ABSTRACT
Erythromycin is one of the few compounds that remarkably increase ether-a-go-go-related gene (hERG) inhibition from room temperature (RT) to physiological temperature (PT). Understanding how erythromycin inhibits the hERG could help us to decide which compounds are needed for further studies. The whole-cell patch clamp technique was used to investigate the effects of erythromycin on hERG channels at different temperatures. While erythromycin caused a concentration-dependent inhibition of cardiac hERG channels, it also shifted the steady-state activation and steady-state inactivation of the channel to the left and significantly accelerated the onset of inactivation at both temperatures, although temperature itself caused a profound change in the dynamics of hERG channels. Our data also suggest that the binding pattern to S6 of the channels changes at PT. In contrast, cisapride, a well-known hERG blocker whose inhibition is not affected by temperature, does not change its critical binding sites after the temperature is raised to PT. Our data suggest that erythromycin is unique and that the shift in hERG inhibition may not apply to other compounds.
Subject(s)
Erythromycin , Ether-A-Go-Go Potassium Channels , Erythromycin/pharmacology , Temperature , Cisapride/metabolism , Cisapride/pharmacology , Heart , ERG1 Potassium Channel , Potassium Channel Blockers/pharmacologyABSTRACT
The fruit of Morus alba L. (MAF) has been consumed as a food worldwide. MAF has also been widely used in traditional medicine for thousands of years in East Asia, and its diverse bioactivities have been reported in numerous publications. However, no prokinetic activity has been reported for MAF or its components. In the present study, therefore, we investigated the effects of MAF on gastrointestinal motor function by measuring the intestinal transit rate (ITR) of Evans blue in mice in vivo. The ITR values accelerated by MAF were significantly higher than those accelerated by cisapride or metoclopramide, suggesting that MAF has potential as a new prokinetic agent to replace cisapride and metoclopramide. We also investigated the effects of MAF on myogenic and neurogenic contractions in human intestinal smooth muscles by measuring spontaneous contractions of smooth muscle strips, smooth muscle contractions induced by neural stimulation, and migrating motor complexes from intestinal segments in the human ileum and sigmoid colon in situ. MAF increased both myogenic and neurogenic contractions to enhance ileal and colonic motility in the human intestine. Taken together, these results indicate that MAF enhanced intestinal motility by increasing both myogenic and neurogenic contractions, thereby accelerating the ITR.
Subject(s)
Morus , Humans , Mice , Animals , Cisapride/pharmacology , Metoclopramide , Fruit , Gastrointestinal MotilityABSTRACT
BACKGROUND: Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches is accelerating gastric emptying (GE) by means of prokinetic agents. Their efficacy has been demonstrated, although the association between symptom improvement and acceleration of emptying is less clear. Meta-analyses have found contradictory results. Differences in applied methodology and included trials might drive these contradictions. OBJECTIVE: To provide a transparent meta-analysis update to elucidate the association between symptom improvement and acceleration of GE due to gastroprokinetic agents available for long-term use in patients with gastroparesis. DESIGN: Two approaches from earlier meta-analyses were executed and compared. One analyzed the relative changes on active treatment versus baseline, the other compared the change from baseline on active treatment versus the change from baseline on placebo. Papers that reported sufficient numerical data for both analyses were selected. Both analyses included the same trials. RESULTS: Overall, both approaches yield the same positive direction of association between symptom improvement and acceleration of emptying (0.291 (-0.391, 0.972), p = 0.4 and 0.453 (0.123, 0.782), p = 0.007 for the active-only and placebo-controlled analysis respectively). The association between symptom improvement and GE acceleration for studies using optimal GE tests was either 0.028 (p > 0.9) or 0.463 (p = 0.007), and for sub-optimal GE tests was either 0.370 (p = 0.4) or 0.052 (p > 0.9) depending on the used meta-analysis methodology. CONCLUSIONS: The applied methodology for GE testing, and the meta-analysis substantially impacts the conclusion. When considering the clinically relevant outcome of improvement from baseline, symptoms and emptying improve with prokinetics, but no correlation is found between both aspects. When the change over placebo is considered, limiting the analysis to scientifically more rigorous study approaches, changes in emptying rate and symptom improvement are positively associated.
