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Gastric electrical stimulation inhibits postprandial antral tone partially via nitrergic pathway in conscious dogs.

Gastric electrical stimulation (GES) has recently been explored as a therapeutic option for gastrointestinal motility disorders or obesity. The mechanism behind it is not fully elucidated. The aims of this study were to assess the effects of GES with different parameters on antral tone and to explore the involvement of the nitrergic pathway. Eight dogs equipped with a gastric cannula and one pair of serosal electrodes in the greater curvature 4 cm above the pylorus were studied on separate days. The study was composed of seven randomized sessions in the fed state [control, GES with different parameters, and GES plus neuronal nitric oxide synthase (nNOS) inhibitor]. Each session included three consecutive 30-min periods (baseline, GES, and recovery). GES was performed with long pulses or pulse trains. The antral volume was measured using an intragastric balloon connected with a barostat device. Behaviors of the dogs during each stimulation period were also noted. We found that 1) postprandial antral tone was reduced with GES with all tested parameter settings, reflected as a significant and substantial increase in antral volume ranging from 179 to 309%; 2) the inhibitory effect of GES on antral tone was partially blocked (decreased by 39.5%) with an nNOS inhibitor; and 3) mild symptoms were induced with GES and found to be correlated with the GES-induced increase in antral volume. We conclude that retrograde GES with long pulses or pulse trains inhibits antral tone, and this inhibitory effect is partially mediated via the nitrergic pathway. These results suggest that retrograde GES may have a therapeutic potential for obesity.

Animals↗

Neural mediation of the motilin motor effect on the human antrum.

To elucidate the mode of action of motilin on the stimulation of human gastrointestinal motility, we studied the effect of exogenous motilin during muscarinic or serotoninergic pharmacological blockade. Manometric recording of the interdigestive antroduodenal motility was carried out in 27 healthy volunteers until the appearance of a spontaneous antral phase III. The tested blocker was then administered intravenously and was followed 30 min later by a 10-min infusion of synthetic human motilin (50 ng/kg). Motilin administered on a background of saline induced a premature phase III migrating from the antrum to the duodenum in every tested subject (n = 5). A low dose of atropine (5 micrograms.kg-1.h-1 for 90 min) inhibited the motilin effect in two of five subjects [not significant (NS)], whereas a high dose of atropine (15 micrograms/kg given in 30 min) blocked the motilin-induced premature antral phase III in all instances (n = 5, P < 0.01). Exogenous motilin given with low-dose ondanseton (8 mg given in 15 min followed by 1 mg/h for 90 min) or high-dose ondansetron (32 mg given in 30 min) was without effect in three of seven (NS) or in two of five (NS) subjects, respectively. During the administration of 15 micrograms/kg atropine, when exogenous motilin always failed to induce a premature antral phase III motor, a phase III-type activity was generated at the duodenum in four of five subjects. We conclude that the induction by motilin of phase III activity in human antrum is dependent on muscarinic mediation and that the contractile effect of motilin on human duodenum involves a noncholinergic mechanism, different therefore from the antral pathway.

Adolescent↗

Beta3-adrenoceptors: relaxant function and mRNA detection in smooth muscle cells isolated from the human colon.

Functional involvement of beta3-adrenoceptors in controlling human gastrointestinal motility has not been unequivocally assessed yet. The direct myogenic contribution of these receptors was examined, by in vitro functional studies and analysis of mRNA expression, on smooth muscle cells separately isolated from taenia coli and circular muscle layers of the human colon. Isoproterenol, a nonselective beta-adrenoceptor agonist, relaxed, in a concentration-dependent manner, both human taenia coli and circular colonic smooth muscle cells, although displaying a higher intrinsic activity (65.3 +/- 2.3 vs. 55.2 +/- 1.4% maximal relaxation) and potency (pEC50: 7.41 +/- 0.07 vs. 6.32 +/- 0.08) were greater on taenia coli than circular cells. In the presence of the beta1-antagonist CGP20712A and of the beta2-antagonist ICI 118,551, a 25-30% decrease in isoproterenol intrinsic activity was observed on both cell types and on taenia coli, the nonselective beta1/beta2-antagonist propranolol produced a rightward shift of the isoproterenol concentration-response curve with mean estimated pKB values (8.12 +/- 0.27 at 0.1 microM and 6.45 +/- 0.13 at 1 microM) lower than that expected for both beta1- and beta2-adrenoceptors. CGP12177A and SR 58611A, two beta3-adrenoceptor agonists, presented an intrinsic activity comparable to that of isoproterenol in the presence of beta1- and beta2-antagonists, the former being more potent on taenia coli than on circular smooth muscle cells. Beta3-adrenoceptor mRNA was detected by reverse transcription PCR on both cell types. These results strongly suggest a direct functional role of beta3-adrenoceptors in the human colon.

