.007). There was no difference in gastric emptying (P = 0.778). Median small intestinal transit time was 3.8 (range: 1.4–5.5) hours in patients versus 4.4 (range: 1.8–7.2) hours in healthy subjects (P = 0.044). Median colorectal transit time was 5.2 (range: 2.9–40.1) hours in patients versus 18.1 (range: 5.0–134.0) hours in healthy subjects (P = 0.012). Median frequency of pansegmental colonic movements was 0.45 (range: 0.03–1.02) per hour in patients and 0.07 (range: 0–0.61) per hour in healthy subjects (P = 0.045).ConclusionsThree-dimensional Transit allows assessment of regional GITT in patients with diarrhea. Patients with carcinoid diarrhea have faster than normal gastrointestinal transit due to faster small intestinal and colorectal transit times. The latter is caused by an increased frequency of pansegmental colonic movements.

The role of polydextrose in body weight control and glucose regulation.

The purpose of this review was to highlight recent research developments on effects of the dietary fibre polydextrose (PDX) on appetite, satiety and energy intake and glucose metabolism. For this purpose, clinically relevant human studies were reviewed and putative mechanisms and pathways were discussed. A number of acute human intervention studies provide strong indications for an energy and glucose metabolism-regulating role of PDX. These effects might be mediated via a reduced gastro-intestinal transit reducing glycaemia and insulinemia after PDX ingestion and the potential of PDX as soluble dietary fibre to alter the intestinal microbial composition, which might lead to changes in signalling in both peripheral and central pathways involved in energy metabolism and glucose homeostasis. In acute studies, PDX seems to have an inhibiting effect on energy intake and satiety and to reduce glycaemic and insulinemic response through effect on gastro-intestinal transit time and macronutrient absorption as well as through effects of the microbial products such as short-chain fatty acids on energy and substrate metabolism. In particular, well controlled human intervention studies are required to confirm these effects in the long term. Overall, supplement PDX to the daily diet may be a promising approach for the management and treatment of obesity and associated metabolic disorders.

PTU-175 Prolonged gastrointestinal transit is present in type 1 diabetes mellitus prior to the development of symptoms

<h3>Introduction</h3> The wireless motility capsule (WMC) is a minimally invasive ambulatory technology that concurrently measures intraluminal pH, temperature and pressure as it traverses the gastrointestinal (GI) tract. Knowledge gaps remain concerning regional GI transit times with type 1 diabetes mellitus (T1DM) with established sensory neuropathy. Moreover, pH drop across the ileocaecal valve (ICV) has been recently proposed as a surrogate biomarker for bacterial fermentation in the caecum. <h3>Method</h3> 24 patients with T1DM (17 male, mean age 54 years, range 36–66), with confirmed sensory neuropathy but no GI symptoms, and 22 healthy controls (17 male, mean age 54 years, range 38–72) ingested a WMC together with a standardised meal. Gastric emptying time (GET), small bowel transit time (SBTT), colon transit time (CTT) and whole gut transit time (WGTT) and pH drop across the ICV were calculated using the WMC. <h3>Results</h3> In patients with T1DM, GET (350 min ± 65.8 vs. 206 ± 11.8, <i>p = </i>00.05), CTT (2188 min ± 235 vs. 1302 ± 155, <i>p = </i>0.004) and WGTT (2831 min ± 271 vs. 1893 ± 199, <i>p = </i>0.009) was longer in comparison to healthy controls. pH drop across the ICV was higher in T1DM patients when compared to controls (−1.73 ± 0.4 vs. −1.3 ± 0.5, <i>p = </i>0.005) and was associated slower CTT (r = −0.6, <i>p = </i>0.002). Multivariate linear regression, controlling for age, gender and glycaemic control were not associated with changes in regional or whole gut transit times. <h3>Conclusion</h3> In patients with T1DM with sensory neuropathy, but without GI symptoms, GET, CTT and WGTT are prolonged in comparison to controls and had a larger pH drop across the ileocaecal valve suggesting heightened caecal fermentation. Whether changes in the microbiota contribute to such changes in transit times in T1DM warrants further study as it may represent a potential therapeutic target prior to the development of symptomatic dysmotility. <h3>Disclosure of interest</h3> None Declared.

