piperidines and Diarrhea

A prior systematic review on the efficacy of halofuginone (HFG) treatment to prevent or treat cryptosporidiosis in bovine calves was inconclusive. We undertook an updated synthesis and meta-analyses on key outcomes for the treatment of calves with HFG. Evaluated outcomes were oocyst shedding, diarrhoea, mortality and weight gain. Experiments had to describe results for same age animals in contemporary arms. Most doses were 100-150 mcg kg-1 day-1. Results were subgrouped by study design, experiments with the lowest risk of bias and lack of industry funding. Eighteen articles were found that described 25 experiments. Most evidence came from randomized controlled trials in Europe. Significantly lower incidence of oocyst shedding, diarrhoea burden and mortality was reported when treatment started before calves were 5 days old. Most studies reported on outcomes for animals up to at least 28 days old. Publication bias was possible in all outcomes and seemed especially likely for diarrhoea outcomes. Beneficial results when HFG treatment was initiated in calves older than 5 days were also found. Prophylactic treatment to prevent cryptosporidiosis is effective in preventing multiple negative outcomes and is beneficial to calf health and will result in a reduction of environmental contamination by Cryptosporidium oocysts.

Topics: Animals; Cattle; Cattle Diseases; Coccidiostats; Cryptosporidiosis; Cryptosporidium parvum; Diarrhea; Feces; Oocysts; Piperidines; Quinazolinones; Weight Gain

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.. We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's. As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.. May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.. Lower levels of total T3 were strongly correlated with in-hospital mortality in patients with SCMP. A low T3 level might suggest poor prognosis in patients with SCMP.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Bacterial; Anxiety Disorders; Arecaceae; Arrhythmias, Cardiac; Autonomic Nervous System; Bacterial Proteins; Behavior Therapy; Burkholderia pseudomallei; Caco-2 Cells; Campylobacter; Campylobacter Infections; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Chickens; Computer Simulation; Coumarins; COVID-19; Cross-Sectional Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diabetes Mellitus, Type 1; Diarrhea; Dietary Supplements; Echocardiography; Educational Measurement; Electrocardiography, Ambulatory; Endoribonucleases; Exercise; Exercise Therapy; Faculty, Dental; Farms; Fear; Female; Flame Retardants; Florida; Gene Expression Regulation, Plant; Halogenated Diphenyl Ethers; Hearing Loss, Sudden; Heart Rate; HIV Infections; Hospital Mortality; Humans; Hypertension; Hypoglycemia; Immunity; In Situ Hybridization; Japan; Kinetics; Kuwait; Lung Neoplasms; Macaca mulatta; Macrophages; Male; Masked Hypertension; Melioidosis; Methyltransferases; Mice; Mice, Inbred BALB C; Middle Aged; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocardium; Oryza; Patient Education as Topic; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Piperidines; Plant Extracts; Plant Proteins; Platelet Count; Poultry Diseases; Prevalence; Protease Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Rabbits; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Resistance Training; Retrospective Studies; Risk Factors; SARS-CoV-2; Saudi Arabia; Severe acute respiratory syndrome-related coronavirus; Students; Substance-Related Disorders; Surveys and Questionnaires; Swine; Tachycardia, Ventricular; Takotsubo Cardiomyopathy; Thyroid Gland; Transcriptome; Transfection; Tropism; United Arab Emirates; Virulence; Virulence Factors; Writing

Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Animals; Arrhythmias, Cardiac; Arthralgia; Benzamides; Diarrhea; Hemorrhage; Humans; Hypertension; Infection Control; Infections; Male; Piperidines; Protein Kinase Inhibitors; Pyrazines

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

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Arthralgia; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diarrhea; Drug Eruptions; Drug Interactions; Exanthema; Fatigue; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Medication Adherence; Myalgia; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

Bruton's tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, heavily pre-treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Diarrhea; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Nausea; Piperidines; Protein-Tyrosine Kinases; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Sulfonamides

Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. As a class of medications, BCR inhibitors have some unique side effects including redistribution lymphocytosis. Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Age Factors; Atrial Fibrillation; Diarrhea; Hemorrhage; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Neoplasm Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Pneumonia; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell

Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib).

Topics: Adenine; Aged; Aspirin; Diarrhea; Hemorrhage; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines

The efficacy of combined vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibition in patients with advanced non-small-cell lung cancer (NSCLC) was well studied. However, few studies focused on the risk and adverse events (AEs) of combined targeted therapy. The aim of this meta-analysis was to evaluate the safety profile of combined targeted therapy against EFGR and VEGF in patients with advanced NSCLC. A comprehensive literature search in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts and ESMO Abstracts was conducted. Eligible studies were randomized clinical trials (RCTs) that compared safety profile of combined therapy inhibiting EFGR and VEGF pathways with control groups (placebo, single EGFR or VEGF inhibition therapy, chemotherapy or a combination of them) in patients with advanced NSCLC. The endpoints included treatment discontinuation, treatment-related deaths and AEs. The search identified 15 RCTs involving 6,919 patients. The outcomes showed that three of four pairwise comparisons detected more discontinuation due to AEs in combined targeted therapy, with odds ratio (OR) compared with the control groups ranged from 1.97 to 2.29. Treatment with combined inhibition therapy was associated with several all-grade and grade 3 or 4 AEs (e.g. rash, diarrhea and hypertension). Also, there was a significantly higher incidence of treatment-related deaths in combined inhibition using vandetanib versus single EGFR inhibition therapy (OR = 1.97, 95% CI 1.19-3.28). In conclusion, combined inhibition therapy against EGFR and VEGF in patients with advanced NSCLC was associated with increased toxicity. Increased AEs hinder patient compliance and reduce their quality of life, leading to dose reduction or discontinuation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarrhea; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Fatigue; Humans; Lung Neoplasms; Outcome Assessment, Health Care; Piperidines; Quinazolines; Randomized Controlled Trials as Topic; Signal Transduction; Vascular Endothelial Growth Factor A

New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival.. Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroid-stimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary.. So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Diarrhea; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

Alzheimer's disease is common, incurable and disabling. It is expected to grow dramatically in prevalence over the next 50 years. At current, the standard of care for patients with mild and moderately severe Alzheimer's disease includes the use of acetylcholinesterase inhibitors. Donepezil (Aricept) is a highly selective acetylcholinesterase inhibitors with a pharmacokinetic profile allowing once-daily dosing. There is an extensive knowledge base derived from published clinical trials of donepezil in Alzheimer's disease, revealing consistent efficacy in cognition, global clinical ratings and daily function. Donepezil is also associated with additional meaningful outcomes such as reduced risk for, or delay to, nursing home placement. Despite a sense of limited efficacy of this drug class among prescribers, number needed-to-treat analyses suggest donepezil is highly effective at reducing the long-term adverse outcomes associated with Alzheimer's disease.

Topics: Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Dementia; Diarrhea; Donepezil; Drug Interactions; Humans; Indans; Nausea; Piperidines; Treatment Outcome; Vomiting

To review preclinical and clinical information on flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), tested as an antitumor agent.. Primary and review articles were identified by MEDLINE search (1990-June 2001). Abstracts from recent meetings were also used as source materials.. Flavopiridol was reviewed with regard to its mechanisms, preclinical and clinical results, pharmacokinetics, and metabolism.. Flavopiridol is an inhibitor of several CDKs and displays unique anticancer properties. In addition to direct CDK inhibition, flavopiridol also exhibited other features such as inducing apoptosis in many cancer cell lines, decreasing cyclin D1 concentration, and inhibiting angiogenesis. Preclinical xenograft models showed significant antitumor activity for flavopiridol. The regimen using 72-hour continuous infusion every 2 weeks has been most extensively applied in clinical trials, with a 1-hour infusion currently being explored to achieve higher peak concentrations. Several Phase I and II trials have been reported, with some evidence of antitumor activity noted. Further Phase I and II trials using flavopiridol as a single agent and in combination with standard chemotherapeutic regimens and various tumor types are ongoing.. Flavopiridol is the first CDK inhibitor to enter clinical trials. Several Phase I and Phase II clinical trials with different regimens (72-h or 1-h infusion) have been completed. Initial clinical trials have been intriguing, but many questions remain: What is the best regimen (< or =72-h infusion)? Does optimal future development of this drug depend on the combination with other chemotherapy? What is the best combination of flavopiridol with other chemotherapy?

Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Cyclin-Dependent Kinases; Diarrhea; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fatigue; Flavonoids; Humans; Infusion Pumps; Kidney Neoplasms; Lymphoma, Non-Hodgkin; Neoplasms; Neutropenia; Piperidines

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of donepezil are reviewed. Donepezil is a synthetic noncovalent reversible inhibitor of acetylcholinesterase (AChE) for the treatment of mild to moderate dementia associated with Alzheimer's disease. In contrast to tacrine hydrochloride, the only comparable agent currently approved by FDA, donepezil exhibits a relatively high degree of selectivity for neuronal AChE as opposed to butyrylcholinesterase. It has a half-life of 60 hours in young adults and 104 hours in elderly patients. In clinical trials, donepezil has been associated with significant improvements in Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Interview-Based Impression of Change scores. The most common adverse effects associated with donepezil are nausea, diarrhea, anorexia, and vomiting, which are most likely to occur during dose initiation or adjustment. Hepatotoxicity, a dose-limiting adverse effect that sometimes requires discontinuation of tacrine, has not been reported with donepezil. Donepezil does not appear to interact with theophylline, cimetidine, warfarin, or digoxin. Ketoconazole and quinidine inhibit the metabolism of donepezil in vitro, but there is a lack of clinical data showing that these drugs decrease the clearance of donepezil. The initial recommended dosage is 5 mg daily before bedtime, with a dosage increase to 10 mg after four to six weeks according to the patient's response and tolerance. Donepezil appears to be preferable to tacrine as the initial agent for patients with mild to moderate dementia associated with Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Anorexia; Cholinesterase Inhibitors; Diarrhea; Donepezil; Drug Administration Schedule; Drug Interactions; Humans; Indans; Nausea; Piperidines

Loperamide is a safe and effective antidiarrheal for the treatment of acute diarrhea. Efficacy data suggest that loperamide is more effective than the prescription drug diphenoxylate and an over-the-counter bismuth subsalicylate preparation. Loperamide is a safe drug, with few adverse reactions reported worldwide. It also lacks significant abuse potential. Loperamide may prove to be the antidiarrheal agent of choice when compared with currently available nonprescription treatments for acute diarrhea.

Topics: Acute Disease; Clinical Trials as Topic; Diarrhea; Dose-Response Relationship, Drug; Humans; Loperamide; Nonprescription Drugs; Piperidines; Self Medication

Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses. In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery. It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.

Topics: Acute Disease; Animals; Chronic Disease; Clinical Trials as Topic; Diarrhea; Gastrointestinal Motility; Humans; Loperamide; Narcotics; Piperidines

Topics: Adult; Benzilates; Benzoates; Colonic Diseases, Functional; Cyclohexanecarboxylic Acids; Cyclohexanes; Diarrhea; Diethylamines; Female; Gastrointestinal Motility; Humans; Male; Middle Aged; Parasympatholytics; Phenethylamines; Piperidines; Scopolamine; Scopolamine Derivatives; Spasm; Syndrome

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

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Diarrhea; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Phosphorylation; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Treatment Outcome

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Atrial Fibrillation; Diarrhea; Drug Tolerance; Fatigue; Female; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Safety

This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Outcome Assessment, Health Care; Piperidines; Pyrazoles; Pyrimidines

This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.

Topics: Adenine; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Erythromycin; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Neutropenia; Piperidines; Polymorphism, Single Nucleotide; Pyrazoles; Pyrimidines; Voriconazole

Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.. In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073.. Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).. These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis.. AB Science (Paris, France).

Topics: Adult; Aged; Aged, 80 and over; Asthenia; Benzamides; Diarrhea; Double-Blind Method; Exanthema; Female; Humans; Male; Mastocytosis, Systemic; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyridines; Severity of Illness Index; Thiazoles; Treatment Outcome; Urticaria; Young Adult

Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.. Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients.. Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment.. Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data.. Pharmacyclics LLC, an AbbVie Company.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Diarrhea; Epistaxis; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Lymphoma, Mantle-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Rituximab; Treatment Outcome

Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.. We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.. The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.. Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Topics: Adenine; Aged; Antineoplastic Agents; Chlorambucil; Diarrhea; Disease-Free Survival; Fatigue; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Survival Analysis

In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.. In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.. At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.. Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cough; Diarrhea; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence; Survival Rate

The present study evaluated the efficacy of lafutidine, a histamine H2 receptor antagonist, for reducing gastrointestinal toxicities during adjuvant chemotherapy using oral fluorouracil anticancer drugs for gastric cancer.. Patients with stage II (T1 cases excluded) or stage III gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy achieving R0 resection from 2011 to 2013 were prospectively enrolled in the study. Patients were randomly assigned to either S-1 treatment or S-1 plus lafutidine treatment. Quality of life and gastrointestinal toxicity were evaluated before chemotherapy and at 2, 4, and 6 weeks after the beginning of treatment.. The incidence of diarrhea during chemotherapy was significantly lower in the S-1 plus lafutidine group than in the group treated with S-1 alone (10% vs. 83%, respectively; p=0.002). The grades of diarrhea and nausea during chemotherapy were also significantly lower compared to those before chemotherapy in patients receiving S-1 plus lafutidine than in those administered S-1 alone. The rate of patients requiring a dose reduction or interruption of S-1 was significantly lower in the S-1 plus lafutidine group than in the group treated with S-1 alone (30% vs. 83%, respectively; p=0.027).. Lafutidine might be useful not only for preventing gastrointestinal toxicities during adjuvant chemotherapy for gastric cancer, but also for improving compliance with taking oral fluorouracil anticancer drugs. However, this indication needs to be confirmed in a larger, prospective, randomized, controlled trial.

Topics: Acetamides; Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Diarrhea; Drug Combinations; Female; Fluorouracil; Gastrectomy; Gastrointestinal Tract; Histamine H2 Antagonists; Humans; Lymph Node Excision; Male; Middle Aged; Nausea; Oxonic Acid; Piperidines; Prospective Studies; Pyridines; Quality of Life; Stomach Neoplasms; Tegafur

BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514.. In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD.. In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways.. This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Diarrhea; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Exanthema; Female; Humans; Lung Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Neoplasm Metastasis; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Receptor, ErbB-2; Treatment Outcome; Triazines; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-3

This randomized, phase II study investigated whether benefit could be obtained by giving vandetanib, an oral inhibitor of vascular endothelial and epithelial growth factor receptor, as a maintenance treatment in non-small cell lung cancer (NSCLC).. Patients were randomly assigned to either vandetanib or placebo after completion of 4 cycles of first-line chemotherapy. A progression-free survival (PFS) rate at 3 months was selected as the primary endpoint. We set a maximum PFS rate at 3 months to 30% (null hypothesis), and a minimum PFS rate at 3 months to 50% (alternative hypothesis).. At the interim analysis, 9 of 24 patients in the vandetanib arm were progression-free at 3 months, whereas 7 of 24 in the placebo arm were progression-free. The placebo arm was closed at the first stage. The vandetanib arm proceeded to the second stage, and recruited a total of 75 patients. At the second stage, 28 out of 63 evaluable patients receiving vandetanib achieved PFS at 3 months. The alternative hypothesis that the PFS rate at 3 months is at least 50% was accepted. The median PFS was 2.7 months (95% CI, 1.9-4.4 months) in the vandetanib arm and 1.7 months (95% CI, 0.9-2.6 months) in the placebo arm. The most common adverse events in patients receiving vandetanib were rash (77.3%) and diarrhea (60.0%).. Maintenance therapy with vandetanib for patients with NSCLC after standard platinum doublet chemotherapy is well tolerated and may prolong PFS compared with placebo, and needs additional investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Diarrhea; Disease-Free Survival; Exanthema; Female; Humans; Lung Neoplasms; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Piperidines; Platinum Compounds; Quinazolines; Vascular Endothelial Growth Factor A

Vandetanib is a tyrosine kinase inhibitor of both the vascular endothelial growth factor (VEGFR) and epidermal growth factor (EGFR) receptors. The primary objectives of this study were to determine the maximum tolerated dose of vandetanib with capecitabine and oxaliplatin, without and with bevacizumab, for the first line treatment of metastatic colorectal cancer (mCRC), and to define the dose limiting toxicities.. Three cohorts of patients were studied, with capecitabine at 1,000 mg/m(2) twice daily p.o. on days 1-14 of a 3 week cycle, with oxaliplatin i.v. at 130 mg/m(2) on day 1. Vandetanib dosing was 100 mg/day in cohort 1 and 300 mg/day in cohorts 2 and 3. Bevacizumab was added in cohort 3 at 7.5 mg/kg i.v. on day 1 every 3 weeks.. Thirteen patients were enrolled and received from one to eight cycles per patient. Grade 4 dermatitis developed in one patient in the first cohort, and the cohort was expanded to six patients with no further dose limiting toxicities (DLT). The second cohort of 3 patients was well tolerated. The third cohort resulted in grade 3 diarrhea, requiring several days of hospitalization and i.v. hydration, in 3 of the 4 patients. Given the severity and duration of diarrhea, each of these was considered a DLT, and therefore cohort 3 was considered to be above the maximum tolerated dose. Six of the 13 patients achieved a partial or complete remission (46%). The time to progression ranged from 2 to 14 months.. Vandetanib at doses of 100 mg and 300 mg daily in combination with capecitabine and oxaliplatin was well tolerated. However, the addition of bevacizumab resulted in severe diarrhea in three out of four patients. Bevacizumab was not well tolerated with vandetanib and XELOX in combination.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Diarrhea; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Metastasis; Oxaloacetates; Piperidines; Protein Kinase Inhibitors; Quinazolines; Vascular Endothelial Growth Factor Receptor-2

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095.. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group).. Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted.. AstraZeneca.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Papillary; Diarrhea; Disease-Free Survival; Double-Blind Method; Electrocardiography; ErbB Receptors; Female; Heart Conduction System; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Survival Analysis; Thyroid Cancer, Papillary; Thyroid Neoplasms; Young Adult

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Topics: Adolescent; Carotid Arteries; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Farnesyltranstransferase; Fatigue; Female; Humans; Male; Piperidines; Progeria; Pulse Wave Analysis; Pyridines; Treatment Outcome; Vomiting; Weight Gain

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.

