piperidines and Constipation

Chronic lymphocytic leukemia (CLL) is a rare hematological malignancy classified in the non-Hodgkin's lymphoma category. Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor has been approved for use in the treatment of CLL. This drug has shown beneficial effects including a higher overall response rate, sustained remissions, and a tolerable toxicity level. In this meta-analysis, we aimed to compare the adverse drug events which were associated with the use of ibrutinib for the treatment of patients with CLL.. A careful search was carried out through the Cochrane Central, EMBASE, MEDLINE (PubMed), and through www.ClinicalTrials.com. The following criteria for inclusion were considered: Both randomized trials and observational cohorts; Studies comparing the adverse drug events observed with the use of ibrutinib versus a control group for the treatment of CLL. The RevMan software (version 5.3) was used to carry out this analysis and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI).. A total number of 2456 participants with CLL were included in this analysis. One thousand one hundred thirteen participants were treated with ibrutinib whereas the remaining 1343 participants were assigned to the control (non-ibrutinib) group. Results of this current analysis showed Ibrutinib not to be associated with significantly higher risk of anemia (RR: 0.90, 95% CI: 0.67-1.21; P = .49), thrombocytopenia (RR: 0.61, 95% CI: 0.32-1.14; P = .12), neutropenia (RR: 0.50, 95% CI: 0.25-1.00; P = .05), and febrile neutropenia (RR: 0.89, 95% CI: 0.32-2.49; P = .83) in these patients with CLL. The risk for respiratory tract infection was also similarly manifested (RR: 1.01, 95% CI: 0.78-1.30; P = .96). However, ibrutinib was associated with a high risk of abdominal manifestations in comparison to the control group (RR: 1.62, 95% CI: 1.32-2.00; P = .00001). The risk for diarrhea was also significantly higher in the Ibrutinib group (RR: 2.14, 95% CI: 1.44-3.17; P = .0002).. During the treatment of CLL, ibrutinib was not associated with significantly higher risks of anemia, thrombocytopenia, or neutropenia compared to the control group. However, abdominal manifestations were significantly higher with ibrutinib. Advanced phase trials should further confirm this hypothesis.

Topics: Abdominal Pain; Adenine; Constipation; Diarrhea; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Vomiting

To summarize and evaluate the existing literature regarding medications to treat opioid-induced constipation (OIC) in patients with chronic noncancer pain (CNCP).. PubMed, EMBASE, and Web of Science were searched using the following terms: constipation, opioid, chronic, pain, noncancer, nonmalignant, methylnaltrexone, alvimopan, lubiprostone, naloxegol, and naldemedine.. The search was limited to randomized controlled trials reporting human outcomes. Data extracted included the following: study design, population, intervention, control, outcomes related to OIC and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool.. After assessment, 16 of the 190 studies were included: methylnaltrexone (n = 4), naloxegol (n = 3), naldemedine (n = 2), lubiprostone (n = 3), and alvimopan (n = 4). Lubiprostone was the only nonperipherally acting µ-opioid receptor antagonist included. Only 1 study (naloxegol) used "usual care" (nonstudy laxative) rather than placebo as a comparator. Placebo-controlled trials demonstrated benefit for methylnaltrexone, naloxegol, naldemedine, and lubiprostone, with conflicting evidence for alvimopan. No data suggest that one agent is better than another. Overall risk of bias across all studies was low to moderate.. With risk of bias determined to be low to moderate, published data to date suggest that methylnaltrexone, naloxegol, and naldemedine may be appropriate to treat OIC in patients with CNCP.

Topics: Analgesics, Opioid; Chronic Pain; Constipation; Evidence-Based Practice; Humans; Laxatives; Lubiprostone; Morphinans; Naltrexone; Narcotic Antagonists; Piperidines; Polyethylene Glycols; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.. A PubMed search of μ-opioid antagonists to counter μ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.. The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.. Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ-opioid antagonist effect.

Topics: Analgesics, Opioid; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Agents; Humans; Morphinans; Narcotic Antagonists; Pain; Piperidines; Polyethylene Glycols; Receptors, Opioid, mu; Treatment Outcome

Topics: Analgesics, Opioid; Cancer Pain; Constipation; Enema; Gastrointestinal Agents; Gastrostomy; Humans; Laxatives; Morphinans; Naltrexone; Piperidines; Polyethylene Glycols; Practice Guidelines as Topic; Quaternary Ammonium Compounds

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care.. To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data.. We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced.. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE.. We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (. In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Topics: Constipation; Defecation; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Male; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Related Disorders; Oxycodone; Palliative Care; Piperidines; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

Constipation is a common adverse effect of opioids. As an example, constipation is reported in 52% of people with advanced malignancy, and this figure rises to 87% in people who are terminally ill and taking opioids. There is no reason to believe that people with chronic non-malignant disease who are prescribed opioids will be any less troubled by this adverse effect.. We conducted a systematic overview and aimed to answer the following clinical question: What are the effects of opioid antagonists for constipation in people prescribed opioids? The population we studied included people with any condition, although most studies were in people with cancer pain. We searched Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).. At this update, searching of electronic databases retrieved 162 studies. After deduplication and removal of conference abstracts, 84 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 47 studies and the further review of 37 full publications. Of the 37 full articles evaluated, two systematic reviews and one RCT were included at this update. We performed a GRADE evaluation for three PICO combinations.. In this systematic overview we categorised the efficacy for three interventions based on information relating to the effectiveness of alvimopan, methylnaltrexone, and naloxone.

Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Treatment Outcome

There has been no definitive synthesis of the evidence for any benefit of available pharmacological therapies in opioid-induced constipation (OIC). We conducted a systematic review and meta-analysis to address this deficit.. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through to December 2012 to identify placebo-controlled trials of μ-opioid receptor antagonists, prucalopride, lubiprostone, and linaclotide in the treatment of adults with OIC. No minimum duration of therapy was required. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Effect of pharmacological therapies was reported as relative risk (RR) of failure to respond to therapy, with 95% confidence intervals (CIs).. Fourteen eligible randomized controlled trials (RCTs) of μ-opioid receptor antagonists, containing 4,101 patients, were identified. These were superior to placebo for the treatment of OIC (RR of failure to respond to therapy=0.69; 95% CI 0.63-0.75). Methylnaltrexone (six RCTs, 1,610 patients, RR=0.66; 95% CI 0.54-0.84), naloxone (four trials, 798 patients, RR=0.64; 95% CI 0.56-0.72), and alvimopan (four RCTs, 1,693 patients, RR=0.71; 95% CI 0.65-0.78) were all superior to placebo. Total numbers of adverse events, diarrhea, and abdominal pain were significantly commoner when data from all RCTs were pooled. Reversal of analgesia did not occur more frequently with active therapy. Only one trial of prucalopride was identified, with a nonsignificant trend toward higher responder rates with active therapy. Two RCTs of lubiprostone were found, with significantly higher responder rates with lubiprostone in both, but reporting of data precluded meta-analysis.. μ-Opioid receptor antagonists are safe and effective for the treatment of OIC. More data are required before the role of prucalopride or lubiprostone in the treatment of OIC are clear.

Topics: Alprostadil; Analgesics, Opioid; Benzofurans; Constipation; Female; Gastrointestinal Agents; Humans; Lubiprostone; Male; Naloxone; Naltrexone; Narcotic Antagonists; Peptides; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Topics: Analgesics, Opioid; Combined Modality Therapy; Constipation; Delayed-Action Preparations; Diet Therapy; Humans; Laxatives; Life Style; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds

Symptoms associated with disorders of the motility of colon and rectum are common problems in clinical practice. Advances in this field continue to expand our understanding of these disorders and provide new and different treatments with promising results.. This article reviews new advances in the past year on the measurement and diagnosis of colonic transit. Recently published data question the importance of dietary fiber in the prevention of colonic diverticulosis and diverticulitis, and support the efficacy of a number of different therapies aimed at improving colonic motility and visceral sensation in constipation and reversing the effects of opioid induced constipation with peripherally acting opioid antagonists.. The articles referenced in this review help inform the reader on new developments in the diagnosis and management of patients with colonic and rectal motility disorders.

Topics: Constipation; Diet; Dipeptides; Diverticulosis, Colonic; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Naltrexone; Narcotic Antagonists; Peptides; Piperidines; Quaternary Ammonium Compounds; Rectal Diseases; Thiazepines; Tryptophan Hydroxylase

Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal mu-, kappa- and delta-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, beta-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.

Topics: Animals; Constipation; Gastrointestinal Tract; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid

Constipation and other gastrointestinal symptoms are frequent adverse effects of either short-term postoperative or chronic opioid therapy. The review authors have identified 23 studies to evaluate the efficacy of micro-opioid antagonists for the prevention and treatment of these complications. The data on safety and efficacy of the traditional antagonists naloxone and nalbuphine are insufficient. The results of studies with the newer, peripherally-acting antagonists alvimopan and methylnaltrexone are promising. Methylnaltrexone resulted in four studies with healthy probands in a significant shortening of the gastrointestinal transit time (-52 min). In the postoperative setting, five studies showed a significant improvement of the hazard ratios for different outcomes (e. g., bowel movement, tolerance of solid food) in the alvimopan group. Future studies will be needed to show whether these results can be reproduced in different patient groups on a larger scale. Also, with regard to other pharmacological (e. g., lactulose) and non-pharmacological interventions, the role of the above-mentioned not yet approved medications needs to be defined.

Topics: Analgesics, Opioid; Clinical Trials as Topic; Constipation; Gastrointestinal Transit; Humans; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life.. To compare the efficacy and safety of traditional and peripherally active opioid antagonists versus conventional interventions for OBD.. We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in January 2007. Additional reports were identified from the reference lists of retrieved papers.. Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD.. Data were extracted by two independent review authors and included demographic variables, diagnoses, interventions, efficacy, and adverse events.. Twenty-three studies met inclusion criteria and provided data on 2871 opioid antagonist-treated patients. The opioid antagonists investigated were alvimopan (nine studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate.. Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.