Dietary carbohydrate and food processing affect the digestive physiology ofPiaractus mesopotamicus

The responses of the digestive physiology of juvenile pacu to different diet processing were studied. Fish were fed with isoproteic diets with 260 g kg−1 of crude protein (CP) containing different levels of carbohydrate (DCh) (400 or 500 g kg−1), and two diet processing (pelletization or extrusion) for 90 days. Fish fed with extruded diets showed decrease of the gastrointestinal transit time (GI transfer) and of the amylase activity, but maltase activity did not alter. Protease activity of intestine depicted increase when the DCh was raised. The increase of DCh also caused enhancement of the apparent digestibility coefficient of CP (ADCCP) in fish fed with extruded diets. Fish fed with pelletized diets showed increase of the amylase activity in pyloric caecum independently of the dietary carbohydrate level. No interaction was observed between dietary carbohydrate level and diet processing. Maltase activities from the stomach and intestine of pacu were not responsive to the carbohydrate level. The extrusion process improved the carbohydrate availability and the digestion efficiency of protein in pacu. Digestive enzymes of pacu were modulated either by nutrients or diet processing.

Therapeutic effects of Lactobacillus casei Qian treatment in activated carbon-induced constipated mice.

In the present study, the therapeutic effects of Lactobacillus casei Qian (LC-Qian), the key microorganism in Tibetan yak yoghurt, on activated carbon-induced constipation were determined in vivo. ICR mice were treated with LC-Qian for nine days by oral administration. The body weight, defecation status, gastrointestinal transit and defecation time of mice were assessed, and the serum levels of motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) were further evaluated. Bisacodyl was used as the positive control. The time until the first black stool defecation following carbon intake of the normal, control, 100 mg/kg bisacodyl-treated, Lactobacillus bulgaricus (LB)-treated, LC-Qian (L)-and LC-Qian (H)-treated mice was 93, 231, 121, 194, 172 and 157 min, respectively. Following treatment with LC-Qian, the gastrointestinal transit was increased to 52.4% [LC-Qian (L)] and 65.8% [LC-Qian (H)], while that in the group treated with the common lactic acid bacteria of LB was 40.3%. The MTL, Gas, ET, AChE, SP and VIP serum levels were significantly increased and levels of SS were reduced in mice following LC-Qian treatment compared with those in the control mice (P<0.05). Reverse transcription quantitative polymerase chain reaction indicated that LC-Qian raised the c-Kit, GDNF as well as SCF mRNA expression levels and reduced the TRPV1 and NOS expression levels in tissue of the small intestine in mice. These results suggested that lactic acid bacteria prevent constipation in mice, among which LC-Qian was the most effective.

Interactive roles of gut microbiota and gastrointestinal motility in the development of inflammatory disorders

Gut microbiota play essential roles in host physiology. The gut microbiota both influence and are influenced by gastrointestinal (GI) motility. Disruption of intestinal homeostasis and alterations of the gut microbiota are considered to contribute to the pathogenesis of several disorders. Patients suffering from inflammatory disorders, such as inflammatory bowel disease (IBD) and non-alcoholic steatohepatitis (NASH), reportedly have prolonged orocecal transit times with small intestinal bacterial overgrowth and alterations of gut microbiota. These forms of dysbiosis have been suggested to elicit distinct intestinal immune responses, increased intestinal permeability and bacterial translocation, thereby contributing to the pathogenesis of IBD and/or NASH. In a recent report, we raised the possibility that a drug affecting GI motility might influence gut microbiota and the development of NASH. Thus, we investigated the effects of the gastroprokinetic agent mosapride citrate (MC) using a methionine-choline deficient (MCD) diet-induced NASH rodent model. MC treatment exerted a protective effect against MCD diet-induced GI transit time delay, diminished lactic acid bacteria and colonic inflammation, thereby ameliorating NASH with reduced serum endotoxin and increased glucagon-like peptiede-1. Recently, the correction of dysbiosis employing probiotics or fecal transplantation has been investigated as a therapeutic strategy for IBD and NASH. Given the interactive functions of gut microbiota and mediators of GI motility, there is possibility that altering GI motility also has potential as a therapeutic strategy.