Subject(s)
Dyspepsia , Gastroparesis , Humans , Gastric Emptying , Gastroparesis/drug therapy , Gastrointestinal Agents/therapeutic use , Gastrointestinal Agents/pharmacology , Cisapride/pharmacology , Cisapride/therapeutic use , Dyspepsia/drug therapy , Dyspepsia/complicationsABSTRACT
Mutations in KCNH6 has been proved to cause hypoinsulinemia and diabetes in human and mice. Cisapride is a stomach-intestinal motility drug used to treat gastrointestinal dysfunction. Cisapride has been reported to be a potential inhibitor of the KCNH family, but it remained unclear whether cisapride inhibited KCNH6. Here, we discovered the role of cisapride on glucose metabolism, focusing on the KCNH6 potassium channel protein. Cisapride reduced blood glucose level and increased serum insulin secretion in wild-type (WT) mice fed standard normal chow/a high-fat diet or in db/db mice, especially when combined with tolbutamide. This effect was much stronger after 4 weeks of intraperitoneal injection. Whole-cell patch-clamp showed that cisapride inhibited KCNH6 currents in transfected HEK293 cells in a concentration-dependent manner. Cisapride induced an increased insulin secretion through the disruption of intracellular calcium homeostasis in a rat pancreatic ß-cell line, INS-1E. Further experiments revealed that cisapride did not decrease blood glucose or increase serum insulin in KCNH6 ß-cell knockout (Kcnh6-ß-KO) mice when compared with WT mice. Cisapride also ameliorated glucose-stimulated insulin secretion (GSIS) in response to high glucose in WT but not Kcnh6-ß-KO mice. Thus, our data reveal a novel way for the effect of KCNH6 in cisapride-induced hypoglycemia.
Subject(s)
Blood Glucose , Hypoglycemia , Humans , Rats , Mice , Animals , Blood Glucose/metabolism , Cisapride , Insulin/metabolism , Potassium Channels , HEK293 Cells , Glucose/metabolism , Ether-A-Go-Go Potassium Channels/genetics , Ether-A-Go-Go Potassium Channels/metabolismABSTRACT
BACKGROUND AND PURPOSE: Before advancing to clinical trials, new drugs are screened for their pro-arrhythmic potential using a method that is overly conservative and provides limited mechanistic insight. The shortcomings of this approach can lead to the mis-classification of beneficial drugs as pro-arrhythmic. EXPERIMENTAL APPROACH: An in silico-in vitro pipeline was developed to circumvent these shortcomings. A computational human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model was used as part of a genetic algorithm to design experiments, specifically electrophysiological voltage clamp (VC) protocols, to identify which of several cardiac ion channels were blocked during in vitro drug studies. Such VC data, along with dynamically clamped action potentials (AP), were acquired from iPSC-CMs before and after treatment with a control solution or a low- (verapamil), intermediate- (cisapride or quinine) or high-risk (quinidine) drug. KEY RESULTS: Significant AP prolongation (a pro-arrhythmia marker) was seen in response to quinidine and quinine. The VC protocol identified block of IKr (a source of arrhythmias) by all strong IKr blockers, including cisapride, quinidine and quinine. The protocol also detected block of ICaL by verapamil and Ito by quinidine. Further demonstrating the power of the approach, the VC data uncovered a previously unidentified If block by quinine, which was confirmed with experiments using a HEK-293 expression system and automated patch-clamp. CONCLUSION AND IMPLICATIONS: We developed an in silico-in vitro pipeline that simultaneously identifies pro-arrhythmia risk and mechanism of ion channel-blocking drugs. The approach offers a new tool for evaluating cardiotoxicity during preclinical drug screening.
