Use of tegaserod along with polyethylene glycol electrolyte solution for colonoscopy bowel preparation: a prospective, randomized, double-blind, placebo-controlled study.

BACKGROUND: Polyethylene glycol electrolyte solution (PEG-EL) used for colonoscopy preparation is not well tolerated by several patients. A significant number of patients have inadequate bowel preparation despite taking PEG-EL. AIMS: To determine the effect of prokinetic agent, tegaserod when given in addition to PEG-EL on patient tolerance, quality of colonic preparation and adverse side effects experienced. METHODS: In this prospective, randomized, placebo-controlled, double-blind study, a total of 130 patients scheduled for colonoscopy were enrolled. They were instructed to take three pills of either tegaserod 6 mg each or placebo (one pill twice on the day prior to and third pill in the morning on the day of colonoscopy) in addition to standard 4L of PEG-EL in the evening prior to the day of colonoscopy. Patient tolerance of preparation, quality of bowel preparation, overall satisfaction and adverse side effects were compared between the two groups. RESULTS: Fifty-five patients in placebo group and 58 patients in tegaserod group completed the study. There was no difference between the two groups in the tolerance of preparation, quality of bowel preparation, overall satisfaction and the side effects. CONCLUSION: Addition of tegaserod to polyethylene glycol electrolyte solution during colonoscopy preparation does not improve patient tolerance, quality of colonic preparation or the adverse side effects.

Improving compliance with postpolypectomy surveillance guidelines: an interventional study using a continuous quality improvement initiative.

BACKGROUND: Despite guidelines, physicians tend to perform postpolypectomy surveillance colonoscopies too frequently. OBJECTIVE: The objective of the study was to determine the baseline compliance rate with postpolypectomy guidelines in our unit and to determine the influence of a continuous quality improvement (CQI) intervention on improving the compliance rate and on decreasing the potential additional costs because of the scheduling of postpolypectomy surveillance colonoscopies earlier than indicated. DESIGN: This was a single-arm, pretest-posttest design. SETTING: This study took place at a tertiary care, academic medical center. PATIENTS: The medical records of all patients who underwent colonoscopy with polypectomy in our unit retrospectively during 6 months preceding (baseline period) and prospectively for 6 months after an intervention (postintervention period) were reviewed for patient demographics, colonoscopy findings, and scheduling of repeat colonoscopies. INTERVENTION: We used 3 components: (1) distribution of a wallet-size card with a summary of postpolypectomy guidelines to all endoscopists, (2) placement of guideline charts near computers used for typing endoscopy reports, and (3) distribution and reinforcement of the guidelines in a monthly continuous quality improvement meeting. MAIN OUTCOME MEASURES: The main outcome measures were compliance rates, mean times to repeat colonoscopy, and additional costs from surveillance colonoscopies being scheduled earlier than indicated were compared between the two periods. RESULTS: There were 278 patients in the baseline period and 242 in the postintervention period, with similar patient and polyp characteristics. After the intervention, the compliance rate with guidelines improved from 57.2% to 81% (p < 0.001). The mean time to a repeat colonoscopy increased from 4.5 to 5.2 years (p = 0.003) (i.e., a 14% reduction in the number of postpolypectomy surveillance colonoscopies performed per year). This would result in a reduction of a total of 73 surveillance colonoscopies per year in our unit, with a projected cost savings of 171,331 dollars per year (cost of a colonoscopy assumed at 2347 dollars). LIMITATIONS: The limitation of the study was possible enhanced performance secondary to being observed (Hawthorne effect). Because more than 1 intervention was used, we do not know which one is more effective. CONCLUSIONS: Relatively simple and easy-to-implement quality improvement initiatives can significantly enhance compliance with postpolypectomy guidelines and result in cost savings because of a reduction in the number of postpolypectomy surveillance colonoscopies being scheduled earlier than recommended guidelines.

Afternoon colonoscopies have higher failure rates than morning colonoscopies.