Topics: Aged; Analysis of Variance; Cholinesterase Inhibitors; Cognition; Cross-Over Studies; Diarrhea; Donepezil; Double-Blind Method; Electroencephalography; Female; Hippocampus; Humans; Indans; Magnetic Resonance Imaging; Male; Memory; Middle Aged; Nausea; Piperidines; Vomiting

Following a 48-week, double-blind, randomized, placebo-controlled trial of donepezil in 821 patients with amnestic mild cognitive impairment (aMCI), safety and tolerability of donepezil (10 mg) were further evaluated in a 28-week extension study. Of 499 participants who completed the double-blind phase, 145 enrolled in the open-label study. Adverse events (AEs) were recorded throughout. Overall, 57.4% of participants in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE, with the most frequent treatment-emergent AEs being diarrhea, muscle spasms, insomnia, and nausea. Most were mild to moderate in severity and were more common in the first several weeks after treatment initiation. More participants in the placebo/donepezil group (22.1%) discontinued donepezil due to an AE compared with the donepezil/donepezil group (10.3%). These findings support the safety of donepezil in patients with aMCI. When compared with other studies, however, the data suggest that patients with Alzheimer's tolerate donepezil better than patients with MCI.

Topics: Adult; Aged; Aged, 80 and over; Amnesia; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Middle Aged; Nausea; Neuropsychological Tests; Piperidines; Psychiatric Status Rating Scales; Severity of Illness Index; Sleep Initiation and Maintenance Disorders; Spasm; Time Factors; Treatment Outcome

The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated.

Topics: Adolescent; Behavior; Caregivers; Child; Cholinesterase Inhibitors; Cognition Disorders; Diarrhea; Donepezil; Dose-Response Relationship, Drug; Double-Blind Method; Down Syndrome; Drug Tolerance; Female; Humans; Indans; Learning; Male; Neuropsychological Tests; Piperidines; Severity of Illness Index; Vomiting

Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients.. The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/day, plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively.. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered.. The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Piperazines; Piperidines; Pyridines; Pyrimidines; Treatment Failure; Treatment Outcome; Vomiting

Flavopiridol is a cyclin-dependent kinase inhibitor that prevents cell cycle progression and tumor growth. In initial phase I studies, encouraging responses were seen in advanced renal cell cancer (RCC). In a phase II study of flavopiridol given as a 72-h continuous infusion every 2 weeks in RCC, a response rate of 6% was seen but with considerable grade 3 or 4 asthenia, diarrhea, and thrombosis. Subsequently, an alternative 1-h bolus schedule was reported to have enhanced tolerability in a phase I trial. We therefore conducted a phase II study of this bolus regimen.. A total of 38 patients with advanced RCC were entered into this multi-institutional phase II study. Flavopiridol (50 mg/m(2) per day) was administered by bolus intravenous injection daily for three consecutive days, repeated every 3 weeks.. Out of 34 eligible patients, one complete response and three partial responses were observed, for an overall response rate of 12% (95% CI 3-27%). Of the 34 patients, 14 (41%) had stable disease (SD). The probability of not failing treatment by 6 months was 21% (95% CI 9-35%). Median overall survival time was 9 months (95% CI 8-18 months). The most common grade 3 or 4 toxicities were diarrhea (35%) and tumor pain (12%) along with anemia, dyspnea, and fatigue (9% each).. Flavopiridol at this dose and schedule is feasible with an acceptable toxicity profile. Flavopiridol has some modest biologic activity against advanced RCC, as evidenced by its single-agent objective response and SD rates.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Diarrhea; Drug Administration Schedule; Female; Flavonoids; Humans; Injections, Intravenous; Kidney Neoplasms; Male; Middle Aged; Pain; Piperidines; Survival Analysis; Treatment Outcome

To determine the efficacy and safety of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase with additional activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously treated metastatic breast cancer.. Eligible patients had histologically confirmed metastatic breast cancer and had received prior treatment with an anthracycline and taxane; measurable disease was required. Patients were enrolled sequentially into one of two dose cohorts, 100 or 300 mg orally once daily; 28 days defined one cycle. The primary end point was objective response rate; pharmacokinetics and serial pharmacodynamic studies were obtained.. Forty-six patients were enrolled between May 2002 and April 2003, and 44 were evaluable for response. Diarrhea was the most commonly reported toxicity and seemed dose related (grade >/=2: 4.5% and 37.5% in the 100 and 300 mg cohorts, respectively). Rash was reported by 26% of patients but was never worse than grade 2. Seven patients in the 300 mg cohort had asymptomatic grade 1 prolongation of the QTc interval. Hypertension requiring treatment was not reported. There were no objective responses; one patient in the 300 mg cohort had stable disease >/=24 weeks. All patients in the 300 mg cohort and 90% of patients in the 100 mg cohort achieved steady-state concentrations exceeding the IC(50) for VEGF inhibition in preclinical models.. ZD6474 monotherapy was generally well tolerated but had limited monotherapy activity in patients with refractory metastatic breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Bridged-Ring Compounds; Diarrhea; Dose-Response Relationship, Drug; ErbB Receptors; Female; Humans; Middle Aged; Nausea; Neoplasm Metastasis; Piperidines; Quinazolines; Taxoids; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC).. Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin.. Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1.. Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Cell Line, Tumor; Cisplatin; Cohort Studies; Diarrhea; Dose-Response Relationship, Drug; Female; Flavonoids; Humans; Immunoblotting; Leukocytes, Mononuclear; Male; Middle Aged; Nausea; Neoplasms; Piperidines; Proto-Oncogene Proteins c-bcl-2; STAT3 Transcription Factor; Treatment Outcome; Tumor Suppressor Protein p53

To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors.. Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3.. Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 micromol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2).. The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Child, Preschool; Diarrhea; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Neoplasms; Neutropenia; Piperidines

To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system.. Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles.. 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received >/=90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity.. Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.

Topics: Adult; Aged; Anorexia; Antineoplastic Agents; Cyclin-Dependent Kinases; Diarrhea; Fatigue; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Neoplasm Metastasis; Piperidines; Treatment Outcome; Vomiting

At present, there is no proven pharmacologic treatment for cognitive or language impairments in Down syndrome (DS). Cholinergic deficits have been documented in DS and linked to cognitive deficits. This study is a 24-week open-label clinical trial of donepezil hydrochloride for the treatment of language deficits in adults with DS. To our knowledge, this is the first prospective study to evaluate systematically the effects of donepezil, a cholinesterase inhibitor, on specific language domains in DS. The main finding that emerged was an improvement in expressive language performance following donepezil therapy. Despite the multiple methodological limitations, the results raise important questions regarding the role of the cholinergic system in language function and the specific effect of cholinergic therapy in the treatment of language impairment in DS. The results support the need for large-scale controlled studies of the effects of donepezil treatment on language and on other cognitive domains in DS.

Topics: Adult; Appetite; Cholinesterase Inhibitors; Diarrhea; Donepezil; Dose-Response Relationship, Drug; Down Syndrome; Female; Follow-Up Studies; Humans; Hypotension; Indans; Language Disorders; Language Tests; Male; Muscle Cramp; Nausea; Piperidines; Treatment Outcome

In a 5-year survey regarding its prevalence and importance in five German state veterinary laboratories Cryptosporidium was diagnosed annually in 19-36% of faecal samples either submitted to the laboratories or taken post mortem. In approximately half of the cases no other enteropathogens were detected. However, only 73% of 30 laboratories participating in a questionnaire survey routinely tested for this parasite, and the majority of researchers considered cryptosporidiosis to be of minor importance. In a placebo-controlled field study 152 suckling calves were treated daily against cryptosporidiosis either with sulfadimidine or with halofuginone (Halocur, Intervet) over 1 week. Treatment by oral drench started at the onset of diarrhoea in the herd. Oocyst excretion, faecal consistency and health status were recorded five times for a 3-week period. Oocyst excretion peaked 7-14 days in the placebo group after the onset of diarrhoea, and during that period prevalence and intensity of excretion were significantly lower in the halofuginone-treated group compared to the sulfadimidine and the placebo control groups. The health status (diarrhoea, dehydration) declined in all groups but was significantly (P<0.05-0.001) better in the halofuginone group in the first 2 weeks. Halofuginone effectively (P<0.05-0.001) reduced oocyst excretion and improved the health status of the treated animals, while sulfadimidine had no effect against Cryptosporidium.

Topics: Animals; Anti-Infective Agents; Cattle; Cattle Diseases; Coccidiostats; Cryptosporidiosis; Cryptosporidium; Dairying; Diarrhea; Feces; Female; Germany; Oocysts; Piperidines; Prevalence; Quinazolines; Quinazolinones; Sulfamethazine; Surveys and Questionnaires

To determine the response rate and toxicity of flavopiridol in patients with previously untreated or relapsed mantle-cell lymphoma.. Adult patients with previously untreated or in first or second relapse of previously responsive mantle-cell lymphoma were given flavopiridol 50 mg/m2/d by intravenous bolus for 3 consecutive days every 21 days with antidiarrheal prophylaxis. Flavopiridol was continued until disease progression, unacceptable toxicity, or stable disease for four cycles. Disease was reassessed every two cycles.. From 33 registered patients, 30 were eligible after pathology review, 30 were assessable for toxicity, and 28 were assessable for response. A median of four cycles of treatment was administered; 90% of patients received at least 90% of planned dose-intensity. No complete responses were seen; three patients had a partial response (11%), 20 patients had stable disease (71%), and five patients had progressive disease (18%). The median duration of response was 3.3 months (range, 2.8 to 13.2 months). The most common toxicities were diarrhea (97%), fatigue (73%), nausea (47%), and vomiting (27%). At least one nonhematologic grade 3 or 4 toxicity was seen in 14 patients (47%). Hematologic toxicity was modest.. Flavopiridol given as a daily bolus for 3 consecutive days every 3 weeks has modest activity as a single agent for mantle-cell lymphoma. The number of stable and partial responses that was seen indicates that it is biologically active and may delay progression. Future studies in mantle-cell lymphoma should test this agent with other active agents and using different schedules.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diarrhea; Disease Progression; Fatigue; Female; Flavonoids; Humans; Injections, Intravenous; Lymphoma, Mantle-Cell; Male; Middle Aged; Nausea; Piperidines; Treatment Outcome; Vomiting

Clinical observations suggest that patients with vascular dementia (VaD) may benefit from treatment with cholinesterase inhibitors. This study evaluated the efficacy and safety of donepezil for relieving symptoms of dementia in VaD.. Patients (n=603; mean age, 73.9 years; 55.2% men) with probable (70.5%) or possible (29.5%) VaD, according to criteria of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), were randomized to 24 weeks of treatment with donepezil 5 mg/d (n=198), donepezil 10 mg/d (5 mg/d for first 28 days; n=206), or placebo (n=199). Analyses were based on the intent-to-treat population.. At week 24, both donepezil groups showed significant improvement in cognition versus placebo on the Alzheimer's Disease Assessment Scale-cognitive subscale (mean change from baseline score effect size: donepezil 5 mg/d, -1.90; P=0.001; donepezil 10 mg/d, -2.33; P<0.001). Significant improvements in patients' global function were seen versus placebo at week 24 (observed cases), on the Clinician's Interview-Based Impression of Change-Plus version only for patients on donepezil 5 mg/d (P=0.014), and on the Sum of the Boxes of the Clinical Dementia Rating only for patients on 10 mg/d (P=0.007). Donepezil-treated patients showed significant benefits in activities of daily living over placebo on the Alzheimer's Disease Functional Assessment and Change Scale (mean change from baseline score effect size at week 24: donepezil 5 mg/d, -1.31, P=0.02; donepezil 10 mg/d, -1.31, P=0.02). Donepezil was well tolerated. Withdrawal rates due to adverse events were relatively low (placebo, 11.1%; donepezil 5 mg/d, 11.1%; donepezil 10 mg/d, 21.8%; P=0.005 versus placebo).. These data demonstrate that donepezil is an effective and well-tolerated treatment for VaD and show it may have an important place in the management of this condition.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Cardiovascular System; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Diarrhea; Donepezil; Double-Blind Method; Female; Headache; Humans; Indans; Internationality; Male; Middle Aged; Nausea; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Treatment Outcome

Flavopiridol, a novel flavone derivative, inhibits cyclin-dependent kinase-1. We initiated a Phase I trial in patients with refractory solid tumors to determine the maximum tolerated dose and characterize the adverse effect profile.. To characterize the clinical pharmacology of flavopiridol.. Serial plasma samples were collected and analyzed by HPLC using electrochemical detection. The pharmacokinetics were analyzed by noncompartmental analysis. Enterohepatic recirculation was studied by analyzing fecal samples, with an attempt to correlate cholecystokinin and post-infusional peak concentrations. The plasma protein binding was studied using equilibrium dialysis.. Seventy-six patients were treated with flavopiridol at 13 dose levels for a total of 504 cycles of treatment. The average steady-state concentration was 26.5 and 253 nM at 4 and 122.5 mg/m2, respectively. The clearance ranged from 49.9 to 2943 mL/min, with nonlinearity at doses >50 mg/m2/d. A post-infusional increase in plasma flavopiridol concentrations was noted in a subset of patients and generally occurred between 3 and 24 hours after the end of infusion. Flavopiridol was found in fecal matter, suggesting enterohepatic recirculation. There was nonsaturable plasma protein binding of flavopiridol (fu = 6%).. The dose-limiting toxicity for the Phase I trial of flavopiridol was secretory diarrhea. We failed to identify a clear relationship between dose or concentration and diarrhea. At 50 and 78 mg/m2/d, the mean steady-state plasma concentrations were 278 and 390 nM. These concentrations were well above those noted for in vitro antiproliferative activity. Nonlinear elimination was observed at doses above 50 mg/m2/d, and postinfusional peaks appear to be related to enterohepatic recirculation.

Topics: Adult; Aged; Diarrhea; Feces; Female; Flavonoids; Food; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pharmacology, Clinical; Piperidines; Protein Binding; Time Factors

Flavopiridol is the first cyclin-dependent kinase (cdk) inhibitor to enter clinical trials. Serum levels of flavopiridol obtained during phase I studies were sufficient to inhibit in vitro cancer cell growth. Because responses were observed in kidney cancer patients in the phase I trials, we performed a phase II trial of flavopiridol in this patient population.. Thirty-five minimally pretreated patients were accrued using a standard two-step mechanism. Flavopiridol (50 mg/m(2)/d) was administered by continuous infusion for 72 hours every 2 weeks, and response was evaluated every 8 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, at completion of drug infusion, and on day 7 of the first therapy cycle, and cell cycle parameters after phytohemagglutinin and interleukin-2 stimulation were assessed.. There were two objective responses (response rate = 6%, 95% confidence interval, 1% to 20%). The most common toxicities were asthenia, occurring in 83% of patients (grade 3 or 4 in 9%), and diarrhea, occurring in 77% of patients (grade 3 or 4 in 20%). Also, nine patients (26%) experienced grade 3 or 4 vascular thrombotic events, including one myocardial infarction, two transient neurologic ischemic attacks, four deep venous thrombosis, and two pulmonary emboli. Cell cycle studies did not reveal any effect of flavopiridol on stimulated PBMCs.. Flavopiridol, at the dose and schedule administered in this trial, is ineffective in metastatic renal cancer. In addition to the diarrhea observed in phase I studies, we also observed a higher incidence of asthenia and serious vascular thrombotic events than expected.

Topics: Adult; Aged; Antineoplastic Agents; Asthenia; Bone Neoplasms; Carcinoma, Renal Cell; Diarrhea; Drug Administration Schedule; Female; Flavonoids; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Thrombosis; 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

Pre-clinical studies indicate that the 5-hydroxytryptamine (5-HT)4 receptor may be involved in the pathophysiology of irritable bowel syndrome and that antagonism of this receptor may be an effective therapeutic strategy.. To investigate the effects of SB-207266-A, a selective 5-HT4 receptor antagonist on rectal sensitivity and small bowel transit in patients with irritable bowel syndrome.. Eighteen patients with diarrhoea-predominant irritable bowel syndrome and a history of increased rectal sensitivity were randomized to receive either SB-207266-A (20 mg) or placebo for 10 days. Following a washout period, patients were then crossed over to receive the alternative therapy for 10 days. Rectal sensitivity and orocaecal transit time were assessed on day 10 of each treatment period. In addition, patients were asked whether they had experienced any changes in their symptoms.. Fifteen patients completed the study. SB-207266-A significantly increased orocaecal transit time towards normal (placebo: 5.3 h (4.0-7.2 h), mean (IQR) vs. SB-207266-A: 6.5 h (4.8-8.0 h); P=0.027) and tended to decrease rectal sensitivity (volume to discomfort 89 mL (60-150 mL), geometric mean (IQR) vs. 107 mL (75-150 mL); P=0.134). Eleven out of 15 patients reported symptomatic improvements with SB-207266-A but none with placebo. SB-207266-A was well tolerated.. Our results support a role for the 5-HT4 receptor in the pathophysiology of irritable bowel syndrome and suggest that the selective 5-HT4 antagonist, SB-207266-A, is worthy of further evaluation in this disorder.

