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PubMedDate not supplied

The effect of delayed gastric emptying and absorption on pharmacokinetic parameters of lithium.

Gastrointestinal motility is one of the most important factors than can influence drug absorption from gastrointestinal tract. The aim of the present study was to investigate the effect of delayed gastric emptying and intestinal transit on pharmacokinetic parameters of lithium. Treatment animals were administered an anticholinergic agent (propantheline bromide, 4 mg/kg, p.o.) 10 min before lithium chloride (1.5 mM/kg, p.o.) administration, whereas the control group was administered the same dose of lithium p.o., alone. Plasma lithium levels were measured by flame spectrophotometry and calculated with a computer programme (SIPHAR). Differences detected in AUC, fractionated AUC values, Cmax and tmax suggest that using delayed absorption process, it is possible to prolong by 272% the plateau time of the drug in the therapeutic range and this approach might be an alternative way to prevent some undesirable effects due to peak plasma levels above the maximal therapeutic level. This approach might be more important as an alternative for suitable slow release formulations.

Animals↗
PubMed2000

Distal stomach appears essential in the regulation of gastrointestinal transit.

Stomach and small bowel both influence gastrointestinal motility. We studied which portion of the stomach was essential for the regulation of gastrointestinal movement and determined the role of vasoactive intestinal polypeptide in this regulation. The study subjects consisted of 45 controls, 46 patients after subtotal gastrectomy, and 13 patients after total gastrectomy for stomach cancer. Orocecal transit time was measured, using the hydrogen breath test, to represent gastrointestinal movement, while plasma vasoactive intestinal polypeptide level was simultaneously assessed. The orocecal transit times in the study groups were (means +/- SD) 91.1 +/- 45.0, 57.1 +/- 34.3, and 60.8 +/- 34.8 min, respectively (P < 0.01). In the subtotal gastrectomy patients, age showed a negative correlation with orocecal transit time (r = -0.388; P < 0.01). In the total gastrectomy patients, no particular demographic factor influenced orocecal transit. Plasma vasoactive intestinal polypeptide levels in the three groups were 20.7 +/- 10.8, 22.7 +/- 10.9, and 20.6 +/- 9.1 pg/ml, respectively (NS). We conclude that both types of gastrectomies enhanced gastrointestinal movement, showing a similar effect, and that the distal stomach plus pylorus are most likely to exert an important inhibitory mechanism in the regulation of this movement. Vasoactive intestinal polypeptide is not a major peptide mediating this regulation.

Aged↗
PubMed2004

Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats.

BACKGROUND: Ghrelin may stimulate gastric motility via the vagal nerve pathway. However, the mechanism of ghrelin-induced changes in gastrointestinal motility has not yet been clearly defined. The present study was designed to investigate whether ghrelin accelerates gastric emptying via capsaicin-sensitive afferent neurones and directly affects the enteric neuromuscular function. METHODS: Gastric emptying of nutrient solids was assessed after intravenous administration of saline or ghrelin in conscious rats. The effects of ghrelin on gastric emptying were also examined in rats pretreated with capsaicin. Gastric emptying and intestinal transit of non-caloric liquids were evaluated using 51Cr solution. The effects of ghrelin on spontaneous contractile activities of isolated strips from stomach and jejunum were also investigated and the influence of ghrelin on motor responses to carbachol and electrical field stimulation was examined. RESULTS: Ghrelin significantly accelerated gastric emptying of both nutrient solids and non-caloric liquids in conscious rats. The intestinal transit of non-caloric liquids was also enhanced by ghrelin. Pretreatment with capsaicin prevented the ghrelin-induced acceleration of gastric emptying of nutrient solids. Ghrelin did not modulate spontaneous and carbachol-induced contractions of strips of gastric body, gastric antrum and jejunum. However, electrical field stimulation-induced contractions were significantly enhanced by ghrelin in the gastric body. CONCLUSIONS: The results suggest that the stimulatory effects of ghrelin on gastric motility are mediated by direct stimulation of the enteric neural pathway and capsaicin-sensitive afferent neurones.

Afferent Pathways↗
PubMed2001

Gut transit time after ileal pouch-anal anastomosis using a radiopaque marker.