Subject(s)
Cardiotoxicity , Induced Pluripotent Stem Cells , Action Potentials , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/metabolism , Cardiotoxicity/metabolism , Cisapride , Drug Evaluation, Preclinical/methods , HEK293 Cells , Humans , Ion Channels/metabolism , Myocytes, Cardiac/metabolism , Quinidine/pharmacology , Quinine , VerapamilABSTRACT
According to the ICH S7B guideline, drug candidates are screened for hERG block prior to first-in-human testing to predict the likelihood of delayed repolarization associated with a rare, but life-threatening, ventricular tachyarrhythmia. The new ICH E14 Q&As guideline allows hERG results to be used in later clinical development for decision-making (Q&As 5.1 and 6.1). To pursue this path, the hERG assay should be conducted following the new ICH S7B Q&A 2.1 guideline, which calls for best practice considerations of the recording temperature, voltage protocol, stimulation frequency, recording/data quality, and concentration verification. This study investigated hERG block by cisapride, dofetilide, terfenadine, sotalol, and E-4031 - positive controls commonly used to demonstrate assay sensitivity - using the manual whole cell patch clamp method and an action potential-like voltage protocol presented at 0.2 Hz. Recordings were conducted at room and near physiological temperature. Drug concentrations were measured using samples collected during real patch clamp experiments and satellite experiments. Results showed temperature effects for E-4031, terfenadine, and sotalol, but not cisapride and dofetilide. Cisapride and terfenadine showed substantial concentration losses, largely due to nonspecific binding to the perfusion apparatus. Using concentrations measured from the real and satellite experiments to assess block potencies yielded comparable results, indicating that satellite sample collection may be viable for drugs with nonspecific binding concerns only. In summary, this study provides block potencies for 5 hERG positive controls, and serves as a case study for hERG assays conducted, and results illustrated in accordance with the new ICH E14/S7B Q&As.
Subject(s)
Ether-A-Go-Go Potassium Channels , Sotalol , Cisapride , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Phenethylamines , Sotalol/pharmacology , Sulfonamides , Temperature , Terfenadine/pharmacologyABSTRACT
The Comprehensive in vitro Proarrhythmic Assay (CiPA) has promoted use of in silico models of drug effects on cardiac repolarization to improve proarrhythmic risk prediction. These models contain a pharmacodynamic component describing drug binding to hERG channels that required in vitro data for kinetics of block, in addition to potency, to constrain them. To date, development and validation has been undertaken using data from manual patch-clamp. The application of this approach at scale requires the development of a high-throughput, automated patch-clamp (APC) implementation. Here, we present a comprehensive analysis of the implementation of the Milnes, or CiPA dynamic protocol, on an APC platform, including quality control and data analysis. Kinetics and potency of block were assessed for bepridil, cisapride, terfenadine and verapamil with data retention/QC pass rate of 21.8% overall, or as high as 50.4% when only appropriate sweep lengths were considered for drugs with faster kinetics. The variability in IC50 and kinetics between manual and APC was comparable to that seen between sites/platforms in previous APC studies of potency. Whilst the experimental success is less than observed in screens of potency alone, it is still significantly greater than manual patch. With the modifications to protocol design, including sweep length, number of repetitions, and leak correction recommended in this study, this protocol can be applied on APC to acquire data comparable to manual patch clamp.
Subject(s)
Ether-A-Go-Go Potassium Channels , Terfenadine , Bepridil , Cisapride/pharmacology , Kinetics , Terfenadine/pharmacology , Verapamil/pharmacologyABSTRACT
BACKGROUND AND AIM: Patients with functional dyspepsia often select different pharmacological treatments. We aimed to compare and rank the efficacy of different pharmacological interventions in treating functional dyspepsia. METHODS: We searched EMBASE, PubMed, Cochrane, Web of Science and MEDLINE from the date of database inception to March 28, 2019. A random-effects model was selected to conduct traditional meta-analysis to directly examine the efficacy of different pharmacological interventions. The consistency model was selected to conduct a network meta-analysis to evaluate the relative effects and rank probability of different pharmacological interventions. RESULTS: We included 58 trials (15,629 participants and 21 pharmacological treatments). Network meta-analysis showed that cisapride, domperidone, itopride, and levosulpiride were better than placebo, especially in short term (< 4 weeks). And levosulpiride was significantly more effective than 15 other drugs and placebo (ORs ranging between 0.05 and 0.15). Cisapride was significantly more effective than lansoprazole (OR 0.30, 95% CrI 0.09-0.99) and tegaserod (OR 0.26, 95% CrI 0.07-0.98). The rank probability showed that levosulpiride was most likely to be rank 1 (77%), cinitapride rank 2 (17%), and cisapride rank 3 (23%). CONCLUSIONS: Our study confirmed the effectiveness of several pharmacological treatments for ameliorating functional dyspepsia. Furthermore, levosulpiride relatively ranked the best in managing FD. Physicians should be encouraged to apply promising pharmacological interventions (e.g., levosulpiride and cisapride). However, the results should be interpreted with caution due to small study effects.