Establishment of rat slow transit constipation model by selective chemical ablation of the enteric plexus

To establish an innovative rat model of slow transit constipation by selective chemical ablation of the colon enteric plexus. Sprague Dawley rats, 5-6 weeks old, were randomly divided into normal control group, sham operation group, treatment group I, II, III, IIII. The normal control group did not receive treatment. Rats in the sham operation group and the treatment groups received abdominal operation under anesthesia, and the gauze containing 0.9% normal saline, 0.05%, 0.1%, 0.25%, 0.5% benzalkonium chloride (BAC) was applied into colon for 30 minutes. Two weeks after operation, the number of feces, fecal dry weight in 24 h and gastrointestinal transit time were recorded, then hematoxylin-eosin (HE) staining, immunohistochemistry, ELISA were used for the evaluation of colonic pathology, enteric plexus, Interstitial cells of Cajal and neurotransmitters 5-hydroxytryptamine(5-HT). Compared to the normal control group and the sham operation group, the gastrointestinal transit time was significantly prolonged and fecal dry weight was lower in the treatment group II, III (all P<0.05). HE and immunohistochemical staining showed varying degrees of pathological changes in the treatment groups and in line with the pathological changes of slow transit constipation. 5-HT concentration reduced significantly in treatment group III compared to other groups (P<0.01). The animal model of STC is successfully established by applying 0.25% BAC selective chemical ablation of the colon enteric plexus. This model is simple, stable, and is more in line with pathological changes of slow transit constipation.

Menstrual cycle, sex hormones in female inflammatory bowel disease patients with and without surgery.

Healthy women at reproductive age experience a cyclical alteration of gastrointestinal (GI) symptomatology during their menstrual cycle. Additionally, the majority of healthy women also complain of worsening of GI symptoms either during the premenstrual or menstrual phase. Despite conflicting evidence, studies suggest that sex hormones may increase GI transit time during the luteal phase. Similar phenomenon is also observed in women with underlying inflammatory bowel disease (IBD). The mechanism underlying this complex pathophysiology is still not completely understood. However, a possible influence of sex hormones on the brain-gut-microbiota axis is hypothesized. The diagnosis of IBD is associated with a delay in menarche as well as menstrual function irregularities including alterations in cycle length and the duration of flow. There is little data on the effect of menopause on IBD disease activity and conflicting data on the effect of IBD diagnosis on the onset of menopause. The role of contraceptives and hormone replacement therapies on the development or disease activity of IBD has not been yet established. Moreover, IBD patients with concomitant dysmenorrhea report heightened pain during menses. The effect of non-steroidal anti-inflammatory drugs in treating primary dysmenorrhea on the disease course of IBD is unknown. In addition, the effect of IBD medications including immunomodulators and biologics on menstrual function remains unclear. Also, the role of IBD surgery on menstrual irregularities needs to be fully elucidated. Hence, understanding the influence of menstrual function on IBD disease activity and vice versa and the maintenance of normal menstrual function in those patients is important in improving overall reproductive health and fertility and outcome of IBD.

The novel CGRP receptor antagonist BIBN4096BS alleviates a postoperative intestinal inflammation and prevents postoperative ileus.