Adrenergic beta-Agonists↗

Electrogastrography in patients with Parkinson's disease.

BACKGROUND: Impaired gastrointestinal motility in Parkinson's disease may affect absorption of levodopa and contribute to the disabling response fluctuations (RF). In this study gastric myoelectric activity was recorded with electrogastrography in patients with PD and correlated with the duration, severity and the presence of RF. METHOD: Electrogastrography (EGG) was performed in 36 patients with PD of which 22 were men. The mean age was 67 years (48-81), mean duration of disease was 7.07 years (1-20), and mean duration of treatment with levodopa was 5.07 years (1-20). Gastric dysrhythmia was diagnosed when either preprandial or postprandial dysrhythmia for more than 30% of the recording period was detected. RESULTS: The EGG was abnormal in 24 of 36 patients. Significant association was found between preprandial dysrhythmia and duration of disease (P=0.002); duration of levodopa treatment (P=0.003), severity of 86RF (P=0.001), but not with age (P=0.076). Out of 18 patients with RF, 17 had at least one pattern of dysrhythmia. In 11 out of the 18 patients without RF, the EGG was normal while the remaining seven had at least one pattern of dysrhythmia. CONCLUSION: Abnormal EGG was quite common in this group of patients with PD, particularly in those with RF. The most common pattern of abnormality was preprandial dysrhythmia, which was positively associated with disease duration and length of levodopa treatment. Although frequently asymptomatic, preprandial dysrhythmia leading to impaired gastric emptying may contribute to irregular absorption of levodopa from the small intestine and contribute to disabling response fluctuations.

Aged↗

Interaction between atrial natriuretic peptide and vasoactive intestinal peptide in guinea pig cecal smooth muscle.

BACKGROUNDS & AIMS: The role of atrial natriuretic peptide (ANP) in gastrointestinal motility is still unclear. The aim of this study was to investigate the relationship between ANP and vasoactive intestinal peptide (VIP) in guinea pig cecal circular smooth muscle cells. METHODS: The inhibition of 125I-ANP binding or 125I-VIP binding to cecal smooth muscle cells was assessed using unlabeled peptides (i.e., ANP, ANP fragments, VIP, secretin, and peptide histidine isoleucine); the effect of ANP, ANP fragments, and VIP on muscle contraction stimulated by 1 mumol/L carbachol was assessed; and the inhibitory effects of ANP 1-11 on VIP-induced relaxation, ANP 1-11 and VIP 10-28 (a VIP antagonist) on ANP-induced relaxation, and nitric oxide production inhibitors on ANP-induced relaxation were assessed. RESULTS: The specific binding of 125I-ANP was inhibited completely by unlabeled ANP and VIP in a dose-dependent manner but only slightly inhibited by secretin and peptide histidine isoleucine. ANP 1-11 and C-atrial natriuretic factor inhibited the binding of 125I-ANP with a lower affinity than ANP. ANP only partly inhibited 125I-VIP binding. ANP and VIP inhibited 1 mumol/L carbachol-induced contraction in a dose-dependent manner. ANP 1-11 significantly inhibited VIP-induced relaxation. ANP 1-11, VIP 10-28, and NO production inhibitors completely inhibited ANP-induced relaxation. CONCLUSIONS: The results of the study showed that ANP 1-11 antagonized ANP-induced relaxation and that ANP stimulated NO production and subsequently induced relaxation via a receptor to which VIP binds.

Animals↗

Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: influence on postoperative ambulation and pulmonary function.