Topics: Constipation; Defecation; Gastrointestinal Agents; Humans; Intestinal Diseases; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Constipation is a worldwide problem that affects many children. Treatment of constipation is largely based on clinical experience rather than on evidence-based controlled clinical trials. Stool softeners and cathartic agents in combination with behavioral interventions constitute the programs most commonly used to facilitate painless and frequent defecation. Long-term treatment is needed for most patients, and approximately 30% of children beyond puberty continue to struggle with symptoms of constipation, such as infrequent, painful evacuation of stools and fecal incontinence. Not surprisingly, chronicity of these bowel complaints may cause significant interference with the child's emotional growth and development. Development of new therapeutic strategies is necessary in order to treat these challenging patients more effectively. This review provides an overview of novel and alternative therapies, such as new drugs, surgery, and probiotics, that are being proposed for the treatment of childhood chronic constipation.

Topics: Acupuncture Therapy; Alprostadil; Botulinum Toxins; Child; Complementary Therapies; Constipation; Electric Stimulation; Fatty Acids; Humans; Indoles; Lubiprostone; Massage; Piperidines; Probiotics; Serotonin Receptor Agonists

Cancer-related constipation is common and a significant detractor from patient quality of life. It has many possible causes and is still not well understood. Information is lacking on therapies for cancer-related constipation among current medications approved by the US Food and Drug Administration (FDA). Most agents have only been formally tested in comparison with placebo in chronic idiopathic constipation if at all. Few comparative studies of laxatives have been performed to establish superiority or synergy. As we understand more about the physiology of the gastrointestinal tract, new targeted therapies have become available. These include a selective chloride channel activator, lubiprostone, and a selective 5HT4 serotonin receptor agonist, tegaserod, both of which have been FDA approved for chronic idiopathic constipation. The role of these agents in cancer-related constipation remains to be seen. On the horizon are two investigational peripherally acting opioid receptor antagonists, alvimopan and methylnaltrexone. Preliminary results in cancer-related constipation suggest that these agents may be important additions to our treatment repertoire.

Topics: Alprostadil; Constipation; Fatty Acids; Gastrointestinal Agents; Humans; Indoles; Lubiprostone; Naltrexone; Narcotic Antagonists; Neoplasms; Piperidines; Quaternary Ammonium Compounds; Serotonin Receptor Agonists

Alvimopan is a novel, peripherally acting mu-opioid antagonist that is being developed for the management of acute postoperative ileus and for the reversal of the delayed gastrointestinal and colonic transit that result in symptoms such as constipation, nausea and motility disorders in patients treated with opiate analgesics. There is a clinical need for effective medications for the treatment of postoperative ileus and opiate-induced constipation and other motility disorders. This review addresses the basic and applied pharmacology and current evidence for the use of the medication, alvimopan, in clinical gastroenterology.

Topics: Animals; Constipation; Gastrointestinal Motility; Humans; Ileus; Narcotic Antagonists; Piperidines; Postoperative Complications; Receptors, Opioid, mu

Alvimopan is a synthetic peripherally restricted mu-receptor opioid antagonist. Alvimopan has a greater affinity for the mu-receptor than the kappa- or sigma-opioid receptors (Ki = 0.77 nM). The polarity of the molecule limits gastrointestinal absorption and central nervous system penetration. It has limited systemic bioavailability and higher affinity for the mu-opioid receptor than naloxone (Ki = 3.7 nM). Completed Phase III trials suggest efficacy in accelerating the recovery of gastrointestinal function after abdominal surgery. Adverse events with all doses have been similar to placebo groups. Further efficacy in alleviating opioid-induced bowel dysfunction in patients with chronic opioid usage has also been demonstrated. This evidence-based review assesses this new drug and discusses its potential role in clinical practice.

Topics: Abdomen; Administration, Oral; Adult; Analgesics, Opioid; Constipation; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Ileus; Male; Middle Aged; Narcotic Antagonists; Piperidines; Postoperative Complications; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

The gut is a neurological organ, which implies that many neuroactive drugs such as opioid analgesics can seriously disturb gastrointestinal function, because many of the transmitters and transmitter receptors present in the brain are also found in the enteric nervous system. One of the most common manifestations of opioid-induced bowel dysfunction is constipation which results from blockade of peristalsis and intestinal fluid secretion. The discovery of opioid receptor antagonists with a peripherally restricted site of action, such as N-methylnaltrexone and alvimopan, makes it possible to normalize bowel function in opiate-treated patients without compromising central opioid analgesia. There is emerging evidence that opioid receptor antagonists may also have prokinetic actions, reversing pathological states of gastrointestinal hypomotility that are due to overactivity of the enteric opioid system.

Topics: Analgesics, Opioid; Animals; Constipation; Enteric Nervous System; Gastrointestinal Motility; Humans; Naltrexone; Narcotic Antagonists; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid

Topics: Adult; Animals; Child; Cisapride; Constipation; Esophageal Motility Disorders; Gastrointestinal Diseases; Gastrointestinal Motility; Gastroparesis; Humans; Infant; Intestinal Pseudo-Obstruction; Piperidines

Cisapride appears to be useful as therapy for chronic constipation that is not associated with underlying organic abnormalities or pregnancy and that is refractory to other treatments, such as increased dietary fiber intake or bulk laxatives. Dosages of cisapride that have demonstrated efficacy in chronic constipation range from 5 mg po tid to 20 mg po bid. Treatment for 8-12 weeks may be necessary for an optimal effect to occur. Further studies are needed to evaluate the most effective dosage regimen for the treatment of constipation and to compare the efficacy and cost-efficiency of cisapride with those of conventional therapy. Until these studies are completed, cisapride should not be recommended routinely for patients with constipation. However, it may be a viable option for patients with chronic idiopathic constipation that is refractory to conventional therapy.

Topics: Chronic Disease; Cisapride; Clinical Trials as Topic; Constipation; Female; Gastrointestinal Agents; Humans; Male; Pilot Projects; Piperidines

To summarize the pharmacology, pharmacokinetics, efficacy, and safety of cisapride, and to evaluate its potential therapeutic role.. A computerized search of the MEDLINE database was used to identify English-language publications of cisapride data in humans. The MEDLINE search was supplemented by review article bibliographies. There was no attempt to limit the search to a specific gastrointestinal motility disorder.. The MEDLINE search alone identified 165 citations. Because of the volume of available human cisapride data, the focus of the efficacy section is on complete published reports of controlled clinical studies. Abstracts and uncontrolled data are discussed only when other information is unavailable to address important aspects.. Information regarding study design, study population, results, and safety was recorded from each publication. The placebo response to gastrointestinal complaints in patients with motility disorders is high. Therefore, objective evidence of improvement was emphasized when documentation was available.. Cisapride stimulates the motility of smooth muscle lining the esophagus, stomach, small intestine, and colon, and increases the tone of gut sphincters in vitro and in vivo. In controlled investigations, cisapride was superior to placebo in relieving symptoms associated with reflux esophagitis, nonulcer dyspepsia, and gastroparesis. Similar symptom and healing effects were observed with cisapride and histamine (H)2-antagonists in reflux esophagitis. Cisapride was either equal to or superior to metoclopramide in relieving reflux symptoms. However, metoclopramide was associated with significantly more central nervous system adverse effects. Cisapride was well tolerated, with adverse effects limited primarily to the gastrointestinal tract.. Cisapride represents an attractive alternative to metoclopramide for the treatment of a variety of motility disorders. Because it addresses a primary underlying cause of reflux esophagitis, cisapride may also prove to be an effective alternative to acid suppressants in the management of this disorder.

Topics: Adult; Anti-Ulcer Agents; Cisapride; Clinical Trials as Topic; Constipation; Double-Blind Method; Dyspepsia; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Infant; Infant, Newborn; Parasympathomimetics; Piperidines

Topics: Cisapride; Constipation; Dyspepsia; Esophagitis; Esophagus; Forecasting; Gastric Emptying; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Hydrogen-Ion Concentration; Intestinal Pseudo-Obstruction; Intestines; Manometry; Piperidines; Serotonin Antagonists; Stomach

Topics: Cisapride; Constipation; Drug Evaluation; Gastrointestinal Motility; Humans; Piperidines

Topics: Biofeedback, Psychology; Cathartics; Chronic Disease; Cisapride; Constipation; Humans; Narcotic Antagonists; Piperidines; Serotonin Antagonists

Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine.. In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D).. A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group.. Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

Topics: Adolescent; Adult; Aged; Calcitonin Gene-Related Peptide Receptor Antagonists; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Migraine Disorders; Nausea; Piperidines; Pyridines; Pyrroles; Spiro Compounds; Young Adult

Agonists of 5-hydroxytryptamine 4 receptor are potential agents for irritable bowel syndrome with predominant constipation (IBS-C). However, only tegaserod has been approved for a very limited population in the US.. To evaluate the efficacy and safety of minesapride in patients with Rome IV defined IBS-C.. A double-blind, placebo-controlled, dose-finding study was performed. Overall, 411 patients were randomised to receive minesapride at 10, 20 or 40 mg/d, or placebo for 12 weeks. The primary endpoint was Food and Drug Administration (FDA) composite endpoint (responder: a patient who reported an increase in one or more complete spontaneous bowel movements from baseline and improvement of ≥30% from baseline in weekly average of worst abdominal pain score, both in the same week for ≥6/12 weeks).. The FDA composite responder rate was 13.6% (14/103) in the placebo group, 13.6% (14/103) in the 10 mg group, 19.2% (20/104) in the 20 mg group and 14.9% (15/101) in the 40 mg group, and no dose-response relationship was found. A greater percentage of minesapride 40 mg-treated patients than placebo-treated patients met both responder requirements for ≥9/12 weeks as the stricter composite evaluation (P < 0.05). Furthermore, minesapride 40 mg significantly increased SBM frequency compared with placebo (adjusted P < 0.001 at Week 12). The most common adverse event was mild diarrhoea.. Minesapride was safe and well-tolerated. Although the primary endpoint was negative, minesapride 40 mg is likely to improve the stricter composite endpoint and SBM frequency. Japan Pharmaceutical Information Center Number: Japic CTI-163459.

