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Sample records for cisapride

  1. Cisapride

    MedlinePlus

    ... take cisapride if you are taking bepridil (Vascor); chlorpromazine (Thorazine); clarithromycin (Biaxin); erythromycin (E.E.S., E-Mycin, ... a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www. ...

  2. Drug interactions with cisapride: clinical implications.

    PubMed

    Michalets, E L; Williams, C R

    2000-07-01

    Cisapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders, particularly gastro-oesophageal reflux disease in adults and children. Since 1993, 341 cases of ventricular arrhythmias, including 80 deaths, have been reported to the US Food and Drug Administration. Marketing of the drug has now been discontinued in the US; however, it is still available under a limited-access protocol. Knowledge of the risk factors for cisapride-associated arrhythmias will be essential for its continued use in those patients who meet the eligibility criteria. This review summarises the published literature on the pharmacokinetic and pharmacodynamic interactions of cisapride with concomitantly administered drugs, providing clinicians with practical recommendations for avoiding these potentially fatal events. Pharmacokinetic interactions with cisapride involve inhibition of cytochrome P450 (CYP) 3A4, the primary mode of elimination of cisapride, thereby increasing plasma concentrations of the drug. The macrolide antibacterials clarithromycin, erythromycin and troleandomycin are inhibitors of CYP3A4 and should not be used in conjunction with cisapride. Azithromycin is an alternative. Similarly, azole antifungal agents such as fluconazole, itraconazole and ketoconazole are CYP3A4 inhibitors and their concomitant use with cisapride should be avoided. Of the antidepressants nefazodone and fluvoxamine should be avoided with cisapride. Data with fluoxetine is controversial, we favour the avoidance of its use. Citalopram, paroxetine and sertraline are alternatives. The HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir inhibit CYP3A4. Clinical experience with cisapride is lacking but avoidance with all protease inhibitors is recommended, although saquinavir is thought to have clinically insignificant effects on CYP3A4. Delavirdine is also a CYP3A4 inhibitor and should be avoided with cisapride. We also recommend

  3. Treatment of chronic constipation with cisapride and placebo.

    PubMed Central

    Müller-Lissner, S A

    1987-01-01

    The effect of cisapride (20 mg bid), a new prokinetic drug, on bowel habits and laxative consumption was studied in patients with idiopathic painless constipation and chronic laxative intake. After a four week base line period, spontaneous defection (frequency without laxative intake) and total defecation (total frequency) were measured. Patients with a spontaneous defecation of less than three stools per week entered the treatment period and were randomly assigned to double blind treatment with either cisapride (n = 64) or placebo (n = 62). After eight weeks of treatment, a four week run out phase on single blind placebo medication was conducted. Cisapride and placebo increased spontaneous stool frequency from 1.1 +/- 0.2 SEM to 3.0 +/- 0.2 per week (p less than 0.001) and from 1.2 +/- 0.1 to 1.5 +/- 0.2 (p greater than 0.05), respectively. Laxative consumption was decreased from 3.6 +/- 0.3 to 1.8 +/- 0.2 doses/week by cisapride (p less than 0.001) and from 3.3 +/- 0.3 to 2.8 +/- 0.3 by placebo (p less than 0.05). Both drugs improved constipation as assessed by the patient by means of a visual analogue scale, but cisapride did so to a larger extent than placebo. The effects of cisapride partly outlasted active medication by at least four weeks. It is concluded that cisapride improves bowel habits in patients with idiopathic constipation and reduces laxative consumption. PMID:3311905

  4. Randomised controlled trial of cisapride in preterm infants

    PubMed Central

    McClure, R; Kristensen, J; Grauaug, A

    1999-01-01

    AIM—To determine the effect of cisapride on gastrointestinal motility in preterm infants.
METHODS—Cisapride (0.2 mg/kg, 8 hourly ) or placebo was given first for seven days in a double blind randomised crossover study of 10 preterm infants. Gastrointestinal motility was assessed on day 3 of each treatment. The half gastric emptying time (GET1/2) was determined by using ultrasonography to measure the decrease in the gastric antral cross sectional area after a feed. The whole gastrointestinal transit time (WGTT) was assessed by timing the transit of carmine red through the gut. Treatments were compared using the Wilcoxon matched pairs signed ranks test.
RESULTS—Median (range) birthweight was 1200 (620, 1450) g and postconceptional age 33 (29, 34) weeks at recruitment. GET1/2 was significantly longer during cisapride treatment than during placebo; the median of the differences (95% confidence interval) was 19.2 (11, 30minutes, p=0.008). WGTT was also longer during cisapride treatment, but the difference was not significant; the median of the differences was 11(−18, 52 hours, p=0.1).
CONCLUSIONS—Cisapride delays gastric emptying and may delay WGTT in preterm infants. Its use to promote gastrointestinal motility in this group cannot be recommended.

 PMID:10212076

  5. Effects of cisapride on gastric emptying of oil and aqueous meal components, hunger, and fullness.

    PubMed Central

    Jones, K L; Horowitz, M; Carney, B I; Sun, W M; Chatterton, B E

    1996-01-01

    To evaluate the effects of cisapride on gastric emptying of extracellular fat and hunger and fullness 10 volunteers consumed a meal consisting of 60 ml technectium-99m (99mTc)-V-thiocyanate labelled olive oil and 290 ml indium-113m (113mIn) labelled soup after taking cisapride (10 mg four times daily orally) and placebo, each for four days, in randomised, double blind fashion. Gastric emptying was quantified scintigraphically. Hunger and fullness before and after the meal were evaluated using visual analogue scales. Cisapride accelerated gastric emptying of oil and aqueous components by reducing the lag phase mean (SEM) (20.3 (7.0) min v 40.7 (4.1) min (p < 0.05) for oil and 4.1 (2.5) min v 10.0 (3.1) min (p < 0.05) for aqueous). Cisapride had no effect on the post-lag emptying rate of oil. Treatment with cisapride was associated with reduced retention of oil in the proximal stomach (p < 0.05). Subjects were more hungry before ingestion of the meal while receiving cisapride (6.7 (0.9) v 3.9 (0.7), p < 0.001). The scores for hunger at 120 and 180 minutes were inversely related to gastric emptying of oil on both cisapride (r > -0.62, p < 0.05) and placebo (r > -0.86, p < 0.001). Fullness increased after the meal while receiving placebo (p < 0.01), but not cisapride and postprandial fullness was less with cisapride at (30 min; 0.4 (0.3) v 3.3 (1.0), p < 0.05). With placebo, but not cisapride, the score for fullness at 15 minutes was inversely related to emptying of the aqueous phase (r = 0.68, p < 0.05). These results show that in normal volunteers after ingestion of an oil/aqueous meal: (a) postprandial hunger is inversely related to gastric emptying of oil, while fullness is inversely related to gastric emptying of the aqueous phase, (b) cisapride affects the intragastric distribution and accelerates gastric emptying of both oil and aqueous meal components, and (c) cisapride increases preprandial hunger and reduces postprandial fullness. PMID:8675080

  6. Effects of cisapride on ulcer formation and gastric secretion in rats: comparison with ranitidine and omeprazol.

    PubMed

    Alarcón de la Lastra, C; Martin, M J; La Casa, M; López, A; Motilva, V

    1996-12-01

    1. The antiulcerogenic effects of cisapride, a potent benzamide-stimulating gastrointestinal motility agent, were studied on cold-resistant and pylorus-ligated gastric ulcers. Acidity, composition of gastric secretion, and quantitative and qualitative changes on mucus glycoprotein content were also determined. These effects were compared with those of ranitidine (50 mg/kg) and omeprazol (10 mg/kg). 2. Oral cisapride (10-100 mg/kg) dose-relatedly and significantly (P < 0.01, P < 0.05) decreased the severity of the lesions induced by cold-resistant stress. In stressed rats, cisapride increased the amount of mucus secretion and markedly enhanced the glycoprotein content. Morphometric evaluation of mucus secretion revealed a significant increase in both the PAS area (neutral glycoproteins) and Alcian blue area (sulfated glycoproteins). 3. In 4 h pyloric-ligated animals, cisapride (10-100 mg/kg) showed a significant reduction in the number and severity of ulcers (P < 0.01) and histamine concentration (P < 0.01, P < 0.001). In addition, at the highest doses (50-100 mg/kg), cisapride produced a significant decreases in acidity; however, it did not alter the gastric volume secretion or pepsin concentrations. 4. These results suggest that cisapride shows antiulcerogenic effects which could possibly be explained through antisecretory and cytoprotective mechanisms involving an enhancement of cuality and production of gastric mucus.

  7. Effects of cisapride in patients with cystic fibrosis and distal intestinal obstruction syndrome.

    PubMed

    Koletzko, S; Corey, M; Ellis, L; Spino, M; Stringer, D A; Durie, P R

    1990-11-01

    In a double-blind, placebo-controlled, crossover trial, we investigated the effects of the prokinetic drug cisapride in patients with cystic fibrosis and chronic recurrent distal intestinal obstruction syndrome (DIOS). After a baseline period, 17 patients (12.9 to 34.9 years; 12 boys) received, in random order, cisapride (7.5 to 10 mg) and placebo three times daily by mouth, each for 6 months. Gastrointestinal symptoms (flatulence, abdominal pain, fullness, abdominal distension, nausea, anorexia, heartburn, diarrhea, vomiting and regurgitation) were scored three times monthly and physical examinations assessed. At baseline and at each 6-month period, assessment included food intake for 7 days, 3-day stool collection, pulmonary function tests, and abdominal radiographs. During cisapride therapy compared with placebo, there were significant reductions in flatulence (p less than 0.005), fullness, and nausea (p less than 0.05). Patients with the worst symptom scores benefited most from cisapride. With cisapride, 12 patients felt better and three worse (p less than 0.05); physicians judged 11 patients improved and two worse (p less than 0.05). No side effects were noted. There were no significant differences between cisapride and placebo periods in nutritional status, x-ray scores, pulmonary function, food intake (fat, protein, calories), stool size and consistency, and fecal losses of fat, bile acids, chymotrypsin, and calories. For acute episodes of DIOS, intestinal lavage was needed 6 times in 4 patients during treatment with cisapride, and 11 times in 6 patients receiving placebo. In comparison with unselected patients with cystic fibrosis and pancreatic insufficiency who were receiving enzyme supplements and who had no distal intestinal obstruction, fecal fat losses (percentage of intake) were almost twice as high in the study group with DIOS (31.2 +/- 20.6% vs 16.2 +/- 17.6%; p less than 0.01). We conclude that in the dosage used, long-term treatment with

  8. [A new granular effervescent 10-mg formulation of cisapride in the treatment of gastroesophageal reflux].

    PubMed

    Grossi, L; Di Felice, F; Marzio, L

    1993-02-01

    The efficacy and tolerability of Cisapride effervescent granules for treatment of gastroesophageal reflux disease were compared to a metoclopramide-dimeticone combination. The double-blind study was performed in two groups of 10 patients each who received 3 sachets daily of either drug for 8 weeks. Cisapride effervescent granules induced a statistically significant improvement of 75% of symptoms (6/8) while this improvement was obtained with the reference drug for only 60% (3/5). Statistical evaluation showed Cisapride effervescent granules to be more effective than the reference drug for 2 of 5 evaluable symptoms; mean global improvement amounted to 83 vs 58%. Final physician opinion was more favorable to Cisapride effervescent granules than to the reference drug (p < 0.005). Treatment did not have to be withdrawn nor were clinically significant changes of laboratory values observed. Both drugs were found to be well tolerated without differences between the two groups. Three patients treated with Cisapride effervescent granules complained of short-lasting mild abdominal discomfort the relations of which to the drug was doubtful, and which subsided spontaneously without need to withdraw treatment or to apply other types of therapy.

