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PubMed2006

Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.

OBJECTIVE: Gastric acidity (GA) inhibitors, including histamine-2 receptor antagonists (H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reflux disease (GERD) treatment. A prolonged GA inhibitor-induced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections. In addition, a number of papers and a meta-analysis have shown an increased risk of pneumonia in H2-blocker-treated intensive care patients. More recently, an increased risk of community-acquired pneumonia associated with GA inhibitor treatment has been reported in a large cohort of adult patients. These findings are particularly relevant to pediatricians today because so many children receive some sort of GA-blocking agent to treat GERD. To test the hypothesis that GA suppression could be associated with an increased risk of acute gastroenteritis and pneumonia in children treated with GA inhibitors, we conducted a multicenter, prospective study. METHODS: The study was performed by expert pediatric gastroenterologists from 4 pediatric gastroenterology centers. Children (aged 4-36 months) consecutively referred for common GERD-related symptoms (for example, regurgitation and vomiting, feeding problems, effortless vomiting, choking), from December 2003 to March 2004, were considered eligible for the study. Exclusion criteria were a history of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic fibrosis, immunodeficiency, food allergy, congenital motility gastrointestinal disorders, neuromuscular diseases, or malnutrition. Control subjects were recruited from healthy children visiting the centers for routine examinations. The diagnosis of GERD was confirmed in all patients by standard criteria. GA inhibitors (10 mg/kg ranitidine per day in 50 children or 1 mg/kg omeprazole per day in 50 children) were prescribed by the physicians for 2 months. All enrolled children were evaluated during a 4-month follow-up. The end point was the number of patients presenting with acute gastroenteritis or community-acquired pneumonia during a 4-month follow-up study period. RESULTS: We obtained data in 186 subjects: 95 healthy controls and 91 GA-inhibitor users (47 on ranitidine and 44 on omeprazole). The 2 groups were comparable for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment. Rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was significantly increased in patients treated with GA inhibitors compared with healthy controls during the 4-month follow-up period. In the GA inhibitor-treated group, the rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was increased when comparing the 4 months before and after enrollment. No differences were observed between H2 blocker and PPI users in acute gastroenteritis and pneumonia incidence in the previous 4 months and during the follow-up period. On the contrary, in healthy controls, the incidence of acute gastroenteritis and pneumonia remained stable. CONCLUSIONS: This is the first prospective study performed in pediatric patients showing that the use of GA inhibitors was associated with an increased risk of acute gastroenteritis and community-acquired pneumonia in GERD-affected children. It could be interesting to underline that we observed an increased incidence of intestinal and respiratory infection in otherwise healthy children taking GA inhibitors for GERD treatment. On the contrary, the majority of the previous data showed that the patients most at risk for pneumonia were those with significant comorbid illnesses such as diabetes or immunodeficiency, and this points to the importance of GA suppression as a major risk factor for infections. In addition, this effect seems to be sustained even after the end of therapy. The results of our study are attributable to many factors, including direct inhibitory effect of GA inhibitors on leukocyte functions and qualitative and quantitative gastrointestinal microflora modification. Additional studies are necessary to investigate the mechanisms of the increased risk of infections in children treated with GA inhibitors, and prophylactic measures could be considered in preventing them.

Achlorhydria↗

PubMed2007

Neural stem cells for the treatment of disorders of the enteric nervous system: strategies and challenges.

The main goal of this review is to summarize the status of the research in the field of stem cells transplantation, as it is applicable to the treatment of gastrointestinal motility. This field of research has advanced tremendously in the past 10 years, and recent data produced in our laboratories as well as others is contributing to the excitement on the use of neural stem cells (NSC) as a valuable therapeutic approach for disorders of the enteric nervous system characterized by a loss of critical neuronal subpopulations. There are several sources of NSC, and here we describe therapeutic strategies for NSC transplantation in the gut. These include using NSC as a relatively nonspecific cellular replacement strategy in conditions where large populations of neurons or their subsets are missing or destroyed. As with many other recent "breakthroughs" stem cell therapy may eventually prove to be overrated. However, at the present time, it does appear to provide the hope for a true cure for many currently intractable diseases of both the central and the peripheral nervous system. Certainly more extensive research is needed in this field. We hope that our review will encourage new investigators in entering this field of research ad contribute to our knowledge of the potentials of NSC and other cells for the treatment of gastrointestinal dysmotility.

