Motility Of Gastrointestinal Tract Research Articles

Quercetin Inhibits Pacemaker Potentials via Nitric Oxide/cGMP-Dependent Activation and TRPM7/ANO1 Channels in Cultured Interstitial Cells of Cajal from Mouse Small Intestine

Background: Quercetin regulates gastrointestinal (GI) motor activity but the molecular mechanism involved has not been determined. The authors investigated the effects of quercetin, a flavonoid present in various foods, on the pacemaker activities of interstitial cells of Cajal (ICCs) in murine small intestine in vitro and on GI motility in vivo. Materials and Methods: Enzymatic digestion was used to dissociate ICCs from mouse small intestines. The whole-cell patch-clamp configuration was used to record pacemaker potentials in cultured ICCs in the absence or presence of quercetin and to record membrane currents of transient receptor potential melastatin (TRPM) 7 or transmembrane protein 16A (Tmem16A, anoctamin1 (ANO1)) overexpressed in human embryonic kidney (HEK) 293 cells. The in vivo effects of quercetin on GI motility were investigated by measuring the intestinal transit rates (ITRs) of Evans blue in normal mice. Results: Quercetin (100-200 μM) decreased the amplitudes and frequencies of pacemaker activity in a concentration-dependent manner in current clamp mode, but this action was blocked by naloxone (a pan-opioid receptor antagonist) and by GDPβS (a GTP-binding protein inhibitor). However, potassium channels were not involved in these inhibitory effects of quercetin. To study the quercetin signaling pathway, we examined the effects of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of guanylate cyclase, and of RP-8-CPT-cGMPS, an inhibitor of protein kinase G (PKG). These inhibitors blocked the inhibitory effects of quercetin on pacemaker activities. Also, L-NAME (100 μM), a non-selective NO synthase (NOS) inhibitor, blocked the effects of quercetin on pacemaker activity and quercetin stimulated cGMP production. Furthermore, quercetin inhibited both Ca²⁺-activated Cl^- channels (TMEM16A, ANO1) and TRPM7 channels. In vivo, quercetin (10-100 mg/kg, p.o.) decreased ITRs in normal mice in a dose-dependent manner. Conclusions: Quercetin inhibited ICC pacemaker activities by inhibiting TRPM7 and ANO1 via opioid receptor signaling pathways in cultured murine ICCs. The study shows quercetin attenuates GI tract motility, and suggests quercetin be considered the basis for the development of novel spasmolytic agents for the prevention or alleviation of GI motility dysfunctions.

Use of gastric emptying and emesis models to improve the assessment of upper gastrointestinal tract motility

Use of gastric emptying and emesis models to improve the assessment of upper gastrointestinal tract motility

Evaluation of an improved sustained-release buprenorphine formulation for use in mice.

To evaluate analgesic effects of an improved sustained-release buprenorphine (BUP-SR) formulation administered to mice. 36 male Swiss-Webster mice. Mice were assigned to each of 3 treatment groups (n = 12 mice/group). Treatments were administered SC (vehicle [control treatment], 1.5 mg of buprenorphine hydrochloride [BUP-HCl]/kg, and 1.5 mg of BUP-SR/kg). Mice were evaluated (total activity, gastrointestinal tract motility, respiratory rate, cataleptic behavior, and tall-flick and hot plate nociception tests) to determine behavioral and physiologic responses at 4, 24, and 48 hours after treatment administration. Body weight and respiratory rate were measured before and at each time point after treatment administration. SC administration of BUP-SR resulted in significant antinociception effects for 48 hours for the hot plate and tall-flick nociception tests without substantial adverse effects. Gastrointestinal tract motility and total activity were higher at 4 hours for mice receiving BUP-SR than for mice receiving the vehicle, but values were the same between these groups at 24 and 48 hours. The BUP-SR group had a lower respiratory rate than did the control group at all times after treatment administration. Mice treated with BUP-SR had no significant changes in body weight during the study, whereas mice treated with BUP-HCl had a significant decrease in body weight at 24 and 48 hours. BUP-SR administration resulted in antinociception effects for 48 hours. Results of this study indicated that the improved BUP-SR formulation could be safely administered SC and conferred superior analgesia, compared with that for BUP-HCl, in mice.