Abdominal surgery results in neuronal mediator release and subsequent acute intestinal hypomotility. This phase is followed by a longer lasting inflammatory phase resulting in postoperative ileus (POI). Calcitonin gene-related peptide (CGRP) has been shown to induce motility disturbances and in addition may be a candidate mediator to elicit neurogenic inflammation. We hypothesized that CGRP contributes to intestinal inflammation and POI. The effect of CGRP in POI was tested in mice treated with the highly specific CGRP receptor antagonist BIBN4096BS and in CGRP receptor-deficient (RAMP-1(-/-) ) mice. POI severity was analyzed by cytokine expression, muscular inflammation and gastrointestinal (GI) transit. Peritoneal and muscularis macrophages and mast cells were analyzed for CGRP receptor expression and functional response to CGRP stimulation. Intestinal manipulation (IM) resulted in CGRP release from myenteric nerves, and a concurrent increased interleukin (IL)-6 and IL-1β transcription and leukocyte infiltration in the muscularis externa and increased GI transit time. CGRP potentiates IM-induced cytokine transcription within the muscularis externa and peritoneal macrophages. BIBN4096BS reduced cytokine levels and leukocyte infiltration and normalized GI transit. RAMP1(-/-) mice showed a significantly reduced leukocyte influx. CGRP receptor was expressed in muscularis and peritoneal macrophages but not mast cells. CGRP mediated macrophage activation but failed to induce mast cell degranulation and cytokine expression. CGRP is immediately released during abdominal surgery and induces a neurogenic inflammation via activation of abdominal macrophages. BIBN4096BS prevented IM-induced inflammation and restored GI motility. These findings suggest that CGRP receptor antagonism could be instrumental in the prevention of POI.

Altered Gastrointestinal Motility in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) patients often experience constipation, but the etiology of this symptom is unknown. To study this in an animal model, we tested the hypothesis that mice with experimental autoimmune encephalomyelitis (EAE) would exhibit altered gastrointestinal (GI) transit and they would have circulating antibodies directed against targets in enteric ganglia. EAE was induced in C57BL/6J mice by injection of complete Freund's adjuvant (CFA) and myelin oligodendrocyte glycoprotein. After somatic motor symptoms developed, small intestinal transit was measured by calculating the leading edge (LE) and geometric center (GC) 20 minutes after oral gavage of rhodamine dextran. Whole GI transit time was determined by oral gavage of carmine red and timing the appearance in fecal pellets. Antibody targets were evaluated by immunohistochemical staining of guinea pig intestine with EAE and control plasma. Small intestinal transit was significantly slower in EAE mice than in controls (LE, p&lt;0.02; GC, p&lt;0.01), and was not altered in CFA controls. The rate of whole GI transit was significantly longer in EAE mice versus healthy controls (p&lt;0.05). Plasma from EAE mice yielded more intense immunoreactivity in myenteric ganglia than plasma from control animals, with immunostained structures including neurons and nerve processes. In summary, EAE is associated with slowed intestinal motility compared to healthy control mice, which could be representative of the bowel dysmotility exhibited by multiple sclerosis patients. The symptomology may involve the presence of enteric ganglion‐targeted antibodies in the blood of EAE mice. Funding: National MS Society

The efficacy of the probiotic bifidobacterium animalis subsp. lactis bb‐12 on regional gut transit times in a healthy population