Topics: Adult; Aged; Catheterization; Colonic Diseases, Functional; Cross-Over Studies; Diarrhea; Double-Blind Method; Female; Gastrointestinal Transit; Humans; Indoles; Intestine, Small; Male; Manometry; Middle Aged; Piperidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Rectum; Serotonin Antagonists

We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks.. Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling.. Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred.. The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cyclin-Dependent Kinases; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Flavonoids; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; 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

A controlled multi-centre clinical trial was conducted for evaluating the efficacy and safety of cisapride in the treatment of 414 cases of functional dyspepsia with 169 cases as control. Cisapride were given 5mg three times daily for 4 weeks. The results showed that cisapride could significantly improve the symptoms including early satiety, abdominal distention, epigastric pain and nausea. Total efficacy rate of cisapride and placebo were 92.99% and 41.42% respectively. There were statistically significant difference between the two groups. Side-effects are abdominal pain and diarrhoea but most of the patients can endure. The above results indicated that the cisapride was safe and effective in treatment of functional dyspepsia.

Topics: Abdominal Pain; Adolescent; Adult; Aged; Cisapride; Diarrhea; Dyspepsia; Female; Humans; Male; Middle Aged; Piperidines

Topics: Diarrhea; Drug Combinations; Drug Therapy, Combination; Electrolytes; Glucose; Humans; Loperamide; Male; Piperidines; Randomized Controlled Trials as Topic

Loperamide is a safe and effective antidiarrheal for the treatment of acute diarrhea. Efficacy data suggest that loperamide is more effective than the prescription drug diphenoxylate and an over-the-counter bismuth subsalicylate preparation. Loperamide is a safe drug, with few adverse reactions reported worldwide. It also lacks significant abuse potential. Loperamide may prove to be the antidiarrheal agent of choice when compared with currently available nonprescription treatments for acute diarrhea.

Topics: Acute Disease; Clinical Trials as Topic; Diarrhea; Dose-Response Relationship, Drug; Humans; Loperamide; Nonprescription Drugs; Piperidines; Self Medication

An open-label, parallel comparison of loperamide hydrochloride (Imodium A-D) and bismuth subsalicylate (Pepto-Bismol) was conducted using nonprescription dosages in adult students with acute diarrhea (three or more unformed stools in the preceding 24 hours plus at least one additional symptom of enteric infection). For the two-day study period, the daily dosage was limited to 8 mg (40 ml) for loperamide-treated subjects and to 4.9 g for bismuth subsalicylate-treated subjects. At these dosages, loperamide significantly reduced the average number of unformed bowel movements relative to bismuth subsalicylate. Following the initial dose of treatment, control of diarrhea was maintained significantly longer with loperamide than with bismuth subsalicylate. Time to last unformed stool was significantly shorter with loperamide than with bismuth subsalicylate. In providing overall subjective relief, subjects rated loperamide significantly better than bismuth subsalicylate at the end of the 24 hours. Both treatments were well tolerated, and none of the minor adverse effects reported resulted in discontinuation of therapy. It was concluded that loperamide is effective at a daily dosage limit of 8 mg (40 ml) for the treatment of acute nonspecific diarrhea and provides faster, more effective relief than bismuth subsalicylate.

Topics: Acute Disease; Adult; Bismuth; Clinical Trials as Topic; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Loperamide; Male; Nonprescription Drugs; Organometallic Compounds; Piperidines; Salicylates

The efficacy of nonprescription doses of loperamide hydrochloride (Imodium A-D) was compared with nonfibrous activated attapulgite (Diasorb) in a randomized, parallel, open-label study of adult patients with acute diarrhea. The results of the study showed loperamide to be more effective than attapulgite in the control of diarrhea. Loperamide significantly reduced stool frequency compared with attapulgite, particularly within the first 12-hour period following the start of therapy, and significantly shortened the mean time to last unformed stool (loperamide, 14.2 hours, versus attapulgite, 19.5 hours). Subjective evaluations of severity of enteric symptoms, overall relief following treatment, and overall relief after 48 hours of treatment were equivalent for both drugs. Both treatments were well tolerated, and there was no difference between treatments with respect to the proportion of patients reporting adverse experiences.

Topics: Acute Disease; Adult; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Loperamide; Magnesium; Magnesium Compounds; Male; Nonprescription Drugs; Piperidines; Randomized Controlled Trials as Topic; Silicon; Silicon Compounds

1. Imodium (loperamide) produced by Chemical Works of Gedeon Richter, Budapest, is a useful preparation for the symptomatic treatment of both acute and chronic diarrhoea of various etiologies. 2. In chronic diarrhoea cases the best results were obtained in the treatment of functional disorders of the guts. 3. Side effects occurred only in few patients and with low intensity, the treatment had to be interrupted in none of the cases.

Topics: Acute Disease; Chronic Disease; Clinical Trials as Topic; Diarrhea; Humans; Loperamide; Piperidines

In a randomized, double-blind, placebo-controlled trial, 227 US adults with acute diarrhea in Mexico received a single dose of sulfamethoxazole and trimethoprim (1600/320 mg) or 3 days of therapy with loperamide hydrochloride (4-mg loading dose, then 2 mg orally after each loose stool), sulfamethoxazole-trimethoprim (800/160 mg orally twice daily), or the combination of both. Subjects treated with the combination had the shortest average duration of diarrhea compared with the placebo group (1 hour vs 59 hours), took the least amount of loperamide after the loading dose (3.8 mg), and had the shortest duration of diarrhea associated with fecal leukocytes or blood-tinged stools (4.5 hours). A single dose of sulfamethoxazole-trimethoprim was also efficacious (28 vs 59 hours), but loperamide alone was significantly effective only when treatment failures were treated with antibiotics (33 vs 58 hours). The combination of sulfamethoxazole-trimethoprim plus loperamide can be highly recommended for the treatment of most patients with traveler's diarrhea.

Topics: Adult; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Fluid Therapy; Humans; Loperamide; Mexico; Piperidines; Prospective Studies; Randomized Controlled Trials as Topic; Travel; Trimethoprim, Sulfamethoxazole Drug Combination; United States

To determine if loperamide is effective and safe in treating watery diarrhoea, we randomly assigned 50 adult expatriates in Bangladesh with more than three unformed stools in the previous 24 hours and illness of less than 72 hours to receive loperamide or a placebo. On entry into the five day study patients took two capsules (one loperamide capsule = 2 mg) and one after each unformed stool up to a maximum of eight per day. The groups did not significantly differ in pretreatment features or pathogens identified. Mean number of stools on study day 1 was 2.6 in the loperamide group and 4.0 in the placebo group (p = 0.035); on day 2 it was 1.3 versus 3.4 (p less than 0.001). Differences in stool frequencies during the final three study days, or proportion of patients with cramps, nausea, or vomiting on any study day, were not significant. No serious side effects occurred in either group. We conclude that loperamide, by decreasing stool frequency during the early part of illness, may have a role in the symptomatic treatment of this self-limiting disease.

Topics: Acute Disease; Adult; Aged; Bangladesh; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Europe; Female; Humans; Loperamide; Male; Middle Aged; North America; Piperidines; Random Allocation; Travel

Twenty-five patients with chronic diarrhoea were included in an open, randomized crossover trial comparing the effect of loperamide with ispaghula and calcium. Nineteen patients completed both treatments. Before treatment the median number of daily stools was 7 (range, 4-13), stool consistency was loose in all, and urgency was present in 16 out of 19 patients. Both treatments halved stool frequency, but with regard to urgency and stool consistency ispaghula and calcium was significantly better. A combination of ispaghula and calcium seems to be a cheap and effective alternative to conventional treatment of chronic diarrhoea. Moreover, side effects were minimized.

Topics: Adult; Aged; Calcium; Chronic Disease; Clinical Trials as Topic; Diarrhea; Drug Combinations; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Psyllium; Random Allocation

Fifty-three young children with acute diarrhoea were included in a hospital-based, double-blind trial of loperamide at two dose levels (0.4 and 0.8 mg/kg/day), given with standard oral rehydration therapy versus placebo plus oral rehydration therapy. The differences in the overall recovery rate were significant (P less than 0.05), the fastest being in the group given 0.8 mg/kg and slowest in the placebo group. Comparison between weights on admission and weights by day 3 showed that more children in the loperamide groups gained weight than in the placebo group (P less than 0.05). No serious side effects of loperamide were observed. The drug was withdrawn in one child because of excessive lethargy and sleep. The results indicate that loperamide in the doses employed is safe and may be a useful adjunct to oral rehydration in certain children.

Topics: Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Fluid Therapy; Humans; Infant; Loperamide; Piperidines; Saudi Arabia

The effects of loperamide in patients with IBS (all had diarrhoea as a main symptom) were studied in a double-blind placebo controlled trial. Subjective overall response stool consistency and six individual symptoms (urgency, pain, frequency, flatulence, borborygmi and painful propulsions) were studied over a 13 week long treatment period. Twenty-one patients out of 25 completed the trial, 11 in the loperamide group and 10 in the placebo group. A significant advantage for loperamide was found for stool consistency (p less than 0.001), pain (p less than 0.02) and urgency (p less than 0.05). Subjective overall response was also significantly better in the loperamide group (p less than 0.03). Self-titration of dose and administration in a single nightly dose was safe and efficient.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Colonic Diseases, Functional; Diarrhea; Double-Blind Method; Female; Humans; Loperamide; Male; Middle Aged; Patient Compliance; Piperidines; Random Allocation

One hundred and twelve patients with acute infectious diarrhoea were entered in a double-blind randomised study in order to compare loperamide with a placebo. Of 82 evaluable patients, 38 received loperamide and 44 placebo for a maximum of 5 days. There were no significant differences in the number of loose stools during the first day of treatment, in the total number of tablets taken or in the total duration of the period of diarrhoea between the two treatment groups. The loperamide-treated patients had significantly fewer loose stools during the observation period of 5 days than did the placebo treated patients, median five vs. seven, a difference of little clinical importance. Excretion of bacterial pathogens was followed weekly in 13 of the loperamide treated patients (median 35.5 days) and in 18 of the placebo treated patients (median 22.5 days). This difference in the duration of excretion was not significant.

Topics: Acute Disease; Adolescent; Adult; Aged; Bacterial Infections; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Time Factors

Topics: Antidiarrheals; Clinical Trials as Topic; Diarrhea; Duodenitis; Gastroenteritis; Humans; Loperamide; Peptic Ulcer; Piperidines

The efficacy of 1-(2,6-dimethylphenyl)-3-methyl-amidinourea hydrochloride (lidamidine HCl, WHR-1142 A) an aryl-substituted amidinourea recently synthesized, was compared with that of loperamide in 32 patients with acute diarrhoea. The results of the study show that lidamidine HCl and loperamide had comparable effects in the pharmacological treatment of acute non-specific diarrhoea. Lidamidine HCl was also shown to be well tolerated; side-effects were generally minor and self-limiting.

Topics: Acute Disease; Antidiarrheals; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Female; Humans; Loperamide; Male; Phenylurea Compounds; Piperidines; Random Allocation

Effects of opiates on intestinal motor activity and transport of water and electrolytes have been studied separately in previous investigations. The aim of these experiments was to evaluate simultaneously the effects of a synthetic opiate, loperamide, on motor activity and transport in the human intestine. Jejunal, ileal, and colonic perfusions were performed in 9 healthy volunteers. After application of loperamide (12 mg), cyclically recurring migrating motor complexes in the small intestine occurred at a significantly higher frequency than after application of placebo. This was primarily due to a decrease in the duration of irregular motor activity (phase II). Loperamide increased the transit time in the jejunum but not in the ileum or in the colon. Transport rates of water and electrolytes and transmural electrical potential differences were not significantly affected by the drug. These results suggest that opiates exert their constipating effect by inhibiting phase II-related irregular motor activity.

Topics: Adult; Biological Transport; Colon; Diarrhea; Gastrointestinal Motility; Humans; Ileum; Intestinal Absorption; Jejunum; Loperamide; Male; Manometry; Piperidines; Stimulation, Chemical; Water-Electrolyte Balance

Loperamide hydrochloride was compared with bismuth subsalicylate for the treatment of acute nondysenteric travelers' diarrhea in 219 students visiting seven countries in Latin America. Subjects whose condition was not improved with therapy could elect to take trimethoprim-sulfamethoxazole. Persons receiving loperamide passed fewer unformed stools when compared with the bismuth subsalicylate group during the first four hours of therapy, from four to 24 hours, and from 24 to 48 hours after therapy was initiated. Among subjects with disease due to enterotoxigenic Escherichia coli, Shigella sp, other pathogens, and unknown agents, fewer unformed stools were passed by the loperamide-treated subjects than the bismuth subsalicylate-treated subjects for all time periods studied. No significant prolongation of disease was seen in subjects with shigellosis treated with loperamide. Eight of the loperamide-treated subjects experienced constipation compared with one in the bismuth subsalicylate-treated group; otherwise, there was no difference in minor side effects experienced between both treatment groups. We conclude that loperamide is a safe and effective alternative to bismuth subsalicylate for the treatment of nondysenteric travelers' diarrhea.

Topics: Acute Disease; Adult; Antidiarrheals; Bismuth; Diarrhea; Humans; Latin America; Loperamide; Organometallic Compounds; Piperidines; Salicylates; Travel; United States

Infants aged 4 to 36 months with acute diarrhoea (rotavirus 66%) were treated as outpatients with oral fluids and a rapid return to full feedings. In addition, the infants were randomized to receive for 3 days either cholestyramine 2 g twice daily (N = 10), an equivalent placebo 2 g twice daily (N = 15), or loperamide 0.10 mg/kg divided in three doses (N = 16). The duration of watery diarrhoea from the beginning of treatment was 0.9 +/- 1.0 days in the cholestyramine group, 2.5 +/- 1.3 days in the loperamide group, and 3.3 +/- 1.6 days in the placebo group (p less than 0.001 cholestyramine vs. placebo, p less than 0.005 cholestyramine vs. loperamide). The infants receiving cholestyramine also had a better weight gain than those receiving the placebo, and their metabolic acidosis was corrected sooner. There was no hyperchloraemia associated with the cholestyramine treatment. It is concluded that cholestyramine 2 g twice daily for 3 days can be safely used to shorten the course of acute diarrhoea. The use of loperamide in acute infantile diarrhoea does not appear justified.

Topics: Acute Disease; Ambulatory Care; Child, Preschool; Cholestyramine Resin; Clinical Trials as Topic; Diarrhea; Diarrhea, Infantile; Fluid Therapy; Humans; Infant; Loperamide; Piperidines; Water-Electrolyte Balance

Symptom scores, stool data, and the transit of a standard, solid meal were measured in 28 patients with irritable bowel syndrome (IBS) during baseline conditions and after five weeks of treatment with placebo and loperamide, given as a flexible dosage regime in the form of a double-blind, cross-over trial. All patients had undergone a comprehensive series of diagnostic investigations and had failed to respond to dietary supplementation with coarse wheat bran (10-30 g daily). Loperamide treatment accelerated gastric emptying, compared with placebo (1.2 +/- 0.1 vs 1.5 +/- 0.1 hr; P less than 0.001) and delayed both small bowel (6.2 +/- 0.3 vs 4.3 +/- 0.3 hr; P less than 0.001) and whole gut transit (56 +/- 5 vs 42 +/- 4 hr; P less than 0.01). Eighteen patients said they felt better taking loperamide compared with placebo and, at follow up, 15 of these patients remained satisfied with the effects of the drug. Most symptoms improved significantly on placebo compared with the baseline period, but three of these [diarrhea (P less than 0.01), urgency (P less than 0.01) and borborygmi (P less than 0.05)] showed a further significant improvement on loperamide. Improvement in diarrhea was not associated with any change in stool weight but was associated with reductions in stool frequency (P less than 0.001), passage of unformed stools (P less than 0.01), and incidence of urgency (P less than 0.001). Urgency was the only symptom that was significantly more common in the success group, compared with the group who did not feel better on loperamide.

Topics: Adult; Clinical Trials as Topic; Colonic Diseases, Functional; Consumer Behavior; Diarrhea; Double-Blind Method; Female; Follow-Up Studies; Food; Gastric Emptying; Humans; Intestine, Small; Intestines; Loperamide; Male; Middle Aged; Piperidines; Placebos; Time Factors

The results from the clinical study on the preparation Imodium, production of the Hungarian firm "Gedeon Richter"--Budapest, are reported. The drug was tried on 53 patients with chronic and acute diarrheal syndrome chronic or acute enterocolitis, ulcerous colitis-- ChUHC, dyskinesia coli, biliary-colic fistula, Crohn's disease, gastric carcinoma with diarrheal syndrome, postresectional syndrome and some other diseases) with a very good result. The feces of the greater part of the patients normalized their consistence after the treatment of half to 10 days with a dose 6-8 mg daily, and their defecations were reduced to 1-2 for 24 h. In II patients an initial constipation occurred that was eliminated with the discontinuation of the preparation. Very good effect was attained in 37 and good in 16 patients. Furthermore, the preparation was very well tolerated and no adverse effects were observed. The good and rapid effect of Imodium developed in the majority of the patients observed, in 21 of the patients (42%) its effect was realized in half to two days, and in 19 of the patients (35%)--to 5 days, and in the rest 23%--from 6 to 10 days.