  9. Clinical recovery of chronic intestinal pseudo-obstruction with cisapride in a complex pediatric patient.

    PubMed

    Cameron, Jean-Christy F; Vaillancourt, Régis; Major-Cook, Nathalie; Boland, Margaret; Zucker, Marc; Lariviere, Doris

    2013-06-01

    Cisapride is a gastrointestinal prokinetic that facilitates or restores motility along the entire gastrointestinal tract. It has been used successfully to treat acute and chronic intestinal pseudo-obstructions (CIPs) in adults, but there is a paucity of literature surrounding the treatment of CIP in pediatric patients and therapies for CIP are limited and their impact is often unsatisfactory. This case report presents the use of cisapride in the management of pseudo-obstruction. Treatment with cisapride substantially improved the patient's symptoms and improved feeding tolerance. It improved his prognosis remarkably and prevented the need for end-of-life care. He experienced no adverse effects throughout the course of therapy. The treatment regimen is discussed in this case report.

  10. Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions

    PubMed Central

    Bohets, H; Lavrijsen, K; Hendrickx, J; van Houdt, J; van Genechten, V; Verboven, P; Meuldermans, W; Heykants, J

    2000-01-01

    Cisapride is a prokinetic drug that is widely used to facilitate gastrointestinal tract motility.Structurally, cisapride is a substituted piperidinyl benzamide that interacts with 5-hydroxytryptamine-4 receptors and which is largely without central depressant or antidopaminergic side-effects.The aims of this study were to investigate the metabolism of cisapride in human liver microsomes and to determine which cytochrome P-450 (CYP) isoenzyme(s) are involved in cisapride biotransformation. Additionally, the effects of various drugs on the metabolism of cisapride were investigated.The major in vitro metabolite of cisapride was formed by oxidative N-dealkylation at the piperidine nitrogen, leading to the production of norcisapride.By using competitive inhibition data, correlation studies and heterologous expression systems, it was demonstrated that CYP3A4 was the major CYP involved. CYP2A6 also contributed to the metabolism of cisapride, albeit to a much lesser extent.The mean apparent Km against cisapride was 8.6±3.5 μM (n=3). The peak plasma levels of cisapride under normal clinical practice are approximately 0.17 μM; therefore it is unlikely that cisapride would inhibit the metabolism of co-administered drugs.In this in vitro study the inhibitory effects of 44 drugs were tested for any effect on cisapride biotransformation. In conclusion, 34 of the drugs are unlikely to have a clinically relevant interaction; however, the antidepressant nefazodone, the macrolide antibiotic troleandomycin, the HIV-1 protease inhibitors ritonavir and indinavir and the calcium channel blocker mibefradil inhibited the metabolism of cisapride and these interactions are likely to be of clinical relevance. Furthermore, the antimycotics ketoconazole, miconazole, hydroxy-itraconazole, itraconazole and fluconazole, when administered orally or intravenously, would inhibit cisapride metabolism. PMID:10780971

  11. [Efficacy and tolerability of cisapride in a new formula of 10 mg effervescent capsules for the treatment of functional dyspepsia].

    PubMed

    Grossi, L; Di Felice, F; Marzio, L

    1993-06-01

    The efficacy and tolerability of Cisapride effervescent granules and a metoclopramide-dimethicone combination were compared double-blind in two comparable groups of 15 patients each with dyspepsia. All patients received three sachets daily of either drug for 6 consecutive weeks. As for efficacy, Cisapride effervescent granules was found to reduce 85% (11/13) of symptoms to a statistically significant extent, as against 42% (5/12) in the reference group. Statistical analysis showed Cisapride effervescent granules to be more effective than the reference drug for 6 out of 11 evaluable symptoms. Mean global improvement was 86% for Cisapride effervescent granules vs 41% for the reference combination. Final judgment by the physician was more favorable for Cisapride effervescent granules than for the reference drug (p < 0.0001). Treatment withdrawal was never necessary and no significant changes of laboratory values were observed. No statistically significant difference between the two treatments as to tolerability was observed. In conclusion, Cisapride effervescent granules was found to have a better risk/benefit ratio than the reference combination.

  12. Effects of cisapride on gall bladder emptying, intestinal transit, and serum deoxycholate: a prospective, randomised, double blind, placebo controlled trial

    PubMed Central

    Veysey, M; Malcolm, P; Mallet, A; Jenkins, P; Besser, G; Murphy, G; Dowling, R

    2001-01-01

    BACKGROUND—Octreotide inhibits gall bladder emptying and prolongs intestinal transit. This leads to increases in the proportion of deoxycholic acid in, and cholesterol saturation of, gall bladder bile, factors that contribute to the pathogenesis of octreotide induced gall stones.
AIMS—To see if an intestinal prokinetic, cisapride, could overcome these adverse effects of octreotide and if so, be considered as a candidate prophylactic drug for preventing iatrogenic gall bladder stones.
METHODS—A randomised, double blind, placebo controlled, crossover design was used to examine the effects of cisapride (10 mg four times daily) on gall bladder emptying, mouth to caecum and large bowel transit times, and the proportions of deoxycholic acid and other bile acids, in fasting serum from: (i) control subjects (n=6), (ii) acromegalic patients not treated with octreotide (n=6), (iii) acromegalics on long term octreotide (n=8), and (iv) patients with constipation (n=8).
RESULTS—Cisapride had no prokinetic effect on the gall bladder. In fact, it significantly increased both fasting and postprandial gall bladder volumes. However, it shortened mouth to caecum (from 176 (13) to 113 (11) minutes; p<0.001) and large bowel (from 50 (3.0) to 31 (3.4) h; p<0.001) transit times. It also reduced the proportion of deoxycholic acid in serum from 26 (2.3) to 15 (1.8)% (p<0.001), with a reciprocal increase in the proportion of cholic acid from 40 (3.5) to 51 (3.8)% (p<0.01). There were significant linear relationships between large bowel transit time and the proportions of deoxycholic acid (r=0.81; p<0.001) and cholic acid (r=−0.53; p<0.001) in fasting serum.
INTERPRETATION/SUMMARY—Cisapride failed to overcome the adverse effects of octreotide on gall bladder emptying but it countered octreotide induced prolongation of small and large bowel transit. Therefore, if changes in intestinal transit contribute to the development of octreotide induced gall bladder stones

  13. Design and evaluation of hydrophobic coated buoyant core as floating drug delivery system for sustained release of cisapride

    PubMed Central

    Jacob, Shery; Nair, Anroop B; Patil, Pandurang N

    2010-01-01

    An inert hydrophobic buoyant coated–core was developed as floating drug delivery system (FDDS) for sustained release of cisapride using direct compression technology. Core contained low density, porous ethyl cellulose, which was coated with an impermeable, insoluble hydrophobic coating polymer such as rosin. It was further seal coated with low viscosity hydroxypropyl methyl cellulose (HPMC E15) to minimize moisture permeation and better adhesion with an outer drug layer. It was found that stable buoyant core was sufficient to float the tablet more than 8 h without the aid of sodium bicarbonate and citric acid. Sustained release of cisapride was achieved with HPMC K4M in the outer drug layer. The floating lag time required for these novel FDDS was found to be zero, however it is likely that the porosity or density of the core is critical for floatability of these tablets. The in vitro release pattern of these tablets in simulated gastric fluid showed the constant and controlled release for prolonged time. It can be concluded that the hydrophobic coated buoyant core could be used as FDDS for gastroretentive delivery system of cisapride or other suitable drugs. PMID:24825997

  14. High-resolution manometric evaluation of the effects of cisapride on the esophagus during administration of solid and liquid boluses in awake healthy dogs.

    PubMed

    Ullal, Tarini V; Kass, Philip H; Conklin, Jeffrey L; Belafsky, Peter C; Marks, Stanley L

    2016-08-01

    OBJECTIVE To validate the use of high-resolution manometry (HRM) in awake, healthy dogs and compare the effects of bolus type (liquid vs solid) and drug treatment (saline [0.9% NaCl] solution [SS] vs cisapride) on esophageal pressure profiles. ANIMALS 8 healthy dogs. PROCEDURES In a crossover study, each dog received SS (10 mL) IV, and HRM was performed during oral administration of 10 boluses (5 mL each) of water or 10 boluses (5 g each) of canned food. Cisapride (1 mg/kg in 60 mL of SS) was subsequently administered IV to 7 dogs; HRM and bolus administration procedures were repeated. Two to 4 weeks later, HRM was repeated following administration of SS and water and food boluses in 4 dogs. Pressure profile data were obtained for all swallows, and 11 outcome variables were statistically analyzed. RESULTS After SS administration, predicted means for the esophageal contractile integral were 850.4 cm/mm Hg/s for food boluses and 660.3 cm/mm Hg/s for water boluses. Predicted means for esophageal contraction front velocity were 6.2 cm/s for water boluses and 5.6 cm/s for food boluses after SS administration. Predicted means for residual LES pressure were significantly higher following cisapride administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HRM was feasible and repeatable in awake healthy dogs of various breeds and sizes. Stronger esophageal contractions and faster esophageal contraction velocity occurred during solid bolus and liquid bolus swallows, respectively. Lower esophageal sphincter pressure increased significantly following cisapride administration. Esophageal contractions and bolus transit latency should be further evaluated by HRM in clinically dysphagic dogs.

  15. Cisapride a green analytical reagent for rapid and sensitive determination of bromate in drinking water, bread and flour additives by oxidative coupling spectrophotometric methods

    NASA Astrophysics Data System (ADS)

    Al Okab, Riyad Ahmed

    2013-02-01

    Green analytical methods using Cisapride (CPE) as green analytical reagent was investigated in this work. Rapid, simple, and sensitive spectrophotometric methods for the determination of bromate in water sample, bread and flour additives were developed. The proposed methods based on the oxidative coupling between phenoxazine and Cisapride in the presence of bromate to form red colored product with max at 520 nm. Phenoxazine and Cisapride and its reaction products were found to be environmentally friendly under the optimum experimental condition. The method obeys beers law in concentration range 0.11-4.00 g ml-1 and molar absorptivity 1.41 × 104 L mol-1 cm-1. All variables have been optimized and the presented reaction sequences were applied to the analysis of bromate in water, bread and flour additive samples. The performance of these method was evaluated in terms of Student's t-test and variance ratio F-test to find out the significance of proposed methods over the reference method. The combination of pharmaceutical drugs reagents with low concentration create some unique green chemical analyses.

  16. Cisapride a green analytical reagent for rapid and sensitive determination of bromate in drinking water, bread and flour additives by oxidative coupling spectrophotometric methods.

