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Biomedical subjects

W J Snape

Publications and source records attributed to W J Snape.

At least 19 recordsLinked to original sources
PubMed2002

Long-term safety of tegaserod in patients with constipation-predominant irritable bowel syndrome.

BACKGROUND: Tegaserod is a 5-hydroxytryptamine-4 receptor partial agonist. Oral administration causes gastrointestinal effects resulting in increased gastrointestinal motility and attenuation of visceral sensation. AIM: : To determine the long-term safety and tolerability of tegaserod in patients suffering from irritable bowel syndrome with constipation as the predominant symptom of altered bowel habits. METHOD: A multicentre, open-label study with flexible dose titration of tegaserod in out-patients suffering from constipation-predominant irritable bowel syndrome. RESULTS: A total of 579 patients with constipation-predominant irritable bowel syndrome were treated with tegaserod. Of these, 304 (53%) completed the trial. The most common adverse events, classified as related to tegaserod for any dose, were mild and transient diarrhoea (10.1%), headache (8.3%), abdominal pain (7.4%) and flatulence (5.5%). Forty serious adverse events were reported in 25 patients (4.4% of patients) leading to discontinuation in six patients. There was one serious adverse event, acute abdominal pain, classified as possibly related to tegaserod. There were no consistent differences in adverse events between patients previously exposed to tegaserod and those treated de novo. No pattern-forming tegaserod-related abnormalities in haematological and biochemical laboratory tests, urinalysis, blood pressure, pulse rate or electrocardiograms were found. CONCLUSIONS: Tegaserod appears to be well tolerated in the treatment of patients with constipation-predominant irritable bowel syndrome. The adverse event profile, clinical laboratory evaluations, vital signs and electrocardiogram recordings revealed no evidence of any unexpected adverse events, and suggest that treatment is safe over a 12-month period.

Abdominal Pain↗
PubMed1998

Effect of leuprolide acetate in treatment of abdominal pain and nausea in premenopausal women with functional bowel disease: a double-blind, placebo-controlled, randomized study.

We have previously reported impressive results in using a gonadotropin-releasing hormone analog, leuprolide acetate (Lupron), in the treatment of moderate to severe symptoms (especially abdominal pain and nausea) in patients with functional bowel disease (FBD). Pain is the hallmark of patients with FBD, and there is no consistent therapy for the treatment of these patients. The purpose of the present study was to expand the investigation to study similar patients (menstruating females) in a multicenter, double-blind, placebo-controlled, randomized study using Lupron Depot (which delivers a continuous dose of drug for one month), 3.75 mg (N = 32) or 7.5 mg (N = 33), or placebo (N = 35) given intramuscularly every four weeks for 16 weeks. Symptoms were assessed using daily diary cards to record abdominal pain, nausea, vomiting, early satiety, anorexia, bloating, and altered bowel habits. Additional assessment tools were quality of life questionnaires, psychological profile, oral-to-cecal transit using the hydrogen breath test, antroduodenal manometry, reproductive hormone levels, and global evaluations by both patient and investigator. Patients in both Lupron Depot-treated groups showed consistent improvement in symptoms; however, only the Lupron Depot 7.5 mg group showed a significant improvement for abdominal pain and nausea compared to placebo (P < 0.001). Patient quality of life assessments and global evaluations completed by both patient and investigators were highly significant compared to placebo (P < 0.001). All reproductive hormone levels significantly decreased for both Lupron Depot-treated groups by week 4 and were significantly different compared to placebo at week 16 (P < 0.001). This study shows that leuprolide acetate is effective in controlling the debilitating symptoms of abdominal pain and nausea in patients with FBD.

Abdominal Pain↗
PubMed1998

Role of motility measurements in managing upper gastrointestinal dysfunction.

Nausea, vomiting, and abdominal pain are common symptoms that suggest many diagnoses. The patient's symptoms may be related to an anatomical defect such as a peptic ulcer or a mechanical small bowel obstruction. However, no anatomical abnormality may be identified despite radiological, endoscopic, or laboratory studies. The cause of the patient's symptoms may have significant impact on the patient's quality of life (nonulcer dyspepsia) and life span (intestinal pseudo-obstruction). Abnormal antroduodenal motility may be the underlying cause of the patient's symptoms. Normally, coordinated phasic contractions in the stomach and small intestine maintain digestion and absorption of food. A prolonged set of phasic contractions (phase 3 of the migrating complex) begins in the stomach and propagates down the small intestine to excrete nondigestible foods, bacteria, and dead cells. Any disturbance in the normal motility pattern can lead to maldigestion and symptoms of upper intestinal dysfunction. Objective tests of motility disturbances in the stomach and small intestine include measurement of gastric emptying, intestinal transit, contractions of the stomach and duodenum, and electrogastrography. Abnormal antroduodenal motility may be secondary to an abnormality in the smooth muscle (myopathy) or the nerves in controlling smooth muscle contractions (neuropathy). Antroduodenal motility measurements may help identify a partial small bowel obstruction, the cause of small intestinal overgrowth, and the cause of chronic abdominal visceral pain. Motility studies may suggest useful drugs for correcting the underlying pathophysiology and relieving symptoms.