Animals↗

PubMed2005

Intestinal electric stimulation modulates neuronal activity in the nucleus of the solitary tract in rats.

Intestinal electric stimulation (IES) has been shown to produce an inhibitory effect on gastric motility and secretion. The possible central mechanism of this entero-gastric inhibitory effect induced by IES is unknown. The objective of this study was to evaluate the effects of various IES on the activity of neurons in nucleus tractus solitarii (NTS). We examined the extracellular neuronal activity in NTS of the medulla in pentobarbital anesthetized, paralyzed, ventilated male adult rats. The aortic depressor, superior laryngeal, and carotid sinus nerves were crushed or sectioned bilaterally to avoid neuronal responses in NTS to cardiovascular baroreceptors. After NTS neurons with gastric input were identified, responses of single neurons in NTS to IES were determined. IES with different parameters was performed via a pair of platinum electrodes sutured onto the serosal surface of the duodenum 2 cm below the pylorus. IES with different parameters activated 39--72% of the solitary tract nucleus neurons responsive to gastric distension. Moreover, we demonstrated that IES activated the neuronal activity in NTS, which was stimulation energy dependent. The modulatory effect of IES on the central neurons receiving vagal inputs may contribute to the neural mechanisms of IES therapy for the treatment of patients with obesity and gastrointestinal motility disorders.

Action Potentials↗

PubMed1999

Octreotide in the treatment of refractory diarrhea.

Refractory chronic diarrhea that does not respond to specific antimicrobial therapy or standard unspecific medication may present a challenging and serious clinical problem. Octreotide is a candidate drug for the treatment of these patients as it inhibits gastrointestinal motility, pancreatic secretion and inhibits intestinal absorption. Only few mostly uncontrolled studies in small patient groups were published evaluating the efficacy of octreotide in the treatment of patients with chemotherapy-induced diarrhea, short-bowel syndrome, AIDS-associated diarrhea and other conditions with chronic diarrhea not responding to standard treatment. Most of these studies are not conclusive as they yielded either negative or controversial results. Octreotide may be tried in the treatment of refractory diarrhea, in particular AIDS-associated diarrhea if patients do not respond to conventional treatment strategies. Well-designed controlled trials in large patient groups are needed in order to define the place of octreotide in the treatment of patients with refractory diarrhea.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Evidence of a specific pancreatic polypeptide receptor in rat arterial smooth muscle.

Pancreatic polypeptide (PP) is a member of the PP fold family of regulatory peptides. Studies have shown that neuropeptide Y, peptide YY, and PP increased gastrointestinal motility. The GI effects of neuropeptide Y and peptide YY were accompanied by an increase in mean arterial blood pressure; however, PP decreased mean arterial blood pressure. Cloning of a receptor of the neuropeptide Y family with high affinity for PP has been reported. This Y4 receptor is present in intestine, pancreas, and prostate, and its mRNA has been detected in brain and coronary artery. We found in vitro evidence of PP-mediated inhibition of arterial neurogenic vasoconstriction. We have also detected Y4 mRNA in rat peripheral arteries. These findings suggest a potential role for the Y4 receptor in regulating vascular tone.

Animals↗

PubMed2005

Urocortin 3/stresscopin in human colon: possible modulators of gastrointestinal function during stressful conditions.