Topics: Adult; Aged; Antidiarrheals; Capsules; Clinical Trials as Topic; Defecation; Diarrhea; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Solutions; Time Factors

A total of 315 young children with acute diarrhoea were included in a double blind, hospital based multicentre trial of loperamide at two dose levels (0.8 mg and 0.4 mg/kg/24 h), given with standard oral rehydration therapy versus placebo plus oral rehydration therapy. The overall recovery rate was slowest in the placebo group and fastest in the group given loperamide 0.8 mg. Comparisons between weights on admission and weights by day 3 showed that a larger proportion of children in the loperamide groups gained weight than in the placebo group. No serious side effects of loperamide were observed, but the drug was withdrawn in one infant because of mild abdominal distention. The results indicate that loperamide, in the doses employed, is safe and may in selected cases be a useful adjunct to oral rehydration in the management of acute diarrhoea in well nourished children.

Topics: Acute Disease; Body Weight; Child, Preschool; Clinical Trials as Topic; Combined Modality Therapy; Diarrhea; Double-Blind Method; Feces; Fluid Therapy; Humans; Infant; Loperamide; Piperidines; Time Factors

Seventy adults in the United States with acute diarrhea who were attending classes in Guadalajara, Mexico, enrolled in a double-blind placebo-controlled treatment study of an anticholinergic drug, mepenzolate bromide (MZB). Thirty-five patients received MZB (50 mg) and 35 received placebo each taken 4 times daily for 48 hours. No significant difference was detected between the MZB- and placebo-treated patients in symptoms or in the frequency or character of stools. Recovery rates of 24.1% and 31% for placebo- and MZB-treated patients were similar. Despite the occurrence of anticholinergic side effects in 51% of MZB- versus 14% of placebo-treated patients (P less than 0.001), therapeutic efficacy was not detected. We do not recommend anticholinergic drugs for therapy in acute infectious diarrhea.

Topics: Acute Disease; Adolescent; Adult; Benzilates; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Female; Humans; Male; Middle Aged; Parasympatholytics; Piperidines; Travel

The effect of loperamide and diphenoxylate on diarrhoea following jejuno-ileostomy for morbid obesity was investigated in 27 patients by means of a randomized fixed sample size, three-period cross-over trial. Both loperamide and diphenoxylate had significant effect on the diarrhoeas when compared with no treatment, but no significant difference was found between the two drugs. Loperamide is an acceptable alternative in the treatment of diarrhoea following jejuno-ileostomy.

Topics: Adult; Clinical Trials as Topic; Diarrhea; Diphenoxylate; Female; Humans; Ileum; Isonipecotic Acids; Jejunum; Loperamide; Male; Obesity; Piperidines; Postoperative Complications; Random Allocation

Loperamide hydrochloride (4 mg t.d.s.) was compared with codeine phosphate (60 mg t.d.s.) in a double blind crossover study of patients with loose output from their ileostomies. Both drugs significantly decreased the daily output and water content of ileostomy fluid. Daily losses of sodium and potassium were less when the patients were treated with loperamide. Loperamide was also associated with less side effects. It is concluded that loperamide hydrochloride was more effective in the treatment of ileostomy diarrhoea than codeine phosphate. In this group of patients those with the highest outputs from their ileostomies benefited most from this treatment.

Topics: Adult; Aged; Body Weight; Clinical Trials as Topic; Codeine; Diarrhea; Double-Blind Method; Electrolytes; Female; Humans; Ileostomy; Loperamide; Male; Middle Aged; Nausea; Piperidines; Postoperative Complications; Potassium; Sodium

We have investigated the effect of loperamide (4 mg tds) on the continence to a standard volume of rectally infused saline and anorectal manometry in 26 patients complaining of chronic diarrhea complicated by fecal incontinence and severe urgency. Each patient was treated for one week with loperamide (4 mg tds) and for one week with an identical placebo in a double-blind cross-over trial. Our results showed that as well as its established effects of improving stool consistency and reducing stool weight, frequency and episodes of incontinence and severe urgency, loperamide also significantly improved continence to a standard volume of rectally infused saline. This action was associated with an increase in the maximum basal sphincter pressure, an increase in the rectal volume required to abolish recovery of the rectoanal inhibitory reflex, and a reduction in rectal compliance. These results suggest that loperamide may have a specific action on the anal sphincter, which may aid continence in patients who complain of diarrhea and fecal incontinence.

Topics: Adult; Aged; Anal Canal; Diarrhea; Fecal Incontinence; Female; Humans; Loperamide; Male; Manometry; Middle Aged; Piperidines; Rectum

A double-blind cross-over study of the antidiarrhoeal effects of loperamide and diphenoxylate in 29 patients with chronic diarrhoea due to intestinal resection is presented. Most of these subjects had had surgery for Crohn's disease which was in a stable and nonactive phase during the study. Loperamide and diphenoxylate were presented as identical capsules. Each was administered for a minimum duration of 25 days. The number of capsules required to control diarrhoea was significantly smaller in the loperamide group than in the diphenoxylate group. Loperamide was also statistically superior to diphenoxylate at reducing the number of stools and improving the faecal consistency. Nineteen of the 29 patients considered loperamide to be the most effective antidiarrhoeal drug, five preferred diphenoxylate and five did not notice any difference.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Crohn Disease; Diarrhea; Diphenoxylate; Double-Blind Method; Female; Humans; Intestines; Isonipecotic Acids; Loperamide; Male; Middle Aged; Piperidines; Postoperative Complications; Random Allocation

The effects of oral loperamide, in doses of 2-6 mg per day, on the stool consistency, daily number of bowel movements and general inconvenience was investigated in seven children and juveniles suffering from incontinence and abnormal bowel habits due to congenital abnormalities. The study was conducted as a double-blind, cross-over analysis. According to the data collected loperamide essentially improves the quality of life of these patients.

Topics: Adolescent; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Fecal Incontinence; Female; Humans; Loperamide; Male; Piperidines; Postoperative Complications

Topics: Chronic Disease; Clinical Trials as Topic; Codeine; Diarrhea; Diphenoxylate; Double-Blind Method; Humans; Isonipecotic Acids; Loperamide; Piperidines

As no adequate comparison of these widely used drugs has been made, we have performed a double-blind cross-over trial in 30 individuals with chronic diarrhea. Each underwent three randomized treatment periods of 4 wk duration. Patients were instructed to increase the daily dose gradually until control was achieved or side effects became intolerable. Stool frequency, consistency, urgency, and incontinence were then compared when a stable dose was reached. Though 2.3 capsules (4.6 mg) of loperamide, 2.3 capsules (103.5 mg) of codeine and 2.5 capsulses (12.5 mg) of diphenoxylate all reduced stool frequency to the same extent, diphenoxylate was significantly less effective in producing a solid stool. Before treatment 95% of patients experienced urgency, sometimes associated with fecal incontinence, often as their major diability. Loperamide and codeine were more effective in relieving this than was diphenoxylate. Side effects, particularly central nervous effects, were greatest with diphenoxylate and least with loperamide. Approximately equal numbers discontinued each preparation; poor control and central-nervous-system side effects were the usual reasons for stopping diphenoxylate and codeine, and abdominal pain and constipation for stopping loperamide. We conclude that both loperamide and codeine phosphate are superior to diphenoxylate in the symptomatic treatment of chronic diarrhea.

Topics: Antidiarrheals; Chronic Disease; Clinical Trials as Topic; Codeine; Diarrhea; Diphenoxylate; Double-Blind Method; Humans; Isonipecotic Acids; Loperamide; Piperidines; Random Allocation; Time Factors

A new antidiarrhoeal compound, loperamide (Imodium; (Janssen) Ethnor) has been evaluated in the treatment of patients with chronic nonspecific diarrhoea. In a double-blind trial its effect was compared with that of a placebo. The results of this trial indicate that loperamide is an effective antidiarrhoeal compound.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chronic Disease; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Female; Humans; Loperamide; Male; Middle Aged; Piperidines

Topics: Acute Disease; Adolescent; Adult; Atropine; Diarrhea; Diphenoxylate; Drug Therapy, Combination; Humans; Isonipecotic Acids; Loperamide; Piperidines

Loperamide is an effective and safe antidiarrheal agent which served as a very useful adjunct in the treatment in 79% of 47 patients with chronic diarrhea. One of the major advantages of loperamide to the patient with chronic diarrhea is its convenience. Usually, a single dose in the morning effectively controlled diarrhea during the day. Patients with nocturnal or early morning diarrhea obtained good control with a second bedtime dose of the drug.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Diarrhea; Female; Humans; Long-Term Care; Loperamide; Male; Piperidines; Placebos

Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses. In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery. It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.

Topics: Acute Disease; Animals; Chronic Disease; Clinical Trials as Topic; Diarrhea; Gastrointestinal Motility; Humans; Loperamide; Narcotics; Piperidines

Loperamide (R 18 553) was compared with placebo in a double-blind crossover study of 21 patients with chronic diarrhoea caused by ileocolic disease or resection. Eighteen patients completed the trial. At a median daily dose of 6 mg the new antidiarrhoeal preparation was found to be superior to placebo in controlling chronic diarrhoea. The frequency and weight of stools significantly decreased, the stools became more solid, and carmine transit time was prolonged during loperamide therapy. Loperamide was consistently preferred to placebo by the patients. Gastrointestinal side-effects were few and comparable during both treatment periods.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Crohn Disease; Diarrhea; Female; Gastrointestinal Motility; Humans; Intestines; Loperamide; Male; Middle Aged; Piperidines

Topics: Adult; Aged; Bile Acids and Salts; Calcium; Chlorides; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Feces; Female; Humans; Ileostomy; Ileum; Loperamide; Male; Middle Aged; Piperidines; Placebos; Potassium; Rectum; Sodium; Water

A multicentre trial was conducted to compare Lomotil and Imodium in the treatment of acute non-specific diarrhoea in general practice. A total of eighty-three patients contributed to the study and were randomly allocated to one of the two treatments. No statistically significant differences were found betwwen the drugs in their efficacy and speed of action in alleviating diarrhoea or in their palliative effect on nausea/vomiting and abdominal pain when present.

Topics: Acute Disease; Adult; Clinical Trials as Topic; Diarrhea; Diphenoxylate; Female; Humans; Isonipecotic Acids; Loperamide; Male; Piperidines

Topics: Adult; Biopharmaceutics; Child, Preschool; Clinical Trials as Topic; Diarrhea; Diphenoxylate; Double-Blind Method; Female; Humans; Loperamide; Male; Piperidines; Placebos; Pregnancy

Topics: Clinical Trials as Topic; Diarrhea; Drug Combinations; Humans; Kaolin; Loperamide; Morphine; Piperidines

Loperamide was compared double-blind with diphenoxylate and a placebo in 59 women with diarrhoea due to prostaglandin administration for mid-trimester abortion. Treatment was started with the intake of two capsules two hours before the first intramuscular injection of 15(S-)15 methyl prostaglandin F2alpha and was then adapted individually, i.e. one capsule after each unformed stool, with a maximum of ten per 24 hours. Both antidiarrhoeals were significantly more effective than the placebo in preventing diarrhoea, and loperamide was found to be more active than diphenoxylate. The course of abortion, BP and vital signs, or prostaglandin side-effects other than diarrhoea were not affected by either antidiarrhoeal, nor could any adverse experience be specifically attributed to them.

Topics: Abortion, Induced; Adult; Blood Pressure; Body Temperature; Capsules; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Diarrhea; Diphenoxylate; Double-Blind Method; Female; Heart Rate; Humans; Isonipecotic Acids; Loperamide; Piperidines; Placebos; Prostaglandins; Respiration; Time Factors

42 outpatients with chronic diarrhoea of varying origin received individually adapted doses (2--12 mg) of loperamide for a median time of 543 days (range 140--1,159 days). In most cases, the mean daily stool frequency dropped significantly and stool consistency improved clearly; the beneficial effects of the drug were maintained over the entire treatment period. Also, patients with diarrhoea of organic origin tended to react more favourably to loperamide than patients with functional diarrhoea. No drug-related changes in laboratory parameters could be detected and clinical side effects were virtually nil. No morphine-like effect of loperamide could be evidence by means of the pupil diameter changes after naloxone administration.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Drug Evaluation; Female; Humans; Isotonic Solutions; Loperamide; Male; Middle Aged; Naloxone; Piperidines; Pupil; Sodium Chloride; Time Factors

Twenty-seven patients with chronic diarrhea due to Crohn's disease, ulcerative colitis, short bowel syndrome, and idiopathic (functional) causes participated in a multiphase study (open, double blind, and long term open) of loperamide HCl, a new single entity, oral antidiarrheal agent. In the open phase of the study, loperamide effectively relieved symptoms of diarrhea in 21 of 27 patients. The average number of stools dropped from eight in the initial relapse period to two stools after 1 month of treatment (P = 0.0001). Efficacy was confirmed in the double blind and long term open phases of the study. Four patients who were not relieved while on therapy had discontinued the drug because of abdominal cramping. No other side effects attributable to the drug were observed. Loperamide has been found to be a safe and effective agent for the treatment of chronic diarrhea.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Diarrhea; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Placebos

Loperamide, a novel antidiarrheal agent, was compared with diphenoxylate in a double blind crossover study of 23 patients with chronic diarrhea of various etiologies. Both agents were found to be capable of controlling or greatly reducing chronic diarrhea. Loperamide was superior to diphenoxylate in its abiltiy to decrease the frequency and improve the consistency of the stools, even at a 2.5-fold lower dose level.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Diarrhea; Diphenoxylate; Feces; Female; Humans; Isonipecotic Acids; Loperamide; Male; Middle Aged; Piperidines

Fifteen patients (20 to 66 years) with long-standing chronic diarrhea of varying etiology were selected for an open trial of loperamide 2 mg capsules. The optimal daily dose for substantial reduction of the diarrhea ranged from two to seven capsules. Eleven patients showed a significant improvement in stool consistency and stool frequency, and a decrease of abdominal cramps. Loperamide appeared to be ineffective in two patients with cholerrheic diarrhea, and in one patient with laxative-induced diarrhea, and in one patient with diarrhea of unknown etiology. The eleven successfully treated patients then entered a double-blind placebo-controlled trial for ten days or until relapse, the daily dose being identical to the optimal one previously determined in the open phase. The investigator was able to guess the code correctly in ten out of eleven cases. Twenty ileostomy patients (ages 25 to 73 years) volunteered for the evaluation of the inhibitory activity on small intestinal peristalsis by loperamide in a double-blind placebo-controlled cross-over study. Mean daily ileostomy output decreased by 22% in the loperamide period, as compared with the drug-free study phase (P less than 0.001). Of the 20 patients, 16 were able to guess their code correctly, whereas four were uncertain, although their fecal weights were lower with loperamide. Many patients noticed an increased urinary production and experienced an improvement in their ileostomy care during loperamide treatment. Because of its effectiveness, its low side-effect liability and its lack of toxicity, loperamide is considered a promising drug in the symptomatic treatment of chronic diarrhea, and as a reliable agent in the treatment of ileostomy patients.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Colonic Diseases, Functional; Diarrhea; Female; Humans; Ileostomy; Loperamide; Male; Middle Aged; Piperidines

Topics: Adolescent; Adult; Aged; Amides; Antidiarrheals; Child; Chlorobenzenes; Clinical Trials as Topic; Clioquinol; Diarrhea; Diphenoxylate; Female; Humans; Male; Middle Aged; Piperidines; Placebos

Fifteen patients (20-66 years) with persistent diarrhoea of varying aetiology were selected for an open trial of loperamide 2 mg capsules. The optimal daily dose for substantial reduction of the diarrhoea ranged from two to seven capsules. Eleven patients showed a significant improvement in stool consistency, a highly significant decrease in stool frequency and a decrease of abdominal cramps. One ileostomy patient with abundant ileostomy output and intermittent leaking of the ileosotmy appliance at night experienced a substantial reduction of the stoma output with virtual disappearance of soiling accidents as night. Loperamide appeared to be ineffective in two patients with cholerrhoeic diarrhoea; in one patient with laxative-induced diarrhoea and in one patient with probable nervous diarrhoea. The eleven successfully treated patients then entered a doubleblind placebo-controlled trial for ten days or util relaps, the daily dose being indentical to the optimal one previously determined in the open phase of the study. The investigator was able to guess the code correctly in ten out of eleven cases. The drug was well tolerated. Because of its considerable efficacy and low side-effect liability, loperamide has to be considered a promising drug in the treatment of chronic diarrhoea.