Gastrointestinal Diseases↗
PubMed1997

Managing the patient with atypical chest pain.

Since angina and heartburn can feel the same, excluding cardiac disease may be the first order of business. That done, clinical findings and laboratory tests can help identify the esophageal disturbance. Gastric acid reflux, motility disorders, and visceral nerve hypersensitivity--alone or in combination--can cause chest pain, and each may call for a different pharmacologic regimen.

Adrenergic Uptake Inhibitors↗
PubMed1997

Expression of insulin-like growth factor I receptors and binding proteins by colonic smooth muscle cells.

We recently demonstrated upregulation of insulin-like growth factor I (IGF-I) binding sites in the smooth muscle layer of inflamed rat colon. The increase in binding sites was due to increased expression of IGF binding proteins (IGFBPs), which modulate the effects of IGF. To further study the role of IGF in the colon, we investigated whether cultured colonic smooth muscle cells (SMC) express IGF-I receptors and IGFBPs. SMC were isolated by collagenase digestion from rat colonic smooth muscle and grown in primary culture. Equilibrium binding experiments using (125)I-labeled IGF-I showed the presence of an IGF-I receptor with a dissociation constant of 1.96 nM and a maximal binding constant of 53,000 receptors/cell. Competition binding studies with IGF-II and insulin, together with chemical cross-linking experiments, corroborated this conclusion. Western ligand blotting of conditioned medium and Northern analysis of total RNA demonstrated that the cells expressed and secreted IGFBP-4, -5, and -3 with molecular masses of 25, 31, and 45 kDa, respectively. These results, together with our in vivo studies in the rat, support a role for IGF in tissue fibrosis and stricture formation during chronic intestinal inflammation.

Animals↗
PubMed1997

Role of colonic motility in guiding therapy in patients with constipation.

Constipation is a common condition defined by less than three bowel movements per week. Often constipation is secondary to altered motility of the colon. Tests that measure colonic motility lead the clinician to appropriate therapy. Colonic transit measured with either radionuclides or radio-opaque markers determine whether the transit through the colon is truly slow, and then identify the potential region of the colon that impedes the movement of intraluminal contents. Patients with normal colonic transit do not require further evaluation of their colonic motor function. Colonic and anorectal manometry differentiate patients in to 3 groups: (1) functional anal outlet obstruction; (2) uncoordinated distal colonic phasic contractions, and (3) colonic inertia. Functional outlet obstruction may be treated successfully by increasing the water content of their stools and biofeedback. Antispasmodics including anticholinergics, nitrates and calcium channel blockers may decrease the functional obstruction caused by phasic colonic contractions. The prokinetics such as cisapride have successfully improved constipation due to colonic inertia, Parkinson's disease or spinal cord injury as well as idiopathic inertia. Occasionally patients with inertia may require colectomy with ileorectal anastomosis to treat severe constipation.

Colon↗
PubMed1997

Clinical considerations in GERD (gastroesophageal reflux disease) therapy: focus on cisapride.

Heartburn, the major symptom of gastrointestinal reflux disease (GERD), is a common condition that is usually self-treated with over-the-counter products. For patients with severe or recurrent symptoms of GERD, pharmacologic therapy includes acid suppression with H2-receptor antagonists and proton pump inhibitors, and, alternatively, the use of prokinetic agents. While all of these are efficacious, given its high efficacy in nonerosive and mild-to-moderate erosive esophagitis, the prokinetic agent cisapride deserves significant consideration in this patient population.

Cisapride↗
PubMed1995

Antibodies in patients with inflammatory bowel disease and the apparent influence of medications.