Topics: Abdominal Pain; Adult; Constipation; Diarrhea; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Morpholines; Piperidines; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Young Adult

Pain management following major spine surgery requires high doses of opioids and is associated with a risk of opioid-induced constipation. Peripheral mu-receptor antagonists decrease the gastrointestinal complications of perioperative systemic opioid administration without antagonizing the analgesic benefits of these drugs.. To investigate the impact of alvimopan in opioid-naive patients undergoing major spine surgery.. Patients undergoing >3 levels of thoracic and/or lumbar spine surgery were enrolled in this prospective, randomized, double-blind study to receive either alvimopan or placebo prior to and following surgery. Opioid consumption; pain scores; and time of first oral intake, flatus, and bowel movement were recorded.. A total of 24 patients were assigned to the active group and 25 were assigned to the placebo group. There was no significant difference in demographics between the groups. Postoperatively, the alvimopan group reported earlier time to first solid intake [median (range): alvimopan: 15 h (3-25) vs placebo: 17 h (3-46), P < .001], passing of flatus [median (range): alvimopan: 22 h (7-63) vs placebo: 28 h (10-58), P < .001], and first bowel movement [median (range): alvimopan: 50 h (22-80) vs placebo: 64 h (40-114), P < .001]. The alvimopan group had higher pain scores (maximum, minimum, and median); however, there was no significant difference between the groups with postoperative opioid use.. This study shows that the perioperative use of alvimopan significantly reduced the time to return of bowel function with no increase in postoperative opioid use despite a slight increase in pain scores.

Topics: Adult; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Middle Aged; Pain; Piperidines; Prospective Studies; Receptors, Opioid, mu; Recovery of Function; Spinal Diseases; Young Adult

Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.. We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.. Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).. Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.. F Hoffmann-La Roche.

Topics: Adult; Aged; Alanine Transaminase; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Aspartate Aminotransferases; Carbazoles; Carcinoma, Non-Small-Cell Lung; Constipation; Creatine Kinase; Crizotinib; Drug Resistance, Neoplasm; Edema; Fatigue; Female; Humans; Lung Neoplasms; Male; Middle Aged; Myalgia; Piperidines; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Response Evaluation Criteria in Solid Tumors; Retreatment

Gastrointestinal (GI) side effects are common with opioid medication, and constipation affects ∼40% of patients. Such symptoms considerably impair patients' quality of life. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist approved in the US for short-term, in-hospital management of postoperative ileus in patients undergoing bowel resection. This double-blind, placebo-controlled trial was conducted as part of a recently discontinued clinical program, in which alvimopan was being developed for opioid-induced constipation (OIC). Patients (N = 518) receiving opioids for non-cancer pain were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo for 12 weeks. The primary efficacy endpoint was the proportion of patients experiencing ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period and an average increase from baseline of ≥ 1 SBM per week. A significantly greater proportion of patients in the alvimopan .5 mg twice-daily group met the primary endpoint compared with placebo (72% versus 48%, P < .001). Treatment with alvimopan twice daily improved a number of other symptoms compared with placebo and reduced the requirement for rescue laxative use. The opioid-induced bowel dysfunction Symptoms Improvement Scale (SIS) responder rate was 40.4% in the alvimopan .5 mg twice daily group, versus 18.6% with placebo (P < .001). In general, alvimopan .5 mg once daily produced qualitatively similar but numerically smaller responses than twice-daily treatment. Active treatment did not increase the requirement for opioid medication or increase average pain intensity scores. Over the 12-week treatment period, alvimopan appeared to be well tolerated.. These results demonstrate the potential for a PAM-OR antagonist to improve the symptoms of OIC without antagonizing opioid analgesia.

Topics: Analgesics, Opioid; Constipation; Double-Blind Method; Humans; Intestines; Narcotic Antagonists; Pain; Piperidines; Placebos

The balance between the pain relief provided by opioid analgesics and the side effects caused by such agents is of particular significance to patients who take opioids for the long-term relief of non-cancer pain. The spectrum of signs and symptoms affecting the gastrointestinal (GI) tract associated with opioid use is known as opioid-induced bowel dysfunction. Alvimopan is an orally administered, systemically available, peripherally acting mu-opioid receptor (PAM-OR) antagonist, approved in the US for the management of postoperative ileus in patients undergoing bowel resection (short-term, in-hospital use only). Alvimopan was under clinical development for long-term treatment of opioid-induced constipation (OIC) but this program has been discontinued. This double-blind, placebo-controlled trial, part of the former OIC development program, enrolled patients (N = 485) receiving opioids for non-cancer pain. Patients were randomized to receive alvimopan .5 mg once daily, alvimopan .5 mg twice daily, or placebo, for 12 weeks. The primary efficacy endpoint was the proportion of patients who experienced ≥ 3 spontaneous bowel movements (SBMs; bowel movements with no laxative use in the previous 24 hours) per week over the treatment period, and an average increase from baseline of ≥ 1 SBM per week. There were greater proportions of SBM responders in both alvimopan treatment groups (63% in both groups) compared with placebo (56%), although these differences were not statistically significant. Secondary efficacy analyses indicated that alvimopan was numerically superior to placebo in improving opioid-induced bowel dysfunction symptoms and patients' global assessment of opioid-induced bowel dysfunction, and reduced the requirement for rescue laxatives. Active treatment was well tolerated and alvimopan did not antagonize opioid analgesia.. Although the primary endpoint was not met in this study, the magnitude of alvimopan-induced improvements versus baseline, together with previous study results, suggest that a PAM-OR antagonist has the potential to improve OIC.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Constipation; Double-Blind Method; Female; Humans; Intestines; Male; Middle Aged; Narcotic Antagonists; Pain; Piperidines; Placebos; Young Adult

In recent years, there has been an increased interest in using a multimodal approach with combined agents to treat postoperative nausea and vomiting. This study evaluated whether the addition of an oral dose of the neurokinin-1 receptor antagonist casopitant improved the antiemetic efficacy of an intravenous dose of ondansetron hydrochloride.. The authors enrolled 702 premenopausal or perimenopausal, nonsmoking, female patients aged 18-55 yr with a history of postoperative nausea and vomiting and/or motion sickness undergoing a laparoscopic or laparotomic gynecologic surgical procedure or laparoscopic cholecystectomy with general anesthesia. Subjects were randomized to one of five treatment arms: standard ondansetron 4 mg with casopitant at 0, 50, 100, or 150 mg, or 0 mg ondansetron with casopitant at 150 mg (the latter arm was considered an exploratory study group and was included in the safety analysis but not in the efficacy analysis).. A significantly greater proportion of patients in all of the active casopitant plus ondansetron groups achieved a complete response (i.e., no vomiting, retching, rescue medication, or premature withdrawal) during the first 24 h postoperatively versus those in the ondansetron-alone group (59-62% vs. 40%, respectively; P = 0.0006). All active doses seemed to be well tolerated; headache, dizziness, and constipation were the most frequently reported adverse events.. Compared with ondansetron alone, the casopitant and ondansetron combination results in superior emesis prevention during the first 24 h postoperatively in female patients with known risk factors for postoperative nausea and vomiting.

Topics: Administration, Oral; Adolescent; Adult; Anesthesia, General; Antiemetics; Cholecystectomy, Laparoscopic; Constipation; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Gynecologic Surgical Procedures; Headache; Humans; Middle Aged; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Postoperative Nausea and Vomiting; Risk Factors; Treatment Outcome; Young Adult

The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC).. Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) -based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.. A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.. All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.

Topics: Administration, Oral; Alopecia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Constipation; Cyclophosphamide; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Headache; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Neutropenia; Ondansetron; Piperazines; Piperidines; Treatment Outcome; Vomiting

Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or=25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or=30 mg oral morphine/day were randomized to alvimopan 0.5mg twice daily (BID), 1mg once daily (QD), 1mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

Topics: Adult; Analgesics, Opioid; Colic; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enteric Nervous System; Female; Gastrointestinal Motility; Humans; Intestines; Male; Middle Aged; Narcotic Antagonists; Pain; Piperidines; Placebos; Receptors, Opioid, mu; Risk Assessment; Treatment Outcome

Alvimopan has been shown to reverse the inhibitory effect of opioids on gastrointestinal transit without affecting analgesia. We evaluated oral alvimopan, 0.5 or 1 mg, versus placebo, once daily for 21 days, in 168 patients with opioid-induced bowel dysfunction (OBD) who were receiving chronic opioid therapy (minimum, 1 month) for nonmalignant pain (n = 148) or opioid dependence (n = 20). The primary outcome was the proportion of patients having at least one bowel movement (BM) within 8 hours of study drug on each day during the 21-day treatment period. Averaged over the 21-day treatment period, 54%, 43%, and 29% of patients had a BM within 8 hours after alvimopan 1 mg, 0.5 mg, or placebo, respectively (P < .001). Secondary outcomes of median times to first BM were 3, 7, and 21 hours after initial doses of 1 mg, 0.5 mg, and placebo, respectively (P < .001; 1 mg vs placebo). Weekly BMs and overall patient satisfaction were increased after the 1-mg dose (P < .001 at weeks 1 and 2 vs placebo, and P = .046, respectively). Treatment-emergent adverse events were primarily bowel-related, occurred during the first week of treatment, and were of mild to moderate severity. Alvimopan was generally well tolerated and did not antagonize opioid analgesia. Patients treated with chronic opioid therapy often experience opioid-induced bowel dysfunction as a result of undesirable effects on peripheral opioid receptors located in the gastrointestinal tract. Alvimopan, a novel peripheral opioid mu-receptor antagonist, has demonstrated significant efficacy for the management of opioid-induced bowel dysfunction without compromise of centrally mediated opioid-induced analgesia.