Some probiotics are hypothesized to modulate gut health, including GI transit time. A randomized crossover study was conducted to investigate the efficacy of the probiotic bacterium Bifidobacterium animalis subsp. lactis BB‐12 (B. lactis) delivered in a yogurt smoothie or a supplement (capsule) on gut transit time (GTT) in 36 healthy adults (Age: 18‐40 years; BMI: 20‐35 kg/m2). Regional transit times, such as gastricemptying time (GET), small bowel transit time (SBTT) and colonic transit time (CTT) were measured by a wireless motility capsule (SmartPill®). After the 4 week intervention period, regional transit times were not influenced by either the yogurt smoothie or the supplement. Interestingly, regardless of the treatment, 35 % of the subjects (non‐responders) increased GET and 65 % of the subjects (responders) decreased GET compared to baseline. In subgroup analyses, higher levels of total cholesterol (172 mg/dl, 158 mg/dl, respectively) and LDL cholesterol (97 mg/dl, 85 mg/dl, respectively) were found in non‐responders compared to responders (p&lt;0.001). Additionally, the level of the short chain fatty acid propionate was lower in non‐responders compared to responders (p=0.0043). In summary, probiotic bacterium added to a yogurt smoothie or supplement did not influence GTT in 36 healthy subjects. However, consistent with animal studies, individuals with higher levels of propionate had decreased GET. Collectively, in the present study we have shown that GTT may be influenced by individuals' cardiovascular risk factorsand gut short chain fatty acids.

751 Collagen IV-Pten Signaling Regulates Adult Enteric Neurogenesis In Vitro and In Vivo

G A A b st ra ct s model. Methods: Sepsis was induced in Swiss-OF1 mice by cecal ligation and puncture (CLP). Sham-operated animals served as controls. Mice received either GTS-21 8mg/kg i.p. (GTS) or vehicle (veh) 1h before the procedure, and subsequently once daily. Occurrence of ileus was confirmed by studying the geometric center (GC) of beads. At day 2 following CLP, mice were anesthetized and underwent a laparotomy, during which the colon was ligated and injected with 100μL of a 9% Evans blue (EB) solution. Mice were sacrificed 1h later via cardiac puncture and serum samples were analyzed for IL-6. Colons were rinsed and incubated for 24h in formamide to extract the EB from the colon wall. Whole blood and homogenized MLN were plated directly onto agar plates and cultured for 24h to quantify bacterial translocation. RT-PCR was performed on colons to determine cell adhesion molecules. Results: CLP resulted in a significant prolongation of GI transit times, while GTS was able to reverse this (GC: sham+veh 4.9±0.3, sham+GTS 4.2±0.3, CLP+veh 2.5±0.4*, CLP+GTS 4.3±0.4). IL-6 levels rose significantly after CLP and GTS was able to reduce these (sham+veh 2.6±0.5, sham+GTS 3.5±0.7, CLP+veh 243.6±54.9*, CLP+GTS 90.3±31.3 pg/ mL). Sepsis resulted in an increased colonic permeability, whereas GTS-21 was able to ameliorate the impaired colonic barrier (sham+veh 56.2±4.3, sham+GTS 43.7±3.8, CLP+veh 105.6±22.1*, CLP+GTS 49.5±6.9 μg EB/100mg colon). GTS appears to reduce the number of positive blood and MLN cultures following CLP-induced sepsis ( table 1). Sepsis caused a significant increase in the mRNA expression of all cell adhesion molecules ( table 2), with an additional increase in the mRNA expression of claudin-1 caused by GTS. Conclusion: CLP resulted in the occurrence of septic ileus with an increased colonic permeability and subsequent increased risk of bacterial translocation. GTS was able to ameliorate GI motility, suppress inflammation, normalize the permeability of the colonic wall, and decrease the number of positive cultures. The increase in mRNA expression of cell adhesion molecules following CLP presumably represents an attempted repair response. Targeting the α7nAChR appears to be an interesting therapeutic strategy in inflammation.

Breath Methane Excretion Is not An Accurate Marker of Colonic Methane Production in Irritable Bowel Syndrome.