Urocortin 3 (Ucn 3) or stresscopin (SCP) is a new member of the corticotropin-releasing factor (CRF) neuropeptide family and is a specific ligand for CRF type 2 receptor (CRF2). CRF receptors are known to be expressed in the gastrointestinal tract and are considered to play pathophysiological roles, for example, in gastrointestinal motility under stress. We, therefore, examined Ucn 3 expression in the normal human large intestine obtained from surgery and autopsy in order to clarify this local response to stress in human intestine. Both immunohistochemistry and mRNA in situ hybridization demonstrated Ucn 3 expression in myenteric and submucosal nervous plexus, in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) of blood vessels in subserosa, in smooth muscle layers of the large intestine, and in enterochromaffin cells. In contrast to Urocortin 1 (Ucn 1), Ucn 3 was hardly detected in lamina propria (LP) inflammatory cells in colonic mucosa. In addition, immunohistochemistry demonstrated CRF2 expression in myenteric and submucosal nervous plexus, in smooth muscle layers, in VECs, in VSMCs and in lamina propria inflammatory cells. Immunoreactive Ucn 3 was also detected in the large intestine by RIA, with high concentrations detected in the rectum (15.4+/-9.5 pmol/g wet weight, mean+/-SEM, n=3) and sigmoid colon (6.5+/-3.5 pmol/g wet weight, n=5). Reverse-phase HPLC of the human large intestine disclosed peaks eluting in the position of synthetic Ucn 3 or SCP. These findings all suggest that Ucn 3 plays some physiological or pathological roles in the modulation of gastrointestinal functions during stressful conditions in different manners from Ucn 1.

Colon↗

PubMed2003

In vitro and in vivo opioid activity of [DPro(6)]dermorphin, a new dermorphin analogue.

To study the effects of inducing stereo-chemical modifications in the structure of dermorphin (DM) so as to improve its mu-opioid receptor affinity and its resistance to C-terminal enzymatic degradation, in the Institute of Molecular Genetics of Moscow, we synthesized a new DM analogue ([DPro(6)]DM) and analyzed the changes induced in the biological activities of DM by substituting the Pro(6) residue with DPro(6). We compared the activity of the new DM analogue and DM in in vitro assays and in in vivo tests of analgesia, thermoregulation, heart rate recordings, and gastrointestinal motility in rats. In the in vitro tests, guinea pig ileum (GPI) and mouse vas deferens (MVD), although the opioid activities of [DPro(6)]DM indicated that the peptide was always less potent than DM, its lower IC(50) ratios (mu/delta) showed that it had higher mu-opioid receptor selectivity. In the in vivo analgesic test, [DPro(6)]DM, when injected intraperitoneally (i.p.) (0.5-5 and 10mg/kg) in rats, had the same antinociceptive efficacy as DM and when injected intranasally (i.n.) (0.005 and 0.02 mg/kg) it induced a more stable and long-lasting analgesia than DM (the AUC was about 91% higher for [DPro(6)]DM than for DM). Moreover, these data confirm that the intranasal route is advantageous for peripheral drug administration. In the heart rate study, [DPro(6)]DM and DM (0.5mg/kg, i.p.), induced a similar, weak bradycardia. The only difference was that [DPro(6)]DM induced a longer-lasting effect than DM. Conversely, in body temperature regulation [DPro(6)]DM induced weaker inhibitory activity than DM (56% of the DM-induced response); it did so only in a cold environment and at the maximal used dose (0.5mg/kg, i.p.) without inducing vasomotor effects. In the gastrointestinal study, [DPro(6)]DM and DM (0.005, 0.05, and 0.5mg/kg, i.p.) significantly slowed upper gastrointestinal transit of a charcoal meal and inhibited colonic propulsion. Comparison of the ED(50) values of [DPro(6)]DM (0.03 mg/kg) and DM (0.009 mg/kg) showed that the DM analogue was about three times less potent than DM in slowing gastrointestinal and colonic transit. In conclusion, all these data overall suggest that structural maneuvering in the Pro(6)-residue of the DM molecule changes its affinity for mu-opioid receptor subtypes and confirms the usefulness of experimental studies involving structural modifications in obtaining new therapeutic agents.

Analgesics, Opioid↗

PubMed1985

Pirenzepine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in peptic ulcer disease and other allied diseases.