BACKGROUND: There are several known predictors of an incomplete colonoscopy or difficult colonoscopy. In addition, inadequate bowel preparation has been reported in procedures scheduled later in the day. Operator fatigue, which tends to be higher as the day passes on, may also impact colonoscopy completion rate. AIMS: To determine the influence of performing outpatient colonoscopies in the afternoon versus morning on the completion rates of colonoscopy and adequacy of bowel preparation. METHODS: Retrospective chart review of all outpatient colonoscopies performed between November 2003 and October 2004 in the Division of Gastroenterology at MetroHealth Medical Center in Cleveland, Ohio. Patient demographics, indications for procedure, and colonoscopic findings were reviewed. Patients received polyethylene glycol electrolyte-based bowel preparation in the evening prior to the day of the scheduled colonoscopy. RESULTS: A total of 2,087 colonoscopies was performed, of which 1,084 were in the morning and 999 were in the afternoon. Patients in the morning and afternoon were similar in regards to the known risk factors predictive of an incomplete colonoscopy. The incompletion rate was significantly higher in the afternoon compared to the morning (6.5% vs 4.1%, P= 0.013, OR for incompletion was 1.64, CI 1.11-2.44). Inadequate bowel preparation was found in 167 out of 1,084 (15.4%) colonoscopies in the morning and 197 out of 999 (19.7%) colonoscopies in the afternoon (P= 0.011). Even after excluding incomplete colonoscopies due to poor bowel preparation precluding examination, the incompletion rate was still higher in the afternoon (5% vs 3.2%, P= 0.043, OR 1.60, CI 1.03-2.51). CONCLUSIONS: Scheduling of colonoscopies in the afternoon compared to the morning may be an independent predictor of an incomplete colonoscopy and inadequate bowel preparation. According to our study findings, scheduling of all outpatient colonoscopies preferentially in the morning would avoid suboptimal procedures in 5% of patients and the need for unnecessary repeat colonoscopy or an alternative imaging study in 2.4% of patients.

P2X and P2X receptor expression in human bladder urothelium and changes in interstitial cystitis.

OBJECTIVE: To investigate whether the expression of P2X(3) receptors (implicated in the pathophysiology of pain) is altered in human bladder urothelium from patients with interstitial cystitis (IC, a major symptom of which is pain), and as P2X(2) receptors can be co-expressed with P2X(3) receptors, to assess their expression also. PATIENTS AND METHODS: Bladder tissue samples were collected from patients undergoing cystectomy or radical prostatectomy. Patients with IC were diagnosed using the international criteria. RNA protein expression levels of both receptors were evaluated using reverse transcription-polymerase chain reaction (PCR), real-time quantitative PCR and Western blot analysis. RESULTS: P2X(2) was expressed in the human urothelium, in a glycosylated form. There was less gene expression of P2X(3) in IC urothelium, whereas P2X(2) gene expression was unchanged. This contrasted with the protein expression, which was increased for both P2X(2) and P2X(3). CONCLUSION: This is the first report of the expression of the P2X(2) receptor in human bladder urothelium. There was greater protein expression of both P2X(2) and P2X(3) in IC bladder urothelium which did not directly correlate with the gene expression. Changes in expression of P2X(2) and P2X(3) receptors may contribute to the pain that patients with IC have, and might provide novel drug targets.

Distribution of P2X(1) and P2X(3) receptors in the rat and human urinary bladder.

Adenosine 5'-triphosphate (ATP) is known to play a significant role as a neurotransmitter in smooth muscle. There is evidence to show that ATP can cause bladder contractions and may also be involved in the processing of sensory information in the urinary bladder. These effects are likely to be mediated by P2X receptors, namely P2X(1) and P2X(3), respectively. This study set out to investigate their distribution in rat and human urinary bladders. P2X(1) receptor immunoreactivity was found on detrusor muscle fibres and P2X(3) receptor immunoreactivity was found in the urothelium of both species. This is the first demonstration of a non-neuronal localisation for P2X(3) receptors. No clear evidence was found for the presence of P2X(3) receptors on calcitonin gene-related peptide-containing sensory nerves and therefore P2X(3) receptors may not have a direct role in the mediation of sensory responses to ATP in the urinary bladder.

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells.

Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by approximately 50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G(1) and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.

Activation of epithelial Na(+) channel activity in the rabbit urinary bladder by cAMP.

The rabbit urinary bladder actively absorbs Na(+) from the urine. The rate-limiting step in this process is the diffusion of Na(+) across the apical membrane of bladder epithelial cells, mediated by amiloride-sensitive epithelial Na(+) channels. We have investigated the effects of cAMP on epithelial Na(+) channel activity in the rabbit bladder by measuring the amiloride-sensitive short-circuit current across bladders mounted in Ussing chambers. Three agents that raise intracellular cAMP levels (forskolin, dibutyryl-cAMP and 3-isobutyl-1-methylxanthine (IBMX)) increased the amiloride-sensitive short-circuit current relative to control preparations. The forskolin-induced increase in amiloride-sensitive short-circuit current was significantly inhibited by the vesicle fusion inhibitor brefeldin A and the protein synthesis inhibitor cycloheximide. These findings, together with the magnitude and protracted time course of the cAMP effects, suggests that cAMP stimulates the insertion of new Na(+) channels into the apical membrane of the rabbit bladder epithelium.