Carthami Flos Depolarizes the Interstitial Cells of Cajal and Increases the Motility in Gastrointestinal Tract

Carthami Flos Depolarizes the Interstitial Cells of Cajal and Increases the Motility in Gastrointestinal Tract

Recovery of gastrointestinal tract motility detection using Naive Bayesian and minimum statistics

Loss of gastrointestinal motility is a significant medical setback for patients who experience abdominal surgery and contributes to the most common reason for prolonged hospital stays. Recent clinical studies suggest that initiating feeding early after abdominal surgery is beneficial. Early feeding is possible when the patients demonstrate bowel motility in the form of bowel sounds (BS). This work provides a data collection, processing and analysis methodology for detection of recovery of gastrointestinal track motility by observing BSs in auscultation recordings. The approach is suitable for real-time long-term continuous monitoring in clinical environments. The system was developed using a Naive Bayesian algorithm for pattern classification, and Minimum Statistics and spectral subtraction for noise attenuation. The solution was tested on 59h of recordings and 94.15% recognition accuracy was observed.

Effect of biliary cirrhosis on neurogenic relaxation of rat gastric fundus and anococcygeus muscle: role of nitric oxide pathway.

Cirrhosis, associated with a host of hemodynamic abnormalities, could affect the gastrointestinal (GI) tract motility. On the other hand, the nonadrenergic noncholinergic (NANC) neurotransmission has been shown to play a pivotal role in GI tract motility and has been linked with release of nitric oxide (NO) on electrical stimulation. In this study, we investigated the effect of biliary cirrhosis on the neurogenic relaxation of rat gastric fundus and anococcygeus muscle and also the possible role of nitric oxide system in this manner. Isolated gastric fundus and anococcygeus strips of sham-operated and biliary cirrhotic (4weeks after bile duct ligation) rats were mounted under tension in a standard organ bath. Electrical stimulation was applied to obtain NANC-mediated relaxations in precontracted gastric fundus and anococcygeus muscle. The neurogenic relaxations were examined in the presence of different doses of NO synthase inhibitor, N (w)-Nitro-L-Arginine Methyl Ester (L-NAME). The concentration-dependent relaxant responses to the NO donor sodium nitroprusside were also evaluated. The neurogenic relaxation of both gastric fundus and anococcygeus muscle was significantly (P<0.001) increased in cirrhotic animals. L-NAME (0.03-1,000µM) inhibited relaxations in both groups in a dose-dependent manner (P<0.001), but cirrhotic groups were more resistant to the inhibitory effects of L-NAME (P<0.01). Sodium nitroprusside-mediated relaxations were similar in two groups. This study for the first time demonstrated that cirrhosis increases the NO-mediated neurogenic relaxation of both rat gastric fundus and anococcygeus muscle, suggesting a crucial role for the neurogenic NO in the pathophysiology of disturbed GI motility in cirrhosis.

Isolation, expansion and transplantation of postnatal murine progenitor cells of the enteric nervous system.

Neural stem or progenitor cells have been proposed to restore gastrointestinal function in patients suffering from congenital or acquired defects of the enteric nervous system. Various, mainly embryonic cell sources have been identified for this purpose. However, immunological and ethical issues make a postnatal cell based therapy desirable. We therefore evaluated and quantified the potential of progenitor cells of the postnatal murine enteric nervous system to give rise to neurons and glial cells in vitro. Electrophysiological analysis and BrdU uptake studies provided direct evidence that generated neurons derive from expanded cells in vitro. Transplantation of isolated and expanded postnatal progenitor cells into the distal colon of adult mice demonstrated cell survival for 12 weeks (end of study). Implanted cells migrated within the gut wall and differentiated into neurons and glial cells, both of which were shown to derive from proliferated cells by BrdU uptake. This study indicates that progenitor cells isolated from the postnatal enteric nervous system might have the potential to serve as a source for a cell based therapy for neurogastrointestinal motility disorders. However, further studies are necessary to provide evidence that the generated cells are capable to positively influence the motility of the diseased gastrointestinal tract.