Subject(s)
Dyspepsia/drug therapy , Gastrointestinal Agents/pharmacology , Cisapride/pharmacology , Comparative Effectiveness Research , Humans , Network Meta-Analysis , Sulpiride/analogs & derivatives , Sulpiride/pharmacologyABSTRACT
BACKGROUND: Cystic fibrosis (CF) is the most common, life-limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well-recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. OBJECTIVES: To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 09 September 2021. We also searched online trial registries. Date of last search: 12 October 2021. SELECTION CRITERIA: Randomised and quasi-randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross-over trials were judged on an individual basis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the certainty of the evidence using GRADE criteria. MAIN RESULTS: We included one cross-over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro-prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias. Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of -7.60 (95% confidence interval (CI) -14.73 to -0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD -0.90 (95% CI -2.39 to 0.59) or abdominal pain, MD -0.4 (95% CI -2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05). We assessed the available data to be very low certainty. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the certainty a further level for precision. AUTHORS' CONCLUSIONS: There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta-analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice. Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.
Subject(s)
Cystic Fibrosis , Intestinal Obstruction , Cisapride , Constipation/etiology , Constipation/prevention & control , Cystic Fibrosis/complications , Humans , Intestinal Obstruction/etiology , Intestinal Obstruction/prevention & control , Quality of Life , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Asthma and gastro-oesophageal reflux disease (GORD) are common medical conditions that frequently co-exist. GORD has been postulated as a trigger for asthma; however, evidence remains conflicting. Proposed mechanisms by which GORD causes asthma include direct airway irritation from micro-aspiration and vagally mediated oesophagobronchial reflux. Furthermore, asthma might precipitate GORD. Thus a temporal association between the two does not establish that GORD triggers asthma. OBJECTIVES: To evaluate the effectiveness of GORD treatment in adults and children with asthma, in terms of its benefits for asthma. SEARCH METHODS: The Cochrane Airways Group Specialised Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and online clinical trial databases were searched. The most recent search was conducted on 23 June 2020. SELECTION CRITERIA: We included randomised controlled trials comparing treatment of GORD in adults and children with a diagnosis of both asthma and GORD versus no treatment or placebo. DATA COLLECTION AND ANALYSIS: A combination of two independent review authors extracted study data and assessed trial quality. The primary outcome of interest for this review was acute asthma exacerbation as reported by trialists. MAIN RESULTS: The systematic search yielded a total of 3354 citations; 23 studies (n = 2872 participants) were suitable for inclusion. Included studies reported data from participants in 25 different countries across Europe, North and South America, Asia, Australia, and the Middle East. Participants included in this review had moderate to severe asthma and a diagnosis of GORD and were predominantly adults presenting to a clinic for treatment. Only two studies assessed effects of intervention on children, and two assessed the impact of surgical intervention. The remainder were concerned with medical intervention using a variety of dosing protocols. There was an uncertain reduction in the number of participants experiencing one or more moderate/severe asthma exacerbations with medical treatment for GORD (odds ratio 0.53, 95% confidence interval (CI) 0.17 to 1.63; 1168 participants, 2 studies; low-certainty evidence). None of the included studies reported data related to the other primary outcomes for this review: hospital admissions, emergency department visits, and unscheduled doctor visits. Medical treatment for GORD probably improved forced expiratory volume in one second (FEV1) by a small amount (mean difference (MD) 0.10 L, 95% CI 0.05 to 0.15; 1333 participants, 7 studies; moderate-certainty evidence) as well as use of rescue medications (MD -0.71 puffs per day, 95% CI -1.20 to -0.22; 239 participants, 2 studies; moderate-certainty evidence). However, the benefit of GORD treatment for morning peak expiratory flow rate was uncertain (MD 6.02 L/min, 95% CI 0.56 to 11.47; 1262 participants, 5 studies). It is important to note that these mean improvements did not reach clinical importance. The benefit of GORD treatment for outcomes synthesised narratively including benefits of treatment for asthma symptoms, quality of life, and treatment preference was likewise uncertain. Data related to adverse events with intervention were generally underreported by the included studies, and those that were available indicated similar rates regardless of allocation to treatment or placebo. AUTHORS' CONCLUSIONS: Effects of GORD treatment on the primary outcomes of number of people experiencing one or more exacerbations and hospital utilisation remain uncertain. Medical treatment for GORD in people with asthma may provide small benefit for a number of secondary outcomes related to asthma management. This review determined with moderate certainty that with treatment, lung function measures improved slightly, and use of rescue medications for asthma control was reduced. Further, evidence is insufficient to assess results in children, or to compare surgery versus medical therapy.