Topics: Adult; Capsules; Chronic Disease; Clinical Trials as Topic; Diarrhea; Female; Humans; Loperamide; Middle Aged; Piperidines

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Diarrhea; Dimethylamines; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Pain; Piperidines; Placebos

Topics: Adolescent; Adult; Aged; Benzilates; Bromides; Clinical Trials as Topic; Codeine; Colonic Diseases, Functional; Diarrhea; Female; Humans; Male; Middle Aged; Parasympatholytics; Piperidines; Quaternary Ammonium Compounds

Topics: Adult; Aged; Amides; Antidiarrheals; Chlorobenzenes; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Colonic Diseases, Functional; Crohn Disease; Diarrhea; Drug Evaluation; Female; Gastrointestinal Agents; Humans; Isonipecotic Acids; Male; Middle Aged; Naloxone; Nitriles; Piperidines; Placebos; Reflex, Pupillary

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Amides; Antidiarrheals; Atropine; Capsules; Chlorobenzenes; Clinical Trials as Topic; Diarrhea; Drug Evaluation; Female; Gastrointestinal Agents; Humans; Isonipecotic Acids; Male; Middle Aged; Nitriles; Piperidines; Time Factors

Topics: Atropine; Codeine; Diarrhea; Duodenal Ulcer; Humans; Piperidines; Placebos; Postoperative Complications; Pylorus; Vagotomy

Topics: Clinical Trials as Topic; Diarrhea; Humans; Piperidines; Postoperative Complications; Vagotomy

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials as Topic; Codeine; Diarrhea; Female; Humans; Male; Middle Aged; Piperidines

Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

Topics: Adult; Aged; Atrial Fibrillation; Diarrhea; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Follicular; Musculoskeletal Pain; Piperidines; Pneumonia; Pyrazoles; Pyrimidines; Sepsis

Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor used in B-cell lymphoproliferative disorders. Patients with genetic BTK deficiency are susceptible to recurrent and severe Campylobacter infections. We report 4 patients treated with ibrutinib who developed chronic or extra-digestive campylobacteriosis resembling ibrutinib-related adverse events including diarrhea (n = 4), panniculitis (n = 2), and arthritis (n = 1). Microbiological explorations identified Campylobacter jejuni (n = 3) or Campylobacter coli (n = 1). All the patients completely recovered after a short course of oral antibiotic therapy. In patients treated with ibrutinib presenting with chronic diarrhea, dermatological, or rheumatological manifestations, campylobacteriosis should be ruled out before attributing the symptoms to ibrutinib and discuss its discontinuation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Campylobacter Infections; Diarrhea; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors.. Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial.. Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks.. Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Creatinine; Diarrhea; Edema; Exons; Humans; Hypoalbuminemia; Lung Neoplasms; Mutation; Nausea; Piperidines; Pleural Effusion; Protein Kinase Inhibitors; Pyridazines; Pyrimidines; Vomiting

Lubeluzole, a neuroprotective anti-ischemic drug, was tested for its ability to act as both antibiotic chemosensitizing and antipropulsive agent for the treatment of infectious diarrhea.. In the present report, the effect of lubeluzole against antidiarrheal target was tested. The antimicrobial activity towards Gram-positive and Gram-negative bacteria was investigated together with its ability to affect ileum and colon contractility.. Concerning the antimicrobial activity, lubeluzole showed synergistic effects when used in combination with minocycline against four common Gram-positive and Gram-negative bacteria (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 25922), although relatively high doses of lubeluzole were required. In ex vivo experiments on sections of gut smooth muscles, lubeluzole reduced the intestinal contractility in a dose-dependent manner, with greater effects observed on colon than on ileum, and being more potent than reference compounds otilonium bromide and loperamide.. All above results identify lubeluzole as a possible starting compound for the development of a novel class of antibacterial adjuvants endowed with spasmolytic activity.

Topics: Animals; Anti-Bacterial Agents; Antidiarrheals; Bacteria; Colon; Diarrhea; Dose-Response Relationship, Drug; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Guinea Pigs; Ileum; Loperamide; Male; Microbial Sensitivity Tests; Muscle Contraction; Neuroprotective Agents; Piperidines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Thiazoles

Recent reports highlighting the global significance of cryptosporidiosis among children have renewed efforts to develop control measures. We evaluated the efficacy of bumped kinase inhibitor (BKI) 1369 in the gnotobiotic piglet model of acute diarrhea caused by

Topics: Acute Disease; Animals; Animals, Newborn; Antiprotozoal Agents; Cryptosporidiosis; Cryptosporidium; Diarrhea; Disease Models, Animal; Germ-Free Life; Oocysts; Parasite Load; Piperidines; Pyrimidines; Quinolines; Swine

Intestinal mucositis accompanied by severe diarrhea is one of the most common side effects during cancer chemotherapy. Lafutidine, a histamine H2 receptor antagonist with mucosal protective properties via sensory afferent neurons, is used for the treatment of upper gastrointestinal diseases. The present study investigated the effects of lafutidine on 5-fluorouracil (5-FU)-induced intestinal mucositis induced in mice. Male C57BL/6 wild-type (WT), sensory deafferented mice, and transient receptor potential vanilloid subfamily 1 knockout (TRPV1KO) mice were used. Animals were administered 5-FU once daily, while lafutidine and famotidine were administered twice daily for 6 days. Repeated administration of 5-FU caused severe intestinal mucositis, characterized by shortening of villi and destruction of crypts and was accompanied by diarrhea and body weight loss. Daily administration of lafutidine reduced the severity of intestinal mucositis, diarrhea and body weight loss in a dose-dependent manner, while famotidine had no effect on intestinal mucositis. The preventive effects of lafutidine were completely abolished in sensory deafferented and TRPV1-KO mice. Lafutidine significantly suppressed 5-FU-increased MPO activity and inflammatory cytokine expression on day 6, but not apoptosis induction in intestinal crypts on day 1. Lafutidine induced Alcian Blue and PAS-positive mucus production in the small intestine. These findings suggest that lafutidine attenuates 5-FU-induced intestinal mucositis, most likely by increasing mucus production via activation of sensory afferent neurons. Furthermore, intact TRPV1 signaling is essential for the activation of sensory afferent neurons induced by lafutidine. Therefore, lafutidine is more useful than other common antacids for the treatment of intestinal mucositis during cancer chemotherapy.

Topics: Acetamides; Animals; Antimetabolites, Antineoplastic; Diarrhea; Famotidine; Fluorouracil; Histamine H2 Antagonists; Interleukin-1beta; Intestinal Mucosa; Intestines; Male; Mice, Inbred C57BL; Mice, Knockout; Mucositis; Peroxidase; Piperidines; Pyridines; RNA, Messenger; Tumor Necrosis Factor-alpha

Recent data demonstrated that activation of the muscarinic M

Topics: Allosteric Regulation; Amphetamine; Animals; Ataxia; Diarrhea; Dogs; Donepezil; Drug Design; Female; Humans; Indans; Isoindoles; Lactams; Male; Mice, Inbred C57BL; Microsomes, Liver; Oxazoles; Piperidines; Rats, Wistar; Receptor, Muscarinic M1; Scopolamine; Seizures; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Vomiting

Secretory diarrhoea is a leading cause of mortality and morbidity worldwide. Our aim was to characterize the effect of inhibition of selected enzymes involved in the synthesis or degradation of endocannabinoids on electrolyte equilibrium in the mouse colonic tissue. The aim of this study was to evaluate the effects of PF-3845, JZL-184 and RHC-80267, as inhibitors of fatty acid amide hydrolase (FAAH), monoacylglycerol (MAGL) and diacylglycerol lipase (DAGL), respectively on epithelial ion transport in isolated mouse colon stimulated by forskolin (FSK), veratridine (VER) and bethanechol (BET). Next, colonic tissue was co-incubated with selected inhibitors and cannabinoid receptor antagonists: AM 251 and AM 630 (CB

Topics: Amidohydrolases; Animals; Benzodioxoles; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cyclohexanones; Diarrhea; Endocannabinoids; Enzyme Inhibitors; Indoles; Lipoprotein Lipase; Male; Mice; Monoglycerides; Piperidines; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Ibrutinib is a recently approved oral anticancer agent with pharmacokinetics that is very sensitive to metabolic inhibition. We report a serious side effect of ibrutinib potentially attributable to interaction with the moderate CYP3A4 inhibitor verapamil.. A patient with mantle cell lymphoma was admitted to our emergency department with severe diarrhoea. During a prescription review, the clinical pharmacist identified a potential drug interaction between ibrutinib and verapamil present in a branded combination product also containing trandolapril. Ibrutinib was discontinued for 5 days, and verapamil was stopped. Lercanidipine 10 mg daily was prescribed as an alternative antihypertensive drug. The patient was discharged after 3 days with symptomatic treatment for his diarrhoea. Three months later, the patient maintained control with ibrutinib and olmesartan, but without verapamil.. This is the first description of a serious side effect of ibrutinib likely due to an interaction with the CYP3A4 inhibitor verapamil. Prescriptions of ibrutinib must be carefully checked to identify possible interactions with CYP3A4 inhibitors and patients monitored accordingly.

Topics: Adenine; Aged; Antihypertensive Agents; Antineoplastic Agents; Cytochrome P-450 CYP3A Inhibitors; Diarrhea; Dihydropyridines; Drug Interactions; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Verapamil

Many enterotoxigenic Escherichia coli strains produce the heat-stable toxin, STa, which, by activation of the intestinal receptor-enzyme guanylyl cyclase (GC) C, triggers an acute, watery diarrhea. We set out to identify GCC inhibitors that may be of benefit for the treatment of infectious diarrheal disease.. Compounds that inhibit STa-induced cyclic guanosine 3',5'-monophosphate (cGMP) production were selected by performing cyclase assays on cells and membranes containing GCC, or the related GCA. The effect of leads on STa/GCC-dependent activation of the cystic fibrosis transmembrane conductance regulator anion channel was investigated in T84 cells, and in porcine and human intestinal tissue. Their effect on STa-provoked fluid transport was assessed in ligated intestinal loops in piglets.. Four N-2-(propylamino)-6-phenylpyrimidin-4-one-substituted piperidines were shown to inhibit GCC-mediated cellular cGMP production. The half maximal inhibitory concentrations were ≤ 5 × 10(-7) mol/L, whereas they were >10 times higher for GCA. In T84 monolayers, these leads blocked STa/GCC-dependent, but not forskolin/adenylyl cyclase-dependent, cystic fibrosis transmembrane conductance regulator activity. GCC inhibition reduced STa-provoked anion secretion in pig jejunal tissue, and fluid retention and cGMP levels in STa-exposed loops. These GCC inhibitors blocked STa-provoked anion secretion in rectal biopsy specimens.. We have identified a novel class of GCC inhibitors that may form the basis for development of future therapeutics for (infectious) diarrheal disease.

Topics: Adenylyl Cyclases; Adult; Animals; Bacterial Toxins; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Enterotoxigenic Escherichia coli; Enterotoxins; Enzyme Inhibitors; Escherichia coli Proteins; HeLa Cells; Humans; Jejunum; Models, Biological; Piperidines; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction; Swine; Young Adult

Inflammatory bowel diseases, primarily Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract with unknown etiology. The majority of current therapeutic agents focus on controlling proinflammatory molecules. The neuropeptide nociceptin/orphanin FQ (N/OFQ) has been described as a potential immunomodulator for inflammatory bowel diseases. In this study, we asked whether the small molecule N/OFQ antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB612111) would inhibit the development of dextran sodium sulfate-induced colitis in C57BL/6 mice. Inhibition of the N/OFQ receptor (NOP) by SB612111 significantly ameliorated the clinical disease course in these animals, as indicated by reduced fecal bleeding, improved recovery from diarrhea and weight loss, and a reduction in histopathological alterations. In addition, the inflammatory response in the colon was diminished, as demonstrated by reduced cytokine protein and messenger RNA expression for CXCL1/keratinocyte-derived chemokine, interferon-γ, interleukin-1β, interleukin-6, and tumor necrosis factor-α, some of which are known targets for the treatment of this devastating disease. Our results strongly support a role for the receptor-ligand pair NOP-N/OFQ in the pathogenesis of colitis. We conclude that inhibition of NOP receptors with small molecule inhibitors may constitute a novel, urgently needed approach for the treatment of inflammatory bowel diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Cycloheptanes; Cytokines; Dextran Sulfate; Diarrhea; Female; Gastrointestinal Hemorrhage; Gene Expression Regulation; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides; Piperidines; Receptors, Opioid; RNA, Messenger; Signal Transduction; Weight Loss

Δ(9)-Tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB(1) and CB(2) cannabinoid receptors, the role these receptors play in reducing the variety of opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this study was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces naloxone-precipitated morphine withdrawal symptoms in in vivo and in vitro models of opioid dependence. Morphine-dependent mice challenged with naloxone reliably displayed a profound withdrawal syndrome, consisting of jumping, paw tremors, diarrhea, and weight loss. THC and the MAGL inhibitor 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) dose dependently reduced the intensity of most measures through the activation of CB(1) receptors. JZL184 also attenuated spontaneous withdrawal signs in morphine-dependent mice. The FAAH inhibitor N-(pyridin-3-yl)-4-(3-(5-(trifluoromethyl)pyridin-2-yloxy)benzyl)-piperdine-1-carboxamide (PF-3845) reduced the intensity of naloxone-precipitated jumps and paw flutters through the activation of CB(1) receptors but did not ameliorate incidence of diarrhea or weight loss. In the final series of experiments, we investigated whether JZL184 or PF-3845 would attenuate naloxone-precipitated contractions in morphine-dependent ilea. Both enzyme inhibitors attenuated the intensity of naloxone-induced contractions, although this model does not account mechanistically for the autonomic withdrawal responses (i.e., diarrhea) observed in vivo. These results indicate that endocannabinoid catabolic enzymes are promising targets to treat opioid dependence.

Topics: Amidohydrolases; Animals; Arachidonic Acid; Behavior, Animal; Benzodioxoles; Brain Chemistry; Cannabinoid Receptor Modulators; Diarrhea; Dronabinol; Electric Stimulation; Endocannabinoids; Hydrolysis; Ileum; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Monoacylglycerol Lipases; Morphine Dependence; Muscle Contraction; Naloxone; Narcotic Antagonists; Piperidines; Prostaglandins; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance Withdrawal Syndrome; Weight Loss

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

The objective was to investigate the frequency of adverse events (AE) as a cause for discontinuation of donepezil treatment for Alzheimer's dementia (DAT) in a geriatric memory unit.. Five-year retrospective study of 123 donepezil-treated patients diagnosed with DAT or mixed dementia in a geriatric memory unit. The material covers all patients treated with donepezil and surveyed for 12 months in the memory unit during the period from 14th March 2001 to 7th April 2006.. Among the 123 patients, 106 (86%) suffered from DAT and 17 (14%) suffered from mixed dementia. A total of 100 (81%) were female while 23 (19%) were male. The median age was 84 years. In all, 26 (21%) patients discontinued treatment due to AE. The most frequent AE were nausea/vomiting, diarrhoea and loss of appetite.. In 21% of the cases treatment was discontinued within 12 months due to AE. The most frequent AEs were nausea/vomiting, diarrhoea and loss of appetite. For the most part discontinuation took place within the initial three months. However, some treatments were not discontinued until after six months; consequently, treatment should be supervised and patients should have easy access to a memory unit in the case of AE.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Appetite; Cholinesterase Inhibitors; Diarrhea; Donepezil; Female; Humans; Indans; Male; Nausea; Nootropic Agents; Piperidines; Retrospective Studies; Vomiting

This study looked at measurement of endotoxaemia as a tool in determining prognosis and probable response to treatment in scouring lambs. One hundred eighty-three lambs in the first 15-20 days of life, from eight Merino sheep farms located in the region of La Serena, south-west Spain, were used in this experiment. Scouring and normal/control lambs were selected following a clinical examination, the scouring group was further divided into subgroups, specifically those that did or did not survive 72 h following treatment. At the time of the clinical examination, faecal and blood samples were taken. Faecal culture and commercial faecal antigen tests for detection of enteropathogens in faeces and serum endotoxin measurement using chromogenic lymulus amoebocyte lysate (LAL) were carried out. Scouring lambs received 0.07 mg/kg liveweight halofuginone once a day for 3 days, a single oral dose of 0.20 mg/kg liveweight of spectinomycin and oral rehydration fluid. The pathogens isolated were Cryptosporidium spp. and Escherichia coli. The case fatality rate was 51% in the scouring lambs. Postmortem findings were consistent with enterotoxigenic E. coli infection. The concentration of endotoxin was 0.18 +/- 0.12 ng/ml in the control group, 0.35 +/- 0.17 ng/ml in the surviving lambs and 0.46 +/- 0.14 ng/ml in the non-surviving lambs. Significant differences between groups were found. Case fatality rate of the scouring lambs with endotoxaemia below 0.30 ng/ml was 0%, while it was 100% above 0.50 ng/ml. These results may be utilized as a prognostic indicator in lambs affected by E. coli and Cryptosporidium that will help aid in decision-making as to whether to treat a lamb or not based on its chances of survival.

Topics: Age Factors; Animals; Animals, Newborn; Cryptosporidium; Decision Making; Diarrhea; Endotoxemia; Escherichia coli; Feces; Fluid Therapy; Piperidines; Prognosis; Protein Synthesis Inhibitors; Quinazolinones; Sheep; Sheep Diseases; Survival Analysis

Ninety, seven- to 10-day-old calves were allocated to three groups of 30 and treated daily for seven days with either 100 microg/kg halofuginone hydrobromide or 2.5 mg/kg decoquinate orally or left untreated as controls. The levels of diarrhoea and dehydration were monitored daily for 28 days from the first day of treatment (day 0) and samples of faeces were collected on days 0, 7, 14, 21 and 28, to quantify the excretion of Cryptosporidium parvum oocysts. The calves were weighed on days 3 and 28. The treatments had no effect on the levels of diarrhoea or dehydration, the proportions of diarrhoeic calves or the proportions of calves shedding oocysts. However, unlike decoquinate, halofuginone significantly reduced the excretion of oocysts on day 7 (P<0.0001), and decoquinate increased the average daily weight gain of the calves (P=0.049).