Cell cycle delay and apoptosis are induced by high salt and urea in renal medullary cells.

We investigated the effects of hyperosmolality on survival and proliferation of subconfluent cultures of mIMCD3 mouse renal collecting duct cells. High NaCl and/or urea (but not glycerol) reduces the number of viable cells, as measured with 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). Raising osmolality from a normal level (300 mosmol/kg) to 550-1,000 mosmol/kg by adding NaCl and/or urea greatly increases the proportion of cells in the G(2)M phase of the cell cycle within 8 h, as measured by flow cytometry. Up to 600 mosmol/kg the effect is only transient, and by 12 h at 550 mosmol/kg the effect reverses and most cells are in G(1). Flow cytometry with 5-bromodeoxyuridine (BrdU) pulse-chase demonstrates that movement through the S phase of the cell cycle slows, depending on the concentrations of NaCl and/or urea, and that the duration of G(2)M increases greatly (from 2.5 h at 300 mosmol/kg to more than 16 h at the higher osmolalities). Addition of NaCl and/or urea to total osmolality of 550 mosmol/kg or more also induces apoptosis, as demonstrated by characteristic electron microscopic morphological changes, appearance of a subdiploid peak in flow cytometry, and caspase-3 activation. The number of cells with subdiploid DNA and activated caspase-3 peaks at 8-12 h. Caspase-3 activation occurs in all phases of the cell cycle, but to a disproportionate degree in G(0)/G(1) and S phases. We conclude that elevated NaCl and/or urea reduces the number of proliferating mIMCD3 cells by slowing the transit through the S phase, by cell cycle delay in the G(2)M and G(1), and by inducing apoptotic cell death.

Pretreatment with methylprednisolone to prevent ERCP-induced pancreatitis: a randomized, multicenter, placebo-controlled clinical trial.

OBJECTIVE: Pancreatitis remains the major complication of endoscopic retrograde cholangiopancreatography (ERCP). Uncontrolled data suggest a lower incidence of pancreatitis in patients with a history of iodine sensitivity when given pretreatment with corticosteroids. We conducted a clinical trial to assess the efficacy of a commonly prescribed corticosteroid, methylprednisolone, to prevent ERCP-induced pancreatitis. METHODS: Patients were entered into a randomized, multicenter, double-blind, placebo-controlled study of intravenous methylprednisolone (125 mg) versus a saline placebo immediately before the ERCP. All patients were evaluated for early and late complications. RESULTS: Two hundred eighty-six patients were randomized. Thirty-one randomized patients were excluded for technical reasons at the time of ERCP. Overall, the incidence of pancreatitis was 16 of 129 (12.4%, 95% CI: 6.7-18.1%) in the methylprednisolone group and 11 of 126 (8.7%, 95% CI: 4.4-15.1%) in the placebo group, which was not significantly different (p = 0.34). Although there was a higher rate of sphincterotomy performed in the methylprednisolone group compared to the control group (31.8% vs 16.8%, p = 0.005), the incidence of pancreatitis was not different when patients undergoing sphincterotomy were analyzed separately (13.6% in the methylprednisolone group and 9.6% in the placebo group,p = 0.50). There was no significant difference between the two groups for those with ERCP-induced pancreatitis in hospital length of stay (p = 0.22), days of parenteral analgesia (p = 0.09), or days of parenteral nutrition (p = 0.15). CONCLUSION: Intravenous methylprednisolone is not beneficial in preventing ERCP-induced pancreatitis.

ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes--a possible sensory mechanism?

1. The responses of rabbit urinary bladder to hydrostatic pressure changes and to electrical stimulation have been investigated using both the Ussing chamber and a superfusion apparatus. These experiments enabled us to monitor changes in both ionic transport across the tissue and cellular ATP release from it. 2. The urinary bladder of the rabbit maintains an electrical potential difference across its wall as a result largely of active sodium transport from the urinary (mucosal) to the serosal surface. 3. Small hydrostatic pressure differences produced by removal of bathing fluid from one side of the tissue caused reproducible changes in both potential difference and short-circuit current. The magnitude of these changes increases as the volume of fluid removed increases. 3. Amiloride on the mucosal (urinary), but not the serosal, surface of the membrane reduces the transepithelial potential difference and short-circuit current with an IC50 of 300 nM. Amiloride reduces the size of, but does not abolish, transepithelial potential changes caused by alterations in hydrostatic pressure. 4. Field electrical stimulation of strips of bladder tissue produces a reproducible release of ATP. Such release was demonstrated to occur largely from urothelial cells and is apparently non-vesicular as it increases in the absence of calcium and is not abolished by tetrodotoxin. 5. It is proposed that ATP is released from the urothelium as a sensory mediator for the degree of distension of the rabbit urinary bladder and other sensory modalities.