Subject(s)
Asthma/complications , Gastroesophageal Reflux/drug therapy , Gastroesophageal Reflux/surgery , Acute Disease , Adult , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Child , Cisapride/therapeutic use , Disease Progression , Forced Expiratory Volume/drug effects , Gastroesophageal Reflux/complications , Histamine Antagonists/therapeutic use , Humans , Peak Expiratory Flow Rate , Placebos/therapeutic use , Proton Pump Inhibitors , Quality of Life , Randomized Controlled Trials as TopicABSTRACT
In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n = 5 for each dose), dl-sotalol (0, 1, 3, and 10 mg/kg, n = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl-sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl-sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol >bepridil ≥cisapride >verapamil in our study. Since the order was bepridil ≥dl-sotalol >cisapride >verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.
Subject(s)
Atrioventricular Block , Torsades de Pointes , Animals , Bepridil , Cisapride/toxicity , Computer Simulation , Macaca fascicularis , Sotalol/toxicity , Torsades de Pointes/chemically induced , Verapamil/toxicityABSTRACT
Due to their effective analgesic properties, opioids are worthy of consideration for pain management in rabbits. However, this class of drugs causes undesirable effects including reduced gastrointestinal (GI) motility, reduced fecal output, and delays GI transit times and thus increases the risk of GI stasis. The risk of stasis discourages the use of opioids in rabbits, which could affect animal welfare. Gastroprokinetic agents such as cisapride are effective in promoting gastric emptying in many species, but whether this effect occurs in rabbits is unknown. This study assessed the efficacy of cisapride when administered as a single agent and in combination with buprenorphine in rabbits; efficacy was assessed by measuring GI transit times, fecal output, body weight, and food and water intake. Female New Zealand White rabbits (n = 10) were studied in a crossover, randomized design and received either vehicle and buprenorphine, cisapride and saline, cisapride and buprenorphine, or vehicle and saline (control) every 8 h for 2 d. Rabbits were anesthetized and administered radio-opaque, barium-filled spheres via orogastric tube. Feces was assessed via radiography for detection of the barium-spheres to determine GI transit time. GI transit time was significantly longer in buprenorphine groups than in control groups, regardless of the use of cisapride. Fecal output and food and water intake were lower for buprenorphine groups than control groups. Cisapride did not significantly alter GI transit, fecal output, or food and water intake. In addition, treatment group did not significantly affect body weight. In conclusion, buprenorphine treatment (0.03 mg/kg TID) prolonged GI transit time and reduced fecal output and food and water consumption in rabbits. Coadministration of buprenorphine and cisapride (0.5 mg/kg) did not ameliorate these effects, and the administration of cisapride at this dose did not appear to affect GI motility in female rabbits.