Patients with inflammatory bowel disease (IBD) are known to have increased antibodies to several food and bacterial antigens. To assess selected isotype contributions in greater detail, we examined the concentrations of IgA, IgG, IgE, and IgG4 antibodies to five selected antigens, two of bacterial and three of food origin. Thirty patients with IBD and thirty matched healthy controls were studied. Most antibodies were increased in IBD patients compared to controls. Statistically significant increases were more frequent in Crohn's disease (CD) than in ulcerative colitis (UC). An unexpected finding was that IBD patients treated with sulfasalazine had statistically higher levels of most IgA antibodies than healthy controls, while steroid treated patients had lower levels. These findings suggest differing effects on the immune systems of IBD patients by each of these commonly used drugs.

Adult↗
PubMed1994

Antroduodenal manometry in children and adults with severe non-ulcer dyspepsia.

BACKGROUND: Nonulcer dyspepsia is common in adults but has been recognized only recently in children. METHODS: We compared signs, symptoms, and antroduodenal motility findings in 34 children and 35 adults with severe nonulcer dyspepsia. RESULTS: Symptoms and signs were similar in the two groups. Ten children (29%) and one adult (3%) required tube feedings (p = 0.01). Abdominal surgery had been performed on 6 of 34 (18%) children and 18 of 35 adults (51%) (p < 0.01), without relief of symptoms. Esophageal manometry was abnormal in 5 of 23 (22%) children and 6 of 31 (19%) adults. Antroduodenal manometry was suggestive of neuropathy in 25 children and 26 adults and of myopathy in 3 children and 2 adults. Absence of phase 3 of the migrating motor complex was found in 4 children and 17 adults (p = 0.01). Antroduodenal manometry was normal in six children and seven adults. CONCLUSION: Signs, symptoms, and discrete manometric abnormalities of childhood nonulcer dyspepsia resembled those of adult nonulcer dyspepsia. Manometric findings in nonulcer dyspepsia resembled those reported in chronic intestinal pseudo-obstruction, suggesting that these conditions are on a continuum of enteric neuromuscular diseases.

Adolescent↗
PubMed1993

Colonic manometry in children with chronic intestinal pseudo-obstruction.

Pressure changes were evaluated in the transverse, descending, and rectosigmoid colon of 30 children with chronic intestinal pseudo-obstruction. Twenty two had severe lifelong constipation and eight had symptoms suggesting a motility disorder exclusively of the upper gastrointestinal tract. Based on prior antroduodenal manometry, 24 children were diagnosed as having a neuropathic and six a myopathic form of intestinal pseudo-obstruction. On the day of study, endoscopy was used to place a manometry catheter into the transverse colon and intraluminal pressure was recorded for more than four hours. After a baseline recording, we gave a meal to assess the gastrocolonic response. Colonic contractions were noted in 24 children. The six children with no colonic contractions had a hollow visceral myopathy and constipation. In the children with colonic contractions, fasting motility did not differentiate children with and without constipation. After the meal, in all eight children without constipation there was (1) an increase in motility index (3.2 (SEM 0.3) mm Hg/min basal v 8.4 (SEM 1.1) mm Hg/min postprandial; p < 0.001), and (2) at least one high amplitude propagated contraction (HAPC). In the 16 constipated children with colonic contractions the motility index did not significantly increase after the meal (2.1 (SEM 0.3) mm Hg/min basal v 3.1 (SEM 0.4) mm Hg/min postprandial) and 12 of them had no HAPCs (p < 0.01 v group without constipation). In summary, in children with a clinical diagnosis of chronic intestinal pseudo-obstruction, constipation is associated with absence of HAPCs, and the gastrocolonic response or with total absence of colonic contractions. It is concluded that studies of colonic manometry are feasible in children and may document discrete abnormalities in those with intestinal pseudo-obstruction with colonic involvement.

Child↗
PubMed1993

Postnatal changes in receptor-mediated rabbit gastric smooth muscle relaxation.

The aims of this study were to identify mediators of relaxation in rabbit proximal gastric circular smooth muscle and to assess age-dependent changes in tissue response. Vasoactive intestinal peptide (VIP), adenosine, and norepinephrine induced tetrodotoxin-insensitive, concentration-dependent relaxation in bethanechol-precontracted (3 microM) gastric muscle strips from newborns and weanlings. Maximally effective concentrations of 10 microM VIP induced complete relaxation in newborns, but only 30% relaxation in weanlings (p < 0.01). Maximally effective concentrations of adenosine induced complete relaxation at both ages. Adenosine (ED50 3 microM) was more potent than adenosine triphosphate, indicating the presence of P1 purinergic receptors. In newborns norepinephrine induced complete relaxation (ED50 0.5 microM). The response to norepinephrine changed in age-dependent increments from relaxation in newborns to strong contraction in weanlings. In weanlings phentolamine inhibited norepinephrine-stimulated contraction, revealing persistent propranolol-sensitive relaxation. Tetrodotoxin and atropine had no effect on norepinephrine-stimulated contraction. In summary, in rabbit gastric circular smooth muscle: (1) VIP, adenosine, and norepinephrine induce relaxation; (2) VIP loses efficacy with age; (3) there is a beta-adrenergic receptor mediating relaxation in the newborn which persists, and (4) an alpha-adrenergic receptor mediating contraction emerges early in postnatal life. Age-dependent changes in response to VIP and norepinephrine may contribute to the postnatal maturation of the gastric motility.