The role of colonic methane production in functional bowel disorders is still uncertain. In small samples of irritable bowel syndrome (IBS) patients, it was shown that methane breath excretion correlates with clinical presentation and delayed gastrointestinal transit time. The aim of this study was to evaluate the relationship between intestinal production and breath excretion of CH4 and to correlate CH4 production with the presence and the severity of symptoms, in a large cohort of IBS patients and in a group of healthy volunteers. A group of 103 IBS patients and a group of 28 healthy volunteers were enrolled. The presence and severity of symptoms and gastrointestinal transit were evaluated in all subjects, who underwent breath H2/CH4 measurement for 7 h after lactulose to identify breath excretors of these gases; H2 and CH4 were also measured in rectal samples to identify colonic producers. Cumulative H2 and CH4 excretion and production were evaluated by the area under the time-concentration curve calculation (AUC). In IBS patients, CH4 was detected in rectal samples in 48 patients (47%), but only 27 of them (26% of the 103 enrolled patients) excreted this gas with breath. In CH4 producers, the prevalence and severity of symptoms and gastrointestinal transit time were not significantly different with respect to non-producers. IBS subtypes were homogeneously represented in CH4 producers and in non-producers. Healthy volunteers, compared with IBS patients, showed a significantly lower prevalence of CH4 excretion, whereas no difference was found in the prevalence of colonic CH4 production; moreover, in healthy volunteers compared with IBS, CH4 breath excretion and CH4 production were not different in quantitative terms. Our data show that colonic CH4 production is not associated with clinical presentation in IBS patients and does not correlate with symptom severity or with gastrointestinal transit time. Clinical inferences based on breath CH4 excretion should undergo an in-depth revision, as this method is not a good marker of CH4 colonic production.

Symptomatology of irritable bowel syndrome and inflammatory bowel disease during the menstrual cycle.

Gender-related physiological variations in gastrointestinal (GI) symptomatology have been observed in women of reproductive age. Many women experience cyclical changes in GI symptomatology during their menstrual cycle, particularly alteration in their bowel habits. Physiological studies of healthy women during the menstrual cycle showed a prolonged GI transit time during the luteal phase, either in the oro-cecum route or in the colon. Worsened GI symptoms, such as abdominal pain, bloating or diarrhea are observed in patients with irritable bowel syndrome (IBS) during menses. This may be due to elevated prostaglandin levels during menses, with an enhanced perception of viscera-somatic stimuli resulting in nausea, abdominal distension and pain. Also patients with IBS or IBD demonstrate a cyclical pattern more closely related to their bowel habits than healthy controls. Women with inflammatory bowel disease (IBD) also have exacerbated symptoms during menses; however, it is unclear whether this relates to physiological variation or disease exacerbation in IBS or IBD. Studies examining the association of the menstrual cycle and GI symptomatology in patients with IBS or IBD, have not yet clarified the underlying mechanisms. Moreover medications—such as non-steroidal anti-inflammatory drugs and oral contraceptive pills used for dysmenorrhea and menstrual migraine in those patients have not well been controlled for in the previous studies, which can contribute to further bias. Understanding changes in GI symptomatology during the menstrual cycle may help to determine the true extent of disease exacerbation and proper management strategy.

Analysis of small intestinal transit and colon arrival times of non-disintegrating tablets administered in the fasted state

In this study individual data on tablet gastrointestinal transit times (i.e. gastric emptying, small intestinal transit, ileocecal junction residence, and colon arrival times) were obtained from literature in order to present and analyze their distributions and relationships. The influence of the time of food intake after tablet administration in fasted state on gastrointestinal transit times was additionally evaluated.There were 114 measurements from subjects who received the first meal at 4h after tablet administration. Approximately 32% of the tablets arrived into the colon before the meal intake at 4h. An evident increase in the frequency of colon arrival of tablets within 40min after the meal intake at 4h post-dose was observed, where approximately 39% of all tablets arrived into the colon. This is in accordance with findings described in literature where a meal ingested several hours post-dose accelerates tablet transit through the terminal ileum and shortens the transit through the small intestine. The median (min, max) of gastric emptying, small intestinal transit, and colon arrival times in the group where the first meal intake was at 4h post-dose is 35 (0,192), 215 (60,544), and 254 (117,604) minutes, respectively. The dependence of colon arrival times on gastric emptying times was described by the nonparametric regression curve, and compared with the presumed interval of colon arrival times, calculated by summation of observed gastric emptying times and frequently cited small intestinal transit time interval, i.e. 3–4h. For shorter gastric emptying times the trend of colon arrival times was within the presumed interval. At short gastric emptying times many observation points are also within the presumed interval since this interval coincides with short period after meal intake at 4h post-dose. Additionally, in numerous occasions relatively long ileocecal junction residence times were obtained, which may be important information from the point of view of drug absorption. The findings of gastrointestinal transit times are important and should be taken into consideration when predicting the in vivo performance of dosage forms after oral administration.