Subject(s)
Analgesics, Opioid/pharmacology , Buprenorphine/pharmacology , Cisapride/pharmacology , Gastrointestinal Motility/drug effects , Gastrointestinal Transit/drug effects , Rabbits/physiology , Analgesics, Opioid/administration & dosage , Animals , Buprenorphine/administration & dosage , Cisapride/administration & dosage , Cross-Over Studies , Female , Gastric Emptying/drug effects , Gastrointestinal Agents/pharmacology , Random AllocationABSTRACT
Functional dyspepsia is one of the most common functional disorders of the gastrointestinal tract, which resulted from impaired motor skills, visceral hypersensitivity, increased mucosal permeability, disorders of the autonomic nervous system, etc. There is no specific therapy for this disease, which often leads to the irrational use of various groups of drugs. Drug therapy is recommended only during periods of symptoms. The main options of pharmacotherapy include the use of proton pump inhibitors, phytotherapeutic drugs, eradication therapy of Helicobacter pylori. Against the background of possible motor disorders, prokinetics are also one of the possible treatment options, but cisapride has long been withdrawn from sale due to cardiotoxicity, the use of domperidone and metoclopramide is limited due to side effects, especially with long-term therapy, so currently the only prokinetic that can be used in everyday clinical practice is itopride. In refractory cases, tricyclic antidepressants and psychotherapeutic approaches are another effective treatment option.
Subject(s)
Dyspepsia , Helicobacter Infections , Humans , Dyspepsia/diagnosis , Dyspepsia/drug therapy , Dyspepsia/etiology , Cisapride/therapeutic use , Domperidone/pharmacology , Domperidone/therapeutic use , Proton Pump Inhibitors/therapeutic use , Metoclopramide/therapeutic use , Antidepressive Agents, Tricyclic/therapeutic use , Helicobacter Infections/drug therapyABSTRACT
OBJECTIVE: Gastrointestinal dysmotility is common in patients with pediatric intestinal failure (PIF), leading to delays in advancement of enteral nutrition (EN). Few studies have been published regarding the safety and efficacy of cisapride for improvement of enteral tolerance and ability to wean parenteral nutrition. Our objective was to describe a single center experience on the use of cisapride in patients with PIF. METHODS: Retrospective chart review of patients was performed. Demographic, intestinal anatomy, and outcome data were collected. Percentage of EN before initiation of cisapride, progression of EN at 3 and 6 months, and ability to wean parenteral nutrition after initiation of cisapride were calculated. RESULTS: Prokinetics were used in 61 of 106 patients (56.6%); 29 of 60 patients (48.3%) failed to progress EN on other prokinetics and started on cisapride. Before cisapride the progress of EN plateaued for a mean of 42.3 (standard deviation [SD] 60.2) days. The rate of feed progression was 0.14% (SD 0.19)/day pre-cisapride and 0.69%/day (SD 0.31) after cisapride initiation (Pâ<â0.001). Percentage of EN improved significantly from baseline to 3 months postinitiation (23.9% vs 79.4%, respectively; Pâ<â0.001). Electrocardiogram was performed on initiation of cisapride and after every dose change. Medication was discontinued in 2 of 29 (6.8%). CONCLUSION: This retrospective study suggests that cisapride may be beneficial in PIF patients who fail to progress EN on first line prokinetics. The most significant period of improvement occurs within 3 months of cisapride initiation. Cardiac side effects in our cohort were lower than previously reported; however, cardiac monitoring is still recommended.
Subject(s)
Enteral Nutrition , Parenteral Nutrition , Child , Cisapride/therapeutic use , Humans , Parenteral Nutrition, Total , Retrospective StudiesABSTRACT
The aim of this study was to compare the effects of cisapride and tegaserod on intestinal smooth muscle activity in equines. Efficacy was evaluated through measurement of gastrointestinal transit time, bowel movements per day, stool weight, and bowel sounds. Drug safety was evaluated via heart rate, respiratory rate, and rectal temperature. Records were obtained throughout three periods: a control phase without treatment, a period of cisapride administration at a dose of 0.22 mg/kg, and a period of tegaserod treatment at a dose of 0.27 mg/kg. Gastrointestinal transit time, bowel movements per day, and stool weight were significantly improved on administration of both cisapride and tegaserod, as compared with the control phase. With tegaserod administration, gastrointestinal transit time accelerates more than to cisapride administration; however, no significant difference was seen in bowel movements per day and stool weight. In terms of heart rate, respiratory rate, and rectal temperature, no significant variations were seen between the three sample phases. Because of the above findings, tegaserod can be considered an effective stimulant of intestinal smooth muscle, accelerating gastrointestinal transit time in healthy horses and representing a potential therapeutic agent similar to cisapride.