PURPOSE: The aim of this study was to determine the contribution of gastrointestinal motility to bowel function and the pathogenesis of pouchitis after ileal pouch-anal anastomosis. METHODS: Gastrointestinal transit time was assessed by a radiopaque marker technique in 32 patients with ulcerative colitis. RESULTS: Small intestinal transit time and pouch emptying time were 4.1 +/- 2 hours and 4.1 +/- 2.5 hours, respectively. There was no significant difference in pouch emptying time between patients with and without pouchitis. When only patients with acute pouchitis that responded to metronidazole were analyzed, there was a trend toward a prolonged pouch emptying time compared with those without pouchitis (P = 0.095). Whole gut transit time was inversely correlated with 24-hour stool frequency in patients without pouchitis (r = -0.63, P < 0.005). In the analysis of regional transit time, only small intestinal transit time was inversely correlated with 24-hour stool frequency (r = -0.472, P < 0.05). Significant prolongation of small intestinal transit time was demonstrated in patients over a period of 41 months (the median time) after ileostomy closure compared with those whose pouches had been functioning for 6 to 41 months (5.4 +/- 1.7 hours vs. 3.1 +/- 1.3 hours, P < 0.005). CONCLUSIONS: There was an association between small intestinal motility and bowel frequency. Further investigation is necessary in the pathogenesis of acute pouchitis regarding the relationship between delayed pouch emptying and subsequent development of mucosal inflammation.

Adolescent↗
PubMed2003

Mexiletine inhibits nonadrenergic noncholinergic lower oesophageal sphincter relaxation in rabbits.

Nonadrenergic noncholinergic (NANC) nerves are known to be nitrergic and to have an important role in the regulation of gastrointestinal motility and function. Cardiac antiarrhythmic therapy in humans is accompanied by a high incidence of gastrointestinal side-effects. We investigated the effect of mexiletine, a class Ib antiarrhythmic drug, on NANC lower oesophageal sphincter relaxation. Mexiletine concentration dependently inhibited the NANC relaxation induced by 30 mM KCl (EC(50)=4.4 x 10(-6) M); the production of 3',5'-cyclic guanosine monophosphate (cGMP) after KCl stimulation was concentration dependently decreased. The relaxation induced by the exogenous nitric oxide (NO) donor, diethylamine NONOate (10(-5) M), was not inhibited by mexiletine, and the cGMP production after diethylamine NONOate application was not altered. Mexiletine did not alter the activity of NO synthase. These findings suggest that mexiletine inhibits NANC relaxation via NO-cGMP pathway modulation, possibly by inhibiting myenteric nitrergic neurotransmission in the lower oesophageal sphincter in rabbits.

Animals↗
PubMed1998

Opioid tolerance in neonates: mechanisms, diagnosis, assessment, and management.

Opioid tolerance and withdrawal have been challenges for decades. The neurochemical mechanisms of tolerance and dependence are clinically important only because they can affect weaning schedules and the adjustment of doses for neonates. Analgesic effects are characterized by an increased depolarization threshold for the neuron, shorter duration of the action potential generated, and reduced release of neurotransmitters. Tolerance and withdrawal are associated with the reversal of these cellular effects. Adverse clinical effects associated with the use of opioids in neonates include respiratory depression, chest wall rigidity, urinary retention, and decreased gastrointestinal motility. The physiological systems most prominently affected by opioid withdrawal include the central nervous system, gastrointestinal system, and the autonomic nervous system. Opioid withdrawal symptoms in neonates can be assessed by using easily available scoring systems, although these need to be validated for different populations. Management of opioid withdrawal includes the use of other opioids, benzodiazepines and alpha-2 adrenergic receptor antagonist, clonidine. Careful titration of opioids with attention given to appropriate weaning schedules can reduce the incidence of withdrawal in neonates.

Drug Tolerance↗
PubMed1979

Histaminergic involvement in thyrotropin-releasing hormone stimulation of antral tissue in the rat.

The mechanism of action of thyrotropin-releasing hormone on antral motility was investigated in vitro. With the recent detection of thyrotropin-releasing hormone in gastrointestinal tissue, the possibility exists that the peptide may play a physiologic role in gastrointestinal motility. Results indicate that the hormone stimulates antral motility through a non-cholinergic excitatory pathway based on the inability of the muscarinic antagonist, atropine, to block the response. A histaminergic pathway is an attractive possibility to explain the excitatory response, because both pyrilamine and cimetidine inhibit the thyrotropin-releasing hormone induced response and the peptide has no further influence on antral motility after the tissue is exposed to a supramaximal concentration of histamine.