Development and evaluation of colon targeted drug delivery system by using natural Polysaccharides/Polymers

Colon is being extensively investigated as a drug delivery site. This study contains comparison of the usual enteric coating polymers viz. xanthan gum, guar gum, chitosan and ethyl cellulose, as carriers for colon specific drug delivery. Lactose based metoprolol succinate tablets were prepared. These were coated with one of the coating polymers to a varying coat thickness. Tablets were prepared using polysaccharides or synthetic polymer as binders. These included xanthan gum, guar gum, chitosan and ethyl cellulose. Metoprolol Succinate was used as a model drug. The prepared tablets were enteric coated with kollicoat MAE 100 DP to give protection in the stomach. The coated tablets were tested in-vitro for their suitability as colon specific drug delivery systems. The drug release studies were carried out in simulated stomach environment (pH 1.2) for 2 h followed by small intestinal environment at pH 6.8. The dissolution data obtained from tablets demonstrates that the dissolution rate of the tablet is dependent upon the type and concentration of polysaccharide/polymer used as binder. The results demonstrate that enteric coated tablets containing 3% chitosan as a binder, showed only 12.5% drug release in the first 5 h, which is the usual upper gastrointestinal transit time, whereas, tablets prepared using guar gum as binder, were unable to protect drug release under similar conditions. Preparations with xanthan gum as a binder formed time-dependent release formulations. When used in a concentration of 5.92% in the tablets, 28% drug release was observed in the usual upper gastrointestinal tract conditions. It was also found that enteric coated preparation formulated with 8.88% of kollicoat MAE 100 DP as binder could be used to carry water insoluble drug molecules. The above study shows that chitosan could be successfully used as a binder, for colon targeting of water insoluble drugs in preference to guar gum when used in the same concentration. Additionally, formulations developed with chitosan and kollicoat MAE 100 DP would be highly site specific since drug release would be at a retarded rate till microbial degradation or polymer solubilization takes place in the colon. DOI: http://dx.doi.org/10.3329/dujps.v13i1.21874 Dhaka Univ. J. Pharm. Sci. 13(1): 105-113, 2014 (June)

Preventive effect of Dendrobium candidum Wall. ex Lindl. on activated carbon-induced constipation in mice.

The aim of this study was to investigate the effects of Dendrobium candidum Wall. ex Lindl. (D. candidum) on activated carbon-induced constipation in ICR mice. ICR mice were orally administered D. candidum for 9 days. Body weight, defecation status, gastrointestinal (GI) transit and defecation times, in addition to the levels of motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) in serum were used to evaluate the preventive effects of D. candidum on constipation. The laxative drug bisacodyl acted as a positive control. The time to the first defecation of a black stool for the normal, control, bisacodyl-treated (100 mg/kg), 200 and 400 mg/kg D. candidum-treated mice was 84, 202, 126, 161 and 142 min, respectively. Following the consumption of 200 and 400 mg/kg D. candidum or bisacodyl (100 mg/kg), the GI transit was reduced to 57.7, 74.6 and 90.2%, respectively, of the transit in normal mice. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and the serum levels of SS were reduced in the mice treated with D. candidum compared with those in the untreated control mice (P<0.05). These results demonstrate that D. candidum has preventive effects on constipation in mice, and a greater functional activity was observed when a higher concentration was administered.