Subject(s)
Defecation , Indoles , Animals , Cisapride/pharmacology , Horses , Indoles/pharmacology , Muscle, SmoothABSTRACT
Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT4 ) receptor that acts as a partial agonist. Although 5-HT4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.
Subject(s)
Irritable Bowel Syndrome/drug therapy , Long QT Syndrome/chemically induced , Morpholines/adverse effects , Piperidines/adverse effects , Serotonin 5-HT4 Receptor Agonists/adverse effects , Administration, Oral , Adult , Anti-Bacterial Agents/administration & dosage , Arrhythmias, Cardiac/chemically induced , Asian People/ethnology , Benzamides/pharmacokinetics , Case-Control Studies , Cisapride/administration & dosage , Cisapride/adverse effects , Cisapride/therapeutic use , Cross-Over Studies , Double-Blind Method , Electrocardiography/methods , Electrocardiography/statistics & numerical data , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Indoles/therapeutic use , Male , Morpholines/administration & dosage , Morpholines/pharmacokinetics , Moxifloxacin/administration & dosage , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Placebos/administration & dosage , Serotonin 5-HT4 Receptor Agonists/administration & dosage , Serotonin 5-HT4 Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/adverse effects , Serotonin Receptor Agonists/therapeutic useABSTRACT
Cisapride is a selective 5-hydroxytryptamine (5-HT)4 receptor (5-HT4R) agonist. However, the effects of cisapride on osteoclasts and osteoblasts have not been fully explored. We therefore examined the effects of cisapride on osteoclastogenesis in cultured primary bone marrow-derived macrophages (BMMs), and on osteoblast differentiation in cultured primary calvarial pre-osteoblasts. Cisapride significantly inhibited tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and F-actin ring formation during receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. No cytotoxicity was observed. Cisapride also suppressed RANKL-induced expression of NF-ATc1, TRAP, and cathepsin K genes in BMMs. In addition, cisapride significantly stimulated apoptotic cell death of osteoclasts. However, cisapride had no effect on osteoblast differentiation, as assessed by alkaline phosphatase (ALP) activity and mineralized nodule formation in the cultured primary pre-osteoblasts. Overall, our findings suggest that cisapride may improve the clinical management of metabolic bone diseases such as osteoporosis.
Subject(s)
Cisapride/pharmacology , Macrophages/drug effects , Osteoclasts/drug effects , RANK Ligand/pharmacology , Serotonin Receptor Agonists/pharmacology , Animals , Apoptosis/drug effects , Cell Differentiation/drug effects , Cells, Cultured , Female , Gene Expression/drug effects , Macrophages/metabolism , Mice, Inbred ICR , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoclasts/cytology , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteogenesis/geneticsABSTRACT
BACKGROUND & AIMS: Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods. METHODS: With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT4 agonists, D2 receptor antagonist, or ghrelin agonists; trials that measured change in GE (T1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms. RESULTS: Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T1/2) in all studies (mean reduction in T1/2, 16.3 minutes; 95% confidence interval, -22.1 to -10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T1/2, 23.6 minutes; 95% confidence interval, -32.3 to -14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, -0.37 to -0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02). CONCLUSIONS: In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.