Topics: Administration, Oral; Analgesics, Opioid; Cathartics; Chronic Disease; Constipation; Female; Follow-Up Studies; Gastrointestinal Motility; Humans; Male; Middle Aged; Pain; Piperidines; Receptors, Opioid, mu; Treatment Outcome

Donepezil is an acetylcholinesterase inhibitor marketed for treatment of memory loss and behavioral deterioration associated with the acetylcholine deficit of Alzheimer's disease. We investigated the utility and tolerability of donepezil in nongeriatric affective illness for treatment of psychotropic-induced memory loss, dry mouth, and constipation.. Nondemented outpatients with stabilized DSM-IV affective illness took 5 mg/day of donepezil for 3 weeks and then increased to 10 mg/day in open trials. Self-rating scales of target symptoms were completed by patients before and 3 to 4 weeks after starting each dose condition. Patients who chose to continue donepezil therapy returned for clinical monitoring every 4 to 8 weeks.. Eleven women and 11 men (mean +/- SD age = 45.4+/-8.5 years) completed donepezil trials. Nineteen patients with memory loss rated improvement while taking 5 mg/day of donepezil (p<.001); subsequently, 6 rated further improvement with 10 mg/day (p = .057). Donepezil, 5 mg/day, also reduced ratings of dry mouth (N = 16; p<.001) and constipation (N = 11; p<.05). Side effects included insomnia, nausea, vomiting, and diarrhea; surprisingly, 2 bipolar patients became manic within hours of starting donepezil. Sixteen patients (72%) continued donepezil for an average of 7 months. Consideration of family histories suggested that donepezil response in affective illness may be an early indicator of vulnerability to dementia of the Alzheimer's type.. (1) Donepezil can reduce memory loss, dry mouth, and constipation in nongeriatric affective patients, but may trigger mania; and (2) long-term follow-up will reveal the predictive value for dementia of donepezil's memory restoration in nongeriatric subjects.

Topics: Adult; Ambulatory Care; Cholinesterase Inhibitors; Constipation; Depressive Disorder; Diarrhea; Dizziness; Donepezil; Drug Administration Schedule; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Piperidines; Psychotropic Drugs; Sleep Initiation and Maintenance Disorders; Xerostomia

Cisapride improves symptoms in patients with idiopathic constipation. This trial compares the effect of cisapride with that of placebo in patients with irritable bowel syndrome (IBS) and constipation.. Seventy patients were randomized to 12 weeks' treatment with 5 mg cisapride three times daily or placebo in a double-blind trial. The dose could be doubled after 4 weeks in patients without satisfactory improvement. The patients scored their symptoms on a 100-mm visual analogue scale (VAS) (0 = best, 100 = worst), and the investigators evaluated the symptomatic effect.. The dose was doubled in 17 and 23 patients in the cisapride and placebo groups, respectively, after 4 weeks. The patients' mean VAS score for global evaluation of IBS symptoms in the cisapride and placebo groups was 73 and 71 mm, respectively, at the start of treatment and 47 and 41 mm at the end. The difference between cisapride and placebo at the end was 6 mm in favour of placebo (95% confidence interval (CI), -6, 18) (NS). The investigators evaluated the effect as good or excellent in 39.2% and 58.8% in the cisapride and placebo groups, respectively. The difference in favour of placebo was 19.5% (95% CI, -5, 44) (NS). Nor were any statistically significant differences seen between cisapride and placebo in the other effect factors.. The trial seems to exclude a clinically significant effect of 15-30 mg cisapride daily in patients with IBS and constipation during a 12-week treatment period.

Topics: Adolescent; Adult; Aged; Cisapride; Colonic Diseases, Functional; Constipation; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Piperidines; Treatment Outcome

To study the effect of prokinetic treatment with cisapride in patients with constipation-predominant irritable bowel syndrome.. Ninety-six patients were randomly assigned to treatment with either cisapride 5 mg three times daily or placebo three times daily for a period of 12 weeks. The dosage could be doubled after 4 weeks. Presence of the target symptoms abdominal pain, constipation and abdominal bloating was an obligatory criterion for inclusion in the study.. After 12 weeks of treatment, 31%, 56% and 27% of the cisapride treated patients were found to be without the three target symptoms (P < 0.05). The corresponding percentages for the placebo-treated patients were 31%, 58% and 19%, respectively, (P < 0.05). The visual analogue scale (VAS) symptom scores assessed by the patients for global rating of bowel disease, general well-being and frequency of stool passage improved significantly within each treatment group (P < 0.05). Evaluation of efficacy parameters using intention-to-treat analysis showed no statistically significant differences between the groups. Using efficacy analysis, the difficulty of stool passage showed a significantly higher improvement with cisapride (P < or = 0.05).. These results indicate that cisapride is not superior to placebo in the treatment of constipation and abdominal discomfort as components of irritable bowel syndrome. It may, however, be of use in improving the difficulty of stool passage.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Cisapride; Colonic Diseases, Functional; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines

Chronic constipation is a common problem in children. We observed the effects of cisapride in the management of idiopathic constipation in children.. Thirty-seven children with a history of constipation (i.e., pain and difficulty or delay in defecation for > 3 months) were recruited and randomly assigned to 8 weeks of treatment with either cisapride, 0.2 mg/kg three times daily, or matching placebo after a 2-week run-in period in a double-blind, parallel-group study design. In phase 1 (2 weeks), patients had plain abdominal radiographs to assess degree of faecal load, and those with impaction were given laxatives. After satisfactory clearance of faeces, total gastrointestinal transit time and orocaecal transit time were measured. In phase 2, after 8 weeks of treatment with either cisapride or placebo (0.2 mg/kg t.d.s.), the transit studies were repeated.. Compared with placebo, cisapride did not improve either stool frequency or transit time in this study population.. This study did not demonstrate a clinical role for the use of cisapride in the treatment of idiopathic constipation in children.

Topics: Adolescent; Child; Child, Preschool; Cisapride; Constipation; Defecation; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Piperidines; Prospective Studies; Time Factors

Topics: Child; Cisapride; Constipation; Double-Blind Method; Gastrointestinal Agents; Humans; Piperidines

Cisapride has been reported to improve symptoms in patients with constipation-predominant irritable bowel syndrome.. To compare the effects of a 24-h oral dose regimen of cisapride on interdigestive and post-prandial small bowel motor activity in irritable bowel syndrome patients with predominant constipation, irritable bowel syndrome patients with predominant diarrhoea and healthy subjects.. In 12 irritable bowel syndrome patients (11 females, aged 44 +/- 12 years)--constipation-predominant (irritable bowel syndrome-C, n = 5) and diarrhoea-predominant (irritable bowel syndrome-D, n = 7)--and six healthy subjects, small bowel motor activity was continuously recorded using an ambulatory technique over a 48-h period. Subjects received, in single-blind fashion, placebo tablets q.d.s. in the first 24 h then cisapride 10 mg q.d.s. in the second 24 h. Additional control groups were 13 healthy subjects (eight females, aged 39 +/- 13 years) and 10 irritable bowel syndrome patients (10 females, aged 49 +/- 14 years) who were studied in identical fashion but who did not receive cisapride.. Cisapride increased migrating motor complex phase 2 motility index in both irritable bowel syndrome-D (P < 0.01) and irritable bowel syndrome-C (P < 0.05) patients, as well as in healthy subjects (P < 0.01). An increase in fasting discrete clustered contractions occurred in irritable bowel syndrome-D patients (P < 0.001) and in healthy subjects (P < 0.01), but not in irritable bowel syndrome-C patients; the proportion of discrete clustered contractions that were propagated, however, increased only in irritable bowel syndrome-D patients (P < 0.001). In addition, cisapride resulted in an increase in post-prandial motility index in irritable bowel syndrome patients (P < 0.05). Such motor alterations were not observed during the 48-h recording period in the healthy or irritable bowel syndrome patient control groups who did not receive cisapride.. Oral cisapride influences interdigestive and post-prandial small bowel motor activity in both irritable bowel syndrome patients and healthy subjects; the effects of cisapride may be more marked in patients with predominant diarrhoea than in patients with predominant constipation.

Topics: Adult; Cisapride; Colonic Diseases, Functional; Constipation; Diarrhea; Eating; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Intestine, Small; Male; Manometry; Middle Aged; Piperidines; Postprandial Period

Successful treatment of gastro-oesophageal reflux disease (GORD) has traditionally been assessed as healing of reflux oesophagitis, which may not be relevant in patients with moderate disease. In these patients symptom relief and patient satisfaction with therapy are of fundamental importance. Cisapride has well-documented prokinetic effects and may be well suited for long-term therapy of GORD, but its effectiveness in purely symptomatic treatment is unknown. We therefore compared two dosage regimens of cisapride with placebo over a period of 6 months in patients with evidence of gastrooesophageal reflux, initially treated with antisecretory medication, with regard to maintaining symptom relief and satisfaction with treatment.. Five hundred and thirty-five patients with reflux oesophagitis grade 1 (n = 293) or 2 (n = 124) or with no reflux oesophagitis but pathologic 24-h pH-metry (n = 118) achieved satisfactory symptom relief with an H2-receptor antagonist or proton pump inhibitor within 4-8 weeks. In a double-blind randomized, parallel-group study, they were then treated with cisapride, 20 mg at night or 20 mg twice daily, or placebo and followed up for a maximum period of 6 months. Relapse was defined as dissatisfaction with therapy or an average consumption of more than two antacid tablets a day.. Median time to relapse was 63 days for cisapride, 20 mg twice daily; 59 days for cisapride, 20 mg at night; and 49 days for placebo. Time to relapse was not significantly different (P = 0.09). Presence and grade of oesophagitis at base line, type of therapy before randomization, and pattern of non-reflux symptoms at base line did not influence these findings significantly.. The study indicates that cisapride is of limited value in maintenance therapy of GORD in patients in whom symptom relief has been accomplished with potent antisecretory medication. This 'step-down' approach to therapy seems disadvantageous in the long-term therapy of GORD.