Pirenzepine is a 'selective' antimuscarinic agent which, unlike classic anticholinergic agents, inhibits gastric acid secretion at lower doses than are required to affect gastrointestinal motility, salivary, central nervous system, cardiovascular, ocular and urinary functions. On a weight basis, pirenzepine has one-tenth to one-eighth the potency of atropine in inhibiting stimulated gastric acid secretion in humans. Extensive controlled trials utilising endoscopy in outpatients with duodenal ulcers indicate that patient response to pirenzepine is dose related. Doses of 100 to 150 mg/day are superior to placebo in promoting duodenal ulcer healing and in diminishing day and night pain and supplementary antacid consumption. At such doses, the efficacy of pirenzepine appears to be superior to that of gefarnate 300 mg/day and generally not significantly different from that of cimetidine 1 g/day in treating duodenal ulcers. A beneficial effect of pirenzepine in the prevention of duodenal ulcer recurrence was apparent in preliminary studies in small numbers of patients, but its efficacy in this regard needs further confirmation and the optimum dosage determined. Less extensive data on the treatment of benign gastric ulcers suggest that pirenzepine 100 to 150 mg/day is superior to placebo and gefarnate 300 mg/day and does not differ significantly from cimetidine 1 g/day promoting gastric ulcer healing. Pirenzepine is well tolerated by most patients, with a low incidence of typical antimuscarinic effects on the gastrointestinal tract, genitourinary system or heart being reported in clinical studies. However, dry mouth and blurred vision are the more common side effects with clinically effective doses. Thus, pirenzepine appears to have relatively selective antimuscarinic activity, although controlled studies comparing pirenzepine and conventional antimuscarinics in patients with peptic ulcer disease have not been reported.

Benzodiazepinones↗

PubMedDate not supplied

Prolongation of the QT interval related to cisapride-diltiazem interaction.

Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45-year-old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT-interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.

Antihypertensive Agents↗

PubMed2001

Therapeutic options in nonulcer dyspepsia.

Dyspepsia, defined as pain or discomfort centered in the upper abdomen, affects an estimated 25% of the U.S. population each year; accounts for up to 5% of all visits to primary care physicians, and generates over $1.3 billion in prescription drug costs annually. In the majority of patients evaluated, no clear cause of symptoms can be identified, and the condition is termed functional or nonulcer dyspepsia (NUD). The pathophysiology of NUD remains unclear, but disturbances in gastrointestinal motility or sensation are often found. Clinically, NUD can be subdivided into dysmotility-like (in which discomfort, fullness, bloating, early satiety, or nausea [but not pain] predominate) or ulcer-like (in which epigastric pain is predominant). In ulcer-like NUD, antisecretory therapy is useful, but in dysmotility-like NUD, acid suppression is not superior to placebo. Cisapride accelerates gastric emptying and enhances gastric accommodation but probably does not blunt perception. Although cisapride relieves symptoms of dyspepsia without the adverse central nervous system effects often associated with metoclopramide, its cardiac toxicity has led to disuse. Antidepressants are of uncertain efficacy but are widely used. New prokinetics and other enteric neuromodulating agents are being tested in NUD and are likely to find an important place in clinical practice in the future.

Algorithms↗

PubMed1987

[Involvement of opiate receptors in the mode of action of trimebutine].

Several studies in dogs, cats, rabbits and humans have suggested that the motility stimulating properties of trimebutine (TMB) are mediated by peripheral opiate receptors. The present work deals with the capacity of TMB and its N-desmethyl metabolite (NDTMB) to displace mu, delta and kappa specific ligands from their receptors using guinea-pig brain membranes and ileal myenteric plexus synaptosomal membrane preparations. The activity of both compounds on the twitch response induced by transmural stimulation on the guinea-pig ileum as well as the mouse and rabbit vas deferens was also investigated. These preparations have been proposed to be specific for the mu, delta and kappa receptor subtypes respectively. TMB (0.2 to 1.8 microM) and NDTMB (0.3 to 6 microM) displayed a good affinity for all receptor subtypes in brain and myenteric plexus preparations. Both compounds also inhibited the twitch response of all three isolated organ preparations. The decreasing order of IC50's of TMB ranged from 0.75 microM in the guinea-pig ileum to 7.1 and 39 microM in the vas deferens of the rabbit and the mouse respectively. These results indicate that TMB and NDTMB possess mu, delta as well as kappa agonist properties without true specificity for one or the other of these subtypes. They also confirm that activation of peripheral mu, delta and kappa opiate receptors mediate the gastrointestinal motility effect of TMB.