In a randomized double-blind study of thirty grossly obese patients undergoing gastroplasty for weight reduction, the effects of intramuscular and epidural morphine were compared as regards analgesia, ambulation, gastrointestinal motility, early and late pulmonary function, duration of hospitalization, and occurrence of deep vein thrombosis in the postoperative period. The patients were operated on under thoracic epidural block combined with light endotracheal anesthesia. A six-grade scale was devised to quantify postoperative mobilization. A radioactive isotope method using 99mTc -plasmin was employed to detect postoperative deep vein thrombosis. For 14 hr after the first analgesic injection, respiratory frequency was noted every 15 min and arterial blood gases were measured hourly. Peak expiratory flow was recorded daily until the patient was discharged from hospital. Spirometry was performed the day before and the day after surgery. Plasma concentrations of morphine were measured after both intramuscular and epidural administration. Both intramuscular and epidural morphine gave effective analgesia, but the average dose of intramuscular morphine was up to seven times greater than that required by the epidural route. A larger number of patients receiving epidural morphine postoperatively were able to sit, stand, or walk unassisted within 6, 12, and 24 hr, respectively. Being alert and more mobile as a result of superior postoperative analgesia from epidural morphine, patients in this group benefited more from vigorous physiotherapy routine, which resulted in fewer pulmonary complications. Furthermore, earlier postoperative recovery of peak expiratory flow and bowel function presumably contributed to a significantly shorter hospitalization in patients receiving epidural morphine. There was no evidence of prolonged respiratory depression in this high-risk category of patients. The 99mTc -plasmin tests revealed no significant difference between the two groups.

Adult↗

Gastroesophageal reflux in infants: evaluation of a new intraluminal impedance technique.

In this study, pH metry was simultaneously applied with a new technique, the intraluminal multiple electrical impedance (IMP) procedure, for measuring gastrointestinal motility for gastroesophageal reflux (GER) detection. Seventeen infants with clinical symptoms of GER disease such as recurrent apnea, aspiration pneumonia, wheezing, and failure to thrive were investigated during two feeding periods. A single catheter combining a pH electrode with seven electrodes for impedance measurements over a distance of 8.5 cm was used for the investigation. In all patients, 185 acid episodes were detected by pH metry. In 106 of these 185 acid episodes, a unique pattern in the IMP readings was noted, indicated by a retrograde esophageal volume flow. These episodes were regarded as acid GER episodes. Seventy-one of the 185 acid episodes occurred during the clearance process of a preceding acid GER characterized by typical IMP readings of an anterograde bolus transport. Eight of 185 acid episodes were missed in the IMP readings for technical reasons. The IMP pattern described as characteristic for a GER was observed in 490 other episodes not detected by pH metry. More than 75% of all GER detected by IMP reached the pharyngeal space; 73% of all GER occurred during feeding and the first 2 postprandial hours and 27% occurred during the remaining time until the next feeding. Even during the latter period, 34% of GER were detected by IMP only; they were missed by pH metry. Volume clearance indicated by IMP was always completed earlier than acidity clearance. The results show that IMP technique facilitates the detection of all GER, whereas pH metry is confined to the measurement of acid GER. Therefore, this technique might improve the evaluation of GER disease and detection of GER in conditions with gastric hypoacidity.

Electric Impedance↗

Effect of extended parietal cell vagotomy on long-term nutrition and digestive function.

OBJECTIVE: To study the effect of extended parietal cell vagotomy (EPCV) on long-term nutritional status and digestive-absorption function. PATIENTS AND METHODS: Thirty-six patients undergoing EPCV were compared with 30 patients with subtotal gastrectomy (SG) 7-14 years after operation. The patients were evaluated in terms of nutritional status, gastric secretion, gastrointestinal motility, and intestinal digestive-absorption function. RESULTS: The nutritional status was generally less satisfactory in 33.3% patients with anemia after SG and body weight decreased in 54%. The patients after EPCV were all in good nutritional status, and had no symptoms of anemia; 56% of them had body weight increased by more than 3 kg. The mean basal acid output (BAO), maximal acid output (MAO), and peak acid output (PAO) of the EPCV group were significantly reduced after operation (P < 0.01), and moderately reduced as compared with those of the control group (P > 0.05). But the BAO, MAO, and PAO of the SG group were more markedly reduced than those of the control group (P < 0.001) before operation. Vitamin B12, folacin, intrinsic factor and iron protein level of serum in the EPCV group were slightly decreased as compared with those of the control group (P > 0.05), but more significantly decreased in the SG group than in the control group (P < 0.001). Iron protein and intrinsic factor level was lower than the normal level. The gastric emptying time and small intestinal passthrough time of EPCV were more close to the normal physiological status, but in the SG group, they were significantly fast (P < 0.001). The results of intestinal D-xylose absorption test in EPCV and SG groups were similar (P > 0.05). CONCLUSIONS: EPCV is capable of preserving gastric acid of physiologic level and normal digestion-absorption function. The effect of EPCV on long-term nutrition and digestion absorption function was extremely milder than that of SG. Therefore, a theoretical basis is provided for the rationality of EPCV.