Topics: Abdominal Pain; Cisapride; Constipation; Diarrhea; Drug Administration Schedule; Endoscopy; Esophagitis, Peptic; Female; Flatulence; Gastroesophageal Reflux; Gastrointestinal Agents; Heartburn; Humans; Male; Middle Aged; Piperidines; Recurrence; Remission Induction; Severity of Illness Index; Time Factors

The efficacy of cisapride as a treatment for chronic constipation in children with severe brain damage was studied in 20 children. Each subject was randomly assigned to double-blind treatment with either cisapride (N = 10) or placebo (N = 10) for 12 weeks. Stool habits, total gastrointestinal transit time, colonic segmental transit times, and anorectal motility were evaluated in all children before and at the end of the treatment period. Although cisapride significantly (P < 0.05) increased stool frequency from baseline to week 12 and no significant change was documented in the placebo group, the mean change in stool frequency per week from baseline to 12 week was not significantly different between the two treatment groups. The use of laxatives or suppositories was significantly (P < 0.05) decreased by cisapride, but remained unchanged in the placebo group. Furthermore, cisapride significantly (P < 0.05) reduced rectal compliance but had no effect on total gastrointestinal transit time and colonic segmental transit times. In summary, in neurologically impaired children with chronic constipation, cisapride increased bowel frequency but did not alter the delay in total and segmental gastrointestinal transit times.

Topics: Brain Damage, Chronic; Child; Child, Preschool; Chronic Disease; Cisapride; Constipation; Defecation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Infant; Male; Piperidines; Serotonin Receptor Agonists; Statistics, Nonparametric; Time Factors

Topics: Adult; Autonomic Agents; Child; Cisapride; Constipation; Humans; Piperidines; Serotonin Agents

To establish whether cisapride is beneficial in children with intractable constipation, an open trial was performed. Chronically constipated children who had failed at least 12 weeks of medical therapy received cisapride at a dose of 0.2 mg/kg/dose TID for 12 weeks. Children with pelvic floor dyssynergia were excluded. Patients were followed prospectively for at least 12 months. Thirty children were initially enrolled, and 27 (14 boys, 13 girls) completed the study. At the end of 12 weeks of cisapride treatment, there was a significant increase in the number of bowel movements per week (1.43 +/- 0.52 to 6.48 +/- 4.16; p < 0.05) and significant decreases in the number of accidents per day (2.86 +/- 2.71 to 0.52 +/- 1.23; p < 0.05) and doses of laxatives used per week (14.33 +/- 5.84 to 3.37 +/- 7.10; p < 0.05). Encopresis disappeared in 65.2% of cases (p < 0.0001) and improved in 26%. Sixty-nine percent of the patients stopped using laxatives (p < 0.001). After 12 weeks 18 patients (66.6%) were asymptomatic, seven (25.9%) showed some improvement in bowel movement frequency and number of accidents, and two (7.4%) showed no improvement. The cisapride was well tolerated. After long-term follow-up (20 +/- 9.8 months), 37% of patients had recovered (asymptomatic and off laxatives and cisapride) and 29.6% were still asymptomatic but were using laxatives or cisapride. There were no differences in baseline characteristics between recovered and nonrecovered patients. We conclude that cisapride is effective in the treatment of some children with intractable constipation without pelvic floor dyssynergia.

Topics: Anal Canal; Child; Child, Preschool; Cisapride; Constipation; Female; Humans; Male; Manometry; Piperidines; Rectum; Treatment Outcome

The pathophysiological consequences of spinal cord injury (SCI) on function of the colon are complex and poorly understood. Regardless of the mechanism, many patients with SCI have deficient bowel control, which is frustrating and difficult to treat. We designed a study to assess whether a new prokinetic medication, cisapride, might be useful in this setting.. Total and segmental colonic transit time were measured using the radiopaque marker technique in nine subjects with spinal cord injury and seven control subjects after the double-blind administration of cisapride (10 mg q.i.d.) or placebo.. In five quadriplegic subjects with prolonged colonic transit time, administration of cisapride was found to reduce left-sided colonic transit time from 24.2 to 13.8 h. In three of these five subjects, cisapride administration resulted in subjective improvement. No effect of cisapride on right-sided, rectosigmoid, or total colonic transit time was observed.. The data suggest that cisapride might be a useful adjunctive measure in treating a subset of SCI patients with colonic inertia, but a larger study is needed before this can be routinely recommended.

Topics: Adult; Aged; Cisapride; Colon; Constipation; Double-Blind Method; Gastrointestinal Transit; Humans; Male; Middle Aged; Piperidines; Spinal Cord Injuries; Sympathomimetics; Treatment Outcome

To investigate whether dose tapering and, potentially, withdrawal of cisapride is possible without loss of therapeutic effect.. A total of 119 patients with chronic constipation (less than three spontaneous, i.e., not laxative-induced, stools per week).. Randomized double-blind study.. Group A (n = 56) was treated with cisapride 20 mg twice daily for 12 weeks. Treatment was continued for a further 12 weeks during which the patients were allowed to take a maximum of four tablets containing 5 mg cisapride each (maximum daily dose, 20 mg). Group B (n = 63) was treated with cisapride 20 mg twice daily for 6 weeks and then with cisapride 10 mg for 6 weeks. Treatment was then stopped and follow-up was continued for a further 12 weeks.. Stool frequency was increased in both groups during active treatment and was not reduced when the dose was decreased from 20 mg to 10 mg twice daily in group B but was maintained in group A. Laxative intake fell by 50% in both groups, but this effect was maintained during follow-up in group A only. Group A patients took nearly the maximum dosage of cisapride tablets allowed during follow-up (3.3 tablets per day +/- 0.2 SEM).. This study confirmed the efficacy of cisapride in chronic idiopathic constipation. Dose tapering below 15-20 mg per day, however, does not appear to be possible.

Topics: Adult; Chronic Disease; Cisapride; Colon; Constipation; Defecation; Double-Blind Method; Humans; Piperidines

Disorders of autonomic regulation are common in patients with Parkinson's disease (PD). Patients most frequently complain of dysphagia and therapy resistant constipation, as far as the gastrointestinal tract is concerned. These symptoms have to be attributed to a neuronal degeneration. In a pilot study we therefore investigated the effect of stimulation of the myenteric plexus by cisapride. 11 women and 13 men were examined, the average age was 67.3 years, the Webster rating 17 points. In 2 out of 24 patients, colonic transit was prolonged up to the limit, both with and without therapy. The other 22 patients showed an acceleration in transit on response to cisapride. On average the colonic transit of 130 hours was reduced to 79 hours. This objective improvement was associated with a subjective improvement. Central side effects or a worsening of Parkinsonian symptoms were not found. We conclude that cisapride is effective in the treatment of constipation in idiopathic PD.

Topics: Aged; Aged, 80 and over; Cisapride; Colon; Constipation; Cross-Over Studies; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Myenteric Plexus; Parasympathomimetics; Parkinson Disease; Pilot Projects; Piperidines

The effects of prokinetic treatment with cisapride in patients with constipation-predominant irritable bowel syndrome (IBS) were evaluated in a randomized, double-blind, placebo-controlled study. Sixty-nine IBS patients were assigned to a 12-week treatment with either 5 mg cisapride or placebo t.i.d.; this dosage could be changed if necessary. The mean weekly number of days on which a stool was passed in the cisapride and placebo group increased to 5.3 and 4.4 (p less than 0.05) during weeks 8-12 of treatment, and the number of days with stools of normal consistency increased to 3.5 and 1.9 (p less than 0.05), respectively. At week 12, the reduction in severity and frequency scores for abdominal pain was significantly greater (p less than or equal to 0.05) in the cisapride group (60 and 61%) than in the placebo group (40 and 32%), as it was for abdominal distension (p less than 0.05). Cisapride tended to be better than placebo in diminishing flatulence. In 71% versus 39% of the patients the overall rating for the response to treatment was good or excellent at week 12. Cisapride was well tolerated. These results suggest that the drug will be useful for the management of constipation-predominant IBS.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Cisapride; Colonic Diseases, Functional; Constipation; Defecation; Double-Blind Method; Female; Flatulence; Gastrointestinal Motility; Humans; Male; Middle Aged; Piperidines

The efficacy of cisapride, a new prokinetic drug, as a treatment for chronic functional constipation of childhood was studied in 20 constipated children. Each subject had a stool frequency less than 4/week and/or total gastrointestinal transit time greater than 33 hr and was randomly assigned to double-blind treatment with either cisapride (N = 10) or placebo (N = 10) for 12 weeks. Stool habits, total gastrointestinal transit time, and anorectal motility were evaluated in all children before and at the end of the treatment period. Cisapride significantly increased stool frequency from 1.2 +/- 0.6 to 5.1 +/- 1.9 stools/week (mean +/- SD; P less than 0.05), whereas the lesser effect of placebo was not significant (1.2 +/- 0.8 to 2.8 +/- 0.8 stools/week; P = 0.4). Both treatments significantly (P less than 0.05) decreased laxative or suppository use. Total gastrointestinal transit time was decreased by cisapride (90.8 +/- 9.2 hr to 57.2 +/- 20.2 hr; P less than 0.05) but was not affected by placebo. Anorectal manometry showed that cisapride, but not placebo, significantly decreased the rectoanal inhibitory reflex threshold and the conscious rectal sensitivity threshold. It is concluded that cisapride improves gastrointestinal motility and bowel habits in children with chronic idiopathic constipation and may be useful in the management of some children with this disorder.