Animals↗

PubMed2004

Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system.

Gut peptides exert diverse effects regulating satiety, gastrointestinal motility and acid secretion, epithelial integrity, and both nutrient absorption and disposal. These actions are initiated by activation of specific G protein-coupled receptors and may be mediated by direct or indirect effects on target cells. More recent evidence demonstrates that gut peptides, exemplified by glucagon-like peptides-1 and 2 (GLP-1 and GLP-2), directly regulate signaling pathways coupled to cell proliferation and apoptosis. GLP-1 receptor activation enhances beta-cell proliferation and promotes islet neogenesis via activation of pdx-1 expression. The proliferative effects of GLP-1 appear to involve multiple intracellular pathways, including stimulation of Akt, activation of protein kinase Czeta, and transactivation of the epidermal growth factor receptor through the c-src kinase. GLP-1 receptor activation also promotes cell survival in beta-cells and neurons via increased levels of cAMP leading to cAMP response element binding protein activation, enhanced insulin receptor substrate-2 activity and, ultimately, activation of Akt. These actions of GLP-1 are reflected by expansion of beta-cell mass and enhanced resistance to beta-cell injury in experimental models of diabetes in vivo. GLP-2 also promotes intestinal cell proliferation and confers resistance to cellular injury in a variety of cell types. Administration of GLP-2 to animals with experimental intestinal injury promotes regeneration of the gastrointestinal epithelial mucosa and confers resistance to apoptosis in an indirect manner via yet-to-be identified GLP-2 receptor-dependent regulators of mucosal growth and cell survival. These proliferative and antiapoptotic actions of GLP-1 and GLP-2 may contribute to protective and regenerative actions of these peptides in human subjects with diabetes and intestinal disorders, respectively.

Animals↗

PubMed1995

The effects of cisapride on plasma L-dopa levels and clinical response in Parkinson's disease.

Cisapride (CIS) is a prokinetic agent that increases gastrointestinal motility in normal individuals and improves constipation in Parkinson's disease (PD). We studied the effects of CIS on the clinical response and the peripheral pharmacokinetics of orally administered L-dopa given to patients with PD. Twenty patients with idiopathic PD and chronic constipation, whose response to L-dopa was suboptimal or characterized by fluctuations, agreed to participate in an open study that lasted for 2 weeks. Fourteen patients completed the study (mean age 65 +/- 9.3 years, mean duration of treatment 5.7 +/- 4.2 years, mean L-dopa daily doses 658.9 +/- 269.9 mg); six patients were excluded due to lack of compliance or changes in medication during the study. The end points of the study included the mean levels of L-dopa, the height of the peak of L-dopa in plasma, mean plasma levels of 3-OM-dopa, and the speed and quality of gait and visuomanual coordination before and during treatment with CIS. CIS increased peak plasma levels of L-dopa by 37% and the mean plasma levels of L-dopa by 13% with respect to those obtained with the same dose of L-dopa before the addition of CIS. Therefore, CIS appears to increase early absorption of L-dopa through acceleration of gastric emptying. CIS also increased plasma 3-OM-dopa levels, improved visuomanual coordination, and reduced gait disability. CIS improves gastrointestinal function and response to L-dopa in patients with PD and could be a helpful add-on medication in these patients.

Aged↗

PubMed2000

Gut-liver axis.

