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Tachykinin receptors in the gut: physiological and pathological implications.

The tachykinins substance P and neurokinin A participate in the regulation of gastrointestinal motility, secretion, vascular permeability and pain sensitivity. Advances made during the past two years corroborate a causal involvement of tachykinins in inflammation-induced disturbances of gut function, such as dysmotility, secretory diarrhoea, oedema and hyperalgesia. It would therefore appear that tachykinin receptors, which in the digestive system are expressed in a cell-specific manner, represent attractive targets for novel therapeutics in gastroenterology.

Animals↗

Erythromycin induces pyloric relaxation accompanied by a contraction of the gastric body after pylorus-preserving gastrectomy.

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is a function-preserving surgery; however, long-term retention of food in the residual stomach is a frequent complication during the early postoperative period. We reported that gastric stasis after PPG was attributable to the delayed recovery of gastric phase III, in which pyloric relaxation accompanied a contraction of the gastric body. The objective of the present study is to determine whether erythromycin can induce phase III with pyloric relaxation after PPG. METHODS: We studied gastrointestinal motility in dogs after PPG by using strain gauge force transducer. After randomized administration of either erythromycin or saline, interdigestive gastropyloroduodenal motility was recorded. RESULTS: Erythromycin induced phase III with pyloric relaxation in the early postoperative period. Pyloric relaxation accompanied a contraction of the gastric body. Compared with the saline group (body: 87.2 +/- 16.7 mmHg x min, antrum: 69.7 +/- 13.7 mmHg x min, pylorus: 91.7 +/- 22.1 mmHg x min), the erythromycin group showed significantly increased gastropyloric motility indexes (body: 506.2 +/- 33.5 mmHg x min, antrum: 430.9 +/- 53.7 mmHg x min, pylorus: 589.5 +/- 59.5 mmHg x min). CONCLUSIONS: Erythromycin can induce phase III, in which pyloric relaxation accompanied a contraction of the gastric body in the early postoperative period after PPG. Erythromycin might be used as a prokinetic agent for the treatment of early gastric stasis after PPG.

Animals↗

[Long-term effect of extended parietal cell vagotomy on patients' nutrition and digestive function].

In this study, 36 patients undergoing extended parietal cell vagotomy (EPCV) were compared with 30 patients with subtotal gastrectomy 7-14 years after surgery. The patients' nutritional status, gastric sectretion, gastrointestinal motility and intestinal absorption function were evaluated. The nutritional status was generally less satisfactory in 33. 3% patients with anaemia after gastrectomy and decrease of body weight in 54%. The patients after EPCV were all in good nutritional status, with no anemia; 56% of them had a body weight increase of more than 3kg. Therefore, the rationality of EPCV was estalished.

Adult↗

[Pharmacological effects of the gastroprokinetic agent mosapride citrate].

Mosapride citrate (mosapride) is a novel gastroprokinetic agent that enhances the gastrointestinal motility by stimulating the 5-hydroxytryptamine4 (5-HT4) receptor. Mosapride dose-dependently enhanced the gastric emptying of a liquid or solid meal in rats with a potency equal to that of cisapride and more potent than that of metoclopramide. In rats, mosapride improved the gastric emptying delayed by gastroduodenal surgical intervention. In the conscious dogs with force transducers implanted chronically, mosapride stimulated antral and duodenal motility with a potency equal to those of cisapride. In isolated guinea-pig ileal longitudinal muscle preparations, mosapride enhanced the electrically stimulated contractions, and the enhancing effect of mosapride was antagonized by a high dose of tropisetron, a 5-HT4-receptor antagonist. In addition, mosapride inhibited [3H]-GR-113808 binding to 5-HT4 receptor sites of guinea-pig ileum and striatum. Mosapride had no affinity for dopamine D2 receptor, whereas metoclopramide and cisapride had a high affinity for dopamine D2 receptor. In isolated guinea-pig papillary muscles, mosapride did not prolong the duration of action potentials, whereas cisapride concentration-relatedly prolonged it. In conclusion, mosapride is a selective and potent 5-HT4 receptor agonist and improves gastrointestinal symptoms in patients with non-ulcer dyspepsia without causing the extrapyraminal syndrome associated with dopamine-D2-receptor blockage and adverse cardiovascular effects such as torsadoes de points.