Topics: Animals; Cattle; Cattle Diseases; Coccidiostats; Cryptosporidiosis; Cryptosporidium parvum; Decoquinate; Dehydration; Diarrhea; Feces; Female; Male; Parasite Egg Count; Piperidines; Quinazolinones; Random Allocation; Treatment Outcome; Weight Gain

Animal studies exploring the antagonism of irreversible cholinesterase inhibitors (i.e. nerve agents) such as soman and sarin have shown that pretreatment with the reversible centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic drug, scopolamine, antagonizes the lethality and toxicity of these agents. This study evaluated the effects of pretreatment with the oral cholinesterase inhibitor and anti-Alzheimer's agent, donepezil (Aricept) on the hypokinetic, hypothermic and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor, diisopropylfluorophosphate (DFP) in adult Sprague-Dawley rats. Donepezil (2 mg/kg), given acutely (30 min pretreatment) or chronically (10 daily treatments), significantly antagonized the hypothermia, hypoactivity and diarrhea induced by DFP (1.25 mg/kg) administration. The effects were most prominent 4 and 6 h after the injection of DFP and some protection was observed even when the last treatment of the chronic donepezil protocol was given 24 h before the DFP injection. Although these phenomena are not the same as lethality, they may be parallel phenomena, and our results may have therapeutic implications for the treatment of nerve agent toxicity.

Topics: Animals; Behavior, Animal; Body Temperature; Cholinesterase Inhibitors; Diarrhea; Donepezil; Hypokinesia; Indans; Injections, Intramuscular; Injections, Intraperitoneal; Isoflurophate; Male; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

Studies in animals exploring the antagonism of the cholinesterase inhibitors soman and sarin have shown that pretreatment with low doses of the centrally acting cholinesterase inhibitor, physostigmine, alone or in conjunction with the centrally acting anticholinergic agent, scopolamine, is effective against their lethality and toxicity. The current study evaluated the effects of pretreatment with the oral anticholinesterase agent, donepezil (Aricept, 2.0 mg/kg), used to treat Alzheimer's disease, with and without scopolamine in decreasing the hypothermic, hypokinetic, and diarrhea-inducing effects of the irreversible long-acting cholinesterase inhibitor diisopropyl fluorophosphate (DFP, 1.0 mg/kg) in adult Flinders sensitive line (FSL) male rats. Donepezil alone and donepezil plus scopolamine (0.1 mg/kg) to a greater extent antagonized the decrease in temperature, hypoactivity, and induction of diarrhea due to DFP observed at 4 h after its administration. However, donepezil alone induced hypothermia at 1 and 2 h after treatment. Therefore, these preliminary findings are encouraging, but many additional studies are needed to establish the effectiveness of donepezil as a prophylactic agent against irreversible cholinesterase inhibition by DFP.

Topics: Animals; Behavior, Animal; Body Temperature; Cholinesterase Inhibitors; Diarrhea; Donepezil; Drug Interactions; Indans; Isoflurophate; Male; Motor Activity; Muscarinic Antagonists; Neurotoxicity Syndromes; Piperidines; Rats; Scopolamine

The synthesis of new 5-HT(3) receptor antagonists is an interesting field of research because of their wide therapeutic use. The aim of this work is to functionally characterise a new series of benzimidazole derivatives previously described. These compounds bind to 5-HT(3) receptors and have been evaluated using in vitro (rat tunica muscularis mucosae) and in vivo tests (Bezold-Jarisch reflex in rat and gastrointestinal motility and spontaneous motility in mice). Ondansetron and 1-[4-amino-5-chloro-2-(3,5-dimethoxyphenil)methyloxy]-3-[1-[2-methylsulfonylamino]piperidin-4-yl]propan-1-one hydrochloride (RS 39604) were used as well known 5-HT(3) and 5-HT(4) receptor antagonists. These benzimidazole derivatives have proved to be 5-HT(3) receptor antagonists. Interestingly, they are as active as ondansetron when they are intraperitoneally (i.p.) or orally (p.o.) administered and, in mice, they seem to induce fewer behavioural changes at similar effective doses than does ondansetron. The present results confirm the usefulness of the previously proposed pharmacophore and justify the interest in these new benzimidazole derivatives.

Topics: 5-Hydroxytryptophan; Administration, Oral; Animals; Aza Compounds; Behavior, Animal; Benzimidazoles; Carbachol; Diarrhea; Dose-Response Relationship, Drug; Gastric Emptying; Gastrointestinal Motility; In Vitro Techniques; Injections, Intraperitoneal; Injections, Intravenous; Male; Mice; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Ondansetron; Piperidines; Propane; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Reflex; Serotonin; Serotonin Antagonists

Topics: Alzheimer Disease; Diarrhea; Donepezil; Humans; Indans; Nausea; Nootropic Agents; Piperidines; Vomiting

The novel cyclin-dependent kinase inhibitor flavopiridol has recently completed Phase I trials for the treatment of refractory neoplasms. The dose-limiting toxicity observed with this agent was severe diarrhea. Because the compound otherwise showed promise, the present study sought to determine possible mechanisms underlying the diarrheal side effects. Flavopiridol was tested for its ability to modify chloride secretory responses of the human colonic epithelial cell line, T84. Studies were conducted in vitro in modified Ussing chambers. High concentrations of flavopiridol (10(-4) M), above those likely to be clinically relevant, had a direct stimulatory effect on chloride secretion, probably ascribable to an increase in cyclic AMP. Lower, clinically relevant concentrations of flavopiridol (10(-6) M) had no effect on chloride secretion by themselves but potentiated responses to the calcium-dependent secretagogue, carbachol. The drug also potentiated responses to thapsigargin and taurodeoxycholate and reversed the inhibitory effects of carbachol and epidermal growth factor on calcium-dependent chloride secretion. Pretreatment with the cyclic AMP-dependent secretagogue, forskolin, potentiated responses to flavopiridol, but not vice versa. Thus, diarrheal side effects induced by flavopiridol are likely multifactorial in origin and may involve interactions with endogenous secretagogues such as acetylcholine and bile acids. A better understanding of the diarrhea induced by flavopiridol should allow optimization of therapy with this otherwise promising drug and/or the development of related agents with improved toxicity profiles.

Topics: Antineoplastic Agents; Carbachol; Chloride Channels; Chlorides; Cholinergic Agonists; Colforsin; Colon; Cyclic AMP; Cyclin-Dependent Kinases; Diarrhea; Epidermal Growth Factor; Flavonoids; Humans; In Vitro Techniques; Intestinal Mucosa; Piperidines

Peppers are common food ingredients used worldwide. They are also added in traditional antidiarrhoeal formulations of different herbs. Piperine (1) is an alkaloidal constituent of black and long peppers recently established as a bioavailability enhancer of drugs and other substances. As a part of efforts to study its effects on the gastrointestinal tract, the experiments were performed to determine the rationale, if any, for its use in traditional antidiarrhoeal formulations. Antidiarrhoeal activity of 1 against castor oil, MgSO4 and arachidonic acid was studied in mice. It significantly inhibited diarrhoea produced by these cathartics at 8 and 32 mg/kg p.o. dose. Inhibition of castor oil induced enteropooling by 1 suggests its inhibitory effect on prostaglandins. The results validate the rationale for its use in traditional antidiarrhoeal formulations.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidiarrheals; Benzodioxoles; Cathartics; Diarrhea; Digestive System; Male; Mice; Phytotherapy; Piperidines; Plant Extracts; Polyunsaturated Alkamides

The goal of the present study was to elucidate the relationship between cannabinoid and opioid systems in drug dependence. The CB(1) cannabinoid receptor antagonist SR 141716A precipitated both paw tremors and head shakes in four different mouse strains that were treated repeatedly with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). SR 141716A-precipitated Delta(9)-THC withdrawal was ameliorated in mu-opioid receptor knockout mice compared with the wild-type control animals and failed to occur in mice devoid of CB(1) cannabinoid receptors. An acute injection of morphine in Delta(9)-THC-dependent mice undergoing SR 1417161A-precipitated withdrawal dose dependently decreased both paw tremors, antagonist dose 50 (AD(50)) (95% CL) = 0.035 (0.03--0.04), and head shakes, AD(50) (95% CL) = 0.07 (0.04--0.12). In morphine-dependent mice, the opioid antagonist naloxone precipitated head shakes, paw tremors, diarrhea, and jumping. As previously reported, naloxone-precipitated morphine withdrawal failed to occur in mu-opioid knockout mice and was significantly decreased in CB(1) cannabinoid receptor knockout mice. Acute treatment of Delta(9)-THC in morphine-dependent mice undergoing naloxone-precipitated withdrawal blocked paw tremors, AD(50) (95% CL) = 0.5 (0.3--1.0), and head shakes AD(50) (95% CL) = 0.6 (0.57--0.74) in dose-dependent manners, but failed to diminish the occurrence of diarrhea or jumping. Finally, naloxone and SR 141716A failed to elicit any overt effects in Delta(9)-THC-dependent and morphine-dependent mice, respectively. These findings taken together indicate that the mu-opioid receptor plays a modulatory role in cannabinoid dependence, thus implicating a reciprocal relationship between the cannabinoid and opioid systems in dependence.

Topics: Animals; Behavior, Animal; Cannabinoids; Diarrhea; Dronabinol; Drug Implants; Hallucinogens; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Knockout; Morphine; Morphine Dependence; Narcotics; Opioid Peptides; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Receptors, Opioid, mu; Rimonabant; Substance Withdrawal Syndrome

We have evaluated the effect of cannabinoid drugs, administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.) on upper gastrointestinal transit in control and in croton oil-treated mice. The cannabinoid agonists, WIN 55,212-2 (2-239 nmol mouse(-1)) and cannabinol (24-4027 nmol mouse(-1)), decreased while the CB(1) antagonist SR141716A (2-539 nmol mouse(-1)) increased transit in control mice. WIN 55,212-2, cannabinol and SR141716A had lower ED(50) values when administered i.c.v., than when administered i.p. The CB(2) antagonist SR144528 (52 nmol mouse(-1), i.p.) was without effect. During croton oil (0.01 ml mouse(-1), p.o.)-induced diarrhoea, the ED(50) values of i.p. -injected WIN 55,212-2 and cannabinol (but not SR141716A) were significantly decreased (compared to control mice). However, the ED(50) values of WIN 55,212-2 were similar after i.p. or i.c.v. administration. The inhibitory effects of WIN 55,212-2 and cannabinol were counteracted by SR141716A (16 nmol mouse(-1), i.p.) but not by SR144528 (52 nmol mouse(-1), i.p.) both in control and croton-oil treated mice. Ganglionic blockade with hexamethonium (69 nmol mouse(-1), i.p.) did not modify the inhibitory effect of i.p. -injected cannabinoid agonists either in control or in croton-oil treated mice. The lower ED(50) values of cannabinoid drugs after i.c.v. administration suggest a central (CB(1)) site of action. However, a peripheral site of action is suggested by the lack of effect of hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism.

Topics: Animals; Antidiarrheals; Benzoxazines; Camphanes; Cannabinoids; Croton Oil; Diarrhea; Gastrointestinal Transit; Male; Mice; Mice, Inbred ICR; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

5-HT(4) receptor antagonism prevents the ability of exogenous 5-HT or 5-HTP to sensitize the intestinal peristaltic reflex and increase the rate of defecation, generally without affecting non-stimulated intestinal function. In this study we confirmed the ability of the selective 5-HT(4) receptor antagonist SB-207266 1 - 1000 microg kg(-1) p.o., to prevent the increase in defecation evoked over a 60 min period by 5-HTP 10 mg kg(-1) s.c. in conscious mice, in the absence of an apparent constipating action. The role of endogenous 5-HT in the mechanisms of increased defecation and/or diarrhoea was then investigated in conscious, fed rats. This was evoked by 180 min exposure to restraint stress, which increased both the number and mean weight of formed, faecal pellets excreted over the entire time period. SB-207266 1 - 1000 microg kg(-1) p.o. (dosed 30 min before restraint) did not affect the increase in defecation evoked during the first 60 min of restraint stress, but significantly and dose-dependently reduced or prevented the increased defecation during the remaining 120 min of the experiment; this action occurred in the absence of an apparent constipating action of SB-207266. In fasted rats exposed to restraint stress, watery diarrhoea developed and although there was a tendency for SB-207266 1 - 1000 microg kg(-1) p.o. (dosed 30 min before restraint) to reduce the incidence of diarrhoea, this inhibition was not complete. We conclude that selective 5-HT(4) receptor antagonism prevents disruptions in defecation behaviours caused by exogenous or endogenous enteric 5-HT and that this activity is not accompanied by a concomitant suppression of activity (constipation-like) within the intestine itself.

Topics: 5-Hydroxytryptophan; Animals; Defecation; Diarrhea; Dose-Response Relationship, Drug; Fasting; Indoles; Male; Mice; Mice, Inbred ICR; Piperidines; Rats; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Restraint, Physical; Serotonin Antagonists; Stress, Psychological

Flavopiridol, a cyclin-dependent kinase inhibitor currently undergoing clinical evaluation, has a dose-limiting toxicity of diarrhea. Preclinical data on flavopiridol metabolism indicate that flavopiridol undergoes hepatic glucuronidation. The purpose of this study is to evaluate whether the occurrence of diarrhea is related to the systemic glucuronidation of flavopiridol. Parent drug and metabolite concentrations in plasma were measured by high-pressure liquid chromatography in 22 metastatic renal cancer patients treated on a Phase II trial of 50 mg/m2/day of flavopiridol administered every 2 weeks as a 72-h continuous infusion. Pharmacokinetics of flavopiridol and its glucuronide were assessed during the first cycle at 23, 47, and 71 h during the infusion. Flavopiridol concentrations at 23, 47, and 71 h were 389 nM (296-567 nM), 412 nM (297-566 nM), and 397 nM (303-597 nM) [median (interquartile range)], respectively. Flavopiridol glucuronide reached a plateau of 358 nM (196-553 nM) at 47 h. Metabolic ratios of flavopiridol glucuronide:flavopiridol at 71 h showed an apparent bimodal distribution with an antimode of 1.2. Thirteen patients experienced diarrhea and had lower metabolic ratios [0.72 (0.53-0.86)] than patients without diarrhea [2.24 (1.76-2.3); P = 0.002]. Eight of 11 extensive glucuronidators (ratio > 1.2) did not develop diarrhea, whereas 10 of 11 poor glucuronidators (ratio < 1.2) developed diarrhea (P = 0.008). The glucuronidation of flavopiridol is apparently polymorphic, suggesting a genetic etiology. The systemic glucuronidation of flavopiridol is inversely associated with the risk of developing diarrhea.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Cyclin-Dependent Kinases; Diarrhea; Female; Flavonoids; Glucuronates; Humans; Infusions, Intravenous; Kidney Neoplasms; Male; Middle Aged; Piperidines

Topics: Aged; Aggression; Akathisia, Drug-Induced; Antidepressive Agents, Second-Generation; Confusion; Diarrhea; Donepezil; Drug Interactions; Female; Flatulence; Humans; Indans; Male; Nootropic Agents; Paroxetine; Piperidines; Sleep Initiation and Maintenance Disorders

We have studied the effects of the cannabinoid receptor agonists (R)-(+)[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2, 3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2, 0. 3-5 mg/kg, i.p.) and (-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP 55,940, 0.03-1 mg/kg, i.p.), the cannabinoid CB(1) receptor antagonist (N-piperidin-1-yl)-5-(4-chlorophenyl)-1-2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A, 0. 3-5 mg/kg, i.p.) and the cannabinoid CB(2) receptor antagonist N-[-(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazo le- 3-carboxamide (SR144528, 1 mg/kg, i.p.) on intestinal motility, defaecation and castor-oil (1 ml/100 g rat, orally)-induced diarrhoea in the rat. SR141716A, but not SR144528, increased defaecation and upper gastrointestinal transit, while WIN 55,212-2 and CP 55,940 decreased upper gastrointestinal transit but not defaecation. WIN 55,212-3 (5 mg/kg), the less active enantiomer of WIN 55,212-2, was without effect. A per se non-effective dose of SR141716A (0.3 mg/kg), but not of SR144528 (1 mg/kg) or the opioid receptor antagonist, naloxone (2 mg/kg i.p.), counteracted the inhibitory effect of both WIN 55,212-2 (1 mg/kg) and CP 55,940 (0.1 mg/kg) on gastrointestinal motility. WIN 55,212-2 did not modify castor-oil-induced diarrhoea, while CP 55,940 produced a transient delay in castor-oil-induced diarrhoea at the highest dose tested (1 mg/kg), an effect counteracted by SR141715A (5 mg/kg). These results suggest that (i) intestinal motility and defaecation could be tonically inhibited by the endogenous cannabinoid system, (ii) exogenous activation of cannabinoid CB(1) receptors produces a reduction in intestinal motility in the upper gastrointestinal tract but not in defaecation, (iii) endogenous or exogenous activation of cannabinoid CB(2) receptors does not affect defaecation or intestinal motility and (iv) the cannabinoid receptor agonist, CP 55, 940, possesses a weak and transient antidiarrhoeal effect while the cannabinoid receptor agonist, WIN 55,212-2, does not possess antidiarrhoeal activity.