    PubMed

    Al Okab, Riyad Ahmed

    2013-02-15

    Green analytical methods using Cisapride (CPE) as green analytical reagent was investigated in this work. Rapid, simple, and sensitive spectrophotometric methods for the determination of bromate in water sample, bread and flour additives were developed. The proposed methods based on the oxidative coupling between phenoxazine and Cisapride in the presence of bromate to form red colored product with max at 520 nm. Phenoxazine and Cisapride and its reaction products were found to be environmentally friendly under the optimum experimental condition. The method obeys beers law in concentration range 0.11-4.00 g ml(-1) and molar absorptivity 1.41 × 10(4) L mol(-1)cm(-1). All variables have been optimized and the presented reaction sequences were applied to the analysis of bromate in water, bread and flour additive samples. The performance of these method was evaluated in terms of Student's t-test and variance ratio F-test to find out the significance of proposed methods over the reference method. The combination of pharmaceutical drugs reagents with low concentration create some unique green chemical analyses.

  17. Novel oxidative coupling reactions of cisapride or metaclopramide with phenoxazines and their applications in the determination of nitrite at trace level in environmental samples

    NASA Astrophysics Data System (ADS)

    AL-Okab, Riyad Ahmed; Syed, Akheel Ahmed

    2007-11-01

    Phenoxazine (PNZ), 2-chlorophenoxazine (CPN) and 2-trifluoromethylphenoxazine (TPN) were used as new class of spectrophotometric reagents for the determination of nanoamounts of nitrite in presence of cisapride (CSP) and metaclopramide (MCP) as new electrophilic coupling reagents. The methods were based on the oxidation of CSP or MCP by nitrite in hydrochloric acid medium and coupling with PNZ, CPN or TPN to yield red color derivatives which were stable for about 3 h and having an absorbance maximum in the range 520-530 nm. Beer's law is obeyed for nitrite in the concentration range 0.08-0.80 and 0.13-1.60 μg ml -1 for phenoxazine-cisapride and phenoxazine-metaclopramide, respectively. The optimum reaction conditions and other important analytical parameters were established to enhance the sensitivity of these methods. Interference due to various non-target ions was also investigated. The methods were applied to the analysis of nitrite in environmental samples. The performance of proposed methods were evaluated by Student's t-test and variance ratio F-test indicated the significance of proposed methods over the reference spectrophotometric method (Association of Official Analytical Communities (AOAC) method for the determination of nitrite in water samples).

  18. Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride.

    PubMed

    Matsunaga, Yugo; Tanaka, Takao; Yoshinaga, Koji; Ueki, Shigeru; Hori, Yuko; Eta, Runa; Kawabata, Yoshihiro; Yoshii, Kazuyoshi; Yoshida, Kenji; Matsumura, Toshihiro; Furuta, Shigeru; Takei, Mineo; Tack, Jan; Itoh, Zen

    2011-03-01

    Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

  19. Quality of life in patients with functional dyspepsia: Short- and long-term effect of Helicobacter pylori eradication with pantoprazole, amoxicillin, and clarithromycin or cisapride therapy: A prospective, parallel-group study

    PubMed Central

    Buzás, György M.

    2006-01-01

    Background: Quality of life (QOL) is impaired in functional dyspepsia (FD). Little is known about the effects of different therapies on the QOL profile in patients with this condition. Objectives: The aims of this study were to measure baseline QOL in patients with FD and to assess changes in QOL over time associated with Helicobacter pylori eradication and prokinetic treatment. The primary and secondary end points were the improvement in QOL 6 weeks and 1 year after successful eradication of the infection or prokinetic therapy. Methods: This 1-year, single-center, prospective, open-label, controlled, parallel-group trial was conducted at the Department of Gastroenterology, Ferencvdros Health Centre, Budapest, Hungary. The Functional Digestive Disorder Quality of Life (FDDQoL) Questionnaire (MAPI Research Institute, Lyon, France) was translated and validated previously in Hungarian. Male and female subjects aged 20 to 60 years were enrolled and classified as H pylori positive (HP+), H pylori negative (HP-) with FD, or healthy (control group). The HP+ patients received pantoprazole 40 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID for 7 days, followed by on-demand ranitidine (150–300 mg/d) for 1 year. The HP- patients received the prokinetic cisapride 10 mg TID for 1 month, followed by on-demand cisapride (10–20 mg/d) for 1 year. The FDDQoL questionnaire was completed by all 3 groups on enrollment, at 6 weeks, and 1 year. Results: A total of 101 HP+ patients, 98 HP- patients, and 123 healthy controls were included in the study (185 women, 137 men; mean age, 39.0 ears). The mean (SD) baseline QOL scores were significantly lower in the HP+ group (53.3 [9.6]; 95% CI, 54.4-58.2) and the HP- groups (50.0 [9.8]; 95% CI, 58.0–62.0) compared with that in healthy controls (76.2 [8.7]; 95% CI, 74.6–77.8) (both, P < 0.001). Analysis of the short-term domain scores found that the HP+ group had significantly decreased scores in 6 of 8 domains: daily

  20. Hops

    MedlinePlus

    ... verapamil), chemotherapeutic agents (etoposide, paclitaxel, vinblastine, vincristine, vindesine), antifungals (ketoconazole, itraconazole), glucocorticoids, alfentanil (Alfenta), cisapride (Propulsid), fentanyl ( ...

  1. Saquinavir

    MedlinePlus

    ... with ritonavir (Norvir) and other medications to treat human immunodeficiency virus (HIV) infection. Saquinavir is in a ... Vascor); cisapride (not available in the U.S.; Propulsid); chlorpromazine; clozapine (Clozaril, Fazaclo, Versacloz); dapsone (Aczone); disopyramide (Norpace); ...

  2. [Therapy of non-ulcer dyspepsia].

    PubMed

    Cortese, I; Maselli, M A

    1990-04-30

    The authors describe the gastro-kinetic drugs that act on functional dyspepsia including metoclopramide, domperidone, clebopride cisapride. Moreover, in some forms of non-ulcer dyspepsia it is useful to give sulglicotide, a cytoprotective drug that has been shown to induce marked improvement of clinical symptoms and endoscopic findings.

  3. Prokinetic Therapy Reduces Aspiration Pneumonia in Tube-Fed Patients With Severe Developmental Disabilities

    ERIC Educational Resources Information Center

    Pareek, Namita; Williams, John; Hanna, Deborah; Johnson, William D.; Minocha, Anil; Abell, Thomas L.

    2007-01-01

    To evaluate the clinical benefit of prokinetic therapy in aspiration pneumonia in patients with developmental disabilities, we conducted a retrospective study; records of 22 tube-fed patients were reviewed from December 1990 to October 1998 for a mean of 22.7 months before and 38.9 months during Cisapride therapy. Numbers of hospital admissions…

  4. 5HT4 agonists inhibit interferon-gamma-induced MHC class II and B7 costimulatory molecules expression on cultured astrocytes.

    PubMed

    Zeinstra, Esther M; Wilczak, Nadine; Wilschut, Jan C; Glazenburg, Lisa; Chesik, Daniel; Kroese, Frans G M; De Keyser, Jacques

    2006-10-01

    A failure of tight control of MHC class II expression on astrocytes may play a role in the development of autoimmune responses in multiple sclerosis. The 5-HT(4) serotonin receptor agonists cisapride and prucalopride, at concentrations between 10(-10) M and 10(-8) M, reduced interferon-gamma-induced MHC class II immunostaining in cultured astrocytes derived from newborn Wistar rats by approximately 50-60%. The magnitude of MHC class II inhibition by 5-HT(4) agonists was comparable to that of interferon-beta. The alpha(1)-adrenergic receptor agonist phenylephrine was without effect. Cisapride (10(-9) M) also prevented interferon-gamma-induced B7-1 and B7-2 immunostaining. Our results suggest that 5-HT(4) agonists may have therapeutic potential in multiple sclerosis by inhibiting the up-regulation of immune responsiveness of astrocytes in the central nervous system.

  5. [Effects of various prokinetic drugs on gastrointestinal transit times in patients with progressive systemic scleroderma].

    PubMed

    Folwaczny, C; Läritz, M; Meurer, M; Endres, S P; König, A; Schindlbeck, N

    1997-10-01

    The intestine is involved in about half of the cases with progressive-systemic sclerosis. Intestinal transit disturbances which are caused by neuropathy of the enteric nerve system occur frequently. However, upto-date only few studies which determined the effect of prokinetic drugs exist. Patients with intestinal involvement caused by progressive-systemic sclerosis were treated with the prokinetic drugs cisapride (20 mg, TID; n = 9), erythromycin (250 mg, TID; n = 7) and octreotide (50 micrograms s. c., at night time; n = 5) over a period of four weeks. At study entry and after each treatment period the transit times through the stomach, small and large intestine were evaluated by use of the metal-detector test. Gastric emptying was only accelerated by erythromycin (42 +/- 3 min vs. 54 +/- 6 min; p = 0.0422), whereas treatment with cisapride and octreotide did not result in significant changes (48 +/- 4 min; p = 0.3743 and 44 +/- 4 min; p = 0.1975; resp.). Small intestinal transit times were not altered significantly by cisapride (108 +/- 15 min vs. 108 +/- 9 min; p = 0.2733), crythromycin (92 +/- 8 min; p = 0.0707) or octreotide (106 +/- 12 min; p = 0.8927). Furthermore colonic transit was not fastened by none of the prokinetic agents (study entry: 68 +/- 12 h; cisapride: 88 +/- 12 h; p = 0.0569; erythromycin 77 +/- 14 h; p = 0.7349; octreotide 107 +/- 14 h; p = 0.8927). Four patients were withdrawn from the study because of diarrhea. Prokinetic drugs do not seem to have a major impact on intestinal transit times in patients with progressive-systemic sclerosis. The use of these drugs is limited because of frequent side effects.

  6. Elenoside increases intestinal motility

    PubMed Central

    Navarro, E; Alonso, SJ; Navarro, R; Trujillo, J; Jorge, E

    2006-01-01

    AIM: To study the effects of elenoside, an arylnaph-thalene lignan from Justicia hyssopifolia, on gastro-intestinal motility in vivo and in vitro in rats. METHODS: Routine in vivo experimental assessments were catharsis index, water percentage of boluses, intestinal transit, and codeine antagonism. The groups included were vehicle control (propylene glycol-ethanol-plant oil-tween 80), elenoside (i.p. 25 and 50 mg/kg), cisapride (i.p. 10 mg/kg), and codeine phosphate (intragastric route, 50 mg/kg). In vitro approaches used isolated rat intestinal tissues (duodenum, jejunum, and ileum). The effects of elenoside at concentrations of 3.2 x 10-4, 6.4 x 10-4 and 1.2 x 10-3 mol/L, and cisapride at 10-6 mol/L were investigated. RESULTS: Elenoside in vivo produced an increase in the catharsis index and water percentage of boluses and in the percentage of distance traveled by a suspension of activated charcoal. Codeine phosphate antagonized the effect of 25 mg/kg of elenoside. In vitro, elenoside in duodenum, jejunum and ileum produced an initial decrease in the contraction force followed by an increase. Elenoside resulted in decreased intestinal frequency in duodenum, jejunum, and ileum. The in vitro and in vivo effects of elenoside were similar to those produced by cisapride. CONCLUSION: Elenoside is a lignan with an action similar to that of purgative and prokinetics drugs. Elenoside, could be an alternative to cisapride in treatment of gastrointestinal diseases as well as a preventive therapy for the undesirable gastrointestinal effects produced by opioids used for mild to moderate pain. PMID:17131476

  7. The effects of Weichangshu tablet on intracellular Ca²⁺ concentration in cultured rat gastrointestinal smooth muscle cells.