Experimental evidence and mathematical modeling of thermal effects on human colonic smooth muscle contractility.

It has been shown, in animal models, that gastrointestinal tract (GIT) motility is influenced by temperature; nevertheless, the basic mechanism governing thermal GIT smooth muscle responses has not been fully investigated. Studies based on physiologically tuned mathematical models have predicted that thermal inhomogeneity may induce an electrochemical destabilization of peristaltic activity. In the present study, the effect of thermal cooling on human colonic muscle strip (HCMS) contractility was studied. HCMSs were obtained from disease-free margins of resected segments for cancer. After removal of the mucosa and serosa layers, strips were mounted in separate chambers. After 30 min, spontaneous contractions developed, which were measured using force displacement transducers. Temperature was changed every hour (37, 34, and 31°C). The effect of cooling was analyzed on mean contractile activity, oscillation amplitude, frequency, and contraction to ACh (10(-5) M). At 37°C, HCMSs developed a stable phasic contraction (~0.02 Hz) with a significant ACh-elicited mean contractile response (31% and 22% compared with baseline in the circular and longitudinal axis, respectively). At a lower bath temperature, higher mean contractile amplitude was observed, and it increased in the presence of ACh (78% and 43% higher than the basal tone in the circular and longitudinal axis, respectively, at 31°C). A simplified thermochemomechanical model was tuned on experimental data characterizing the stress state coupling the intracellular Ca(2+) concentration to tissue temperature. In conclusion, acute thermal cooling affects colonic muscular function. Further studies are needed to establish the exact mechanisms involved to better understand clinical consequences of hypothermia on intestinal contractile activity.

Su1911 Neuropeptide S: Effects on Motility, Contractility and Inflammation in the Rat and Human Gastrointestinal Tract

Background: Neuropeptide S (NPS) is expressed by gastrointestinal (GI) enteroendocrine cells and macrophages in rat and man. Polymorphisms of the NPS receptor are linked to increased risk of inflammatory bowel disease as well as motor and sensory disturbances of the gut, suggesting a role for NPS in GI disorders. Further knowledge of NPS effects on motility and inflammation is needed. Methods: Studies of motility were carried out in rats with electrodes implanted in the small bowel. NPS was infused IV for 60 min and effects on myoelectrical activity were recorded. Motility effects of NPS were further studied as luminal pressure changes in anaesthetized rats where the proximal small intestine with intact blood supply was perfused with saline for motility recordings. Tissue samples were obtained from rats for evaluation of gene expression and protein elaboration of inflammatory biomarkers. Muscle strips of the human stomach, small intestine and colon were used for pharmacological analysis in organ baths of motility responses to NPS. Localization of the NPS receptor was done with fluorescent-protein tagging using Cy3-NPS. Plasma levels of NPS were measured using ELISA in 5 healthy and 14 IBD patients before and after meal. Results: In conscious rats, NPS 1 nmol kg-1min-1 increased irregular spiking, 4 nmol kg-1min-1 reduced spiking and increased the MMC cycle length (P=0.005). In anesthetized rats, NPS 0.01-1 nmol kg-1min-1 dose-dependently reduced small bowel motility (P<0.001). In rats, NPS also increased the mRNA expression of iNOS, and CXCL1 and IL-1β at the protein level. In human, fluorescent protein-tagging showed the NPS receptor primarily to be present in enolase-positive nerve fibers, but some scattered also in muscle tissue. In organ baths, NPS 1-100 nM caused TTX-dependent relaxations of the smooth muscle. We found no detectable levels of NPS in plasma of neither healthy subjects nor IBD patients. Conclusion: NPS has a smooth muscle-relaxing effect in the GI tract and dampens myoelectrical and contractile motor activity of the small bowel. This is achieved primarily through an inhibition of nerve-mediated relaxation of smooth muscle cells. Circulating NPS levels in humans are undetectable in healthy subjects and in active IBD. This implies that NPS exerts its inhibitory function by a paracrine or neurocrine mechanism in the gut. NPS seems also capable of intervening with inflammation by increasing gut cytokines and iNOS expression.