Topics: Child; Child, Preschool; Cisapride; Constipation; Double-Blind Method; Female; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Male; Piperidines; Placebos; Serotonin Antagonists

Topics: Cisapride; Clinical Trials as Topic; Constipation; Dyspepsia; Gastroesophageal Reflux; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Intestinal Pseudo-Obstruction; Piperidines; Serotonin Antagonists; Stomach Ulcer

Twelve patients with chronic constipation refractory to the vigorous use of emollients, enemas, and/or laxatives were chosen for study of the investigational prokinetic agent, Cisapride. The patients included 8 boys and 4 girls with diagnoses of functional constipation. Ages ranged from 2 to 13 years; duration of symptoms before Cisapride use ranged from 1.5 to 9.75 years; duration of previous treatment ranged from 0.75 to 6 years. The mean number of doses of anticonstipation agents employed per week was 14. Of the 12 patients, 10 had persistent encopresis, while 11 required hospitalization for disimpaction an average of 1.6 times in the year prior to Cisapride use. Three had chronic urinary tract complaints. Anal manometry suggested a sensory deficit in 8 of 10 patients tested. Ganglion cells were identified by rectal biopsy in all 12 patients. Cisapride treatment (0.14-0.3 mg/kg/dose) spanned 26-72 weeks (61 +/- 12). Stool frequency per week was not significantly changed, but five of seven patients who had reported hard stools had softer stools on the drug (p less than 0.05). Encopresis ceased in 8 of 10 cases, while the number of episodes decreased substantially in the other 2 cases (p less than 0.05). All alternate forms of anticonstipation therapy were withdrawn in 8 of 12 cases (p less than 0.001). Urinary problems improved in two of the three patients reporting symptoms. One patient showed no improvement in any parameter while on the agent, despite 26 weeks of administration. Side effects were infrequent, generally occurred early, and were limited to cramping, nausea, mild vomiting, anorexia, and headaches. One patient ceased use of the drug for persistent headaches.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Anal Canal; Child; Child, Preschool; Chronic Disease; Cisapride; Constipation; Encopresis; Female; Humans; Male; Manometry; Piperidines; Serotonin Antagonists

A double-blind cross-over trial of oral cisapride 10 mg before meals and placebo was performed to determine its effects on colonic transit in patients with severe idiopathic constipation. Nine patients with less than 3 spontaneous bowel movements/wk were studied. After passing a tube to the cecum, 50 muCi of 111In-DTPA were instilled into the cecum and followed for 48 h using colonic transit scintigraphy. In the group as a whole, cisapride had little effect on transit. The patients were then divided into two groups based on transit: functional rectosigmoid obstruction (FRSO) and colonic inertia (CI). In the CI group, cisapride accelerated the half emptying time of the cecum and ascending colon from 2.50 to 1.21 h (p less than 0.05). The progression of the geometric center was also faster after cisapride in CI. In FRSO, the geometric center was unchanged by cisapride except at 48 h. Cisapride thus has a prokinetic effect on colonic transit in patients with severe idiopathic constipation, colonic inertia subtype. It may be a useful agent in the treatment of this group of patients.

Topics: Adult; Cisapride; Clinical Trials as Topic; Colon; Constipation; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Piperidines; Radionuclide Imaging; Random Allocation; Serotonin Antagonists

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.

Topics: Cathartics; Chronic Disease; Cisapride; Clinical Trials as Topic; Constipation; Consumer Behavior; Defecation; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Random Allocation

Motor activity of the colon and reflex behaviour of the anal sphincters in normal subjects and in patients with idiopathic constipation were studied using a novel probe with 5 open-end tips to measure pressures, and 3 balloons for stimulation of the distal colon. Constipation appeared to be associated with an increased threshold of the inhibitory relaxation reflex of the internal anal sphincter (41.7 in normals and 65.7 in patients), and in particular with a blunted sensation of the defaecation urge (51.0 in normals and 112.8 in patients). Single-blind comparison with a placebo showed that cisapride, a new gastrointestinal prokinetic substance, had a significant effect on the sensation threshold, which normalized or improved in 15 out of the 16 patients studied.

Topics: Adult; Aged; Anal Canal; Cathartics; Cisapride; Colon; Constipation; Female; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Male; Middle Aged; Piperidines; Reflex; Sensation

Topics: Adult; Aged; Amides; Antidiarrheals; Chlorobenzenes; Clinical Trials as Topic; Codeine; Constipation; Drug Evaluation; Electrocardiography; Female; Gastrointestinal Agents; Humans; Isonipecotic Acids; Male; Middle Aged; Naloxone; Nitriles; Piperidines; Placebos; Reflex, Pupillary

To characterize the effects of blocking calcitonin gene-related peptide (CGRP) activity in a mouse model of gastrointestinal transport.. Migraine management using CGRP modulating therapies can cause constipation of varying frequency and severity. This variation might be due to the different mechanisms through which therapies block CGRP activity (e.g., blocking CGRP, or the CGRP receptor) with antibodies or receptor antagonists. The charcoal meal gastrointestinal transit assay was used to characterize constipation produced by these modes of therapy in transgenic mice expressing the human receptor activity-modifying protein 1 (hRAMP1) subunit of the CGRP receptor complex.. Male and female hRAMP1 mice were dosed with compound or vehicle and challenged with a charcoal meal suspension via oral gavage. The mice were then humanely euthanized and the proportion of the length of the large intestine that the charcoal meal had traveled indicated gastrointestinal transit.. Antibody to the CGRP receptor produced % distance traveled (mean ± standard deviation) of 31.8 ± 8.2 (4 mg/kg; p = 0.001) and 33.2 ± 6.0 (30 mg/kg; p < 0.001) compared to 49.7 ± 8.3 (control) in female mice (n = 6-8), and 35.6 ± 13.5 (30 mg/kg, p = 0.019) compared to 50.2 ± 14.0 (control) in male mice (n = 10). Telcagepant (5 mg/kg, n = 8) resulted in % travel of 30.6 ± 14.7 versus 41.2 ± 8.3 (vehicle; p = 0.013) in male mice. Atogepant (3 mg/kg, n = 9) resulted in % travel of 30.6 ± 12.0, versus 41.2 ± 3.7 (control; p = 0.030) in female mice. The CGRP antibody galcanezumab (n = 7-10; p = 0.958 and p = 0.929) did not have a statistically significant effect.. These results are consistent with reported clinical data. Selectively blocking the CGRP receptor may have a greater impact on gastrointestinal transit than attenuating the activity of the ligand CGRP. This differential effect may be related to physiologically opposing mechanisms between the CGRP and AMY1 receptors, as the CGRP ligand antibody could inhibit the effects of CGRP at both the CGRP and AMY1 receptors.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Charcoal; Constipation; Female; Humans; Intestine, Large; Ligands; Male; Mice; Mice, Transgenic; Piperidines; Pyridines; Pyrroles; Receptor Activity-Modifying Protein 1; Receptors, Calcitonin Gene-Related Peptide; Spiro Compounds

Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro

Topics: Acute Pain; Adenosine Monophosphate; Analgesia; Analgesics, Opioid; Animals; Computer Simulation; Constipation; Drug Design; Fentanyl; Fluorescence Resonance Energy Transfer; GTP-Binding Protein alpha Subunits; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Ligands; Models, Molecular; Pain Management; Piperidines; Protein Binding; Protein Conformation; Rats; Receptors, Opioid, mu; Respiratory Insufficiency; Transfection

Parkinson's disease is associated with early parasympathetic dysfunction leading to constipation and gastroparesis. It has been suggested that pathological α-synuclein aggregations originate in the gut and ascend to the brainstem via the vagus. Our understanding of the pathogenesis and time course of parasympathetic denervation in Parkinson's disease is limited and would benefit from a validated imaging technique to visualize the integrity of parasympathetic function. The positron emission tomography tracer 5-[(11)C]-methoxy-donepezil was recently validated for imaging acetylcholinesterase density in the brain and peripheral organs. Donepezil is a high-affinity ligand for acetylcholinesterase-the enzyme that catabolizes acetylcholine in cholinergic synapses. Acetylcholinesterase histology has been used for many years for visualizing cholinergic neurons. Using 5-[(11)C]-methoxy-donepezil positron emission tomography, we studied 12 patients with early-to-moderate Parkinson's disease (three female; age 64 ± 9 years) and 12 age-matched control subjects (three female; age 62 ± 8 years). We collected clinical information about motor severity, constipation, gastroparesis, and other parameters. Heart rate variability measurements and gastric emptying scintigraphies were performed in all subjects to obtain objective measures of parasympathetic function. We detected significantly decreased (11)C-donepezil binding in the small intestine (-35%; P = 0.003) and pancreas (-22%; P = 0.001) of the patients. No correlations were found between the (11)C-donepezil signal and disease duration, severity of constipation, gastric emptying time, and heart rate variability. In Parkinson's disease, the dorsal motor nucleus of the vagus undergoes severe degeneration and pathological α-synuclein aggregations are also seen in nerve fibres innervating the gastro-intestinal tract. In contrast, the enteric nervous system displays little or no loss of cholinergic neurons. Decreases in (11)C-donepezil binding may, therefore, represent a marker of parasympathetic denervation of internal organs, but further validation studies are needed.