Adult↗

Carbon monoxide activates human intestinal smooth muscle L-type Ca2+ channels through a nitric oxide-dependent mechanism.

Carbon monoxide (CO) is increasingly recognized as a physiological messenger. CO is produced in the gastrointestinal tract with diverse functions, including regulation of gastrointestinal motility, interacting with nitric oxide (NO) to mediate neurotransmission. The aim of this study was to determine the effect of CO on the human intestinal L-type Ca(2+) channel expressed in HEK cells and in native cells using the patch-clamp technique. Extracellular solution contained 10 mM Ba(2+) as the charge carrier. Maximal peak Ba(2+) current (I(Ba)) was significantly increased by bath application of 0.2% CO to transfected HEK cells (18 +/- 3%). The NO donor S-nitroso-N-acetylpenicillamine also increased I(Ba), and CO (0.2%) increased NO production in transfected HEK cells. The CO-induced increase in I(Ba) was blocked when cells were pretreated with 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) or inhibitors of NO synthase (NOS). The PKA inhibitor KT-5720 (0.5 microM) and milrinone (3 microM), a phosphodiesterase (PDE) III inhibitor, blocked the effect of CO on I(Ba). Similar effects were seen in freshly dissociated human intestinal smooth muscle cells. The data suggest that exogenous CO can activate native and heterologously expressed intestinal L-type Ca(2+) channels through a pathway that involves activation of NOS, increased NO, and cGMP levels, but not PKG. Rather, the pathway appears to involve PKA, partly by reducing cAMP breakdown through inhibition of PDE III. CO-induced NO production may explain the apparent discrepancy between the low affinity of guanylyl cyclase for CO and the robust cGMP production evoked by CO.

Calcium Channels, L-Type↗

Epidural analgesia and risk of anastomotic leakage.

BACKGROUND AND OBJECTIVES: Based on case reports of early anastomotic leakage in patients receiving epidural analgesia with local anesthetic and data to document a stimulatory effect of epidural block on gastrointestinal motility, it has been suggested that continuous infusion of epidural local anesthetic may lead to an increased incidence of anastomotic leakage. Therefore, we examined the association between continuous epidural local anesthetic and anastomotic leakage by reviewing the literature. METHODS: Review of controlled, randomized clinical trials aiming to investigate postoperative complications in which continuous postoperative epidural local anesthetic was administered in patients scheduled for colorectal surgery with an anastomosis. Data were obtained from a Medline search (1966-May 2000), previous review articles, references cited in original papers, and personal communication with investigators. Twelve trials including a total of 562 patients met the inclusion criteria. RESULTS: Sixteen of 266 patients (6.0%, 95% confidence interval [CI]: 3.5% to 9.6%) receiving postoperative epidural local anesthetic or epidural local anesthetic-opioid mixtures developed anastomotic leakage, compared with 10 of 296 patients (3.4%, 95% CI: 1.6% to 6.1%) receiving epidural or systemic opioid-based analgesia (P >.05 between groups, Fisher's test). The risk of overlooking a significant difference (type II error) was approximately 67% (power: 33%). Studies including more than 1,037 patients in each group are needed to demonstrate an increased risk of anastomotic leakage from 3.4% to 6.0% with 80% power and 2alpha = 0.05. There was no significant difference (P >.05 between groups, Fisher's test) between subgroups of study design: Epidural local anesthetic-versus systemic or epidural opioid, or epidural local anesthetic-opioid mixtures versus systemic or epidural opioid. CONCLUSIONS: So far, there is no statistically significant evidence from randomized trials to indicate epidural analgesia with local anesthetic to be associated with an increased risk of anastomotic breakdown. However, relatively few patients have been included in randomized trials, indicating a need for more studies to secure valid conclusions.

Analgesia, Epidural↗

Initiation of migrating myoelectric complex in sheep by duodenal acidification and hyperosmolarity: role of vagus nerves.