Animals↗

Effects of etifoxine on stress-induced hyperthermia, freezing behavior and colonic motor activation in rats.

Anxiety disorders are often associated with autonomic symptoms, including heart palpitations, sweating, elevation of body temperature and alterations of gastrointestinal motility. Some of the alterations observed in animals exposed to stress are analogous to changes in a number of physiological and endocrine parameters observed in anxious patients. With the purpose to guide further clinical studies in subtypes of anxious patients, etifoxine, a nonbenzodiazepine anxiolytic compound, was evaluated in two rat models of anxiety with measures of physiological manifestations: stress-induced hyperthermia (SIH) and conditioned-fear-stress-induced freezing behavior and activation of colonic motility. The sequential handling of animals induced a rise in body temperature attenuated by etifoxine (50 mg/kg IP). The emotional stress induced by fear to receive electric foot shocks is accompanied by freezing behavior and an increase of the frequency of ceco-colonic spike bursts: both parameters were reduced by etifoxine (25-50 mg/kg IP), independently of changes in pain perception and memory-related processes. In response to a stressful event, the stimulation of the corticotropin-releasing hormone (CRH) system is probably involved in the observed modifications of body temperature and colonic motility. It is hypothesized that stress-induced CRH activation is attenuated by the enhancement of the inhibitory GABAergic system activity associated with etifoxine. These findings will guide future evaluation of etifoxine in the treatment of selected anxious patients with altered autonomic symptomatology.

Analysis of Variance↗

Abnormal gastrocolic response in patients with intestinal pseudo-obstruction.

Gastrointestinal motility disturbances after endogenous stimuli have been demonstrated only in the esophagus and small intestine in patients with chronic idiopathic pseudo-obstruction. The 1,000-calorie meal stimulated a significant increase in spike and contractile activity in normal subjects. No increase in colonic spike or contractile activity occurred in patients with chronic idiopathic pseudo-obstruction even though colonic motility increased normally following the administration of neostigmine methylsulfate. These findings suggest that the normal response to eating is absent in patients with chronic idiopathic intestinal pseudo-obstruction even though their smooth muscle has been shown to be responsive to cholinergic stimulation. This loss of a gastrocolic response is further evidence for a disorder of the neurohumoral control mechanisms in patients with chronic idiopathic intestinal pseudo-obstruction.

Adult↗

Pharmacokinetics and toxic effects of lithium chloride after intravenous adminstration in conscious horses.

OBJECTIVE: To determine the pharmacokinetics and toxic effects associated with IV administration of lithium chloride (LiCl) to conscious healthy horses. ANIMALS: 6 healthy Standardbred horses. PROCEDURE: Twenty 3-mmol boluses of LiCl (0.15 mmol/L) were injected IV at 3-minute intervals (total dose, 60 mmol) during a 1-hour period. Blood samples for measurement of serum lithium concentrations were collected before injection and up to 24 hours after injection. Behavioral and systemic toxic effects of LiCl were also assessed. RESULTS: Lithium elimination could best be described by a 3-compartment model for 5 of the 6 horses. Mean peak serum concentration was 0.561 mmol/L (range, 0.529 to 0.613 mmol/L), with actual measured mean serum value of 0.575 mmol/L (range, 0.52 to 0.67 mmol/L) at 2.5 minutes after administration of the last bolus. Half-life was 43.5 hours (range, 32 to 84 hours), and after 24 hours, mean serum lithium concentration was 0.13+/-0.05 mmol/L (range, 0.07 to 0.21 mmol/L). The 60-mmol dose of LiCl did not produce significant differences in any measured hematologic or biochemical variables, gastrointestinal motility, or ECG variables evaluated during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Distribution of lithium best fit a 3-compartment model, and clearance of the electrolyte was slow. Healthy horses remained unaffected by LiCl at doses that exceeded those required for determination of cardiac output. Peak serum concentrations were less than steady-state serum concentrations that reportedly cause toxic effects in other species.