Topics: Analgesics; Animals; Antidiarrheals; Benzoxazines; Castor Oil; Cyclohexanols; Defecation; Diarrhea; Dose-Response Relationship, Drug; Gastrointestinal Motility; Gastrointestinal Transit; Loperamide; Male; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

1. We set out to ascertain the role of tachykinins, neurokinin A and substance P, in castor oil-induced diarrhoea in rats as disclosed by the inhibitory effect of the non-peptide NK1- and NK2-receptor antagonists. SR 140333 and SR 48968, respectively. 2. SR 48968 (0.02 to 20 micrograms kg-1, s.c. or p.o.), and the opioid receptor agonist loperamide (1-10 mg kg-1, p.o.), dose-dependently prevented castor oil effects: % inhibition vs castor oil, diarrhoea 0 to 100, increase in faecal mass 7 to 90 and water content 16 to 90. SR 140333 (0.02 to 20 micrograms kg-1, s.c.) and the platelet activating factor antagonist SR 27417 (5 to 500 micrograms kg-1, p.o.) did not prevent the increase in faecal water content, but reduced faecal mass (35 to 66%) and diarrhoea (0 to 57%). 3. The R-enantiomers of tachykinin NK1 and NK2 receptor antagonists, SR 140603 and SR 48605 (both at 2 or 20 micrograms kg-1, s.c.) had no effect other than reducing faecal mass at the highest dose tested. 4. SR 48968 (20 micrograms kg-1, p.o.) but not loperamide (10 mg kg-1, p.o.) given 24 h before castor oil, still slightly but significantly reduced by 30% the increase of faecal mass output; both treatments significantly reduced (30 to 70%) the effect of castor oil on faecal water content, although the incidence of diarrhoea was only slightly less than in controls. 5. In castor oil-treated rats, naloxone (2 mg kg-1, s.c.) completely blocked the antidiarrhoeal action of loperamide (10 mg kg-1, p.o.) but not of SR 48968 (20 micrograms kg-1, p.o.): a similar result was obtained on faecal mass and water content. 6. Castor oil strongly increased the occurrence of manometrically recorded propulsive giant contractions (500 to 1000% over control values) of transverse and distal colon, this effect being significantly prevented (80 to 100%) by SR 48968 and loperamide and partially by SR 140333 (35% distal colon, 70% transverse colon). 7. In castor oil free rats, loperamide but not SR 48968 or SR 140333 significantly reduced by 50% the gastrointestinal transit of a charcoal test meal, as well as 24 h faecal mass output. Consistently, loperamide, unlike the tachykinin receptor antagonists, had a dramatic effect on manometric recordings of intestinal motility, reducing all kinds of colonic contractions. 8. Our findings suggest that castor oil diarrhoea in rats entails activation of NK1 and NK2 receptors by endogenous tachykinins, whose antagonists may have a potential as antidiarrhoeal agents free from t

Topics: Animals; Benzamides; Castor Oil; Colon; Diarrhea; Gastrointestinal Motility; Loperamide; Male; Naloxone; Piperidines; Quinuclidines; Rats; Tachykinins

Castrol-oil induced diarrhea in rats was potently prevented by compounds SR 140333 and SR 48968, the first a tachykinin NK1- and the second a NK2-receptor antagonist. SR 48968 was more effective and also reduced fecal water content.

Topics: Animals; Benzamides; Castor Oil; Diarrhea; Dose-Response Relationship, Drug; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Rats, Inbred Strains; Receptors, Neurokinin-2

The objective of this study was to characterize the receptor(s) to 5-HT mediating 5-HTP-induced diarrhea in mice. The severity of diarrhea in mice was assessed using an arbitary scoring scale ranging from 0 (normal stools) to 3 (watery diarrhea). Administration of 5-HTP (1-30 mg/kg i.p.) produced a dose-dependent increase in diarrhea score (ED50, 1.47 mg/kg i.p.). 5-HTP (10 mg/kg i.p.)-induced diarrhea was unaffected by atropine (3 mg/kg i.p.) but was completely abolished by the aromatic L-amino acid decarboxylase inhibitor benserazide (10 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with DAU 6285, a marginally selective 5-HT4 receptor antagonist, significantly inhibited 5-HTP-induced diarrhea (ID50, 0.58 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with GR 113808 or SB 204070, two highly selective 5-HT4 antagonists, significantly inhibited 5-HTP-induced diarrhea with ID50 estimates of 0.31 and 0.003 mg/kg i.p., respectively. The maximal inhibition produced by DAU 6285, GR 113808 and SB 204070 was 63%, 68% and 36%, respectively. Neither GR 113808 (1 and 3 mg/kg i.p.) nor SB 204070 (0.1 and 1 mg/kg i.p.) had any effect on 16,16-dimethyl prostaglandin E2 (30 micrograms/kg i.p.)-induced diarrhea in mice. DAU 6285 significantly inhibited 16,16-dimethyl prostaglandin E2-induced diarrhea at the highest dose (3 mg/kg i.p.). Pretreatment (30 min before 5-HTP) with methysergide (0.1-3 mg/kg i.p.), metergoline (0.01-0.1 mg/kg i.p.), ketanserin (0.01-1 mg/kg i.p.), YM 060 (0.01-0.1 mg/kg i.p.) or ondansetron (0.01-3 mg/kg i.p.) had no significant effects on 5-HTP-induced diarrhea.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5-Hydroxytryptophan; Animals; Atropine; Benserazide; Benzimidazoles; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Diarrhea; Dioxanes; Indoles; Male; Mice; Parasympathetic Nervous System; Piperidines; Receptors, Serotonin; Sulfonamides

Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

Topics: Animals; Diarrhea; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Intestinal Diseases; Male; Mice; Piperidines; Radioligand Assay; Receptors, Opioid, mu; Structure-Activity Relationship

The pharmacological profile of bethanechol (CAS 674-38-4), metoclopramide (CAS 364-62-5), trimebutine (CAS 39133-31-8) and cisapride (CAS 81098-60-4) was studied in a series of simple pharmacological tests in rats and dogs. Bethanechol stimulated both gastric emptying and intestinal propulsion but displayed also the well-known behavioral effects of a direct muscarinic acetylcholine receptor agonist. Metoclopramide showed the profile of a centrally active dopamine D2 antagonist. In addition, metoclopramide displayed a stimulant effect on spontaneous gastric emptying in rats, an effect that could not be related to dopamine D2 antagonism. The only effect observed with trimebutine was protection from castor oil diarrhea, probably due to its reported interaction with peripheral opiate receptors. Cisapride was a potent stimulant of gastric emptying in rats, 7 times more potent than metoclopramide. Cisapride was also a very specific gastrokinetic, over a large dose range (specificity ratio: greater than or equal to 20) devoid of effects indicative for direct interaction with dopamine or acetylcholine receptors. The relationship between the differential activity profiles of the compounds in the present study and differences in their mechanism of action and side-effect liability is discussed.

Topics: Animals; Apomorphine; Bethanechol Compounds; Cisapride; Conditioning, Operant; Diarrhea; Dogs; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Motility; Metoclopramide; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Serotonin Antagonists; Species Specificity; Trimebutine; Vomiting

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

Topics: Diarrhea; Humans; Infant; Loperamide; Pakistan; Piperidines; Product Surveillance, Postmarketing

Topics: Diarrhea; Humans; Loperamide; Norfloxacin; Piperidines; Travel

Topics: Advertising; Diarrhea; Humans; Loperamide; Nonprescription Drugs; Piperidines; Self Medication

Topics: Chronic Disease; Diarrhea; Humans; Loperamide; Piperidines; Quality of Life

A computerised system for measurement of vibration at the abdominal surface was constructed which was addressed to the evaluation of gastrointestinal (GI) motor function. Preliminary studies revealed a dominant low frequency signal which was synchronous with the heartbeat and was considered representative of aortic pulsation. This was excluded by selective spectral filtration. The remaining signal was processed and measured by computer, with provision of quantitative energy values as well as of graphic display. The developed method, called surface vibration analysis (SVA) has been evaluated clinically; (a) against oral to caecal transit times (OCCT) of a standard solid meal, in five patients with severe postgastrectomy diarrhoea, seven patients with mild idiopathic diarrhoea and 22 healthy volunteers. (b) against prokinetic effects of a gastrointestinal stimulant (cisapride) in nine patients. In (a) postprandial SVA energy measurements were greater (SVA [*X (SEM)] = 406,933 (98,224] and oral to caecal transit of the solid meal was more rapid (OCTT = *90 (29) min) in the severe diarrhoea patients [postgastrectomy] than either the mild diarrhoea group (*SVA = 235,317 (50,780); *OCTT = *199 (42) min) or normal volunteers (*SVA = 212,062 (27,153); *OCTT = 242 (19) min) [p less than 0.01 for SVA and OCTT]. In the total group, an inverse correlation was observed between quantitative SVA energy values and oral to caecal transit times of solids (Spearman's rho = -0.486; p less than 0.01). In (b), drug stimulation of the GI tract caused an increase of fasting SVA measurements from *21,217 (5956) [before] to *41,937 (9606) [after] intravenous cisapride (p less than 0.05). This new technique may be useful for evaluation of gastrointestinal motor activity.

Topics: Adult; Cisapride; Diarrhea; Digestive System; Digestive System Physiological Phenomena; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Microcomputers; Middle Aged; Motor Neurons; Piperidines; Postgastrectomy Syndromes; Transducers; Vibration

Topics: Antineoplastic Agents; Diarrhea; Humans; Loperamide; Piperidines

Patients with chronic severe diarrhoea after truncal vagotomy and pyloroplasty are often difficult to treat using conventional antidiarrhoeal drugs and remain severely disabled. We examined the effect of two drugs, codeine phosphate and loperamide, on upper intestinal transit and carbohydrate absorption, measured non-invasively by serial exhaled breath hydrogen monitoring, in patients with postvagotomy diarrhoea who had previously failed to gain relief from drug therapy. Orocaecal transit was consistently faster in these patients than a group of controls and was associated with malabsorption of glucose. Codeine phosphate 60 mg significantly delayed transit in patients and controls and was associated with a reduction in glucose malabsorption and improvement in symptoms. Loperamide also delayed transit and improved symptoms, but the doses required for this effect (12-24 mg) were higher than usually considered necessary in secretory diarrhoea. These studies indicate that rapid intestinal nutrient transit and associated malabsorption is a factor in the development of diarrhoea postvagotomy and that symptomatic relief can be achieved in most patients by more rational use of existing drugs.

Topics: Adult; Aged; Chronic Disease; Codeine; Diarrhea; Female; Gastrointestinal Transit; Glucose; Humans; Intestinal Absorption; Loperamide; Male; Middle Aged; Piperidines; Vagotomy

Topics: Adult; Aged; Diarrhea; Female; Humans; Loperamide; Male; Middle Aged; Neurotic Disorders; Piperidines

Topics: Adolescent; Adult; Diarrhea; Female; Humans; Loperamide; Middle Aged; Piperidines

The antidiarrheal action of loperamide hydrochloride was tested against diarrhea experimentally induced in calves by intraduodenal infusion of castor oil or hypertonic solution of mannitol. The motility of 4 levels of the digestive tract (abomasum, jejunum, and proximal and spiral loops of the colon) was concomitantly recorded, using an electromyographic technique. Loperamide hydrochloride given per os at 0.4 mg/kg or intraduodenally or subcutaneously at 0.1 mg/kg 1 hour before mannitol or castor oil was given delayed diarrhea. Loperamide hydrochloride given alone orally at a dosage of 0.4 mg/kg did not modify the motility pattern of the digestive tract. Intraduodenally administered loperamide hydrochloride (0.1 mg/kg) increased the frequency of the cyclic activity of the jejunum, whereas subcutaneously administered loperamide hydrochloride at the same dose selectively inhibited the motility of the jejunum. Intraduodenal infusion of mannitol was followed by a disruption of the cyclic activity of the jejunum, and this effect was not antagonized by loperamide hydrochloride, whatever the route of administration. Castor oil infusion was not accompanied with changes in gastrointestinal motility. These results indicate that loperamide hydrochloride is active against an experimentally induced diarrhea in calves and that this action is not mediated through an effect on the digestive motility, at least monitored by this electromyographic technique.

Topics: Abomasum; Animals; Cattle; Cattle Diseases; Colon; Diarrhea; Electromyography; Gastrointestinal Motility; Jejunum; Loperamide; Piperidines

Topics: Diarrhea; Humans; Loperamide; Piperidines

Acute outbreaks of diarrhoea with high mortality rates are frequently observed in rabbits. Amongst various aetiological factors Escherichia coli or its toxins have been found to be commonly incriminated. Sulphonamides or antibiotics are used to treat rabbits with bacterial diarrhoea. The result of the antibiotic treatment is moderately successful. We had good results using oral rehydration treatment in combination with loperamide hydrochloride (Immodium) in a colony of rabbits with E. coli diarrhoea.

Topics: Acute Disease; Animals; Combined Modality Therapy; Diarrhea; Fluid Therapy; Loperamide; Piperidines; Rabbits; Rodent Diseases

Topics: Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Diarrhea; Female; Humans; Loperamide; Male; Middle Aged; Piperidines

The present investigation has been undertaken to illustrate the antibacterial effect on 20 diarrhoea producing enterobacteriaceae of an anti-depressive drug available as femoxetine and its three analogs. It has been shown that the stereo-isomeric trans forms of femoxetine are more than twice as active as the cis forms and inhibited all the strains below 400 microgram/ml (1.2 mM). The two cis compounds only inhibited 11 and 9 of the 20 strains respectively in the investigated area 100 microgram/ml - 800 microgram/ml (0.3 mM - 2.4 mM). Our investigations point out that the bacterial cell has a target for psychopharmacologically active agents. Thus the known psychopharmaca and their stereo-isomeric analogs may represent a pool of potentially new antimicrobial drugs. Furthermore the bacterial model may be useful as a model system in the study of the interaction of neuropharmacological agents and other membrane active compounds with biological membranes.

Topics: Anti-Bacterial Agents; Diarrhea; Enterobacteriaceae; Humans; Piperidines; Stereoisomerism; Structure-Activity Relationship

Aspirin reduced plasma concentrations of prostaglandin (PG) F alpha in 11 of 12 children with toddler diarrhoea, and usually, but not always, controlled the symptom. Loperamide consistently controlled toddler diarrhoea in 10 patients but had no effect on plasma PGF alpha. In eight patients experiencing spontaneous remission of symptoms, plasma PGF alpha was significantly lower than during diarrhoeal episodes. These results suggest that (a) toddler diarrhoea is in some cases mediated by PG, and (b) the effect of loperamide is independent of PG levels.

Topics: Antidiarrheals; Aspirin; Child, Preschool; Cyclooxygenase Inhibitors; Diarrhea; Diarrhea, Infantile; Humans; Infant; Loperamide; Piperidines; Prostaglandins F

Topics: Animals; Carboprost; Diarrhea; Female; Loperamide; Male; Mice; Muscle Contraction; Piperidines; Rats; Uterine Contraction

Prostaglandins and cyclic adenosine monophosphate have been claimed to play a major role in the morphine withdrawal syndrome, but intestinal secretion has not been ruled out as being responsible, at least in part, for the accompanying diarrhea. Therefore, experiments were performed in which the effect of naloxone-induced morphine withdrawal on jejunal and on colonic fluid transport was assessed in tied-off loops of rat intestine in vivo simultaneously with mucosal cyclic adenosine monophosphate levels or colonic luminal release of prostaglandin E2 or 5-hydroxytryptamine. Naloxone-induced withdrawal reversed fluid absorption to secretion without changing cyclic adenosine monophosphate levels, but markedly enhanced local prostaglandin E2 and 5-hydroxytryptamine release (p less than 0.01). Indomethacin and the 5-hydroxytryptamine receptor antagonist ketanserin prevented withdrawal-induced fluid secretion and the increase in prostaglandin E2 release without influencing the release of 5-hydroxytryptamine. In addition, the alpha 2-adrenergic receptor agonist clonidine promoted absorption during withdrawal, whereas atropine failed to influence fluid transport. These data suggest that naloxone-precipitated intestinal fluid secretion may contribute to diarrhea due to morphine withdrawal and that 5-hydroxytryptamine may play an important role in mediating this secretion through stimulation of local prostaglandin formation.