Adenosine↗
PubMed1992

Effect of cell culture on rabbit colonic smooth muscle bradykinin receptors.

The aim of this study was to assess the effect of cell culture on the bradykinin receptor of rabbit colon myocytes. In longitudinal muscle strips prepared from distal colon, bradykinin stimulated dose-dependent contraction that was 62% of the maximal response to bethanecol. At 4 degrees C, [3H]bradykinin binding to fresh muscle homogenates from the distal colon was time dependent, saturable, and linearly related to tissue concentration. Specific binding of 0.6 nmol/L [3H]bradykinin was 80% +/- 2% of total binding. In competitive binding studies, Hill coefficients approached unity, suggesting the presence of a single class of receptors. The order of potency was bradykinin greater than [D-Phe7]bradykinin much greater than des-Arg9, [Leu8]bradykinin, which is consistent with results of a B2 receptor subclass. Colon myocytes from the longitudinal muscle layer achieved confluence and were harvested for studies after 12-14 days in culture. Bradykinin receptors were of high affinity [disassociation constant (Kd) = 672 pmol/L] and numbered 10,217 +/- 2567/cell. To show that the receptors on cultured myocytes were functional, the effect of bradykinin was measured (a) on intracellular calcium concentration using Fura 2 and (b) on prostaglandin E2 concentration in the culture media using radioimmunoassay. In cells grown to confluence on cover slips and preloaded with Fura 2, bradykinin stimulated the threshold response at 1 nmol/L and maximal response (increased intracellular calcium concentration from 229 to 633 nmol/L) at 1 mumol/L. Bradykinin, 100 nmol/L, increased Prostaglandin E2 in the culture media threefold. In summary, colon myocytes express functioning bradykinin receptors, which, unlike muscarinic receptors, persist in culture. Bradykinin appears to be a suitable agonist for studies of receptor-mediated intracellular events in cultured colon myocytes.

Animals↗
PubMed1992

Mechanisms of cAMP-mediated relaxation of distal circular muscle in rabbit colon.

Photolytic release of free adenosine 3',5'-cyclic monophosphate (cAMP) from its caged form was used to evaluate the physiological role of several proposed mechanisms of cAMP-mediated relaxation of circular smooth muscle in the distal rabbit colon. Photolysis of caged cAMP produced a rapid relaxation of bethanechol-contracted distal circular muscle strips that was dependent on ultraviolet exposure time. An increase in release of free cAMP, associated with increased ultraviolet exposure, was confirmed with high-performance liquid chromatography. Vanadate (an ATPase inhibitor) (3 mM) caused a 48% decrease in cAMP-mediated relaxation, while ouabain and a zero K+ bath solution failed to affect relaxation. cAMP-mediated relaxation of KCl-contracted strips was significantly less effective than that of bethanechol-contracted strips. Although this finding suggested that cAMP-mediated relaxation may involve K+ channel modulation, specific (glibenclamide, charybdotoxin) and nonspecific (TEA) K+ channel blockade failed to affect cAMP-mediated relaxation of bethanechol-contracted strips. The photolytic release of cAMP failed to relax Ca(2+)-contracted saponin skinned muscle strips. These studies suggest 1) modulation of Ca2+ pumps plays an important role in this model of relaxation of distal colonic circular muscle in the rabbit colon, 2) modulation of the Na+ pump or sarcolemmal K+ channels may not play an important physiological role in relaxation induced by a rapid rise in intracellular cAMP, and 3) cAMP does not seem to have a significant physiological effect on the Ca2+ sensitivity contractile apparatus.

Animals↗
PubMed1992

Postnatal changes in the substance P receptor on rabbit gastric smooth muscle.