Gastrointestinal motility was studied in conscious sheep by X-radiography and by electromyography from chronically implanted electrodes before and after total thoracic vagotomy. Duodenal infusion of 0.5-3 mmol HCl (0.035-0.1 M-HCl) induced premature duodenal regular spiking activity (r.s.a.) within 1-7 min in fifteen of seventeen sheep studied when infused at 20 min after a natural r.s.a. There was no correlation between abomasal pH and any phase of the migrating myoelectric complex (m.m.c.). Duodenal alkalinization by infusion of 0.3 M-Tris buffer (pH 10.2) or 0.1 M-NaHCO3 had no influence on the occurrence of the m.m.c. Duodenal infusion of 20-50 ml 0.5 M-NaCl induced a premature duodenal r.s.a. within 1-5 min in seven of eight sheep. Vagotomy did not prevent the initiation or migration of the m.m.c., but reduced the rate of propagation of the r.s.a. from 40.5 +/- 7.2 (mean +/- S.E. of mean) to 16.7 +/- 0.1 cm/min in the duodenum, from 27.3 +/- 4.1 to 16.6 +/- 0.8 cm/min in the jejunum, and from 21.4 +/- 1.1 to 13.7 +/- 0.7 cm/min in the proximal ileum. Initially the frequency of r.s.a. increased, especially in the duodenum where they recurred at an interval of 98.4 +/- 6.8 min before vagotomy; and at 23.4 +/- 1.8 min in the first 24 h after vagotomy; the interval had lengthened to 86.7 +/- 5.2 min 2-3 weeks after vagotomy. Premature duodenal r.s.a. was not induced by duodenal infusion of HCl in five, or by duodenal infusion of hyperosmolar NaCl in three chronically vagotomized sheep. It is concluded that the vagus nerves contribute to the regulation of the frequency and propagation of the m.m.c. in sheep; duodenal acidification is not essential nor is it the normal stimulus for initiation of r.s.a., but duodenal infusion of HCl or hyperosmolar NaCl can initiate a premature duodenal r.s.a. via the vagus nerves.

Abomasum↗

Effects of cinitapride on gastric ulceration and secretion in rats.

OBJECTIVE AND DESIGN: The aim of the present study was to examine the effects of cinitapride, a novel prokinetic benzamide-stimulating gastrointestinal motility agent, on gastric secretion and ulceration in rats and elucidate some possible vascular and anti-oxidant mechanisms of such protection. MATERIAL: Male Wistar rats. TREATMENT: Cinitapride (CNT, Lab. Almirall, S.A.) (0.25, 0.5, and 1 mg/kg) and 5-hydroxytryptamine (5-HT, Sigma Chemical Co., St. Louis, MO, USA) (10 mg/kg), administered intraperitoneally (i.p.). METHODS: Gastric ulceration was induced by instillation of 1 mL/100 g animal of 50% (v/v) ethanol in distilled water and by pylorus-ligated rat model. Gastric microvascular changes, and the activity of myeloperoxidase (as a marker of neutrophil infiltration) and glutathione peroxidase (an important enzyme in scavenging of lipid peroxides) were determined. The results were compared with those of 5-HT. The data were evaluated using Student's t-test for paired data and the non-parametric Mann-Whitney U-test. RESULTS: In 4 h pyloric-ligated animals, i.p. CNT did not significantly reduce the incidence of gastric mucosal damage, and no significant differences were found in the values of total volume and acidity. However, CNT caused a marked and dose-dependent reduction of haemorrhagic lesions induced by 50% v/v ethanol. These protective effects were specifically related to a reduction of neutrophil infiltration. CNT at the dose of 1 mg/kg raised the decreased glutathione peroxidase activity to the control level. In contrast, pretreatment with 5-HT worsened the ethanol-induced erosions, but did not significantly induce any gastric microvascular changes. However, the myeloperoxidase activity rose markedly and the glutathione peroxidase levels decreased significantly in the mucosa injured by 50% v/v ethanol. CONCLUSIONS: This study demonstrates a new gastroprotective feature of CNT that could be partly explained not only through reduction of neutrophil toxicity but also by an increased synthesis of free-radical scavenging enzymes such as glutathione peroxidase. Furthermore, it is likely that serotonergic-dependent mechanisms are also involved via 5-HT2-receptor blockade and 5-HT1 receptor activation.

Animals↗

New antiemetic drugs.

Three major areas of medicine are identified in which there is a need for new antiemetic drugs. These are the nausea and vomiting arising from gastrointestinal motility disturbances (functional dyspepsia, diabetic neuropathy, classical migraine), the sickness evoked by abnormal motion, and the severe emesis experienced by cancer patients as a result of certain cytotoxic therapies. For gastrointestinal-related nausea, selective stimulants of gut motility are suggested to form the basis for a new type of antiemetic therapy. In motion sickness, there has been progress in the understanding of the illness, but little advance in the development of new drugs that selectively prevent this type of sickness. In cancer chemo- and radio-therapy, the discovery that selective 5-HT3 (5-HT, 5-hydroxytryptamine) receptor antagonists can prevent severe cytotoxic-evoked emesis now promises to radically change the type of antiemetic therapy given to these patients. This type of antiemetic compound and the pharmacology of the new 5-HT3 receptor antagonists are, therefore, discussed in detail.