Topics: Animals; Atropine; Clonidine; Colon; Cyclic AMP; Diarrhea; Dinoprostone; Female; Humans; Indomethacin; Ketanserin; Morphine Dependence; Naloxone; Piperidines; Prostaglandins E; Rats; Rats, Inbred Strains; Serotonin; Substance Withdrawal Syndrome

Topics: Animals; Cholera Toxin; Cyclic AMP; Diarrhea; Enkephalin, Methionine; Intestinal Mucosa; Loperamide; Male; Naloxone; Piperidines; Rats; Water-Electrolyte Balance

Topics: Adult; Chlorpropamide; Diarrhea; Humans; Loperamide; Male; Medication Errors; Piperidines

To determine whether the antidiarrheal effect of loperamide is due to an effect on intestinal motor function or to an acceleration of the rate of absorption by the intestine (as has been suggested recently), we studied absorption during experimental diarrhea produced by the rapid intragastric infusion of electrolyte solution. In studies in which a 2700-ml bolus of electrolyte solution was infused into the stomach over 90 min, loperamide delayed the appearance of rectal effluent in each of 5 subjects and decreased the volume of rectal effluent from 1090 +/- 118 to 770 +/- 73 ml (p = 0.05). When intragastric infusion was continued for 5 h, producing steady-state total gut perfusion, the volume of effluent produced per unit time and the concentration of a nonabsorbable polyethylene glycol marker in rectal effluent was not different with or without loperamide, indicating that loperamide did not alter the rate of absorption by intestinal mucosal cells. Loperamide also had no effect during steady-state perfusion when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. Loperamide did substantially increase the intraluminal volume of the total gut, from 985 +/- 131 to 1764 +/- 195 ml (p less than 0.02). These results suggest that loperamide exerts its antidiarrheal effect by a change in the motor function of the intestine, which results in increased capacitance of the gut and a delay in the passage of fluid through the intestine. This change in motor function, rather than a change in the rate of absorption by intestinal mucosal cells, is responsible for the antidiarrheal effect of loperamide in our experimental diarrhea model.

Topics: Adult; Antidiarrheals; Diarrhea; Electrolytes; Gastrointestinal Motility; Humans; Intestinal Absorption; Loperamide; Male; Piperidines; Polyethylene Glycols; Vasoactive Intestinal Peptide

The beneficial effect of loperamide in some children with severe protracted diarrhoea which persisted when nil by mouth, made us suspect that loperamide may have an antisecretory action. Using a steady-state perfusion technique in rat jejunum we showed that loperamide inhibits cholera toxin induced secretion of water, sodium and chloride (p less than 0.001). This antisecretory action was blocked by naloxone and not mediated via an effect on tissue cyclic AMP level or adenylate cyclase activity. More recently we have studied the effect of loperamide on secretion of water in the rat jejunum induced by other agents with differing mechanisms of action. The first set of observations suggest that loperamide's antisecretory effect is mediated via opiate receptors either distal to, or separate from the adenylate cyclase/cyclic AMP pathway. Our more recent studies support the notion that loperamide has an effect on specific transport systems rather than non-specific passive diffusional processes.

Topics: Animals; Body Water; Cholera Toxin; Cyclic AMP; Deoxycholic Acid; Diarrhea; Dinoprostone; Intestinal Mucosa; Jejunum; Loperamide; Piperidines; Prostaglandins E; Rats; Rats, Inbred Strains

Both in vitro and in vivo studies of the influence of opiates on ion transport and of their antisecretory activity are described. Morphine and the synthetic opioid, loperamide, are included particularly. It is clear that the opiates have an antisecretory effect and can inhibit secretion induced by a variety of different secretagogues. Secretion induced experimentally in the human jejunum in vivo is reduced by loperamide, indicating a potential role for such an agent in the treatment of secretory diarrhoeas.

Topics: Animals; Chlorides; Diarrhea; Dinoprostone; Humans; In Vitro Techniques; Intestinal Absorption; Intestinal Mucosa; Loperamide; Morphine; Piperidines; Prostaglandins E; Rabbits; Time Factors; Toxins, Biological

Topics: Calcium-Binding Proteins; Calmodulin; Diarrhea; Humans; Loperamide; Phosphoric Diester Hydrolases; Piperidines

19 consecutive patients admitted with severe chronic diarrhoea which had failed to respond to standard therapeutic regimen were treated with 4 to 8 mg of loperamide daily for up to 50 weeks. A marked improvement was achieved in 13 out of the 19 patients (68%). The best results were observed in patients with ulcerative colitis and Crohn's disease. Patients with secretory diarrhoea did not improve. No major side effects were observed. It is concluded that loperamide is a highly effective and safe new drug in the treatment of patients with chronic inflammatory bowel diseases.

Topics: Adult; Aged; Carcinoid Tumor; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Diarrhea; Exocrine Pancreatic Insufficiency; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Short Bowel Syndrome; Time Factors

Topics: Child; Diarrhea; Diarrhea, Infantile; Humans; Intestinal Mucosa; Loperamide; Piperidines; Receptors, Opioid

Topics: Adult; Animals; Bacterial Infections; Child; Diarrhea; Humans; Loperamide; Piperidines; Rats

Topics: Animals; Cholera Toxin; Diarrhea; Electrolytes; Jejunum; Loperamide; Male; Piperidines; Rats; Water

Topics: Acute Disease; Child; Child, Preschool; Diarrhea; Diphenoxylate; Dysentery, Bacillary; Humans; Infant; Loperamide; Piperidines

Topics: Adolescent; Adult; Aged; Chronic Disease; Diarrhea; Female; Humans; Loperamide; Male; Middle Aged; Piperidines

Topics: Adult; Chronic Disease; Colonic Diseases, Functional; Diarrhea; Female; Humans; Intestinal Diseases; Loperamide; Male; Middle Aged; Piperidines

Topics: Diarrhea; Humans; Loperamide; Piperidines

1 Subcutaneous prostaglandin E2 (2.5 mg/kg) produces profuse diarrhoea in fed rats. 2 Pretreatment of rats with subcutaneous loperamide (1.0 mg/kg) completely prevents prostaglandin-induced diarrhoea. If naloxone is administered prior to loperamide injections the activity of the antidiarrhoeal compound is completely destroyed. 3 These data provide strong evidence that the antidiarrhoeal activity of loperamide is mediated via the opiate receptor.

Topics: Animals; Diarrhea; Loperamide; Male; Naloxone; Piperidines; Prostaglandins E; Rats

Effects of loperamide on diarrhea induced by castor oil and prostaglandin E1 were investigated in rats and mice and compared with those of narcotic analgesics, atropine, mecamylamine and local anesthetics. The following results were obtained. Loperamide markedly suppressed the appearance of diarrhea induced by oral administration of castor oil in rats and the ED50 values for 1 and 2 hr protection was 0.082 and 0.42 mg/kg p.o., respectively. Loperamide markedly suppressed the appearance of diarrhea induced by i.v. administration of prostaglandin E1 and the ED50 value for 2 hr protection was 0.24 mg/kg p.o. in rats. The ID120 min value of loperamide which was calculated on the basis of the dose producing a 20% or more inhibition of the charcoal transport in the small intestine for 120 min was 0.8 mg/kg p.o. in mice and this activity was 9.2 times more potent than that of morphine. The analgesic ED50 value (Haffner's method) and LD50 value of loperamide was 149 and 249 mg/kg p.o., respectively. These results suggest that loperamide has a potent anti-diarrheal activity and specificity to the gastrointestinal tract and inhibits the effect of prostaglandin E1 and ricinoleic acid on the intestinal tract in rats.

Topics: Analgesics; Analgesics, Opioid; Anesthetics, Local; Animals; Antidiarrheals; Castor Oil; Diarrhea; Dose-Response Relationship, Drug; Gastrointestinal Motility; Lethal Dose 50; Loperamide; Male; Piperidines; Prostaglandins E; Rats; Time Factors

63 patients (23--78 years) with irradiation-induced diarrhoea, the majority of them resistant to treatment with diphenoxylate, were started on 4-(p-chlorophenyl)-4-hydroxy-N,N'-dimethyl-alpha,alpha-diphenyl-1-piperidine butyramide (loperidine, Imodium) 4 mg daily. Doses were further adapted individually and the trial lasted for 3--72 days. Daily frequency and consistency of stools improved significantly, and abdominal cramps were clearly reduced. Stools became normal in 41 patients after a median time of 16.5 days (median daily dose: 4 mg), they improved in six other patients, but remained unchanged in eight and deteriorated in one patient. The remaining seven cases were not evaluated. No side-effects could be attributed to the drug.

Topics: Abdominal Neoplasms; Adult; Aged; Diarrhea; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Radiotherapy

1-(2,6-Dimethylphenyl)-3-methyl-amidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride) was shown to have potent antimotility, antidiarrheal and intestinal antisecretory activity in mice, rats and dogs. Antimotility activity was demonstrated in charcoal intestinal motility, gastric emptying and gastric and intestinal intraluminal pressure studies. Antidiarrheal activity was evaluated in castor oil-, prostaglandin E2-, carbachol-, and serotonin-induced diarrhea. Intestinal secretion induced by cholera toxin was inhibited by WHR-1142A. In general, WHR-1142A was more potent than diphenoxylate and loperamide although species differences were noted. The ED50 for inhibition of castor oil-induced diarrhea was 1.8 mg/kg p.o. and the duration of action at 16 mg/kg p.o. was at least 6 h. Unlike diphenoxylate, WHR-1142A showed no tolerance.

Topics: Amidines; Animals; Antidiarrheals; Carbachol; Charcoal; Cholera Toxin; Diarrhea; Diphenoxylate; Feces; Gastrointestinal Motility; Isonipecotic Acids; Loperamide; Male; Piperidines; Prostaglandins E; Rats; Serotonin; Stomach

45 patients with diarrheas appearing after exposure of the gastro-intestinal region to ionizing radiation were given loperamide in the course of a study. A few days after administration of the loperamide, normalization of the stools took place, except in three cases. Simultaneous tenesmic gripes, some of the patients had also suffered from, disappeared completely, with the exception of two cases where, however, normalization of the stools was obtained by means of the loperamide therapy. Subjective side-effects did not occur. Also no alterations of the blood count, hematological features, liver function tests or urine have been observed.

Topics: Abdominal Neoplasms; Adult; Aged; Diarrhea; Female; Humans; Loperamide; Middle Aged; Piperidines; Radiation Injuries; Radioisotope Teletherapy

Diarrhea causes considerable absenteeism and loss of working time among employees in the United States. One hundred employees with acute diarrhea at a Ford Motor Company plant were studied for four months to determine if loperamide hydrochloride treatment would control diarrheal symptoms, reduce absenteeism due to the condition, and be well-tolerated. Diarrhea was controlled with a median dosage of three capsules (6 mg total dose) and a range of two to 12 capsules. Ninety-six percent of the subjects were controlled after the first day, 98% by the third day. A statistically significant number were symptom free at their last clinical visits. Side effects were generally minor in nature. Substantially more than 1,000 man-hours of lost time were saved because of the treatment. Known drug dependents did not suffer from CNS effects or "highs". Loperamide acts directly on the intestinal wall to inhibit excessive peristalsis, thereby providing prompt, effective relief, with normal bowel patterns observed in these patients. The simple, individualized dosage is patient-oriented, rather than based on a fixed regimen. Because of its rapid onset of action, effective control of symptoms, low dosage, and being well-tolerated, loperamide meets the criteria for an effective antidiarrheal agent in industry.

Topics: Absenteeism; Acute Disease; Adult; Automobiles; Diarrhea; Female; Humans; Loperamide; Male; Occupational Medicine; Peristalsis; Piperidines

An open study of loperamide in seven chronic diarrhoea patients who were inadequately controlled by previous anti-diarrhoeal therapy is reported. All patients were well controlled by small amounts of loperamide and most could not eat a normal diet. No side-effect were reported.

Topics: Adult; Chronic Disease; Colitis; Diarrhea; Diverticulitis, Colonic; Enteritis; Humans; Loperamide; Piperidines

Loperamide, a new antidiarrhoeal compound, effectively antagonised prostaglandin induced diarrhoea in adult healthy male volunteers and in patients undergoing pregnancy termination with prostaglandins. This compound is effective in inhibiting prostaglandin induced fluid accumulation in the small intestine in rats. Loperamide also blocked smooth muscle stimulating action of prostaglandins, acetylcholine and histamine on gastrointestinal smooth muscle preparations from several laboratory animals.

Topics: Abortion, Induced; Animals; Cricetinae; Diarrhea; Drug Evaluation, Preclinical; Female; Humans; Loperamide; Male; Muscle Contraction; Muscle, Smooth; Piperidines; Pregnancy; Prostaglandin Antagonists; Prostaglandins E; Prostaglandins F; Rats

Topics: Diarrhea; Humans; Loperamide; Piperidines

Topics: Acute Disease; Adolescent; Adult; Aged; Diarrhea; Drug Evaluation; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Tablets

Topics: Antidiarrheals; Diarrhea; Humans; Loperamide; Piperidines

Topics: Child; Child, Preschool; Diarrhea; Drug Evaluation; Humans; Infant; Infant, Newborn; Loperamide; Piperidines

Topics: Animals; Cattle; Cattle Diseases; Dexetimide; Diarrhea; Drug Therapy, Combination; Enteritis; Female; Male; Piperidines

Topics: Child, Preschool; Diarrhea; Humans; Infant; Loperamide; Piperidines

The time-course of castor oil-induced diarrhea in fasted rats was quantified by weighing stools every 15 minutes for 8 hours after the challenge and then after 24 hours. Diarrhea began within 1 hour as a series of rapidly occurring evacuations over 20 to 40 minutes. The mean weight of these stools was 5.7 g; later irregular evacuations increased the weight to 9.4 g at 8 hours. The area of individual time-weight diagrams had a median value of 432 units. Pretreatment with 0.16 mg/kg of loperamide, a new antidiarrheal drug, significantly decreased the area of similarly obtained diagrams; 0.31 mg/kg caused a 50% reduction. This antagonism by loperamide of castor oil-induced diarrhea may involve reduction in the severity of inflammatory changes in the intestinal wall.

Topics: Animals; Body Weight; Castor Oil; Diarrhea; Feces; Female; Loperamide; Piperidines; Rats; Time Factors

Topics: Administration, Oral; Amides; Animals; Antidiarrheals; Castor Oil; Chlorobenzenes; Codeine; Diarrhea; Dogs; Drug Evaluation, Preclinical; Female; Gastrointestinal Agents; Guinea Pigs; Isonipecotic Acids; Lethal Dose 50; Male; Mice; Morphine; Nitriles; Piperidines; Rats; Time Factors

Topics: Animals; Benzyl Compounds; Cattle; Cattle Diseases; Diarrhea; Piperidines

Topics: Administration, Oral; Animals; Animals, Newborn; Anti-Bacterial Agents; Benzyl Compounds; Cattle; Cattle Diseases; Chloramphenicol; Diarrhea; Drug Therapy, Combination; Gastrointestinal Motility; Neomycin; Parasympatholytics; Piperidines; Piperidones; Time Factors

Topics: Animals; Castor Oil; Codeine; Diarrhea; Female; Gastrointestinal Agents; Isonipecotic Acids; Nitriles; Phenylbutyrates; Piperidines; Rats; Structure-Activity Relationship

Topics: Analgesics; Animals; Diarrhea; Ergotamine; Exophthalmos; Female; Male; Methods; Mice; Morphine; Phenothiazines; Piperazines; Piperidines; Serotonin Antagonists; Tryptamines

Topics: Alkaloids; Bronchitis; Chromatography; Diarrhea; Dysentery; Infrared Rays; Optical Rotation; Piperidines; Plant Extracts; Plants; Quinolizines; Spectrum Analysis; Syphilis; Ultraviolet Rays

Topics: Animals; Atropine; Benzyl Compounds; Carbon Isotopes; Diarrhea; Dogs; Female; Guinea Pigs; Ileum; In Vitro Techniques; Isomerism; Lethal Dose 50; Male; Methacholine Compounds; Mice; Muscle Contraction; Parasympatholytics; Pilocarpine; Piperidines; Piperidones; Pupil; Rats; Salivation; Tremorine

Topics: Amines; Animals; Chromatography, Ion Exchange; Chromatography, Thin Layer; Diarrhea; Intestine, Small; Intestines; Piperidines; Pyrrolidines; Swine; Swine Diseases; Weaning

Topics: Animals; Diarrhea; Ganglionic Blockers; Gastrointestinal Motility; Guinea Pigs; Hexamethonium Compounds; Ileum; In Vitro Techniques; Morphine; Muscle Contraction; Muscle, Smooth; Piperidines; Reflex

Topics: Biomedical Research; Colchicine; Colectomy; Colitis; Colitis, Ulcerative; Colonic Diseases; Colonic Diseases, Functional; Crohn Disease; Diabetic Neuropathies; Diarrhea; Diphenoxylate; Diverticulitis; Diverticulitis, Colonic; Drug Therapy; Dysentery; Dysentery, Amebic; Enteritis; Gastroenteritis; Humans; Piperidines; Postgastrectomy Syndromes; Postoperative Complications; Toxicology; Virus Diseases

Topics: Coma; Diarrhea; Female; Humans; Infant; Parasympatholytics; Piperidines

Topics: Diarrhea; Humans; Piperidines

Topics: Cyclohexanes; Diarrhea; Drug Therapy; Humans; Kaolin; Opium; Parasympatholytics; Pectins; Piperidines; Psyllium; Thiophenes; Toxicology

Topics: Antidiarrheals; Child; Diagnosis, Differential; Diarrhea; Iatrogenic Disease; Intestinal Obstruction; Piperidines; Radiography; Toxicology

Topics: Abdomen; Abdominal Neoplasms; Diarrhea; Humans; Neoplasms; Pelvic Neoplasms; Piperidines; Radiation Injuries

Topics: Antidiarrheals; Cyanides; Diarrhea; Piperidines

Topics: Benzilates; Diarrhea; Disease; Double-Blind Method; Humans; Intestinal Diseases; Intestines; Parasympatholytics; Piperidines