The gut and the liver are the key organs in nutrient absorption and metabolism. Bile acids, drugs, and toxins undergo extensive enterohepatic circulation. Bile acids play a major role in several hepatic and intestinal diseases. Endotoxins deriving from intestinal Gram-negative bacteria are important in the pathogenesis of liver and systemic diseases. Chronic liver diseases can influence gastrointestinal motility, which together with other factors may contribute to bacterial overgrowth and in patients with ascites to an increased risk of spontaneous bacterial peritonitis. Patients with end-stage liver disease frequently develop portal hypertension leading to varices, gastric vascular ectasia, and portal hypertensive gastroenteropathy. Several liver and biliary abnormalities are observed in patients with inflammatory bowel disease (primary sclerosing cholangitis, autoimmune hepatitis, cholelithiasis). The primary defect in hemochromatosis is located in the intestine, causing an inappropriate increase in iron absorption, and the liver is the site of earliest and heaviest iron deposition. Elevated transaminases are observed in many patients with celiac disease, and steatohepatitis frequently develops in patients with jejunoileal bypass and short bowel syndrome. Furthermore, the liver is the primary organ for metastasis of intestinal cancer. Many viral, bacterial, fungal, and parasitic diseases affect the intestine as well as the liver and the biliary tract.

Biliary Tract Diseases↗

PubMed2002

Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors.

The glucagon-like peptides include glucagon, GLP-1, and GLP-2, and exert diverse actions on nutrient intake, gastrointestinal motility, islet hormone secretion, cell proliferation and apoptosis, nutrient absorption, and nutrient assimilation. GIP, a related member of the glucagon peptide superfamily, also regulates nutrient disposal via stimulation of insulin secretion. The actions of these peptides are mediated by distinct members of the glucagon receptor superfamily of G protein-coupled receptors. These receptors exhibit unique patterns of tissue-specific expression, exhibit considerable amino acid sequence identity, and share similar structural and functional properties with respect to ligand binding and signal transduction. This article provides an overview of the biology of these receptors with an emphasis on understanding the unique actions of glucagon-related peptides through studies of the biology of their cognate receptors.

Alternative Splicing↗

PubMed2006

Spontaneous bacterial peritonitis: a therapeutic update.

Spontaneous bacterial peritonitis (SBP) is one of the main infectious complications of cirrhosis and occurs in 8-30% of hospitalized patients with ascites. SBP is characterized by infection of the ascitic fluid (AF) in the absence of any primary focus of intra-abdominal infection. The main route by which the AF becomes infected is the hematogenous route. The pathogenic mechanism by which infection develops is bacterial translocation from the intestinal flora to the mesenteric lymph nodes and from there to the bloodstream. Contributing factors are an increased growth of Gram-negative aerobic bacilli in the jejunum, changes in the intestinal barrier and in addition factors which could reduce the local flow of blood. For clinical diagnosis, patients with SBP may present signs of peritoneal irritation and pain, together with changes in gastrointestinal motility, sometimes with nausea, vomiting, diarrhea or ileus. Many patients, however, may not present any symptoms or signs as a result of the presence of SBP. Diagnostic paracentesis of the AF must be performed for every patient with cirrhosis, hospitalized with ascites. Laboratory diagnosis of SBP is carried out by polymorphonuclear count in the AF, together with a positive culture from the AF, which is characteristically monomicrobial. Escherichia coli has been the main bacterium isolated from AF as well as other Gram-negative bacteria from the Enterobacteriaceae family and Streptococcus genus. A more rapid diagnosis of SBP can be obtained via the use of leukocyte esterase, which is present in biological fluids and reacts with a component of the dipstick, changing its color. During the acute phase of SBP, antibiotics should be initiated promptly once the clinical and laboratory diagnosis of SBP has been made, before the result of AF culture. Cefotaxime or other third-generation cephalosporins have been considered the first-choice empirical antibiotics in the treatment of cirrhotic patients with SBP, and is efficacious in approximately 90% of cases. Broad-spectrum quinolones, which are almost completely absorbed after oral administration and diffuse rapidly through the AF, are currently used for oral treatment of uncomplicated SBP. Patients who have already had a previous episode of SBP, with a 69% probability of recurrence within a year, will benefit from prophylactic treatment. Cirrhotic patients with a high risk of SBP and other infections, such as those with gastrointestinal bleeding, also benefit from primary prophylaxis and norfloxacin has been used with success.