Recurrent Gastric Dilatation and Intestinal Dysmotility Possibly Resulting from Autonomic Neuropathy in a Great Dane

A 5 yr old female spayed Great Dane was presented for recurrent episodes of gastric dilatation, intestinal dysmotility, and one episode of gastric rupture. Numerous hematologic, radiographic, and endocrine diagnostic tests were performed with no identifiable underlying cause. Many risk factors have been identified for gastric dilatation and most were present in this Great Dane. A number of symptomatic treatments, aimed primarily at altering the gastrointestinal tract flora and motility were tried, but failed to influence the clinical course of the disease. The dog continued to worsen, experienced more frequent episodes of gastric dilatation, and developed generalized muscle atrophy. Biopsies were collected from the biceps femoris and triceps brachii muscles. A pattern of denervation atrophy was evident in both muscles, consistent with polyneuropathy. The owners elected humane euthanasia and a necropsy was performed. A striking finding at necropsy was severe loss of myelinated fibers with extensive endoneurial fibrosis in the vagus nerve, consistent with an autonomic neuropathy. Autonomic neuropathy is a previously unexplored cause of gastric dilatation and intestinal dysmotility in dogs. These findings should open new directions for exploring pathogenic mechanisms for gastric dilatation in this species.

Tu1399 Therapeutic Strategy for the Overlap Between GERD and Functional Dspepsia —Study of Additive Effect of Acotiamide on Rabeprazole—

Proton pump inhibitors (PPIs), the first-choice agents for the treatment of gastroesophageal reflux disease (GERD), cure most GERD patients, but there are still patients in whom symptom improvement is poor despite remission of esophageal mucosal injury. Since the symptoms of such PPI-refractory GERD patients overlap with those in postprandial distress syndrome and epigastric pain syndrome, it is inferred that GERD sometimes overlaps with functional dyspepsia (FD). Acotiamide is known to improve gastrointestinal tract motility by inhibiting acetylcholine esterase, but the therapeutic effect on the overlap between GERD and FD is unknown.

Interstitial Cajal-Like Cell: A New Player in Cholelithiasis?

To the Editor: Th e incidence of gallstones is relatively high in the developed countries, with ~ 10 % of the whole population being aff ected. Even though there is a lack of clear hypothesis on gallstone formation, a few factors are proved to be responsible for this process: cholesterol supersaturation, hydrophobic bile salts, pronucleating proteins, mucus hypersecretion with gel formation in the gallbladder and disrupted gallbladder motility. Th e gallbladder dysmotility seems to be a “ trigger ” event in the pathogenesis of cholesterol gallstones, providing the time necessary for the precipitation of cholesterol microcrystals from bile supersaturated with cholesterol. Considering increasing knowledge of the role of interstitial cells of Cajal in the regulation of gastrointestinal tract (GI) motility as well as in the pathogenesis of multiple GI disorders, and the fact that these cells were recently described in human gallbladder and biliary tract, we wondered whether interstitial cells of Cajal (or interstitial Cajal-like cells — ICLCs — as they are called when localized in extraintestinal organs) are present in gallbladder wall in patients with cholelithiasis and whether their density decreases or perhaps remains intact. We used indirect double immunofl uorescence method to visualize ICLCs. A characteristic feature of ICLCs is the expression of transmembrane tyrosine kinase receptor proteins, including the c-Kit receptor (CD117), which enables the identifi cation of ICLCs. Unfortunately, the CD117 is present in the mast cells as well, and for that reason we stained slides with anti-mast cell tryptase. ICLCs were defi ned as c-Kitpositive nucleated cells that lacked mast cell tryptase expression ( Figure 1 ). ICLCs were observed throughout the gallbladder, including the fundus, body (corpus), and neck, although they were predominantly located in the corpus, almost exclusively within the muscularis propria. ICLCs had a centrally located nucleus and were mostly fusiform in shape; however, sparse, round tryptase / c-Kit-positive cells were also present ( 1 ). In our study (2), we reported for the fi rst time that interstitial Cajal-like cells are lost or damaged in patients suff ering from cholelithiasis. We observed the cells positive for the c-Kit receptor (CD117) in the gallbladder wall in all cases examined. ICLCs were most frequently located in the muscularis propria. Th e density of ICLCs in the muscularis propria was signifi cantly lower in the patients with gallstones than the density observed in the controls (26.24 ± 10.89 vs. 56.29 ± 13.35 cell mm − 2 in the muscularis propria, P < 0.001). Th e published data on ICLCs in the human gallbladder are still very limited. ICLCs were described in the wall of the human gallbladder by Hinescu et al. ( 3 ) and in the bile ducts by Ahmadi et al. ( 4 ). Both teams reported that ICLCs in the gallbladder formed a cellular network that is likely involved in biliary tract motility. Consequently, animal studies suggested the potential role of ICLCs in functional disturbances of the gallbladder. So far, we have not found any works published on ICLCs in the context of pathogenesis of gallstone in humans. Our studies revealed that ICLCs play a role in the pathogenesis of gallstone disease. Furthermore, from the currently fi nished research ( 5 ) we conclude that bile content may infl uence these cells. It implies some possible future medical interventions .