Animals↗
PubMed1989

Kinins as mediators of intestinal secretion.

Kinins are small peptides that have diverse biological actions. Concentrations of kinins in the nanomolar or subnanomolar range induce intestinal smooth muscle contraction and evoke mucosal electrolyte secretion. Hyperkininemia is associated with effects on gastrointestinal motility and intestinal mucosal inflammation. Bradykinin and kallidin are the predominant kinins with effects on the gastrointestinal tract of mammals. Bradykinin stimulates chloride ion secretion by the guinea pig and rabbit ileum, rabbit colon, rat colon and monolayers of human HCA-7 cells. Kinins directly or indirectly stimulate phospholipase A2 and phospholipase C. Cells in the lamina propria of the mucosa (e.g., fibroblasts, mast cells, leukocytes), by liberating cyclooxygenase and lipoxygenase metabolites of arachidonic acid, are involved in the kinin response; direct effects on epithelial cells cannot be ruled out, however. Antagonists now exist for kinin receptors. Based on studies with these antagonists in smooth muscle preparations, two subgroups of kinin receptor have been identified. The B2-type receptor appears to be responsible for both the contraction of ileal muscle and ileal secretion. Kinins are probably more important as pathophysiological rather than as physiological mediators. They may amplify the effect of inflammatory products that induce intestinal secretion. The precise involvement of kinins in clinical mucosal secretory states and diarrhea will require quantitative assessment of their levels during each phase of mucosal inflammation. Additional studies on the mechanism of action of kinins will be essential in designing therapy to mitigate the symptoms associated with mucosal inflammation.

Animals↗
PubMed1981

Effect of TRH on pentagastrin-induced gastric acid secretion.

Thyrotrophin-releasing hormone (TRH) 20 and 30 micrograms . kg-1 i.v. exerted a moderate inhibition on pentagastrin stimulated gastric secretion in dogs provided with gastric fistula and Heidenhain pouch. The effect was more evident in the main stomach than in the denervated pouch. The inhibitory action of the tripeptide was observed, though to a lesser extent, also in gastric fistula cats, whereas it was completely absent in the anaesthetized rat. Our results showing poor and erratic effects of TRH obtained only with rather high intravenous doses, paralleled those obtained by other authors on gastrointestinal motility and support the suggestion that, if there is a physiological role for TRH in the gastrointestinal tract this is more likely connected with paracrine rather than with endocrine effects of the peptide.

Anesthesia↗
PubMedDate not supplied

Effect of glucagon-(1-21)-peptide on gastroduodenal motility during upper gastrointestinal examination. Randomized trials.

The inhibitory effect of glucagon-(1-21)-peptide on the motility of the stomach and duodenum during radiologic double contrast studies was examined. In a randomized trial of equimolar doses of glucagon and glucagon-(1-21)-peptide on 70 patients, glucagon-(1-21)-peptide showed to have a significantly weaker effect than glucagon. Glucagon caused significant increases in plasma-glucose and plasma-insulin, while glucagon-(1-21)-peptide had no such effects. In a subsequent randomized study on 75 patients glucagon-(1-21)-peptide in various doses was tested against placebo. The effect was insignificant from that of placebo at practically all dose levels. No side effects were registered. It is concluded, that glucagon-(1-21)-peptide probably has a certain relaxing effect on the smooth muscle of the stomach and duodenum, but that this effect is too small for practical clinical use.

Adult↗
PubMed2005

Endothelin receptors in gastrointestinal smooth muscle.

Endothelins (ETs) are a family of peptides with 21-amino-acid residues. ET-1 was identified as a potent vasoconstrictor produced by vascular endothelial cells. Three distinct isoforms of ET, i.e. ET-1, ET-2 and ET-3, have been found to exist in a variety of tissues. ET was later found to cause contraction as well as relaxation of smooth muscle in many physiologic systems. In the gastrointestinal tract, ET causes contraction and/or relaxation of the esophagus, stomach, ileum and colon. In the hepatobiliary system, ET causes contraction of the portal vein, hepatic stellate cells, gallbladder and common bile duct. In mammalian species, two classes of ET receptors, ET(A) and ET(B), have been cloned. ET(A) receptors have higher affinities for ET-1 and ET-2 than ET-3, while ET(B) receptors have the same affinities for ET-1, ET-2 and ET-3. In the gastrointestinal system, ET causes smooth muscle contraction through interaction with ET(A) receptors, ET(B) receptors or both ET(A) and ET(B) receptors, depending on the tissues and species. In addition to contraction, ET causes smooth muscle relaxation through interaction with ET(A) receptors or ET(B) receptors. At the present time, there are no studies showing that ET causes smooth muscle relaxation through interaction with both ET(A) and ET(B) subtypes. ET induces contraction in most of the non-sphincter muscle except the fundus of the stomach. On the other hand, ET causes relaxation and contraction in the lower esophageal and internal anal sphincters. ET may play an important role in the control of human gastrointestinal motility and portal vein pressure.