    PubMed

    Zhou, Shuai; Zhang, Luping; Zhao, Dongmei; Feng, Guoying; Song, Xiaodong; Zhang, Ting; Huang, Fei

    2011-06-01

    The objective of this study was to explore the effects of Weichangshu tablets on free Ca²⁺ concentration of the gastrointestinal smooth muscle cells of rats and the molecular mechanism of the Weichangshu tablets. Cultured SD rat gastrointestinal smooth muscle cells were divided into control group, Cisapride group, Weichangshu group, and control + ethylene glycol tetraacetic acid (EGTA) group, Cisapride + EGTA group, and Weichangshu + EGTA group. Laser scanning microscope and spectrophotometer detection were applied to detect the calcium concentration. The calcium concentrations in Weichangshu group and Cisapride group significantly increased vs. control, and those in Weichangshu group were higher than those in Cisapride group. Ca²⁺ concentration in Weichangshu + EGTA group, Cisapride + EGTA group vs. control + EGTA group were not significantly different. Weichangshu could increase gastrointestinal smooth muscle free Ca²⁺ concentration, and this role may be achieved through the promotion of cells within the flow of calcium ions.

  8. Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders

    PubMed Central

    Tack, J; Camilleri, M; Chang, L; Chey, W D; Galligan, J J; Lacy, B E; Müller-Lissner, S; Quigley, E M M; Schuurkes, J; Maeyer, J H; Stanghellini, V

    2012-01-01

    Summary Background The nonselective 5-HT4 receptor agonists, cisapride and tegaserod have been associated with cardiovascular adverse events (AEs). Aim To perform a systematic review of the safety profile, particularly cardiovascular, of 5-HT4 agonists developed for gastrointestinal disorders, and a nonsystematic summary of their pharmacology and clinical efficacy. Methods Articles reporting data on cisapride, clebopride, prucalopride, mosapride, renzapride, tegaserod, TD-5108 (velusetrag) and ATI-7505 (naronapride) were identified through a systematic search of the Cochrane Library, Medline, Embase and Toxfile. Abstracts from UEGW 2006–2008 and DDW 2008–2010 were searched for these drug names, and pharmaceutical companies approached to provide unpublished data. Results Retrieved articles on pharmacokinetics, human pharmacodynamics and clinical data with these 5-HT4 agonists, are reviewed and summarised nonsystematically. Articles relating to cardiac safety and tolerability of these agents, including any relevant case reports, are reported systematically. Two nonselective 5-HT4 agonists had reports of cardiovascular AEs: cisapride (QT prolongation) and tegaserod (ischaemia). Interactions with, respectively, the hERG cardiac potassium channel and 5-HT1 receptor subtypes have been suggested to account for these effects. No cardiovascular safety concerns were reported for the newer, selective 5-HT4 agonists prucalopride, velusetrag, naronapride, or for nonselective 5-HT4 agonists with no hERG or 5-HT1 affinity (renzapride, clebopride, mosapride). Conclusions 5-HT4 agonists for GI disorders differ in chemical structure and selectivity for 5-HT4 receptors. Selectivity for 5-HT4 over non-5-HT4 receptors may influence the agent's safety and overall risk–benefit profile. Based on available evidence, highly selective 5-HT4 agonists may offer improved safety to treat patients with impaired GI motility. PMID:22356640

  9. Relations between transit time, fermentation products, and hydrogen consuming flora in healthy humans.

    PubMed Central

    El Oufir, L; Flourié, B; Bruley des Varannes, S; Barry, J L; Cloarec, D; Bornet, F; Galmiche, J P

    1996-01-01

    BACKGROUND/AIMS: To investigate whether transit time could influence H2 consuming flora and certain indices of colonic bacterial fermentation. METHODS: Eight healthy volunteers (four methane excretors and four non-methane excretors) were studied for three, three week periods during which they received a controlled diet alone (control period), and then the same diet with cisapride or loperamide. At the end of each period, mean transit time (MTT) was estimated, an H2 lactulose breath test was performed, and stools were analysed. RESULTS: In the control period, transit time was inversely related to faecal weight, sulphate reducing bacteria counts, concentrations of total short chain fatty acids (SCFAs), propionic and butyric acids, and H2 excreted in breath after lactulose ingestion. Conversely, transit time was positively related to faecal pH and tended to be related to methanogen counts. Methanogenic bacteria counts were inversely related to those of sulphate reducing bacteria and methane excretors had slower MTT and lower sulphate reducing bacteria counts than non-methane excretors. Compared with the control period, MTT was significantly shortened (p < 0.05) by cisapride and prolonged (p < 0.05) by loperamide (73 (11) hours, 47 (5) hours and 147 (12) hours for control, cisapride, and loperamide, respectively, mean (SD)). Cisapride reduced transit time was associated with (a) a significant rise in faecal weight, sulphate reducing bacteria, concentrations of total SCFAs, and propionic and butyric acids and breath H2 as well as (b) a significant fall in faecal pH and breath CH4 excretion, and (c) a non-significant decrease in the counts of methanogenic bacteria. Reverse relations were roughly the same during the loperamide period including a significant rise in the counts of methanogenic bacteria and a significant fall in those of sulphate reducing bacteria. CONCLUSIONS: Transit time differences between healthy volunteers are associated with differences in H2

  10. [Chronic colonic pseudo-obstruction secondary to neuroleptics].

    PubMed

    Benlloch, S; Pérez-Aguilar, F; Ponce, J; Berenguer, J

    2001-12-01

    Colonic pseudo-obstruction is characterized by non-mechanical chronic colonic dilatation. It is an infrequent entity that can be provoked by multiple causes, among them pharmacological. We present the case of a 74-year-old female psychiatric patient who presented abdominal bloating, diarrhea, intense electrolytic alterations and marked radiographic colonic dilatation after treatment with a neuroleptic (zuclopenthixol decanoate). Organic obstruction and other causes were ruled out and the final diagnosis was chronic colonic pseudo-obstruction secondary to the use of neuroleptics. Cisapride (20 mg/8 h) produced a slight improvement in symptoms but colonic dilatation was permanent.

  11. Effect of drug utilization reviews on the quality of in-hospital prescribing: a quasi-experimental study

    PubMed Central

    Grégoire, Jean-Pierre; Moisan, Jocelyne; Potvin, Louise; Chabot, Isabelle; Verreault, René; Milot, Alain

    2006-01-01

    Background Drug utilization review (DUR) programs are being conducted in Canadian hospitals with the aim of improving the appropriateness of prescriptions. However, there is little evidence of their effectiveness. The objective of this study was to assess the impact of both a retrospective and a concurrent DUR programs on the quality of in-hospital prescribing. Methods We conducted an interrupted time series quasi-experimental study. Using explicit criteria for quality of prescribing, the natural history of cisapride prescription was established retrospectively in three university-affiliated hospitals. A retrospective DUR was implemented in one of the hospitals, a concurrent DUR in another, whereas the third hospital served as a control. An archivist abstracted records of all patients who were prescribed cisapride during the observation period. The effect of DURs relative to the control hospital was determined by comparing estimated regression coefficients from the time series models and by testing the statistical significance using a 2-tailed Student's t test. Results The concurrent DUR program significantly improved the appropriateness of prescriptions for the indication for use whereas the retrospective DUR brought about no significant effect on the quality of prescribing. Conclusion Results suggest a retrospective DUR approach may not be sufficient to improve the quality of prescribing. However, a concurrent DUR strategy, with direct feedback to prescribers seems effective and should be tested in other settings with other drugs. PMID:16536865

  12. Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: A case report and literature review.

    PubMed

    Angkathunyakul, Napat; Treepongkaruna, Suporn; Molagool, Sani; Ruangwattanapaisarn, Nichanan

    2015-06-14

    Visceral myopathy is one of the causes of chronic intestinal pseudo-obstruction. Most cases pathologically reveal degenerative changes of myocytes or muscularis propia atrophy and fibrosis. Abnormal layering of muscularis propria is extremely rare. We report a case of a 9-mo-old Thai male baby who presented with chronic intestinal pseudo-obstruction. Histologic findings showed abnormal layering of small intestinal muscularis propria with an additional oblique layer and aberrant muscularization in serosa. The patient also had a short small bowel without malrotation, brachydactyly, and absence of the 2(nd) to 4(th) middle phalanges of both hands. The patient was treated with cisapride and combined parenteral and enteral nutritional support. He had gradual clinical improvement and gained body weight. Subsequently, the parenteral nutrition was discontinued. The previously reported cases are reviewed and discussed.

  13. Virtual Screening of DrugBank Reveals Two Drugs as New BCRP Inhibitors

    PubMed Central

    Montanari, Floriane; Cseke, Anna; Wlcek, Katrin; Ecker, Gerhard F.

    2016-01-01

    The breast cancer resistance protein (BCRP) is an ABC transporter playing a crucial role in the pharmacokinetics of drugs. The early identification of substrates and inhibitors of this efflux transporter can help to prevent or foresee drug-drug interactions. In this work, we built a ligand-based in silico classification model to predict the inhibitory potential of drugs toward BCRP. The model was applied as a virtual screening technique to identify potential inhibitors among the small-molecules subset of DrugBank. Ten compounds were selected and tested for their capacity to inhibit mitoxantrone efflux in BCRP-expressing PLB985 cells. Results identified cisapride (IC50 = 0.4 µM) and roflumilast (IC50 = 0.9 µM) as two new BCRP inhibitors. The in silico strategy proved useful to prefilter potential drug-drug interaction perpetrators among a database of small molecules and can reduce the amount of compounds to test. PMID:27401583

  14. [Therapeutic principles in gastroesophageal reflux].

    PubMed

    Chassany, O; Elkharrat, D; Bergmann, J F; Segrestaa, J M

    1995-01-01

    Gastroesophageal reflux is a common disease. Its chronic course, even if mild, is sometimes complicated by erosive oesophagitis. Drug therapy acts against gastric acidity and motility disorders. Treatment of gastroesophageal reflux disease has three aims: improvement of symptoms and quality of life, healing erosive lesions and prevention of symptomatic and endoscopic relapses. Non-drug measures are always useful, even if their efficacy is not well established. Initial therapy of a symptomatic reflux or mild oesophagitis is most of the time effective (antacids, prokinetics, H2 receptor antagonists). Proton-pump inhibitors are also effective in healing and preventing severe oesophagitis. Questions about long-term treatment adverse events with powerful acid inhibitors, such as hypergastrinemia and the risk of gastric carcinoid tumours seem to be resolved. Studies are requested to define the optimal long-term maintenance treatment with cisapride, H2 receptor antagonists or proton-pump inhibitors at low doses in prevention of symptomatic and mild oesophagitis relapses.