Animals↗

Pharmacological study of Stachytarpheta cayennensis Vahl in rodents.

Freeze-dried aqueous extracts (AEs, 0.1-1g/kg body wt., p.o.) obtained from entire or selected parts of Stachytarpheta cayennensis were tested for their effects on gastric secretion, gastric motility, inflammation and pain in rodents, with the purpose of validating the plant's ethnomedical uses. The AE-Total, AE-Flowers and AE-Leaves but not AE-Stems inhibited the gastric acid secretion in pylorus-ligated rats with varying potency. Purification of AEs yielded the semipurifed fractions EtFs rich in iridoids. All the EtFs with exception of EtF-Stems inhibited gastric acid secretion of pylorus ligated mice. While AE-Total stimulated the intestinal transit of mice by 43%, AE-Leaves delayed it by 38%. These effects on intestinal transit were not observed when the EtFs were tested. Only AE-Leaves and AE-Flowers altered the gastric emptying of semisolids, increasing it by 45% and 69%, respectively. These results indicate that the compounds related to inhibition of gastric acid secretion and gastrointestinal motility are different. The AE-Total reduced abdominal writhing induced by acetic acid potently (ED50 value = 700 mg/kg, p. o.) without altering the writhes induced by acetylcholine. Attempts to identify the mechanism of analgesia were unsuccessful since the AE-Total did not show analgesic effects when tested in different models of pain such as formalin and capsaicin or the tail-flick test. Pretreatment of animals with AE-Total did not show antiinflammatory activity in any of the acute (paw edema induced by carrageenin, dextran or histamine, pleurisy induced by carrageenin and capsaicin-induced mouse ear edema) or chronic (air pouch) models used. No toxic signs were observed after administration of the different extracts up to 2 g/kg body wt., p.o. Collectively, the results confirmed folk information indicating presence of analgesic, mild laxative and potent inhibition of gastric secretion activities in the aqueous extracts of S. cayennensis. The results do not, however confirm the folk use of the plant as an antiinflammatory medicine.

Animals↗

The role of Helicobacter pylori infection in non-ulcer dyspepsia.

It is currently unclear whether Helicobacter pylori (H. pylori) infection plays a role in patients who fulfil the criteria for non-ulcer dyspepsia. This paper reviews evidence for H. pylori-induced changes in gastric emptying, gastrointestinal motility, gastric acid secretion, and gastric perception in patients with non-ulcer dyspepsia. Problems in study design and execution of non-ulcer dyspepsia treatment trials are discussed. The results of non-ulcer dyspepsia treatment trials which have been performed in H. pylori-positive patients are reviewed. To date none of them has convincingly shown that cure of the H. pylori infection leads to a sustained improvement in symptoms.

Anti-Ulcer Agents↗

The control mechanisms of gastric emptying are not overridden by motor stimulants.

We wanted to determine if an acceleration of the normal emptying rate by motor stimulants interfers with control mechanisms limiting gastric emptying. Therefore, we studied the effects of 5-hydroxytryptophane (5-HTP) and cisapride on canine gastrointestinal motility and gastric emptying after ingestion of viscous acaloric and nutritive meals. Prolonged contractions and relaxations that change lumen size (isotonic component) and wall tension (isometric component) are defined as "basal contractions" and "basal relaxations", respectively. The nutrient meal emptied much slower than the acaloric meal due to several alterations of gastric, pyloric, and duodenal motility. Both drugs stimulated antral motility but failed to accelerate gastric emptying of the nutrient meal. The main causes for the failure were a basal relaxation of the proximal antrum and a basal contraction of the duodenum. In conclusion, basal contractions of the proximal antrum and duodenum play an important role in the process of gastric emptying, and under physiological conditions the control mechanisms of gastric emptying provide an optimal emptying rate that cannot be markedly accelerated by 5-HTP and cisapride.

5-Hydroxytryptophan↗

Erythromycin for prokinesis: imprudent prescribing?