Animals↗

PubMed2003

Chronic treatment with interleukin-1beta attenuates contractions by decreasing the activities of CPI-17 and MYPT-1 in intestinal smooth muscle.

Interleukin-1beta (IL-1beta) is a proinflammatory cytokine that plays a central role in inflammatory bowel disease (IBD). In order to elucidate the mechanism of motility disorders frequently observed in IBD, we investigated the long term effects of IL-1beta on rat ileal smooth muscle contractility by using an organ culture system. When ileal smooth muscle strips were cultured with IL-1beta (10 ng/ml), contractions elicited by high K+ and carbachol were inhibited in a time-dependent manner. IL-1beta more strongly inhibited the carbachol-induced contractions than high K+ with decreasing myosin light chain phosphorylation. In the alpha-toxin-permeabilized ileal muscle, carbachol with GTP or guanosine 5'-3-O-(thio)triphosphate increased the Ca2+ sensitivity of contractile elements, and this G protein-coupled Ca2+ sensitization was significantly reduced in the IL-1beta-treated ileum. Among the functional proteins involved in the smooth muscle Ca2+ sensitization, CPI-17 expression was significantly reduced after the culture with IL-1beta, whereas the expressions of RhoA, ROCK-I, ROCK-II, MYPT-1, myosin light chain kinase, and myosin phosphatase (PP1) were unchanged. The phosphorylation level of CPI-17 by carbachol was low in accordance with the decrease in CPI-17 expression due to IL-1beta treatment. In contrast, constitutively phosphorylated MYPT-1 was also decreased in the IL-1beta-treated muscles. These results suggest that long term treatment with IL-1beta decreases either CPI-17 expression or MYPT-1 phosphorylation, which may result in an increase in myosin phosphatase activity to reduce force generation. Based on these findings, we consider IL-1beta to be an important mediator of gastrointestinal motility disorders in IBD, and CPI-17 and MYPT-1 are key molecules in the decreased smooth muscle contractility due to IL-1beta.

Animals↗

PubMed2005

The spectrum of irritable bowel syndrome: A clinical review.

BACKGROUND: Irritable bowel syndrome (IBS) is associated with a substantial burden on individual patients, health care systems, and society as a whole. OBJECTIVES: This review article provides an overview of the disease state and discusses treatment options. METHODS: The MEDLINE database was searched for original research and review articles published in English (from 1966 to July 2005) using the medical subject heading irritable bowel syndrome and the following subheadings: diagnosis, economics, pathophysiology, and therapy. Preference was given to articles that focused on new insights regarding pathophysiology and to those that addressed global symptom improvement for IBS. RESULTS: Symptoms of IBS vary with each patient and disease episode. Although improvement in individual IBS symptoms is desirable, the overall goal in managing patients with IBS is to achieve global symptom improvement. Traditional IBS therapies (ie, psychotherapy/behavioral therapy, bulking agents, antidiarrheals, antispasmodics, and tricyclic antidepressants) have lacked demonstrable efficacy in randomized controlled trials. Recent improvements in the understanding of IBS pathophysiology, particularly regarding the role of neurotransmitters and hormones in gastrointestinal motility, secretion, and visceral perception, have resulted in the development of novel treatments for IBS. In clinical trials, IBS-specific treatments (ie, agents that affect serotonergic pathways) have been associated with significant improvements in global symptoms. However, the added cost of treatment with these agents and the potential risks of serious adverse events (eg, severe constipation, severe diarrhea, ischemic colitis) may preclude their widespread use. Initial cost-effectiveness analyses with the novel IBS-specific agents suggest the benefits may outweigh the added costs. From a managed care perspective, the costs incurred by IBS-specific therapies may be offset by subsequent reductions in health care resource utilization by patients with IBS. CONCLUSIONS: IBS-specific agents offer an opportunity for patients with IBS to achieve global symptom improvement. However, when weighing the costs and potential risks against the potential benefits, clinicians should consider the nature and severity of the patient's symptoms, the degree of functional impairment, and the presence of psychosocial comorbidities.

Absenteeism↗