Measuring response in the gastrointestinal tract in systemic sclerosis

Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials. Patient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials. GIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc.

Gastrointestinal Tract Abnormalities Induced by Prenatal Valproic Acid Exposure in Rat Offspring

In-utero exposure to valproic acid (VPA) has been known as a potent inducer of autism spectrum disorder (ASD), not only in humans, but also in animals. In addition to the defects in communication and social interaction as well as repetitive behaviors, ASD patients usually suffer from gastrointestinal (GI) problems. However, the exact mechanism underlying these disorders is not known. In this study, we examined the gross GI tract structure and GI motility in a VPA animal model of ASD. On embryonic day 12 (E12), 4 pregnant Sprague-Dawley (SD) rats were subcutaneously injected with VPA (400 mg/kg) in the treatment group, and with phosphate buffered saline (PBS) in the control group; the resulting male offspring were analyzed at 4 weeks of age. VPA exposure decreased the thickness of tunica mucosa and tunica muscularis in the stomach and ileum. Other regions such as duodenum, jejunum, and colon did not show a significant difference. In high-resolution microscopic observation, atrophy of the parietal and chief cells in the stomach and absorptive cells in the ileum was observed. In addition, decreased staining of the epithelial cells was observed in the hematoxylin and eosin (H&E)-stained ileum section. Furthermore, decreased motility in GI tract was also observed in rat offspring prenatally exposed to VPA. However, the mechanism underlying GI tract defects in VPA animal model as well as the association between abnormal GI structure and function with ASD is yet to be clearly understood. Nevertheless, the results from the present study suggest that this VPA ASD model undergoes abnormal changes in the GI structure and function, which in turn could provide beneficial clues pertaining to the pathophysiological relevance of GI complications and ASD phenotypes.

In vivo and in vitro evaluation of the effects of domperidone on the gastrointestinal tract of healthy horses

To determine the effects of domperidone on in vivo and in vitro measures of gastrointestinal tract motility and contractility in healthy horses. 18 adult horses and tissue samples from an additional 26 adult horses. Domperidone or placebo paste was administered to healthy horses in a 2-period crossover study. Gastric emptying was evaluated after oral administration of domperidone paste (1.1 or 5.0 mg/kg) or placebo paste by means of the acetaminophen absorption test in 12 horses. Frequency of defecation, weight of feces produced, fecal moisture, and stomach-to-anus transit time of microspheres were evaluated after administration of domperidone paste (1.1 mg/kg) or placebo paste in 6 horses. The effect of domperidone on smooth muscle contractile activity in samples of duodenum, jejunum, ileum, or colon obtained from 26 horses immediately after euthanasia (for nonsystemic medical problems) was investigated. Oral administration of 5.0 mg of domperidone/kg increased peak plasma acetaminophen concentration and area under the curve, indicating increased gastric emptying. Administration of 1.1 mg of domperidone/kg had no effect on gastric emptying, transit time, defecation frequency, or amount and moisture of excreted feces. Contractile activities of circular and longitudinal muscle strips from the duodenum, jejunum, ileum, or colon were not altered by domperidone. Dopamine increased contractile activity of longitudinal muscle strips but not that of circular muscle strips from the midjejunum. Domperidone decreased the dopamine-induced contractile activity of midjejunal longitudinal muscle strips. The potential beneficial effects of domperidone in horses with ileus need to be evaluated in horses with decreased gastric emptying or adynamic ileus.