Animals↗
PubMed1994

The effects of pectin and wheat bran on the distribution of a meal in the gastrointestinal tract of the rat.

The effects of wheat bran and pectin on the gastrointestinal distribution of a radiolabelled, homogenized baked-bean meal were investigated in the rat. These fibres were chosen because of their very different physical characteristics; wheat bran is a coarse, particulate, mainly insoluble fibre whilst pectin is a soluble viscous polysaccharide. Sixty male rats were administered orally with control or test meals and five from each group were killed after 50, 100, 200 and 300 min. The gut was removed and the distribution of the meal established scintigraphically. Addition of the fibres altered the distribution of the meal with faster accumulation at the distal and caecal areas. Wheat bran delayed gastric emptying whilst pectin promoted gastric emptying and had a pronounced effect on increasing the distal accumulation of the meal. These alterations in the distribution of a homogenized baked bean meal show that dietary fibres with different physical characteristics may alter gastrointestinal motility in different ways and these differences may have implications for meal absorption and clinical treatments of gastrointestinal disorders.

Animals↗
PubMed1993

Gastrointestinal regulatory peptides in systemic sclerosis.

OBJECTIVE: Gastrointestinal involvement commonly occurs in systemic sclerosis (SSc), but its pathogenesis is not well understood. Since there is evidence of a defect in neurotransmitter release, we were interested in examining the relationship between gastrointestinal dysfunction and plasma concentrations of gastrointestinal regulatory peptides in patients with SSc. We studied 43 consecutive patients, 18 with diffuse and 25 with limited cutaneous disease. METHODS: Levels of corticotropin-releasing hormone (CRH), gastrin, motilin, neuropeptide Y (NPY), and peptide YY (PYY) were determined by radioimmunoassay and high-performance liquid chromatography (HPLC). RESULTS: Plasma concentrations of CRH, motilin, NPY, and PYY were significantly increased among SSc patients compared with healthy control subjects, and HPLC-characterization of motilin, NPY, and PYY showed a different pattern of fragments. No correlation was found between esophageal hypomotility and the concentration of peptide. Acid output did not correlate with gastrin levels, but was more often increased in patients with increased CRH and NPY values. Fat malabsorption, assessed by the triolein breath test, was more common among patients with increased motilin and PYY. CONCLUSION: This study shows that elevated peptide concentrations commonly occur in patients with SSc. Since regulatory peptides are involved in gastrointestinal motility, secretion, and absorption, further characterization of this neuroendocrine system may help in understanding the complex regulation of gastrointestinal dysfunction in SSc.

Adult↗
PubMed2004

Quantitative analysis by flow cytometry of interstitial cells of Cajal, pacemakers, and mediators of neurotransmission in the gastrointestinal tract.

BACKGROUND: Interstitial cells of Cajal (ICCs) are mesenchymal cells that play critical roles in gastrointestinal motility as electrical pacemakers and mediators of neuromuscular neurotransmission. Although depletions of ICCs have been implicated in several gastrointestinal motor disorders, quantification of these cells has been difficult due to their varied morphology, regionally changing network density, and overall scarcity. Our goal was to evaluate flow cytometry (FCM) for the enumeration of ICCs. METHODS: We identified murine ICCs in live gastrointestinal muscles or primary cell cultures grown in the presence or absence of stem cell factor (SCF)-expressing STO fibroblasts with fluorescent Kit (CD117) antibodies. Because this technique also labels resident macrophages nonspecifically, we identified the latter with additional fluorescent antibodies. Dispersed cells were analyzed by FCM. RESULTS: ICCs represented 1.63 +/- 0.17% of the total cell count in the distal stomach (n = 18 mice) and 5.85 +/- 0.84% in the proximal colon and 6.28 +/- 0.61% in the distal colon (n = 3 mice). In fundic muscles of W/WV mice (n = 5) that virtually lack ICCs, very few Kit+ cells were detected. FCM identified approximately 2.6- to 7.3-fold more Kit+ ICCs in small intestinal cell cultures grown on STO fibroblasts expressing membrane-bound SCF (n = 6) than in cultures stimulated with soluble SCF (n = 6). CONCLUSIONS: FCM is a sensitive and specific method for the unbiased quantification of ICCs.