Problems with antibiotic resistant bacteria are increasing in the hospital and particularly in the intensive care unit. Methicillin-resistant Staphylococcus aureus, Acinetobacter baumanii and extended spectrum beta-lactamase producing gram-negative bacilli constitute a therapeutic and infection control challenge. Early enteral feeding improves survival in patients in the intensive care unit. Prokinetic agents are routinely used in patients with inappropriate gastrointestinal motility. The use of erythromycin at sub-therapeutic doses as a prokinetic agent is a cause of concern for the following reasons: it can increase the emergence and spread of antibiotic resistance and the likelihood of Clostridium difficile disease. The use of an antibiotic as a prokinetic agent does not constitute prudent antimicrobial prescribing and should be avoided. Alternative agents, whenever possible, should be used.

Anti-Bacterial Agents↗

Non-antimicrobial activities of macrolides.

While using macrolides for the treatment of infectious diseases, some non-microbiological effects have been observed. The stimulation of gastrointestinal motility, which is a common side-effect of macrolides, may be advantageous in patients with poor upper gut motility. Macrolides, as well as directly inhibiting bacterial growth, may exert immunomodulatory effects. Utilisation of these properties may be useful in the treatment of chronic inflammatory conditions, especially if bacterial infection is also implicated. Preliminary evidence also suggests that the currently available macrolide antibiotics possess antitumour activity. In the future, an increased understanding of the structure-activity relationships of macrolides may result in the development of new structurally related compounds that concentrate on these pharmacological properties in addition to, or instead of, antimicrobial activity.

Anti-Bacterial Agents↗

[Structure, localization and physiologic role of pituitary adenylate cyclase activating polypeptide (PACAP)].

PACAP was isolated on the basis of its ability to stimulate adenylate cyclase in primary anterior pituitary cell culture from ovine hypothalami by Miyata et al. in 1989. This peptide is structurally related to the secretin family and shows a 67% sequence homology with vasoactive intestinal polypeptide (VIP). The amino acid sequence of PACAP has been highly preserved during the evolution that may be connected with its important physiological role. Similar to other "brain-gut peptides" PACAP is localized not only in the central but in the peripheral nervous system and in non-neural tissues as well. In addition to its hypophysiotropic effects in the hypothalamo-hypophysial system PACAP exerts its effects on water-salt balance, cardiovascular functions, gastrointestinal motility and secretion and also on the regulation of reproductive functions. PACAP has a role in certain neuro-immuno-endocrine processes, in the differentiation of the nervous system, and it has neuroprotective effects in the case of ischaemia and various toxic agents. Locally PACAP takes its effects as an auto- and paracrine hormone, a neurotransmitter or a neuromodulator in different organs. Besides VIP, PACAP plays an important role in the function of the photo-neuro-endocrine system.

Amino Acid Sequence↗

Mechanism of pellet egestion in great-horned owls (Bubo virginianus).

To study the mechanism of oral pellet egestion in great-horned owls, bipolar electrodes and strain-gauge transducers were chronically implanted in the esophagus, muscular stomach, and duodenum of six owls. Recordings from conscious owls plus simultaneous radiographic observations revealed characteristic gastrointestinal motility patterns associated with egestion. Beginning at about 12 min before egestion, gastric contractions formed the final shape of the pellet and pushed it into the lower esophagus. The pellet was moved out of the esophagus by antiperistalsis during the last 8--10 s before egestion. During pellet egestion, contractions of abdominal muscles were not detected. Pellet egestion appears to be unlike either emesis in mammals with a simple stomach or regurgitation in ruminants.

Action Potentials↗

Irritable bowel syndrome: an update on therapeutic modalities.

Irritable bowel syndrome (IBS) is the most common condition that a physician faces in the GI clinic. Of the general population, 10 - 25% suffer from symptoms judged to be IBS. The negative impact of this disease includes not only pain, suffering and direct medical expenses but also significant social and job-related consequences. IBS can be the result of dysfunction in any part of the brain-gut axis: alterations in the CNS caused by psychological or other factors, abnormal gastrointestinal motility, or heightened visceral sensations. Diagnosis is based on either the Manning or Rome-II criteria. Education, reassurance and emotional support are the cornerstones of successful treatment. The mainstays of the current therapeutic approach continue to be: stress management strategies, dietary modification entailing addition of dietary fibre and pharmacotherapy. Pharmacotherapy is still limited to treating symptoms. Newer drugs that modulate motility or drugs that modulate visceral sensation may be useful in selected cases. Psychopharmacological agents are useful in the treatment of IBS, especially in those with psychological co-morbidity. Alternative therapies such as homeopathy, acupuncture, special diets, herbal medication and several forms of psychological treatments and hypnotherapy are sought by many patients and are now being offered by physicians as treatment options, either alone or in conjunction with conventional forms of therapy in patients with refractory symptoms.