We used radioligand binding to tissue homogenates and isometric contraction of muscle strips to characterize the substance P (SP) receptor on gastric smooth muscle from 1- (newborn) and 7-day-old and 4- and 11-wk-old (weanling) rabbits. Scatchard analysis for newborns was curvilinear, suggesting the presence of multiple binding sites. In newborns the dissociation constant (Kd) of high-affinity binding site was 2.2 +/- 0.3 nM, and the maximum binding (Bmax) was 0.57 +/- 0.06 pmol/mg DNA. The number of high-affinity binding sites decreased with age, disappearing by 11 wk. The Kd for the low-affinity site was more than two orders of magnitude greater than that of the high-affinity site. In competitive binding studies with [3H]SP, the order of potency for the neurokinins was SP much greater than neurokinin A (NKA) greater than neurokinin B (NKB), suggesting that the high-affinity binding sites were NK-1 receptors. [125I]NKA is also bound to newborn tissue homogenate with high affinity. With [125I]NKA the order was NKA greater than SP greater than NKB, suggesting that NK-2 receptors were also present. In contraction studies, atropine and tetrodotoxin had no effect on tachykinin-stimulated contraction, suggesting solely myogenic tachykinin effects on this tissue. In newborn rabbits, the potency and efficacy of SP and NKA were similar. The half-maximal effective dose (ED50) of SP was nearly two orders of magnitude less in newborn rabbits than in weanlings; the potency of NKA did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

An abnormal rate of actin myosin cross-bridge cycling in colonic smooth muscle associated with experimental colitis.

Previous studies showed that colonic smooth muscle develops less contractile force to neurohumoral stimulation when associated with mucosal inflammation. This study evaluated 1) the Ca2+ dependence for colonic smooth muscle contraction, 2) the maximum velocity of muscle shortening (Vmax), and 3) changes in 20-kDa myosin light-chain (MLC) phosphorylation in distal circular colonic muscle from healthy rabbits and from rabbits with experimental colitis, induced by Formalin and immune complexes. The isometric tension of unskinned muscle stimulated with bethanechol or KCl was less (P less than 0.05) in animals with colitis compared with the control group. In saponin-skinned muscle, the amplitude of the maximal tension at [Ca2+] of 3 x 10(-7) M was decreased (P less than 0.05) in colitis animals (4.3 +/- 0.9 x 10(4) N/m2, n = 7) compared with healthy animals (10.5 +/- 2.4 x 10(4) N/m2, n = 6). However, the ED50 for Ca2+ stimulation was similar (P greater than 0.05) in both groups. When MLC was thiophosphorylated with ATP gamma S, the tension development was decreased in colitis (2.1 +/- 0.3 x 10(4) N/m2, n = 5; P less than 0.01) compared with normals (5.0 +/- 1.4 x 10(4) N/m2, n = 5). In healthy animals, phosphorylation of 20-kDa MLC increased rapidly to 51.2 +/- 3.1% within 15 s after stimulation and subsequently declined to 19.0 +/- 2.1% at 5 min. Vmax was maximal (0.14 Lo/s) 13 s after stimulation and declined before maximal active isometric stress. In colitis animals, the 20-kDa MLC phosphorylation (P less than 0.05) and the Vmax (P less than 0.01) were decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1992

Characterization of colonic circular smooth muscle cells in culture.

The receptor-binding properties of isolated rabbit colonic circular smooth muscle cells in primary culture have been investigated. In intact smooth muscle, acetylcholine, acting through M2 muscarinic receptors, and vasoactive intestinal polypeptide (VIP), acting through VIP receptors, are two of the principal neurotransmitters mediating contraction and relaxation, respectively. The muscarinic receptor was present in very high levels (600,000 receptors/cell) on freshly isolated colonic smooth muscle cells as shown by binding of the muscarinic receptor antagonist N-methylscopolamine (NMS). However, NMS binding sites decreased rapidly when the cells were placed in primary culture. After 21 h in culture, specific binding of [3H]NMS decreased to 20%, and after 48 h to less than 10% that of preculture values. This loss was not associated with a change in receptor affinity, since Kd was unchanged for the receptors still present. In contrast, high-affinity VIP receptors were expressed on cultured smooth muscle cells but could not be detected on freshly isolated cells. Cultured cells responded to VIP with an increase in intracellular adenosine 3',5'-cyclic monophosphate (cAMP), indicating that the VIP receptors were functionally coupled to adenylate cyclase. Cultured cells also responded to calcitonin gene-related peptide (CGRP) and forskolin with increased production of intracellular cAMP. In contrast, neither VIP nor CGRP elicited an increase in intracellular cAMP when added to freshly isolated cells. Furthermore, freshly isolated cells had a greatly diminished response to forskolin, suggesting that the isolation procedure not only destroyed cell surface receptors for VIP and CGRP, but also damaged the cells sufficiently to decrease cellular adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