Topics: Acetylcholinesterase; Adult; Aged; Antiparkinson Agents; Brain; Case-Control Studies; Cholinesterase Inhibitors; Constipation; Digestive System; Donepezil; Female; Heart Rate; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Positron-Emission Tomography; Surveys and Questionnaires; Time Factors

Despite constipation being a common problem, the treatments that are available have side effects and are only partly effective. Recent studies show that centrally penetrant ghrelin receptor agonists cause defecation in humans and other species. Here, we describe some features of a rat model of low fiber-induced constipation, and investigate the effectiveness of the ghrelin agonist, capromorelin.. Rats were given low-fiber diets for 5 weeks. Their colorectal responsiveness to distension and to a behavioral test, water avoidance and colon histology were compared to those of rats on a standard diet.. After the low-fiber diet, distension of the colon produced fewer propulsive contractions, behaviorally induced defecation was reduced, and the lining of the colorectum was inflamed. However, capromorelin was similarly effective in causing defecation in constipated and non-constipated rats.. Low-fiber diet in rats produces a constipation phenotype, characterized by reduced responsiveness of the colorectum to distension and to a behavioral stimulus of defecation, water avoidance. The effectiveness of capromorelin suggests that centrally penetrant ghrelin receptor stimulants may be effective in treating constipation.

Topics: Animals; Colon; Constipation; Defecation; Dietary Fiber; Gastrointestinal Motility; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Rectum

Off-label uses of the peripheral μ-opioid receptor antagonists alvimopan and methylnaltrexone are reviewed.. Alvimopan is approved by the Food and Drug Administration (FDA) for postoperative ileus after surgeries that include partial bowel resection with primary anastomosis, while methylnaltrexone is approved for the treatment of opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care. Literature describing the off-label use of alvimopan in the treatment of OIC and of methylnaltrexone in postoperative ileus was reviewed and included retrospective studies and prospective Phase II-IV trials. Randomized controlled trials did not demonstrate consistent benefit of alvimopan in OIC nor of methylnaltrexone in postoperative ileus. A greater proportion of patients receiving alvimopan for OIC experienced severe adverse cardiovascular events, leading to a risk evaluation and mitigation strategy and discontinuation of its study in this condition. Data are limited and unreplicated for the off-label use of alvimopan for postoperative ileus in patients undergoing abdominal hysterectomy. Individual studies suggest benefit with methylnaltrexone for OIC in unlabeled populations, including patients with non-cancer-related pain, opioid dependence, opioid sedation, and opioid use after orthopedic surgery; however, confirmatory evaluations have not been performed.. Trials of alvimopan in the FDA-approved use of methylnaltrexone (OIC) indicate potentially serious cardiovascular safety concerns and conflicting findings of efficacy. Similarly, trials of methylnaltrexone in the FDA-approved use of alvimopan (postoperative ileus) consistently showed no benefit. Evaluations of both drugs in their labeled conditions in populations not endorsed in their product labeling have been limited and largely unreplicated.

Topics: Analgesics, Opioid; Constipation; Gastrointestinal Agents; Humans; Ileus; Naltrexone; Narcotic Antagonists; Off-Label Use; Piperidines; Postoperative Complications; Quaternary Ammonium Compounds

Animal proof of principle study.. To determine whether capromorelin, a compound that causes defecation by stimulating ghrelin receptors within the lumbosacral defecation centers, is effective after spinal cord injury (SCI), and whether SCI significantly alters sensitivity to the compound.. University of Melbourne and Austin Hospital, Melbourne, Australia.. Rats were subjected to spinal cord contusion injury or were sham-operated. At 6 weeks after surgery, effects of capromorelin on blood pressure, heart rate and propulsive contractions of the colorectum were investigated.. Capromorelin caused robust propulsive activity in the colorectum soon after its application. The compound was similarly effective in naïve, sham-operated and spinal cord-injured rats. Blood pressure increases caused by capromorelin were not exaggerated after SCI, and there was no evidence of phasic blood pressure increases when the colon was contracted by the compound.. Capromorelin is a therapeutic compound that could potentially be used to relieve constipation by triggering defecation in spinal cord-injured patients.

Topics: Animals; Constipation; Defecation; Disease Models, Animal; Growth Hormone; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Spinal Cord Injuries

Dried fruits of Piper nigrum (black pepper) are commonly used in gastrointestinal disorders. The aim of this study was to rationalize the medicinal use of pepper and its principal alkaloid, piperine, in constipation and diarrhea using in vitro and in vivo assays. When tested in isolated guinea pig ileum, the crude extract of pepper (Pn.Cr) (1–10 mg/mL) and piperine (3–300 μM) caused a concentration-dependent and atropine-sensitive stimulant effect. In rabbit jejunum, Pn.Cr (0.01–3.0 mg/mL) and piperine (30–1,000 μM) relaxed spontaneous contractions, similar to loperamide and nifedipine. The relaxant effect of Pn.Cr and piperine was partially inhibited in the presence of naloxone (1 μM) similar to that of loperamide, suggesting the naloxone-sensitive effect in addition to the Ca(2+) channel blocking (CCB)-like activity, which was evident by its relaxant effect on K+ (80 mM)-induced contractions. The CCB activity was confirmed when pretreatment of the tissue with Pn.Cr (0.03–0.3 mg/mL) or piperine (10–100 μM) caused a rightward shift in the concentration–response curves of Ca(2+), similar to loperamide and nifedipine. In mice, Pn.Cr and piperine exhibited a partially atropine-sensitive laxative effect at lower doses, whereas at higher doses it caused antisecretory and antidiarrheal activities that were partially inhibited in mice pretreated with naloxone (1.5 mg/kg), similar to loperamide. This study illustrates the presence of spasmodic (cholinergic) and antispasmodic (opioid agonist and Ca(2+) antagonist) effects, thus providing the possible explanation for the medicinal use of pepper and piperine in gastrointestinal motility disorders.

Topics: Alkaloids; Animals; Antidiarrheals; Benzodioxoles; Calcium Channel Blockers; Cholinergic Agents; Constipation; Diarrhea; Dose-Response Relationship, Drug; Female; Gastrointestinal Diseases; Guinea Pigs; Ileum; Jejunum; Laxatives; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Naloxone; Phytotherapy; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rabbits; Receptors, Opioid

Topics: Cisapride; Constipation; Domperidone; Gastrointestinal Agents; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Indoles; Piperidines; Risk Assessment

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Constipation; Humans; Naltrexone; Narcotic Antagonists; Pain; Piperidines; Pyridines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Topics: Abdomen; Clinical Trials as Topic; Constipation; Digestive System Surgical Procedures; Humans; Ileus; Irritable Bowel Syndrome; Narcotic Antagonists; Piperidines; Postoperative Complications; Receptors, Opioid, mu

The underlying pathophysiology of idiopathic slow transit constipation (ISTC) remains unclear. At present, there is little evidence to implicate a smooth muscle myopathy in the aetiology of this condition. This study compared the effect of cisapride on the cholinergic response of colonic muscle strips from patients with this condition with that of control tissue.. Isometric tension production was recorded from circular smooth muscle strips taken from five patients undergoing colectomy for ISTC in response to cumulative concentrations of carbachol (100 nmol/1-100 mumol/l) alone and in the presence of cisapride 400 nmol/l. Similar dose-response activity was obtained for a control group consisting of six patients undergoing resection for colorectal carcinoma.. In the absence of cisapride, smooth muscle from patients with carcinoma exhibited a significantly lower sensitivity to cholinergic stimulation (agonist concentration required to produce half-maximal activation (EC50) 4.83 mumol/l) than that from patients with ISTC (EC50 1.63 mumol/l, P = 0.036), and also a greater maximal frequency of the oscillatory activity associated with the increase in isometric tension (0.070 versus 0.049 Hz, P = 0.035). Cisapride had no effect on the sensitivity to carbachol of the carcinoma tissue but brought about a significant reduction in the sensitivity of smooth muscle from patients with ISTC (EC50 3.24 mumol/l, P = 0.043).. These findings indicate that colonic smooth muscle from patients with ISTC is hypersensitive to cholinergic stimulation and suggest the existence of a smooth muscle myopathy in this condition.

Topics: Adolescent; Adult; Aged; Carbachol; Cisapride; Colorectal Neoplasms; Constipation; Female; Gastrointestinal Transit; Humans; Isometric Contraction; Middle Aged; Muscle, Smooth; Piperidines

In this study, we examined whether there is a long-term effect of cisapride on colonic transit in Parkinson's disease. Twenty-five patients (11 women, 14 men; average age, 64.4 years; moderate symptoms) were studied and treated initially with cisapride, 5 mg, twice a day, and after the first week with cisapride, 10 mg, twice a day. Colonic transit was measured by radioopaque markers at various stages: after 1 week, 6 months, and 1 year. In untreated patients, transit took 131 h; after 1 week with cisapride, it was accelerated to 81 h. After 6 months, colonic transit time amounted to 99 and 118 h, respectively, after 1 year. Cisapride seems to be highly effective initially. After 6 months, a significant but reduced effect was seen, and after 1 year, only a small effect could be demonstrated.

Topics: Aged; Cathartics; Cisapride; Constipation; Female; Humans; Male; Middle Aged; Parkinson Disease; Peristalsis; Piperidines; Severity of Illness Index; Treatment Outcome

Topics: Animals; Cat Diseases; Cats; Cisapride; Constipation; Female; Parasympathomimetics; Piperidines

We report the case of a 75 old man with chronic constipation due to traumatic spinal cord injury 25 years ago. Following prostatectomy the patient developed retention of urine and urinary incontinence, which improved significantly during a therapy with cisapride (3 x 10 mg/day). While the administration of cisapride is associated with increased detrusor activity and possibly urinary incontinence in neurologically normal persons, patients with urinary retention due to spinal cord injury may benefit from a therapy with this indirect parasympathomimetic agent.