A prospective, double-blind trial of somatostatin analog (octreotide) versus glucagon for the inhibition of small intestinal motility during endoscopic retrograde cholangiopancreatography.

BACKGROUND: Glucagon is effective when used as an antimotility agent during ERCP, but at high doses it may cause nausea and vomiting. Octreotide acetate, a long-acting synthetic analog of somatostatin, inhibits contractility of the small intestine and is generally well tolerated. The purpose of this study was to determine if octreotide given prior to ERCP reduced the requirement for glucagon and enhanced patient tolerance for the procedure. METHODS: Patients undergoing ERCP (n = 100) performed for a variety of indications (but not sphincter of Oddi manometry) were randomly assigned to receive normal saline solution or octreotide at a total dose of 25 micrograms, 50 micrograms, or 100 micrograms diluted in normal saline solution prior to the procedure. Glucagon was subsequently administered (as needed, to inhibit intestinal motility) by endoscopists who were blinded to the test substance given prior to the procedure. RESULTS: For all treatment groups, the dose of glucagon required to inhibit intestinal motility in patients who received octreotide prior to the procedure was not significantly different from the dose administered to patients who received normal saline solution. There was no significant difference in the incidence of nausea and vomiting when individual test groups were compared to the control group. CONCLUSION: Nausea and vomiting after ERCP were uncommon in all treatment groups. Administration of octreotide prior to ERCP did not significantly reduce the dose of glucagon required to inhibit intestinal motility. Tolerance for ERCP was similar for patients given octreotide when compared with those given glucagon to inhibit small intestinal motility.

Inhibitory actions of GABA on rabbit urinary bladder muscle strips: mediation by potassium channels.

1. The actions of gamma-aminobutyric acid (GABA) upon rabbit urinary bladder muscle were investigated to determine whether they were mediated through potassium channels. 2. In vitro experiments were undertaken in which bladder muscle strips were caused to contract with carbachol. Addition of GABA or baclofen reduced the size of such evoked contractions in the case of GABA by 20.7 +/- 3.2%, in the case of baclofen by 22.4 +/- 2.2%. 3. Electrical stimulation of autonomic nerves in bladder wall strips also evoked contractions which were significantly smaller in potassium-free Krebs solution. The size of contractions produced by carbachol on the other hand were unaffected by the absence of potassium in the Krebs solution. 4. The inhibitory actions of GABA and baclofen on carbachol-induced contractions of bladder muscle were detected at much lower concentrations in potassium-free compared with potassium containing solutions. 5. The inhibitory effects of baclofen were completely reversed by tetraethyl ammonium chloride between 1 and 5 mM, caesium chloride between 0.5 and 3 mM and barium chloride between 0.5 and 2.5 mM. The actions of baclofen were only partially reversed by 4-amino-pyridine between 1 and 5 mM. 6. It was concluded that the GABAB receptor-mediated inhibitory actions on rabbit urinary bladder smooth muscle cells were produced by activation of potassium channels.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) remains a disease of unknown etiology. The close association of PSC and inflammatory bowel disease (IBD), especially ulcerative colitis (UC), has been reconfirmed in numerous studies. Much has been learned about the pathogenesis, although the specific cause remains unknown. Copper overload and chronic hepatic bacterial infection have virtually been excluded as causes of PSC. Cytomegalovirus and reovirus remain under investigation. Familial clustering and HLA subtype similarities are seen in PSC with and without IBD. The finding of antineutrophil cytoplasmic antibodies (ANCA) in patients with PSC and those with UC suggests immunological features in the pathogenesis of PSC. Collected series of patients have better characterized clinical features of PSC. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) have provided both diagnostic features and means of therapeutic intervention. Treatment of PSC is symptomatic (pruritus control and vitamin deficiency correction); or experimental (D-penicillamine, ursodeoxycholic acid [UDCA], methotrexate, or corticosteroids). Liver transplantation remains the ultimate treatment for end-stage PSC. Statistical analyses of clinical and laboratory variables in PSC help to determine prognosis and proposed timing for transplantation to achieve maximal longevity and quality of life. PSC affects middle-aged people and is expensive to treat over the natural course of the disease, making it an economically and medically important disease.

Inhibition in the human urinary bladder by gamma-amino-butyric acid.