Animals↗

Effects of 5-hydroxytryptamine (5-HT) on the discharge of vagal mechanoreceptors and motility in the upper gastrointestinal tract of the ferret.

This study was undertaken to investigate the sensitivity of vagal mechanoreceptor afferent fibres from the stomach and small intestine to 5-hydroxytryptamine (5-HT, 10 and 50 micrograms), and to relate this to motor activity. The discharge of single afferent fibres was recorded from the cervical vagus of Urethane anaesthetized ferrets. These had receptive fields in the corpus (15 fibres), antrum (11 fibres), duodenum (3 fibres) or jejunum (1 fibre), and their discharge was excited by distension of the segment containing the receptive field, or by mechanical probing. Conduction velocity was calculated in 7 fibres, and always fell in the C-fibre range (0.84 +/- 0.07 m/s). Injection of 5-HT intra-arterially via the coeliac axis evoked both contraction and relaxation with the dominant effect dependent on region and dose of 5-HT. However, irrespective of the motor response, the mechanoreceptor discharge closely mirrored both the magnitude and the time-course of the motor response. The relationship between the changes in discharge of individual mechanoreceptors and change in intraluminal pressure in all regions in response to both doses of 5-HT fitted a linear regression y = 17.1 +/- 1.2x and was highly significant (P < 0.0001), indicating that 5-HT has no modulatory effect on the sensitivity of mechanoreceptors to changes in intraluminal pressure. This study suggests that vagal mechanoreceptors supplying the gastrointestinal tract respond to changes in motor activity evoked by 5-HT, rather than to 5-HT directly.

Animals↗

Study of bacterial translocation from gut after paraplegia caused by spinal cord injury in rats.

STUDY DESIGN: Normal rats and paraplegic rats with and injured spinal cord were used to study bacterial translocation from gut. OBJECTIVE: To investigate whether bacterial translocation from gut occurs after spinal cord injury. SUMMARY OF BACKGROUND DATA: It has been demonstrated that trauma and operation can lead to gastrointestinal paralysis; disturbance of gastrointestinal motility following trauma may cause bacterial overgrowth in gastrointestinal tract and increase the incidence of bacterial translocation. However, bacterial translocation from gut after spinal cord injury has not been studied. METHODS: Under aseptic manipulation, samples of blood were collected for bacterial cultures and endotoxin determination. In the meantime, samples of mesenteric lymph node, spleen, and liver were collected for bacterial culture. The jejunum and ileum were observed by light and electron microscope. RESULTS: Endotoxemia and bacterial translocation appeared 24 hours and 48 hours correspondingly after spinal cord injury complicated with paraplegia. CONCLUSION: Bacterial translocation from gut would occur after spinal cord injury in rats, which indicated that antibiotics should be administered to paraplegic patients with spinal cord injury as soon as possible to prevent potential bacterial translocation.

Animals↗

Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea.

BACKGROUND: Diarrhea is the most frequently reported adverse event in mycophenolate mofetil (MMF)-treated transplant patients. The aim of this study was to explore the gastrointestinal tract in MMF-treated renal transplant recipients with persistent afebrile diarrhea to characterize its nature and etiology. METHODS: Renal transplant recipients with persistent afebrile diarrhea (daily fecal output >200 g) were prospectively investigated for infections, morphologic, and functional (gastrointestinal motility and intestinal absorptive capacity) integrity of the gastrointestinal tract; 26 patients met the inclusion criteria. RESULTS: All but one patient had an erosive enterocolitis. Seventy percent of the patients had malabsorption of nutrients, contributing to the diarrhea. In +/-60%, an infectious origin was demonstrated and successfully treated with antimicrobial agents without changes in immunosuppressive regimen. In +/-40%, no infection occurred, but a Crohn's disease-like pattern of inflammation was noted. These patients also had a less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough level of mycophenolic acid (MPA). Cessation of MMF, however, was associated with allograft rejection in one third of these patients. CONCLUSIONS: Persistent afebrile diarrhea in renal transplant recipients is characterized by erosive enterocolitis, which is of infectious origin in +/-60%. In +/-40%, a Crohn's disease-like (entero-)colitis was present. Because reduction or cessation of MMF was the only effective therapy, MPA or one of its metabolites may be suggested as a possible cause. However, reduction or cessation of MMF was associated with an increased risk for rejection.

Adult↗