Animals↗
PubMed2002

Is colic a gastrointestinal disorder?

Infantile colic is a distinct, although poorly defined, clinical entity. Whereas a general consensus regarding its cause is lacking, it is most likely multifactorial in genesis. Possible causative factors can be divided into two main groups: gastrointestinal and non-gastrointestinal. Food protein hypersensitivity or allergy is the leading contender in the former group, and disturbances in parental or maternal-child interactions in the latter. In all likelihood, the various factors act in tandem, leading to disturbances in infant gastrointestinal motility that manifests clinically as colic.

Age Factors↗
PubMed2003

Methane production during lactulose breath test is associated with gastrointestinal disease presentation.

It has recently been determined that there is an increased prevalence of bacterial overgrowth in IBS. Since there are two gases (hydrogen and methane) measured on lactulose breath testing, we evaluated whether the different gas patterns on lactulose breath testing coincide with diarrhea and constipation symptoms in IBS and IBD. Consecutive patients referred to the gastrointestinal motility program at Cedars-Sinai Medical Center for lactulose breath testing were given a questionnaire to evaluate their gastrointestinal symptoms. Symptoms were graded on a scale of 0-5. Upon completion of the breath test, the results were divided into normal, hydrogen only, hydrogen and methane, and methane only positive breath tests. A comparison of all subjects and IBS subjects was undertaken to evaluate diarrhea and constipation with regards to the presence or absence of methane. This was further contrasted to Crohn's and ulcerative colitis (UC) patients in the database. After exclusion criteria, 551 subjects from the database were available for comparison. Of the 551 subjects (P < 0.05, one-way ANOVA) and in a subgroup of 296 IBS subjects (P < 0.05, one-way ANOVA), there was a significant association between the severity of reported constipation and the presence of methane. The opposite was true for diarrhea (P < 0.001). If a breath test was methane positive, this was 100% associated with constipation predominant IBS. Furthermore, IBS had a greater prevalence of methane production than Crohn's or UC. In fact, methane was almost nonexistent in the predominantly diarrheal conditions of Crohn's and UC. In conclusion, a methane positive breath test is associated with constipation as a symptom.

Breath Tests↗
PubMed1991

Sensory nerves in the gastrointestinal tract: changing concepts and new perspectives.

In recent years great interest has been directed to study the function of capsaicin-sensitive primary afferents in the gastrointestinal tract. It has been demonstrated that these fibers not only have a sensory role but also play a local efferent function through direct and indirect effects of released neurotransmitters. Peptides released by capsaicin-sensitive nerves are involved in several functions modulating either the local blood flow or the gastrointestinal motility. The analysis of the action of released transmitters may serve to understand the physiology and pathophysiology of the gastrointestinal tract. All data here reported demonstrate that the study of capsaicin-sensitive primary afferents may be helpful to develop new pharmacological treatment of various human disease of the gastrointestinal tract.

Animals↗
PubMed1995

Effect of 4 x 250 mg erythromycin on human gastrointestinal transit.

The motilin agonist erythromycin affects gastrointestinal motility. We studied its influence on gastric, intestinal, and colonic transit of indigestible solids. Ten healthy volunteers measured the gastrointestinal transit of a 6-8 mm metal sphere by metal detector with oral intake of 250 mg erythromycin q.i.d. or placebo in randomized order. Postprandial gastric emptying of the sphere after a standard meal was measured after a single i.v. dose of 250 mg erythromycin, subsequently followed by determination of small and large bowel transit. Motilin serum levels were measured for one hour. Gastric transit of the sphere was shortened from 243 +/- 34 to 72 +/- 46 min (mean +/- SD) (p = 0.002) and shifted from the interdigestive to the digestive phase. Small and large bowel transit were not influenced, and gastric transit times and motilin serum levels were not correlated. In conclusion, 250 mg erythromycin shortened postprandial gastric emptying of indigestible solids, most likely due to overcoming of pyloric sieving function by strong gastric antral contractions without effecting the transit through the lower part of the gastrointestinal tract.

Adult↗