  15. Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: A case report and literature review

    PubMed Central

    Angkathunyakul, Napat; Treepongkaruna, Suporn; Molagool, Sani; Ruangwattanapaisarn, Nichanan

    2015-01-01

    Visceral myopathy is one of the causes of chronic intestinal pseudo-obstruction. Most cases pathologically reveal degenerative changes of myocytes or muscularis propia atrophy and fibrosis. Abnormal layering of muscularis propria is extremely rare. We report a case of a 9-mo-old Thai male baby who presented with chronic intestinal pseudo-obstruction. Histologic findings showed abnormal layering of small intestinal muscularis propria with an additional oblique layer and aberrant muscularization in serosa. The patient also had a short small bowel without malrotation, brachydactyly, and absence of the 2nd to 4th middle phalanges of both hands. The patient was treated with cisapride and combined parenteral and enteral nutritional support. He had gradual clinical improvement and gained body weight. Subsequently, the parenteral nutrition was discontinued. The previously reported cases are reviewed and discussed. PMID:26078585

  16. A randomised controlled trial of four management strategies for dyspepsia: relationships between symptom subgroups and strategy outcome.

    PubMed Central

    Lewin van den Broek, N T; Numans, M E; Buskens, E; Verheij, T J; de Wit, N J; Smout, A J

    2001-01-01

    BACKGROUND: The first step in the management of uncomplicated dyspepsia in primary care often consists of prescribing empirical therapy, but in certain cases prompt endoscopy might be preferred. Any decision is usually based on the patient's symptoms and the presumed underlying pathology that causes these symptoms. AIM: To assess the relationship between symptom subgroups and the effect of management strategies on primary care patients with dyspepsia. DESIGN OF STUDY: Randomised controlled trial. SETTING: All patients presenting successively with a new episode of dyspepsia between January 1995 and November 1997. METHOD: The results of four management strategies in dyspeptic primary care patients were compared and the value of subgrouping within this trial was estimated. Patients were allocated to one of either (a) empirical treatment in which therapy was based on the presented symptoms, or empirical treatment with (b) omeprazole or (c) cisapride regardless of the presented symptoms, or (d) prompt endoscopy followed by the appropriate treatment. Patients were retrospectively classified into the subgroups for each strategy using baseline data. The yield of each strategy was measured by counting the number of strategy failures in the first year. RESULTS: Of the 349 included patients, 326 were analysed. No statistically significant difference could be demonstrated between the strategies or between the symptom subgroups. However, patients in the reflux-like subgroup showed a trend towards a better outcome in all empirical strategies. Ulcer-like dyspepsia seemed to benefit from omeprazole. The non-specific subgroup seemed to benefit from cisapride but also had the highest proportion of strategy failure. Prompt endoscopy did not appear especially useful in any subgroup. CONCLUSION: Although this study has relatively low power, we conclude that the use of symptom subgroups seems to be a sensible approach when choosing empirical therapy in dyspepsia. Patients with reflux

  17. High-content screening of drug-induced cardiotoxicity using quantitative single cell imaging cytometry on microfluidic device.

    PubMed

    Kim, Min Jung; Lee, Su Chul; Pal, Sukdeb; Han, Eunyoung; Song, Joon Myong

    2011-01-07

    Drug-induced cardiotoxicity or cytotoxicity followed by cell death in cardiac muscle is one of the major concerns in drug development. Herein, we report a high-content quantitative multicolor single cell imaging tool for automatic screening of drug-induced cardiotoxicity in an intact cell. A tunable multicolor imaging system coupled with a miniaturized sample platform was destined to elucidate drug-induced cardiotoxicity via simultaneous quantitative monitoring of intracellular sodium ion concentration, potassium ion channel permeability and apoptosis/necrosis in H9c2(2-1) cell line. Cells were treated with cisapride (a human ether-à-go-go-related gene (hERG) channel blocker), digoxin (Na(+)/K(+)-pump blocker), camptothecin (anticancer agent) and a newly synthesized anti-cancer drug candidate (SH-03). Decrease in potassium channel permeability in cisapride-treated cells indicated that it can also inhibit the trafficking of the hERG channel. Digoxin treatment resulted in an increase of intracellular [Na(+)]. However, it did not affect potassium channel permeability. Camptothecin and SH-03 did not show any cytotoxic effect at normal use (≤300 nM and 10 μM, respectively). This result clearly indicates the potential of SH-03 as a new anticancer drug candidate. The developed method was also used to correlate the cell death pathway with alterations in intracellular [Na(+)]. The developed protocol can directly depict and quantitate targeted cellular responses, subsequently enabling an automated, easy to operate tool that is applicable to drug-induced cytotoxicity monitoring with special reference to next generation drug discovery screening. This multicolor imaging based system has great potential as a complementary system to the conventional patch clamp technique and flow cytometric measurement for the screening of drug cardiotoxicity.

  18. Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

    PubMed Central

    Chain, Anne SY; Dubois, Vincent FS; Danhof, Meindert; Sturkenboom, Miriam CJM; Della Pasqua, Oscar

    2013-01-01

    Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID:23351036

  19. Rational pharmacotherapy of gastrointestinal motility disorders.

    PubMed

    Demol, P; Ruoff, H J; Weihrauch, T R

    1989-04-01

    Nervous control of gastrointestinal motility is extremely complex, is regulated by the enteric system, the "brain of the gut", and modulated by extrinsic nerves. This system with its multiplicity of transmitters and receptors does not always allow a clear interpretation of experimental data, especially with compounds lacking specificity. In this review the complex situation is described particularly in relation to receptor populations (cholinergic, adrenergic, dopamine, histamine, 5-hydroxytryptamine, opioid, gamma-aminobutyric acid (GABA), prostanoid and dihydropyridine receptors), therapeutic aspects of drugs and their usefulness in children. Newer principles with known drugs and promising new compounds with a more appropriate kinetic or fewer side-effects, deriving from distinct pharmacological groups, as candidates for the treatment of gastrointestinal disorders are considered e.g. anticholinergics (prifinium or actilonium bromide), adrenergic alpha 2-agonists (clonidine, lidamidine) for diarrhoea in diabetic neuropathy, adrenergic beta-blockers for shortening postoperative ileus (propranolol), dopamine receptor antagonists (metoclopramide, domperidone, alizapride) and another prokinetic substance (cisapride) which may be useful for a number of applications as gastro-oesophageal reflux, gastro-paresis, intestinal pseudo-obstruction, cystic fibrosis and constipation, morphine derivatives (e.g. loperamide) for intractable diarrhoea and calcium antagonists (e.g. nifedipine) for achalasia. Increasing experience in digestive tract pharmacology and reliable clinical studies will furthermore be the basis for a more specific and better tolerated therapy of gastrointestinal motility disorders in adults and children.

  20. Re-examination for pharmacological properties of serotonin-induced tachycardia in isolated guinea-pig atrium.

    PubMed

    Nishio, H; Fujii, A; Nakata, Y

    1996-01-01

    In the presence of 10(-6) M atropine, 5-HT induced a positive chronotropic and inotropic effect in isolated guinea-pig atrium preparation. Both propranolol, a beta-adrenoceptor blocker, and imipramine, a 5-HT uptake inhibitor, did not affect the response induced by 5-HT, indicating that a tyramine-like mechanism is not involved. The positive chronotropic effect of 5-HT was mimicked by several 5-HT3 receptor agonists. N omega-Methyl-5-HT, reported to have a high affinity for 5-HT1B recognition sites, was found to act as a 5-HT3 receptor agonist with higher efficacy. The other 5-HT receptor agonists tested did not produced any responses. The positive chronotropic effect of 5-HT was inhibited by various 5-HT3 receptor antagonists, such as tropisetron, granisetron, ondansetron, cisapride and zacopride, but it was unaffected by various 5-HT receptor antagonists which are not selective for 5-HT3 receptor. Thus, the positive chronotropic response to 5-HT is a direct effect, and it was suggested to be mediated by 5-HT3 receptor subtype with rather an atypical profile.

  1. Mechanisms of gastro-oesophageal reflux in cystic fibrosis.

    PubMed Central

    Cucchiara, S; Santamaria, F; Andreotti, M R; Minella, R; Ercolini, P; Oggero, V; de Ritis, G

    1991-01-01

    Abnormal degrees of gastro-oesophageal reflux (GOR) were detected by 24 hour intraoesophageal pH measurement in 12 of 14 children (mean age 7.9 years; range 5 months-16 years) affected by cystic fibrosis and complaining of symptoms suggesting GOR. These patients underwent combined recording of distal oesophageal motility and intraluminal pH in order to investigate mechanisms of GOR. Inappropriate lower oesophageal sphincter relaxation was the most common mechanism of reflux in all patients. Other mechanisms (appropriate relaxation or lowered pressure of the lower oesophageal sphincter, increased intragastric pressure) were detected less frequently. Frequency of inappropriate lower oesophageal sphincter relaxations was significantly higher in patients with cystic fibrosis than in other study groups (symptomatic GOR, GOR disease complicated by respiratory complaints). Inappropriate lower oesophageal sphincter relaxations occurred with the same frequency in patients with cystic fibrosis and in a group of children with GOR disease complicated by oesophagitis. Abnormalities of distal oesophageal contractions such as decreased amplitude or uncoordinated waves were also recorded in cystic fibrosis patients. Seven patients with cystic fibrosis completed a therapeutic trial for eight weeks consisting of postural treatment and oral cisapride, a new prokinetic drug. The oesophageal acid exposure improved in only three patients. We conclude that pathologic GOR is commonly associated with cystic fibrosis. The predominant reflux mechanism in these patients is a transient inappropriate lower oesophageal sphincter relaxation rather than a low steady state basal lower oesophageal sphincter pressure. PMID:2039253

  2. [Irritable bowel syndrome].

    PubMed

    Kocián, J

    1994-04-01

    Irritable bowel is a functional gastrointestinal disorder with chronic or relapsing symptoms of abdominal pain and impaired frequency and consistency of the faeces caused by obscure structural or biochemical deviations. The frequency of the condition in civilized countries is estimated to amount to 15-20% of the population and it accounts for 25-50% of all patients in gastroenterological ambulatory departments. From the clinical aspect the type with dominant diarrhoea, typically in the morning and very compelling, and the type with pain and constipation are known but even combinations of the two types are encountered. A psychosomatic disorder of the motility of the large bowel and its tonus is involved associated with enhanced pain perception. Despite great efforts to find aetiopathogenetic factors, knowledge still is at the level of obscure theories. The diagnosis is still established per exclusion after all organic causes are ruled out, i.e. we always have to differentiate between an irritable bowel from an irritated one. In therapy the patient's confidence in his doctor is most important and it is essential to gain the patient's active cooperation. In case of diarrhoea a low-residue diet is used, calcium carbonate, codeine, loperamide, conversely in constipation adequate dietary fibre, intake metoclopramide or cisapride. Pain is relieved by spasmolytics or Ca channel blockers in the smooth musculature of the large bowel. The associated dysbiosis is transformed into eubiosis by Lactobacillus or other bacterial products.

  3. KDR-5169, a new gastrointestinal prokinetic agent, enhances gastric contractile and emptying activities in dogs and rats.