Role of Lubiprostone on Gastrointestinal Motility

Lubiprostone is a bicyclic fatty acid derivative of prostaglandin E1 used for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome.1,2 The underlying mechanism of lubiprostone is stimulation of electrogenic chloride secretion by activating chloride channel type-2 (ClC-2)3 and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels4 in the apical membrane of the intestinal epithelial cells. Activation of ClC-2 channels or CFTR chloride channels in intestinal epithelial cells produces an active secretion of chloride ions from cells into the intestinal lumen followed by a passive secretion of electrolytes and water which increases the liquidity of the luminal contents. The luminal distension by increased intestinal fluid promotes the gastrointestinal (GI) tract motility which in turn increases the intestinal and colonic transit. Lubiprostone also has an effect on cystic fibrosis tissue by independent CFTR chloride channels.5 Lubiprostone induced chloride secretory action is mediated by direct activation of ClC-2 channels as well as stimulation of these channels through activating prostaglandin receptors. Besides, lubiprostone enhances and stimulates contraction in colonic as well as gastric muscles through prostaglandin E receptors (EP1 or EP4),6 suggesting the modulatory effects of lubiprostone on GI motility through the activation of prostaglandin receptors. In this issue of Journal of Neurogastroenterology and Motility, Chan and Mashimo7 investigated the effects of lubiprostone on intestinal smooth muscle contractions and pyloric sphincter tones from murine. They found that lubiprostone increased electrical field stimulation-induced contractions of intestinal circular smooth muscles and pyloric sphincter basal tone but not intestinal longitudinal smooth muscles. The excitatory effects of lubiprostone on intestinal circular smooth muscle and pyloric sphincter basal tone were blocked by EP1 antagonist. They speculated that lubiprostone can change the GI motility by prostaglandin receptor activation and the excitatory action of lubiprostone may be another mechanism for the increased intestinal transit and the delayed gastric emptying by lubiprostone.8 Although this study provides that lubiprostone has a role as a prokinetic agent in GI tract, the underlying mechanisms of modulating contractions were not evaluated. Many cells of GI tract express E-type prostanoid receptors including smooth muscle, neuron, macrophage and interstitial cells of Cajal that contribute to modulation of GI motility.9-11 Therefore, to evaluate the clinical effects of lubiprostone for modulating GI motility, further basic studies should be carried out to find underlying mechanisms.

Simulating the Postprandial Stomach: Physiological Considerations for Dissolution and Release Testing

Food effects on drug release and absorption from solid oral dosage forms are a common biopharmaceutical problem. The fed state is characterized by different motility and secretory activity of the complete gastrointestinal (GI) tract compared to fasting conditions. Due to long gastric transit times, the postprandial stomach plays an essential role for drug release and the appearance of food effects. Therefore, a concise comprehension of the relationship between food intake and its effect on drug release from solid oral dosage forms is essential to understand their dissolution behavior under fed conditions. This review describes important aspects of stomach physiology occurring after meal ingestion with particular reference to the FDA standard breakfast. A brief overview of oral and gastric food processing and their potential influence on drug release is given. The key factors affecting the intragastric dissolution of solid oral dosage forms and their regional distribution in the stomach are discussed. Additionally, the effects of food properties on gastric emptying kinetics are presented. Mechanical aspects such as intragastric pressures and hydrodynamics caused by gastric peristalsis are defined. The initial state and the dynamic changes of the gastric content during digestion are characterized since the different physicochemical aspects such as pH value, buffer capacity, rheological properties or surface tension may be essential for the in vivo dissolution profiles of oral dosage forms. Possible effects of the discrete interplay of the physiological factors on the in vivo drug delivery behavior of solid oral dosage forms are discussed.