Topics: Aged; Cisapride; Constipation; Humans; Male; Parasympathomimetics; Piperidines; Spinal Cord Injuries; Urinary Retention

We report a case of oesophageal disease as the first manifestation in a patient with CREST syndrome. A 46-year-old man with achalasia-like syndrome developed CREST syndrome 4 years later. A pneumatic dilatation of the cardia was performed. After pneumatic dilatation the dysphagia and regurgitation disappeared but the patient developed reflux oesophagitis. Four years after diagnosis of oesophageal disease he presented with a clinical picture of CREST syndrome. An acute ileus and constipation developed later. After receiving medical therapy with omeprazole and cisapride the patient is free of oesophageal symptoms and bowel movements are normal. Oesophageal disease is common in patients with limited and diffuse scleroderma, but to our knowledge achalasia-like syndrome has not been previously described as the first manifestation of the systemic disease.

Topics: Anti-Ulcer Agents; Cardia; Cisapride; Constipation; CREST Syndrome; Dilatation; Esophageal Achalasia; Esophagitis, Peptic; Humans; Intestinal Obstruction; Male; Middle Aged; Omeprazole; Piperidines

To evaluate the effect of cisapride on the total and segmental colonic transit times (CTT's) and on the clinical symptoms in patients with chronic idiopathic constipation, and to elucidate whether the correction of the CTT parallels the symptomatic improvement.. An open prospective trial of cisapride, 10 mg t.i.d. orally for 8 weeks, was done in 25 adult patients (M: F6: 19) with chronic idiopathic constipation of 1 year or longer duration. CTT was measured at baseline and after 8 weeks of cisapride therapy. Frequency, consistency and difficulty in passage of bowel movements were evaluated at baseline and after 2, 4 and 8 weeks of cisapride therapy.. 19 cases continued to participate until the end of 4 weeks of therapy and 15 cases completed the entire 8 weeks' trial. No serious side effect was experienced during the study period. Total and right segmental CTT's shortened with 8 weeks of cisapride treatment. Defecation frequency increased and difficulty in stool passage improved with 2 to 8 weeks of treatment. Stool consistency had a tendency toward normal after 8 weeks of treatment (p = 0.06). The global response was excellent in 7 cases (46.7%), good in 5 (33.3%) and poor in 3 (20.0%). If all dropped-out cases were assumed to be poor responders, the good or excellent responders after 8 weeks of cisapride might be 48.0% of all recruited patients. The response to cisapride could not be predicted by the various clinical parameters of the patients.. Cisapride is an effective drug in at least half of the patients with chronic idiopathic constipation.

Topics: Adult; Chronic Disease; Cisapride; Colon; Constipation; Female; Gastrointestinal Motility; Humans; Male; Middle Aged; Piperidines; Prospective Studies

Chronic constipation in patients with spinal cord injury (SCI) has significant impact on quality of life. To measure baseline clinical functioning, colonic transit time and anorectal manometry and the effect of cisapride on these clinical and physiological parameters, we studied 12 SCI patients. Patients initially received baseline clinical scoring, measurement of colonic transit time and anorectal manometry. Patients then received cisapride 20 mg orally three times each day. After one and three months of cisapride therapy, all measurements were repeated. The mean duration cisapride treatment was 5.2 months. Six of 12 (50 percent) reported that symptoms of constipation improved. No patient had worsening of symptoms. Prior to cisapride treatment, 23 percent of patients passed colonic transit markers by day five and 57 percent by day seven; baseline anal manometry revealed variable resting and squeeze pressures. After treatment, 33 percent of patients passed their colonic transit markers by day five and 71 percent by day seven. Six of 12 (50 percent) demonstrated a 10 percent or more increase in resting anal canal pressures. We conclude that about 50 percent of SCI patients have subjective improvement in constipation after cisapride therapy. Cisapride appears to improve both colonic and anorectal function.

Topics: Cisapride; Colostomy; Constipation; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Manometry; Paraplegia; Parasympathomimetics; Piperidines; Quadriplegia; Spinal Cord Injuries

Constipation, a frequent symptom in Parkinson's disease (PD), is probably caused by degeneration of the autonomic nervous system, particularly the myenteric plexus. Cisapride is a drug that causes increased release of acetylcholine in the myenteric plexus. In a pilot study, cisapride therapy was investigated in 20 PD patients, 10 women and 10 men, who suffered from delayed intestinal transit. In all cases, cisapride therapy was associated with a significant acceleration of colonic transit, as measured by radioopaque pellets viewed on radiographs. Pellet count fell from a mean of 53.8 pretreatment to 30.4 after cisapride treatment. No adverse reaction and no "overshoot affects," such as diarrhea, were seen. Our findings suggest that cisapride may alleviate the constipation associated with Parkinson's disease.

Topics: Acetylcholine; Aged; Autonomic Nervous System; Cisapride; Constipation; Female; Humans; Male; Middle Aged; Myenteric Plexus; Parkinson Disease; Pilot Projects; Piperidines; Serotonin Antagonists

This paper identifies the symptom profile associated with the four main diagnoses of functional digestive disorders (dyspepsia, gastro-oesophageal reflux disease (GORD), gastritis, and constipation) made by general practitioners in Belgium. Results are also presented from a multicentre study in which the effects of cisapride, administered as an oral tablet or suspension, were evaluated in patients with these functional digestive disorders. Analysis of symptom patterns revealed that early satiety and postprandial abdominal bloating were the most prominent symptoms, followed by eructation (belching), heartburn, regurgitation, postprandial epigastric burning or discomfort, and nausea. These symptoms occurred in all diagnostic groups. However, different symptom patterns were associated with each of the disorders; for example, heartburn and regurgitation were the core symptoms in patients diagnosed as having GORD, early satiety and abdominal bloating were characteristic of patients diagnosed with dyspepsia, and fasting or postprandial pain were characteristic of patients given the diagnosis of gastritis. Therefore, it appears that these diagnoses used by general practitioners in Belgium closely correspond to reflux-like, dysmotility-like and ulcer-like dyspepsia, as defined by an international working party. Cisapride improved the core symptoms in about 80% of patients with GORD or dyspepsia, relieved all epigastric symptoms in about 80% of patients with gastritis, and significantly decreased the use of laxatives and increased stool frequency in constipated patients. Cisapride was well tolerated and thus appears to be a useful option in the treatment of functional digestive disorders in a general practice setting.

Topics: Adult; Aged; Belgium; Cisapride; Cluster Analysis; Constipation; Dyspepsia; Family Practice; Female; Follow-Up Studies; Gastritis; Gastroesophageal Reflux; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Male; Middle Aged; Piperidines; Treatment Outcome

Topics: Cisapride; Constipation; Diarrhea; Domperidone; Dumping Syndrome; Gastric Emptying; Gastrointestinal Motility; Humans; Intestinal Diseases; Intestinal Pseudo-Obstruction; Intestine, Small; Metoclopramide; Motilin; Parasympathomimetics; Piperidines; Serotonin Antagonists; Stomach Diseases

A patient with progressive spinal stenosis, paraplegia, chronic pain syndrome and simultaneous severe chronic constipation is described. Treatment with cisapride 10 mg, 4 times daily improved her condition, and this was associated with improved small intestinal motility during a 12-hour examination using a computer aided system.

Topics: Cisapride; Constipation; Female; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Intestine, Small; Middle Aged; Neck; Piperidines; Spinal Stenosis; Time Factors; Vomiting

Topics: Cisapride; Colon; Constipation; Gastrointestinal Transit; Humans; Piperidines; Serotonin Antagonists

Topics: Adult; Aged; Cisapride; Constipation; Dyspepsia; Female; Humans; Intestinal Pseudo-Obstruction; Male; Middle Aged; Pilot Projects; Piperidines; Prospective Studies; Simethicone

Paraplegic patients have intractable constipation associated with prolonged colonic transit time. The agent Cisapride significantly reduced the colonic transit time from 7.7 days to 5.1 days. It also improved the intraluminal tone in the rectum, resulting in a significant reduction in maximal rectal capacity from 305.8 ml to 224.3 ml. There was a reduction in residual urine volume from 51.5 ml to 27.7 ml. The increased number of stools containing transit markers showed that intraluminal mixing was increased by cisapride. Faecal water remained unchanged. A side effect was retention of urine in one subject after sudden withdrawal of the drug but this was avoided by its gradual reduction over 2 days.

Topics: Administration, Oral; Adult; Anal Canal; Chronic Disease; Cisapride; Constipation; Female; Gastrointestinal Transit; Humans; Male; Middle Aged; Paraplegia; Piperidines; Rectum; Urination

Two patients with intractable constipation and an atonic bladder due to a partial spinal cord lesion and sacral nerve lesion are described. Treatment with cisapride (4 x 10 mg daily) was undertaken. After a few days the stool passed spontaneously. The effect was dose-dependent and has been maintained for at least 40 months. Normal bladder function was not achieved.

Topics: Adult; Chronic Disease; Cisapride; Constipation; Dose-Response Relationship, Drug; Gastrointestinal Transit; Humans; Lumbosacral Plexus; Male; Middle Aged; Piperidines; Spinal Cord Injuries; Urinary Bladder, Neurogenic

We describe the case of a paraplegic patient who suffered traumatic spinal cord injury at the level of the twelfth thoracic vertebra. Within a short period of time following the injury, urinary (neuropathic bladder) and gastrointestinal (atomic colon) sequelae arose. Treatment with Cisapride (R 51 619, Janssen Pharmaceutica) was undertaken in an attempt to increase colonic motility and to reduce urinary retention. These goals were reached rapidly with a dose of 10 mg q.i.d.; the effect has been maintained for at least 18 months since starting the therapy.

Topics: Bisacodyl; Cisapride; Constipation; Drug Administration Schedule; Drug Therapy, Combination; Humans; Male; Middle Aged; Piperidines; Spinal Cord Injuries; Urinary Bladder, Neurogenic

Topics: Adult; Constipation; Gastrointestinal Motility; Humans; Loperamide; Male; Piperidines

Topics: Constipation; Humans; Piperidines