    PubMed

    Tazawa, Shigeki; Masuda, Naoyuki; Koizumi, Takashi; Kitazawa, Makio; Nakane, Tokio; Miyata, Hiroshi

    2002-01-11

    KDR-5169, 4-amino-5-chloro-N-[1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl]-2-(2-hydroxyethoxy)benzamide hydrochloride dihydrate, is a new prokinetic with a dual action, i.e., stimulation of the 5-HT4 receptor and antagonism of the dopamine D2 receptor. In this study, we determined in vitro activities of KDR-5169 towards both receptors and demonstrated the effect of the compound on gastrointestinal motor activity in conscious dogs and rats. In dogs, intravenous KDR-5169 stimulated upper gastrointestinal motility in the fasting state and also eliminated the depressive effect of 3,4-dihydroxyphenylalanine (L-DOPA) on this motility in the postprandial state. The effect of KDR-5169 on gastric emptying was further characterized by the use of three rat gastroparesis models (dopamine D2 receptor agonist (quinpirol)-, abdominal surgery-, or combined-situation-induced). Domperidone (a dopamine D2 receptor antagonist) was effective in the quinpirol-delay and combination-delay models, and cisapride and mosapride (5-HT4 receptor agonists) were effective in the surgery-delay model. Only KDR-5169 eliminated the delay of gastric emptying in all three models. In addition, KDR-5169 accelerated emptying to above the normal level in the combination-delay model. These results suggest that KDR-5169 would be effective in various types of gastric ileus caused by different mechanisms.

  4. Development and validation of a high-performance liquid chromatographic method using fluorescence detection for the determination of vardenafil in small volumes of rat plasma and bile.

    PubMed

    Cheng, Ching-Ling; Kang, Guei-Jen; Chou, Chen-Hsi

    2007-06-22

    A new, simple and sensitive high-performance liquid chromatography (HPLC) method with fluorescence detection was developed and validated for the determination of vardenafil in small volumes of rat plasma and bile. The absorbance and fluorescence characteristics of vardenafil were studied and factors that affect the HPLC resolution and fluorescence intensity were examined and optimized. Vardenafil and the internal standard cisapride were extracted using acetonitrile. The separation was achieved on a C18 column at 35 degrees C using acetonitrile-50 mM ammonium acetate aqueous solution (pH 6.8) (40:60) as mobile phase. At a flow rate of 1 ml/min, the total run time was 18 min. Fluorescence was measured with excitation and emission set at 280 and 470 nm, respectively. The calibration curves were linear from 10 to 1000 ng/ml and 0.2-100 microg/ml for plasma and bile samples, respectively. The intra- and inter-day imprecision did not exceed 10.8%, and the accuracy was within 9.6% deviation of the nominal concentration. The method was used successfully to investigate the disposition and biliary excretion of vardenafil in rats.

  5. The virtual heart as a platform for screening drug cardiotoxicity

    PubMed Central

    Yuan, Yongfeng; Bai, Xiangyun; Luo, Cunjin; Wang, Kuanquan

    2015-01-01

    To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug–ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug–ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi‐physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro‐arrhythmic effects of cisapride and amiodarone. Using the model we investigated the mechanisms responsible for the differences between the two drugs on pro‐arrhythmogenesis, even though both prolong the QT interval of ECGs. Several challenges for further development of a virtual heart as a platform for screening drug cardiotoxicity are discussed. Linked Articles This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23 PMID:25363597

  6. Modification of distinct ion channels differentially modulates Ca2+ dynamics in primary cultured rat ventricular cardiomyocytes

    PubMed Central

    Li, Xichun; Shen, Liping; Zhao, Fang; Zou, Xiaohan; He, Yuwei; Zhang, Fan; Zhang, Chunlei; Yu, Boyang; Cao, Zhengyu

    2017-01-01

    Primary cultured cardiomyocytes show spontaneous Ca2+ oscillations (SCOs) which not only govern contractile events, but undergo derangements that promote arrhythmogenesis through Ca2+ -dependent mechanism. We systematically examined influence on SCOs of an array of ion channel modifiers by recording intracellular Ca2+ dynamics in rat ventricular cardiomyocytes using Ca2+ specific fluorescence dye, Fluo-8/AM. Voltage-gated sodium channels (VGSCs) activation elongates SCO duration and reduces SCO frequency while inhibition of VGSCs decreases SCO frequency without affecting amplitude and duration. Inhibition of voltage-gated potassium channel increases SCO duration. Direct activation of L-type Ca2+ channels (LTCCs) induces SCO bursts while suppressing LTCCs decreases SCO amplitude and slightly increases SCO frequency. Activation of ryanodine receptors (RyRs) increases SCO duration and decreases both SCO amplitude and frequency while inhibiting RyRs decreases SCO frequency without affecting amplitude and duration. The potencies of these ion channel modifiers on SCO responses are generally consistent with their affinities in respective targets demonstrating that modification of distinct targets produces different SCO profiles. We further demonstrate that clinically-used drugs that produce Long-QT syndrome including cisapride, dofetilide, sotalol, and quinidine all induce SCO bursts while verapamil has no effect. Therefore, occurrence of SCO bursts may have a translational value to predict cardiotoxicants causing Long-QT syndrome. PMID:28102360

  7. A new system for profiling drug-induced calcium signal perturbation in human embryonic stem cell-derived cardiomyocytes.

    PubMed

    Lewis, Kimberley J; Silvester, Nicole C; Barberini-Jammaers, Steven; Mason, Sammy A; Marsh, Sarah A; Lipka, Magdalena; George, Christopher H

    2015-03-01

    The emergence of human stem cell-derived cardiomyocyte (hSCCM)-based assays in the cardiovascular (CV) drug discovery sphere requires the development of improved systems for interrogating the rich information that these cell models have the potential to yield. We developed a new analytical framework termed SALVO (synchronization, amplitude, length, and variability of oscillation) to profile the amplitude and temporal patterning of intra- and intercellular calcium signals in hSCCM. SALVO quantified drug-induced perturbations in the calcium signaling "fingerprint" in spontaneously contractile hSCCM. Multiparametric SALVO outputs were integrated into a single index of in vitro cytotoxicity that confirmed the rank order of perturbation as astemizole > thioridazine > cisapride > flecainide > valdecoxib > sotalol > nadolol ≈ control. This rank order of drug-induced Ca(2+) signal disruption is in close agreement with the known arrhythmogenic liabilities of these compounds in humans. Validation of the system using a second set of compounds and hierarchical cluster analysis demonstrated the utility of SALVO to discriminate drugs based on their mechanisms of action. We discuss the utility of this new mechanistically agnostic system for the evaluation of in vitro drug cytotoxicity in hSCCM syncytia and the potential placement of SALVO in the early stage drug screening framework.

  8. Characterization of putative 5-HT7 receptors mediating tachycardia in the cat

    PubMed Central

    Villalón, Carlos M; Heiligers, Jan P C; Centurión, David; De Vries, Peter; Saxena, Pramod R

    1997-01-01

    , sumatriptan (30, 100 and 300 μg kg−1) and indorenate (300 and 1000 μg kg−1) or the 5-HT4 receptor (partial) agonist cisapride (300 and 1000 μg kg−1) were devoid of effects on feline heart rate per se and failed to modify significantly 5-HT-induced tachycardic responses. Based upon the above rank order of agonist potency, the failure of sumatriptan, indorenate or cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor, the present results indicate that the 5-HT receptor mediating tachycardia in the cat is operationally similar to other putative 5-HT7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine external carotid and coronary arteries, rat systemic vasculature and guinea-pig ileum). Since these responses represent functional correlates of the 5-ht7 gene product, the 5-HT7 receptor appellation is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other 5-HT receptors, can be utilized to characterize and develop new drugs with potential agonist and antagonist properties at functional 5-HT7 receptors. PMID:9249256

  9. Mediation of 5-HT-induced external carotid vasodilatation in GR 127935-pretreated vagosympathectomized dogs by the putative 5-HT7 receptor

    PubMed Central

    Villalón, Carlos M; Centurión, David; Luján-Estrada, Miguel; Terrón, José A; Sánchez-López, Araceli

    1997-01-01

    The vasodilator effects of 5-hydroxytryptamine (5-HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho-inhibitory 5-HT1B/1D receptors and postjunctional 5-HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5-HT with the 5-HT1B/1D receptor antagonist, GR 127935, unmasks a dose-dependent vasodilator effect of 5-HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5-HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 μg kg−1, i.v.).One-minute intracarotid (i.c.) infusions of 5-HT (0.330 μg min−1), 5-carboxamidotryptamine (5-CT; 0.010.3 μg min−1), 5-methoxytryptamine (1100 μg min−1) and lisuride (31000 μg min−1) resulted in dose-dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5-CT>>5-HT⩾5-methoxytryptamine>lisuride, whereas cisapride (1001000 μg min−1, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7 μg kg−1, i.c.), but not cisapride (mean dose of 67±7 μg kg−1, i.c.), specifically abolished the responses induced by 5-HT, 5-CT and 5-methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8-OH-DPAT (33000 μg min−1) produced dose-dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33 μg kg−1, i.c.) the agonist-induced vasodilator responses.The external carotid vasodilator responses to 5-HT, 5-CT and 5-methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)-pindolol (4

  10. Evidence-based recommendations for short- and long-term management of uninvestigated dyspepsia in primary care: an update of the Canadian Dyspepsia Working Group (CanDys) clinical management tool.

    PubMed

    Veldhuyzen van Zanten, Sander J O; Bradette, Marc; Chiba, Naoki; Armstrong, David; Barkun, Alan; Flook, Nigel; Thomson, Alan; Bursey, Ford

    2005-05-01

    The present paper is an update to and extension of the previous systematic review on the primary care management of patients with uninvestigated dyspepsia (UD). The original publication of the clinical management tool focused on the initial four- to eight-week assessment of UD. This update is based on new data from systematic reviews and clinical trials relevant to UD. There is now direct clinical evidence supporting a test-and-treat approach in patients with nondominant heartburn dyspepsia symptoms, and head-to-head comparisons show that use of a proton pump inhibitor is superior to the use of H2-receptor antagonists (H2RAs) in the initial treatment of Helicobacter pylori-negative dyspepsia patients. Cisapride is no longer available as a treatment option and evidence for other prokinetic agents is lacking. In patients with long-standing heartburn-dominant (ie, gastroesophageal reflux disease) and nonheartburn-dominant dyspepsia, a once-in-a-lifetime endoscopy is recommended. Endoscopy should also be considered in patients with new-onset dyspepsia that develops after the age of 50 years. Conventional nonsteroidal anti-inflammatory drugs, acetylsalicylic acid and cyclooxygenase-2-selective inhibitors can all cause dyspepsia. If their use cannot be discontinued, cotherapy with either a proton pump inhibitor, misoprostol or high-dose H2RAs is recommended, although the evidence is based on ulcer data and not dyspepsia data. In patients with nonheartburn-dominant dyspepsia, noninvasive testing for H pylori should be performed and treatment given if positive. When starting nonsteroidal anti-inflammatory drugs for a prolonged course, testing and treatment with H2RAs are advised if patients have a history of previous ulcers or ulcer bleeding.