In vivo and in vitro effects of neostigmine on gastrointestinal tract motility of horses

To determine the response to neostigmine of the contractile activity of the jejunum and pelvic flexure and the effects of a continuous rate infusion (CRI) of neostigmine in horses. 7 adult horses and tissue from 12 adult horses. A CRI of neostigmine (0.008 mg/kg/h) or placebo was administered to 6 horses in a crossover study design. Gastric emptying was evaluated by the acetaminophen test. The frequency of defecation and urination and the consistency and weight of feces were recorded throughout the experiment. The effect of neostigmine on smooth muscle contractile activity was evaluated in tissues from the jejunum and pelvic flexure. The effect of neostigmine and acetylcholine after incubation with muscarinic receptor antagonists (atropine and DAU 5884) and an acetylcholinesterase inhibitor (edrophonium) was also investigated in vitro. No difference was observed between neostigmine and placebo for time to reach peak plasma acetaminophen concentration and absorption rate constant. A CRI of neostigmine increased fecal production and frequency of urination. Neostigmine induced a dose-dependent increase of contractile amplitude in jejunum and pelvic flexure muscle strips. Incubation of muscle strips with atropine and DAU 5884 inhibited the response to acetylcholine and neostigmine. Incubation of smooth muscle strips from the jejunum with edrophonium increased the response to acetylcholine and had no effect on the response to neostigmine in vitro. A CRI of neostigmine increased fecal production and urination frequency in horses. A CRI of neostigmine did not decrease gastric emptying. Neostigmine stimulated contractile activity of jejunum and pelvic flexure smooth muscle strips in vitro.

Metabolic and toxicological considerations for the latest drugs used to treat irritable bowel syndrome

Introduction: The high prevalence of irritable bowel syndrome (IBS), a chronic gastrointestinal (GI) disorder, its lack of satisfactory effective drugs and its complicated pathophysiology lead to the demand of new therapeutic agents. During a new drug development process, the pharmacokinetic profiling is of a great considerable importance comparable to drug's efficacy. This involves the drug's absorption, distribution, metabolism and excretion, all of which are crucial to its usefulness. In addition, the toxicological profile and possible adverse reactions of the drug should be identified. Also its interactions should be identified at different phases of trials. Several pharmacokinetic studies are carried out to achieve drugs with the best absorption and bioavailability and the least adverse effects and lowest toxicity.Areas covered: To make an update on new clinically introduced drugs for IBS and their dynamics and kinetics data, the present systematic review was accomplished. All relevant bibliographic databases were searched from the year 2003 up to May 2012 to identify all clinical trials that evaluated the potential efficacy of a novel agent in IBS.Expert opinion: Some evaluated drugs, such as ramosetron (5-HT3 antagonist) and pexacerfont (CRF1 receptor antagonist), have shown some benefits in diarrhea-predominant IBS (D-IBS), while, prucalopride and mosapride (5-HT4 agonist) with prokinetic effect were found useful in constipation-predominant IBS (C-IBS). Besides, dexloxiglumide, lubiprostone and linaclotide have shown beneficial effects in C-IBS patients. Melatonin regulates GI tract motility and, asimadoline, gabapentin and pregabalin show reduction of pain threshold and visceral hypersensitivity. Glucagon-like peptide analog, calcium-channel blockers and neurokinin receptor antagonists have shown benefits in pain attacks. More time is required to indicate both efficacy and safety in long-term treatment due to multifactorial pathophysiology, variations in individual responses and insufficient assessment methods, which limit the right decision-making process about the efficacy and tolerability of these new drugs.

Butyric acid in irritable bowel syndrome.

Butyric acid (butanoic acid) belongs to a group of short-chain fatty acids and is thought to play several beneficial roles in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as a main source of energy. Moreover, butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflammatory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric acid in IBS.