Subject(s)
Dopamine D2 Receptor Antagonists/pharmacology , Gastric Emptying/drug effects , Ghrelin/agonists , Serotonin 5-HT4 Receptor Agonists/pharmacology , Breath Tests , Cisapride/pharmacology , Domperidone/pharmacology , Dopamine D2 Receptor Antagonists/therapeutic use , Dyspepsia/drug therapy , Gastroparesis/drug therapy , Ghrelin/pharmacology , Humans , Macrocyclic Compounds/pharmacology , Oligopeptides/pharmacology , Radionuclide Imaging , Randomized Controlled Trials as Topic , Serotonin 5-HT4 Receptor Agonists/therapeutic use , Symptom AssessmentABSTRACT
Sympathetic overdrive is a key player in hypertension, where the mesenteric vasculature plays a relevant role in modulating blood pressure. Although 5-HT inhibits noradrenergic mesenteric neurotransmission in normotensive rats, its effect on the mesenteric sympathetic drive in hypertensive rats has not been studied. We investigated the influence of in vivo 5-HT by characterizing the implicated serotonergic receptors on the mesenteric sympathetic outflow in rats with N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Hypertension was induced in male Wistar rats by L-NAME administration (30 mg/kg per day; 21 days) in drinking water. The rats were anesthetized (sodium pentobarbital; 60 mg/kg, i.p.), prepared for the in situ autoperfused rat mesentery, and subjected for monitoring their systemic blood pressure (SBP), heart rate (HR), and mesenteric perfusion pressure (MPP). Electrical stimulation of mesenteric sympathetic nerves resulted in frequency-dependent increases in MPP without altering SBP or HR. The 5-HT and cisapride (5-HT4 agonist) i.a. bolus (1-25 µg/kg) inhibited vasopressor responses by electrical stimulation of the mesenteric nerves, unlike an i.a. bolus (25 µg/kg each) of the agonist 5-carboxamidotryptamine (5-HT1/7 agonist), α-methyl-5-HT (5-HT2), or 1-PBG (5-HT3). However, i.a. cisapride (25 µg/kg) did not affect the noradrenaline-induced vasoconstriction in the mesenteric vasculature. Administration of the selective 5-HT4 receptor antagonist GR 125487 (1 mg/kg, i.v.) completely abolished cisapride- and 5-HT-evoked mesenteric sympatholytic effects. Additionally, ELISA analysis demonstrated higher 5-HT4 receptor expression in mesenteric arteries from L-NAME-hypertensive compared with normotensive rats. Our findings suggest that L-NAME-induced hypertension modifies the 5-HT modulation of the rat mesenteric sympathetic drive: prejunctional 5-HT4 receptors are involved in the serotonergic sympathoinhibitory effect.
Subject(s)
Hypertension/metabolism , Mesenteric Arteries/metabolism , Receptors, Serotonin, 5-HT4/metabolism , Splanchnic Circulation , Sympathetic Nervous System/metabolism , Animals , Cisapride , Disease Models, Animal , Indoles , Male , NG-Nitroarginine Methyl Ester , Rats, Wistar , Sulfonamides , Synaptic Transmission , VasoconstrictionABSTRACT
OBJECTIVES: Retrospective evaluation of a preoperative prokinetic protocol using a constant-rate infusion of a serotonin 5-HT4 receptor agonist, cisapride, and its association with frequency of postoperative aspiration pneumonia in dogs undergoing unilateral arytenoid lateralisation as compared to a historical population at the same institution. MATERIALS AND METHODS: Medical records of dogs undergoing unilateral arytenoid lateralisation for laryngeal paralysis were reviewed for historical findings, imaging findings, anaesthesia and surgery durations, perioperative medications and if surgery was performed as an emergency. Aspiration pneumonia events in the first 72 hours after surgery were recorded. The study group received a preoperative cisapride constant-rate infusion; historical 'controls' did not receive the cisapride protocol. RESULTS: One of 50 dogs in the cisapride group and six of 52 dogs in the historical group developed aspiration pneumonia within the immediate postoperative period. The cisapride protocol was largely well tolerated. A markedly lower rate of aspiration pneumonia in patients administered butorphanol with acepromazine preoperatively and buprenorphine postoperatively was noted, but the overall low frequency of aspiration pneumonia and variation in case management protocols precluded definitive conclusions with respect to optimal perioperative drug choices. CLINICAL SIGNIFICANCE: Laryngeal paralysis is commonly treated by unilateral arytenoid lateralisation, and aspiration pneumonia is one of the most serious potential complications of this procedure. This study suggests that further investigation of a cisapride constant-rate infusion to prevent this complication is warranted.