  11. Adverse effects of drugs used in the management of constipation and diarrhoea.

    PubMed

    Gattuso, J M; Kamm, M A

    1994-01-01

    Most laxatives, if used intermittently in the absence of contraindications, are relatively safe. Bulking agents may diminish absorption of some minerals and drugs, but this is not usually clinically significant. Ispaghula can cause serious allergic reactions. The chronic ingestion of stimulant laxatives has been blamed for the development of the 'cathartic colon', but there are no definitive studies which have demonstrated this. Dantron (danthron) preparations should only be used in older patients and the terminally ill because of the risk of hepatotoxicity with this drug. Oral oxyphenisatine should no longer be used. Senna would appear to be the stimulant laxative of choice during pregnancy and lactation. Bisacodyl is the polyphenolic derivative of choice. Lactulose, sorbitol and lactilol rarely cause significant adverse effects. Magnesium salt laxatives and phosphate enemas can cause serious metabolic disturbances in babies and young children. Liquid paraffin is contraindicated if there is any risk of aspiration. Interference with the absorption of fat soluble vitamins would not appear to be clinically significant. Docusate sodium may potentiate the hepatotoxicity of other drugs, but reports of this are rare. The role of cisapride in constipation has not been established. Antidiarrhoeal drugs are second line drugs whose use is aimed at minimising inconvenience and discomfort. No antidiarrhoeals can be recommended for children under 4 years of age. Loperamide is the drug of choice in older children and adults. The atropine component of diphenoxylate/atropine combinations can cause significant adverse effects. Bismuth salicylate is an inconvenient treatment for travellers' diarrhoea as large frequent doses of the liquid formulation are needed. Some bismuth can be absorbed and there is the potential to cause encephalopathy. Octreotide, methysergide and cholestyramine have a role for specific causes of diarrhoea only. Octreotide is effective in high output states

  12. 5-HT1D receptor inhibits renal sympathetic neurotransmission by nitric oxide pathway in anesthetized rats.

    PubMed

    García-Pedraza, José-Ángel; García, Mónica; Martín, María-Luisa; Morán, Asunción

    2015-09-01

    Although serotonin has been shown to inhibit peripheral sympathetic outflow, serotonin regulation on renal sympathetic outflow has not yet been elucidated. This study investigated which 5-HT receptor subtypes are involved. Wistar rats were anesthetized (sodium pentobarbital; 60mg/kg, i.p.), and prepared for in situ autoperfused rat kidney, which allows continuous measurement of systemic blood pressure (SBP), heart rate (HR) and renal perfusion pressure (PP). Electrical stimulation of renal sympathetic nerves resulted in frequency-dependent increases in PP (18.3±1.0, 43.7±2.7 and 66.7±4.0 for 2, 4 and 6Hz, respectively), without altering SBP or HR. 5-HT, 5-carboxamidotryptamine (5-HT1/7 agonist) (0.00000125-0.1μg/kg each) or l-694,247 (5-HT1D agonist; 0.0125μg/kg) i.a. bolus inhibited vasopressor responses by renal nerve electrical stimulation, unlike i.a. bolus of agonists α-methyl-5-HT (5-HT2), 1-PBG (5-HT3), cisapride (5-HT4), AS-19 (5-HT7), CGS-12066B (5-HT1B) or 8-OH-DPAT (5-HT1A) (0.0125μg/kg each). The effect of l-694,247 did not affect the exogenous norepinephrine-induced vasoconstrictions, whereas was abolished by antagonist LY310762 (5-HT1D; 1mg/kg) or l-NAME (nitric oxide; 10mg/kg), but not by indomethacin (COX1/2; 2mg/kg) or glibenclamide (ATP-dependent K(+) channel; 20mg/kg). These results suggest that 5-HT mechanism-induced inhibition of rat vasopressor renal sympathetic outflow is mainly mediated by prejunctional 5-HT1D receptors via nitric oxide release.

  13. Isolation of the serotoninergic 5-HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines

    PubMed Central

    Mialet, Jeanne; Berque-Bestel, Isabelle; Eftekhari, Pierre; Gastineau, Monique; Giner, Mireille; Dahmoune, Yamina; Donzeau-Gouge, Patrick; Hoebeke, Johan; Langlois, Michel; Sicsic, Sames; Fischmeister, Rodolphe; Lezoualc'h, Frank

    2000-01-01

    RT–PCR technique was used to clone the human 5-HT4(e) receptor (h5-HT4(e)) from heart atrium. We showed that this h5-HT4(e) receptor splice variant is restricted to brain and heart atrium. Recombinant h5-HT4(e) receptor was stably expressed in CHO and C6-glial cell lines at 347 and 88 fmol mg−1 protein, respectively. Expression of h5-HT4(e) receptors at the cell membrane was confirmed by immunoblotting. The receptor binding profile, determined by competition with [3H]-GR113808 of a number of 5-HT4 ligands, was consistent with that previously reported for other 5-HT4 receptor isoforms. Surprisingly, we found that the rank order of potencies (EC50) of 5-HT4 agonists obtained from adenylyl cyclase functional assays was inversely correlated to their rank order of affinities (Ki) obtained from binding assays. Furthermore, EC50 values for 5-HT, renzapride and cisapride were 2 fold lower in C6-glial cells than in CHO cells. ML10302 and renzapride behaved like partial agonists on the h5-HT4(e) receptor. These results are in agreement with the reported low efficacy of the these two compounds on L-type Ca2+ currents and myocyte contractility in human atrium. A constitutive activity of the h5-HT4(e) receptor was observed in CHO cells in the absence of any 5-HT4 ligand and two 5-HT4 antagonists, GR113808 and ML10375, behaved as inverse agonists. These data show that the h5-HT4(e) receptor has a pharmacological profile which is close to the native h5-HT4 receptor in human atrium with a functional potency which is dependent on the cellular context in which the receptor is expressed. PMID:10683202

  14. Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential.

    PubMed

    Yamamoto, Wataru; Asakura, Keiichi; Ando, Hiroyuki; Taniguchi, Tomohiko; Ojima, Atsuko; Uda, Takaaki; Osada, Tomoharu; Hayashi, Seiji; Kasai, Chieko; Miyamoto, Norimasa; Tashibu, Hiroyuki; Yoshinaga, Takashi; Yamazaki, Daiju; Sugiyama, Atsushi; Kanda, Yasunari; Sawada, Kohei; Sekino, Yuko

    2016-01-01

    The aims of this study were to (1) characterize basic electrophysiological elements of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that correspond to clinical properties such as QT-RR relationship, (2) determine the applicability of QT correction and analysis methods, and (3) determine if and how these in-vitro parameters could be used in risk assessment for adverse drug-induced effects such as Torsades de pointes (TdP). Field potential recordings were obtained from commercially available hiPSC-CMs using multi-electrode array (MEA) platform with and without ion channel antagonists in the recording solution. Under control conditions, MEA-measured interspike interval and field potential duration (FPD) ranged widely from 1049 to 1635 ms and from 334 to 527 ms, respectively and provided positive linear regression coefficients similar to native QT-RR plots obtained from human electrocardiogram (ECG) analyses in the ongoing cardiovascular-based Framingham Heart Study. Similar to minimizing the effect of heart rate on the QT interval, Fridericia's and Bazett's corrections reduced the influence of beat rate on hiPSC-CM FPD. In the presence of E-4031 and cisapride, inhibitors of the rapid delayed rectifier potassium current, hiPSC-CMs showed reverse use-dependent FPD prolongation. Categorical analysis, which is usually applied to clinical QT studies, was applicable to hiPSC-CMs for evaluating torsadogenic risks with FPD and/or corrected FPD. Together, this results of this study links hiPSC-CM electrophysiological endpoints to native ECG endpoints, demonstrates the appropriateness of clinical analytical practices as applied to hiPSC-CMs, and suggests that hiPSC-CMs are a reliable models for assessing the arrhythmogenic potential of drug candidates in human.

  15. Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential

    PubMed Central

    Yamamoto, Wataru; Asakura, Keiichi; Ando, Hiroyuki; Taniguchi, Tomohiko; Ojima, Atsuko; Uda, Takaaki; Osada, Tomoharu; Hayashi, Seiji; Kasai, Chieko; Miyamoto, Norimasa; Tashibu, Hiroyuki; Yoshinaga, Takashi; Yamazaki, Daiju; Sugiyama, Atsushi; Kanda, Yasunari; Sawada, Kohei; Sekino, Yuko

    2016-01-01

    The aims of this study were to (1) characterize basic electrophysiological elements of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that correspond to clinical properties such as QT-RR relationship, (2) determine the applicability of QT correction and analysis methods, and (3) determine if and how these in-vitro parameters could be used in risk assessment for adverse drug-induced effects such as Torsades de pointes (TdP). Field potential recordings were obtained from commercially available hiPSC-CMs using multi-electrode array (MEA) platform with and without ion channel antagonists in the recording solution. Under control conditions, MEA-measured interspike interval and field potential duration (FPD) ranged widely from 1049 to 1635 ms and from 334 to 527 ms, respectively and provided positive linear regression coefficients similar to native QT-RR plots obtained from human electrocardiogram (ECG) analyses in the ongoing cardiovascular-based Framingham Heart Study. Similar to minimizing the effect of heart rate on the QT interval, Fridericia’s and Bazett’s corrections reduced the influence of beat rate on hiPSC-CM FPD. In the presence of E-4031 and cisapride, inhibitors of the rapid delayed rectifier potassium current, hiPSC-CMs showed reverse use-dependent FPD prolongation. Categorical analysis, which is usually applied to clinical QT studies, was applicable to hiPSC-CMs for evaluating torsadogenic risks with FPD and/or corrected FPD. Together, this results of this study links hiPSC-CM electrophysiological endpoints to native ECG endpoints, demonstrates the appropriateness of clinical analytical practices as applied to hiPSC-CMs, and suggests that hiPSC-CMs are a reliable models for assessing the arrhythmogenic potential of drug candidates in human. PMID:27923051

  16. An Improved Colonoscopy Preparation Method and its Acceptability by Patients

    PubMed Central

    1995-01-01

    The author presents an improved method of preparation for colonoscopy that involved no dietary limitation on the patient until the day of the examination and that was shown by a randomized questionnaire evaluation to earn good patient tolerance and acceptance. Patients were given 10 mg of cisapride and 75 mg of sodium picosulfate before sleep on the day preceding the examination, and 50 g of magnesium citrate powder (MP) in 1,200 mL lukewarm water before the examination. It was divided into 600-mL portions and ingested slowly during two 30-minute periods. Ninety-five percent of patients classified the taste of a magnesium citrate powder laxative as palatable in the questionnaire given immediately after the procedure. Concerning the quantity, 79.4% replied that it was tolerable, 17.3% considered it somewhat excessive, and 3.3% replied that it was barely tolerable. No patient classified it as intolerable. Symptoms after taking laxatives and lukewarm water such as abdominal pain, nausea and abdominal fullness were observed in 3.8%, 4.4% and 5.6%, respectively, whereas there were no symptoms in 79% of patients. Body weight and serum K level showed a tendency to decrease, whereas the serum Mg level showed an increase before and after colonoscopy. The quality of colonic cleansing evaluated by colonoscopy was excellent, good, or fair in a total of 93.3%. No adverse effects were observed. It was concluded that this method is a clinically beneficial and well-tolerated preparation for colonic examinations. PMID:18493356

  17. A Distributed, Collaborative Intelligent Agent System Approach for Proactive Postmarketing Drug Safety Surveillance

    PubMed Central

    Ji, Yanqing; Ying, Hao; Farber, Margo S.; Yen, John; Dews, Peter; Miller, Richard E.; Massanari, R. Michael

    2014-01-01

    Discovering unknown adverse drug reactions (ADRs) in postmarketing surveillance as early as possible is of great importance. The current approach to postmarketing surveillance primarily relies on spontaneous reporting. It is a passive surveillance system and limited by gross underreporting (<10% reporting rate), latency, and inconsistent reporting. We propose a novel team-based intelligent agent software system approach for proactively monitoring and detecting potential ADRs of interest using electronic patient records. We designed such a system and named it ADRMonitor. The intelligent agents, operating on computers located in different places, are capable of continuously and autonomously collaborating with each other and assisting the human users (e.g., the food and drug administration (FDA), drug safety professionals, and physicians). The agents should enhance current systems and accelerate early ADR identification. To evaluate the performance of the ADRMonitor with respect to the current spontaneous reporting approach, we conducted simulation experiments on identification of ADR signal pairs (i.e., potential links between drugs and apparent adverse reactions) under various conditions. The experiments involved over 275 000 simulated patients created on the basis of more than 1000 real patients treated by the drug cisapride that was on the market for seven years until its withdrawal by the FDA in 2000 due to serious ADRs. Healthcare professionals utilizing the spontaneous reporting approach and the ADRMonitor were separately simulated by decision-making models derived from a general cognitive decision model called fuzzy recognition-primed decision (RPD) model that we recently developed. The quantitative simulation results show that 1) the number of true ADR signal pairs detected by the ADRMonitor is 6.6 times higher than that by the spontaneous reporting strategy; 2) the ADR detection rate of the ADRMonitor agents with even moderate decision-making skills is five

  18. Development of recombinant cell line co-expressing mutated Nav1.5, Kir2.1, and hERG for the safety assay of drug candidates.