OBJECTIVE: To investigate the effects of gamma-amino-butyric acid (GABA) on detrusor activity in man to determine whether it has any inhibitory effect on detrusor contraction. The inhibitory neurotransmitter GABA has been found in mammalian urinary bladders and the effects of GABA on detrusor activity in the rabbit bladder has previously been described [1]. MATERIALS AND METHODS: Human detrusor muscle strips, obtained at cystectomy, were made to contract by electrical stimulation of their autonomic nerves or by the addition of carbachol in a superfusion apparatus. GABA and its analogues were added to the superfusion chamber and any changes in the responses were measured. RESULTS: The electrically evoked nerve-mediated contractions in human bladder muscle were exclusively cholinergic. GABA inhibited nerve-mediated contractions in human detrusor muscle-strips by the activation of the GABAB receptor, since baclofen (a GABAB receptor agonist) produced similar inhibition and muscimol (a GABAA receptor agonist) did not. There was no inhibition of carbachol-mediated contractions by GABA. CONCLUSION: This in vitro study shows that GABA has a peripherally mediated inhibitory effect on excitatory neurotransmission in human detrusor muscle. The site of action is on the post-ganglionic nerves and appears to be mediated via the GABAB receptor.

Surgical decisions in the management of duodenal perforation complicating endoscopic sphincterotomy.

The management of duodenal perforation associated with endoscopic sphincterotomy is controversial. Despite the fact that many patients recover without surgery, surgical opinion tends to favor immediate operation upon diagnosis since the mortality is high when sepsis is advanced. To refine the criteria for operative management, all duodenal perforations after endoscopic sphincterotomy over a 5-year period were studied. In a series of 464 consecutive endoscopic sphincterotomies, 8 duodenal perforations occurred; additionally, 4 patients with duodenal perforation were referred from elsewhere for management. Six patients were managed initially with nonoperative treatment (group I), and six underwent exploratory surgery upon diagnosis or hospital transfer (group II). One patient in group I was operated on 4 days after diagnosis. Of the seven surgically treated patients, three had repair of the duodenal perforation and drainage of the abscess or phlegmon, but four had no gross inflammation or visible duodenal perforation requiring repair at exploration. The clinical features of abdominal pain with physical signs significantly correlated with operative findings of pus or phlegmon (p < 0.05). Improvement in symptoms within 24 hours is correlated with spontaneous recovery (p < 0.01). Neither the presence of retroperitoneal air nor contrast leak is predictive of the need for surgery, and neither correlated with the size of the perforation. It is concluded that duodenal perforation may be treated successfully without surgery when the symptoms are mild and improve rapidly with medical treatment, but surgery should be undertaken if pain and abdominal signs are prominent, if suppuration is suspected, or if symptoms do not improve after a brief period of nonoperative management.

Placement of a feeding button ("one-step button") as the initial procedure.

The procedure of choice for enteral feeding access is now percutaneous endoscopic gastrostomy (PEG). Standard PEG tubes have the disadvantages of clogging, stomal enlargement, and external bulkiness. Button replacement tubes can covert the more cumbersome PEG tubes to low external profile devices. A procedure and an early experience is described for placement of a button as a single-step procedure. This procedure is an over-the-wire, "push" procedure. Sixty-nine buttons were placed, 47 (61%) for neurologic reasons and 22 (32%) for cancer and other reasons. In 49 of the 69 (71%), there was no difficulty at all with insertion, and in only two (3%) could the button not be placed. Complications were assessed at 48 h and at 3 wk. No complications were found in 61 (90%). In only two patients (3%) were there serious complications (gastro-colon-cutaneous fistula and "peritonitis"). The One-Step Button represents a rapid, safe procedure for the placement of a low-profile PEG with its attendant advantages.

Inhibitory role of gamma-amino-butyric acid in the rabbit urinary bladder.

Gamma-amino-butyric acid (GABA) is an established inhibitory neurotransmitter in the central nervous system (CNS) and it has also been identified in the bladder. We have investigated in the rabbit the effect of GABA on detrusor activity. Rabbit detrusor muscle strips were made to contract by electrical stimulation of their autonomic nerves or by the addition of carbachol. The addition of GABA caused substantial inhibition of muscle contraction. GABA acts on 2 classes of receptors-GABAA and GABAB. The inhibition was mediated via the GABAB receptors as its effect was mimicked by baclofen (a GABAB agonist) and inhibited by 2-hydroxysaclofen (a GABAB receptor antagonist). Inhibition was not prevented by bicuculline (a GABAA receptor antagonist). This inhibition may be due to a direct muscle effect since the inhibition, which occurred with carbachol-induced contraction, was not abolished by the addition of tetrodotoxin. GABA, acting via the GABAB receptor, produces substantial inhibition of muscle contraction in the rabbit urinary bladder. This raises the possibility of using GABAB analogues in the treatment of detrusor instability.