Acupuncture Therapy↗

Analgesic effect of bisphosphonates in mice.

Bisphosphonates are analogues of inorganic pyrophosphate and are inhibitors of bone resorption. Many derivatives have been developed for the treatment of enhanced bone resorption; several reports reveal that treatment with bisphosphonates is able to reduce the pain associated with different painful diseases. This study tested the antinociceptive action of four bisphosphonates, clodronate, alendronate, pamidronate and etidronate, in comparison with that of morphine and acetylsalicylic acid using two algesimetric tests in mice, tail-flick and writhing tests. In the tail-flick test, after intravenous (i.v.) injection, a dose-dependent antinociception was present after pamidronate, clodronate and acetylsalicylic acid whereas etidronate and alendronate produced an analgesic effect only with the highest dose tested. We also studied the central effect of clodronate and pamidronate and, after intracerebroventricular injection, both bisphosphonates showed a dose-dependent antinociceptive effect. In the writhing test clodronate and pamidronate showed a statistically significant antinociceptive action after i.v. and intramuscular administration. To verify if clodronate and pamidronate could modulate the peripheral opioid receptors we evaluated the gastrointestinal transit time in mice, but we did not find any effect on the gastrointestinal motility. These data indicate that clodronate and pamidronate present a central and peripheral antinociceptive effect; however, the main mechanism cannot be determined from the present data. We discuss the possible pharmacological hypothesis to interpret the present results. The findings suggest a pharmacological role of the bisphosphonates in the modulation of antinociception even in acute conditions not related to accelerated osteolytic and inflammatory response, with a possible clinical application to control pain.

Abdomen↗

Non-antisecretory activities of H2 antagonists.

Besides the main effect of the H2 antagonists--that is, the inhibition of gastric acid secretion--these drugs possess several other pharmacological activities, which in most cases may be evident only for doses higher than those required to produce the H2 blockade. The non-secretory activities of the H2 antagonists may be classified into true side effects--that is, those independent of the primary action, which may or may not depend on the primary action. They concern the central and autonomic nervous systems, cardiovascular and endocrine systems, digestive system (gut, liver, pancreas), immune system, and so forth. It is obvious that when the actions of the different H2 blockers are completely at variance with regard to the same factor (cimetidine increase the TSH response to TRH, whereas ranitidine decreases it; ranitidine stimulates gastrointestinal motility, whereas oxmetidine inhibits it; ranitidine increases the exocrine pancreatic response to cholecystokinin, whereas oxmetidine decreases it; metiamide and cimetidine increase the activity of histamine methyltransferase, whereas burimamide decreases it), this is a clear demonstration that we are dealing with non-specific effects rather than with H2-receptor blockade. All these effects may be of interest because sometimes they may be useful in potentiating the primary action, and sometimes they may represent adverse reactions. In any case, they characterize pharmacologically the individual molecules of the family.

Autonomic Nervous System↗

Neuronal intestinal dysplasia.

Neuronal intestinal dysplasia (NID) is one of the disorders of gastrointestinal motility with defined pathological changes. Although first described more than 20 years ago, the disease remains controversial. The histological findings do not correlate with the degree of symptoms. The etiology of NID is obscure, but an immunologic process has been suggested. The diagnosis can be made on biopsy specimens performed to identify Hirschsprung's disease, but treatment must be individualized. The clinical course is variable, with spontaneous improvement in some, relentless constipation or severe dysmotility, unresponsiveness to all therapy, in others. Duhamel or Soave pull-through procedures can be effective in selected cases.

Child↗