    PubMed

    Fujii, Masato; Ohya, Susumu; Yamamura, Hisao; Imaizumi, Yuji

    2012-07-01

    To provide a high-throughput screening method for human ether-a-go-go-gene-related gene (hERG) K(+) channel inhibition, a new recombinant cell line, in which single action potential (AP)-induced cell death was produced by gene transfection. Mutated human cardiac Na(+) channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K(+) channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K(+) channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC(50) values to induce the cell death were 3 µM, 19 nM, 17 nM, 74 nM, and 3 µM, respectively, whereas 10 µM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K(+) channel safety assay.

  19. A Simple Sample Preparation with HPLC-UV Method for Estimation of Clomipramine from Plasma

    PubMed Central

    Mostafavi, Sayed Abolfazl; Tahvilian, Reza; Dehghani Poudeh, Masoumeh; Rafeepour, Zeinab

    2010-01-01

    Clomipramine is a tricyclic antidepressant. Different methods for determination of clomipramine hydrochloride in plasma have been described. Most of these procedures favor the use of acidic back-extraction in extraction procedure and HPLC as the analytical technique. In this study, the clomipramine extraction procedure was modified and a direct injection to the column was performed to shorten the time of sample preparation considerably. Furthermore, the method was applied in bioequivalence study of new formulations of clomipramine in comparison with reference tablets. The drug and internal standard were extracted from plasma with heptan : isoamyl alcohol (95:5) and re-extracted with 200 μL of orthophosphoric acid (0.3% v/v). The organic layer was discharged and analysis was performed on C8 reverse phase ODS2 HPLC column with a mobile phase, acetonitrile : water (75:25) and UV detection set at 215 nm. Additionally, a single dose study was carried out with a two-sequence, crossover block-randomized design for bioequivalence study. Clomipramine tablets (3 × 25 mg) of either formulations (reference or test products) were administered separately in two occasions to 12 fasting healthy male volunteers. Blood samples were taken prior to and at 9 points within 48 h after dose administration. The retention time of internal standard (cisapride), clomipramine, and desmethyl clomipramine were 5.6 ± 0.2, 10.3 ± 0.3, and 9.5 ± 0.3 min, respectively. The standard curve covering the concentration ranges of 2.5-120 ng/mL was linear (r2 = 0.9950 and 0.9979) for clomipramine and desmethyl clomipramine. The co-efficient of variation for intra-day and inter-day accuracy and precision was less than 18.3%. The pharmacokinetic parameters Cmax and Tmax were obtained directly from plasma clomipramine concentrations. Kel was estimated by log-linear regression and AUC was calculated by the linear trapezoidal rule. The pharmacokinetic parameters AUC and Cmax were tested for equivalence

  20. Evaluation of the rubidium efflux assay for preclinical identification of HERG blockade.

    PubMed

    Chaudhary, Khuram W; O'Neal, Janet M; Mo, Zun-Li; Fermini, Bernard; Gallavan, Robert H; Bahinski, Anthony

    2006-02-01

    Inhibition of the delayed-rectifier potassium channel current, human ether-a-go-go (hERG), by pharmaceutical agents can lead to acquired long QT syndrome and the generation of potentially lethal arrhythmias and sudden death. There remains an unmet need for higher-throughput assays to screen compounds in preclinical development for the potential to block hERG and cause QT prolongation. We evaluated the rubidium efflux assay for its ability to determine block of the hERG potassium channel. hERG-transfected human embryonic kidney-293 cells were cultured on 96-well assay plates and loaded with rubidium ion by incubating in media in which potassium was replaced by 5.4 mM Rb+. Cells were exposed to test compounds and then depolarized with a K+ channel opening buffer containing 50 mM K+. The supernatant was removed, and cells were lysed using 0.1% Triton X-100. Concentration-response curves were generated for test agents by determining the Rb+ efflux using a flame atomic absorption spectrometer. Multiple trials with cisapride yielded 50% inhibitory concentration values between 308.1 +/- 11 nM to 456.3 +/- 24 nM for inhibition of Rb+ efflux and a Z factor of 0.80 +/- 0.07 (n = 5 plates, 12 wells per plate). The values for inhibition of the hERG channel exhibited a rightward shift in potency as compared to those measured using electrophysiological techniques. In addition, we evaluated 19 blinded compounds at 10 microM in the Rb+ efflux assay, and compared results to those using patch clamp electrophysiology and the dofetilide displacement binding assay. The dofetilide displacement binding assay yielded a good correlation with electrophysiological measurements of hERG block. The rubidium efflux assay lacked sensitivity to consistently identify significant channel blockade. In conclusion, the rubidium efflux assay provides a higher-throughput means to identify potent hERG channel blocking agents, but lacks the sensitivity required to accurately determine the potency of

  1. Effectiveness and safety of a protocol for promotion of early intragastric feeding in critically ill children.

    PubMed

    Briassoulis, G C; Zavras, N J; Hatzis MD, T D

    2001-04-01

    OBJECTIVES: To investigate the feasibility, adequacy, and efficacy of early poststress intragastric feeding (EPIGF) in critically ill children. DESIGN: A prospective clinical study. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Seventy-one consecutively enrolled critically ill children requiring prolonged mechanical ventilation. INTERVENTIONS: Full-strength intragastric tube feedings (Nutrison Pediatric, Standard) were initiated within 12 hrs of the study-entry event. Enteral feedings were advanced to a target volume of energy intake = 1/2, 1, 5/4, 6/4, and 6/4 of the predicted basal metabolic rate (PBMR) on days 1-5, respectively. MEASUREMENTS AND MAIN RESULTS: Nutritional status by the caloric intake, recommended dietary allowances, PBMR, predicted energy expenditure (PEE), anthropometry, and clinical indices were evaluated on days 1 and 5. Safety was assessed by the clinical course of disease, laboratory findings, and occurrence of complications. Success was determined by accomplishment of the PEE target. The early success rate was 94.4% and predicted late enteral feeding success accurately (p =.0001). Caloric intake approached PBMR the second day (43 +/- 1.7 kcal/kg/day vs. 43.2 +/- 1.1 kcal/kg/day) and PEE the fifth day (66.2 +/- 2.7 kcal/kg/day vs. 67.7 +/- 6.4 kcal/kg/day). Multivariate stepwise regression analysis showed that poor outcome and a high Therapeutic Intervention Scoring System score correlated with failure of EPIGF (p <.0001). Patients who succeeded EPIGF had significantly higher myocardial ejection (65% vs. 43%; p <.0001) or shortening fractions (34% vs. 20%; p =.0001) on day 1 than those who failed. Patients tolerated EPIGF well; 9.9% developed nosocomial pneumonia, 5.6% developed diarrhea, and 8.5% needed treatment with cisapride because of a delay of gastric emptying. The mortality rate (5.6%) was different between initial and final success and failure groups (p <.0001) and was lower than predicted

  2. Evidence for 5-HT1B/1D and 5-HT2A receptors mediating constriction of the canine internal carotid circulation

    PubMed Central

    Centurión, David; Ortiz, Mario I; Sánchez-López, Araceli; De Vries, Peter; Saxena, Pramod R; Villalón, Carlos M

    2001-01-01

    The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1–10 μg min−1), sumatriptan (0.3–10 μg min−1; 5-HT1B/1D), 5-methoxytryptamine (1–100 μg min−1; 5-HT1, 5-HT2, 5-HT4, 5-ht6 and 5-HT7) or DOI (0.31–10 μg min−1; 5-HT2), but not 5-carboxamidotryptamine (0.01–0.3 μg min−1; 5-HT1, 5-ht5A and 5-HT7), 1-(m-chlorophenyl)-biguanide (mCPBG; 1–1000 μg min−1; 5-HT3) or cisapride (1–1000 μg min−1; 5-HT4), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 μg kg−1; 5-HT2A/2B/2C) in combination with tropisetron (3000 μg kg−1; 5-HT3/4) or the cyclo-oxygenase inhibitor, indomethacin (5000 μg kg−1), but were abolished by the 5-HT1B/1D receptor antagonist, GR127935 (30 μg kg−1). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 μg kg−1) or ketanserin (100 μg kg−1; 5-HT2A), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT1B/1D and 5-HT2A receptors

  3. Current management of motor fluctuations in patients with advanced Parkinson's disease treated chronically with levodopa.

    PubMed

    Melamed, E; Zoldan, J; Galili-Mosberg, R; Ziv, I; Djaldetti, R

    1999-01-01

    Motor fluctuations after long-term administration of levodopa may be due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of postsynaptic dopaminergic receptors. Peripheral pharmacokinetic mechanisms may be equally important, particularly in motor fluctuations of the "delayed on" (increased time latencies from dose intake to start-up of clinical benefit) and "no-on" (complete failure of a levodopa dose to exert an "on" response) types. Levodopa itself has a very poor solubility. In addition, there is delayed gastric emptying in many advanced patients. Therefore, an oral dose of levodopa may remain in the stomach for long periods of time before it passes into the duodenum where there is immediate absorption. Consequently, in order to overcome response fluctuations caused by impaired pharmacokinetic mechanisms and to improve its absorption, we recommend that levodopa be taken in multiple small doses, on an empty stomach, preferably crushed and mixed with a lot of liquid. Protein intake should be minimized. Prokinetic drugs such as prepulsid (Cisaprid) could be used to facilitate gastric motility and levodopa transit time. Administration of crushed levodopa through nasoduodenal or gastrojejunostomy tubes may be helpful in certain circumstances. Bypassing the stomach with subcutaneous injections of apomorphine may provide dramatic rescue from difficult "off" situations. Oral and s.c. administration of novel, extremely soluble prodrugs of levodopa, e.g., levodopa ethylester, may offer a new approach to overcome difficulties in levodopa absorption. Addition of dopamine agonists, MAO-B inhibitors, COMT inhibitors and controlled release levodopa preparations may be helpful in prolonging the duration of efficacy of each single levodopa dose. Levodopa, administered orally, usually combined with peripheral dopa decarboxylase inhibitors, continues to be the most widely-used and most