piperidines and Chronic-Disease

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; 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Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for inflammatory myositis; histological subsets reported include dermatomyositis, necrotising myopathy and chronic graft-versus-host disease (cGVHD)-related myositis. Though corticosteroids and various immunosuppressive therapies have been used, there is a lack of consensus guidelines dictating therapy.. Recent evidence suggests the fascia as a preferential target in cGVHD myositis, with conditioning regimens promoting fascial microtrauma. Positron emission tomography (PET) can be a useful diagnostic tool, and case reports suggest that the Bruton's tyrosine kinase inhibitor ibrutinib may have therapeutic potential. Emerging therapies include targeted B cell depletion with rituximab, and extracorporeal photophoresis. Clinicians need to be vigilant for the development of inflammatory myositis post-allogeneic HSCT as most patients respond to treatment. Advances in immunohistochemistry to determine the dominant cell type and cytokine profile may enable targeted and individualised therapies.

Topics: Adenine; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Myositis; Piperidines; Pyrimidines; Rituximab

Despite improvements in prevention and treatment of acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor-, patient-, and transplant-related (hematopoietic cell transplant [HCT]) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid-refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.

Topics: Adenine; Adrenal Cortex Hormones; Chronic Disease; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Piperidines

Cough is among the most common complaints for which patients worldwide seek medical attention. In a majority of patients with chronic cough (defined as cough of greater than 8 weeks' duration), successful management results from a thorough evaluation and treatment of underlying causes. In a subgroup of patients, however, cough proves refractory to therapeutic trials aimed at known reversible causes of chronic cough. Such patients are appropriately termed as having refractory chronic cough. At present, safe and effective medications are lacking for this challenging patient population. Currently available therapeutic options are usually ineffective or achieve antitussive effect at the expense of intolerable side effects, typically sedation. Fortunately, the past decade has witnessed great progress in elucidating underlying mechanisms of cough. From that knowledge, aided by the development of validated instruments to measure objective and subjective cough-related end points, numerous antitussive drug development programs have emerged. The most active area of inquiry at present involves antagonists of the purinergic P2X receptors. Indeed, four clinical programs (one in Phase 3 and three in Phase 2) are currently underway investigating antagonists of receptors comprised entirely or partially of the P2X3 subunit as potential antitussive medications. Herein we review the foundation on which P2X receptor antagonists were developed as potential antitussive medications and provide an update on current clinical trials.

Topics: Ageusia; Antitussive Agents; Chronic Disease; Clinical Trials as Topic; Cough; Humans; Imidazoles; Piperidines; Purinergic P2X Receptor Antagonists; Pyridines; Pyrimidines; Receptors, Purinergic P2X3; Sulfonamides

Tofacitinib is an oral Janus kinase (JAK) inhibitor that targets JAK1 and JAK3, and thus regulates immune response. Therefore, tofacitinib is used to treat immune-mediated inflammatory diseases such as chronic plaque psoriasis. The objective of this study was to systematically assess the efficacy and safety of tofacitinib in treating chronic plaque psoriasis.. To systematically review the efficacy and safety of tofacitinib in the treatment of chronic plaque psoriasis, we performed a meta-analysis to evaluate the efficacy and safety of tofacitinib in patients with chronic plaque psoriasis.. Databases including PubMed, Embase, and The Cochrane Library were searched for randomized controlled trials about the efficacy and safety of tofacitinib in treating chronic plaque psoriasis from inception to August 2017 (PROSPERO Code No: CRD42017076587).. Six articles (seven randomized controlled trial studies) involving 3743 patients were included. The meta-analysis results showed that for efficacy, tofacitinib (5 mg or 10 mg) compared with placebo can significantly improve the Physician's Global Assessment response, PASI75, and PASI90 after treatment. For safety, the incidence of adverse reactions was statistically significantly higher for tofacitinib compared with placebo.. Treatment of chronic plaque psoriasis with tofacitinib is effective, but there may be more adverse reactions.

Topics: Chronic Disease; Humans; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Chronic graft-versus-host disease (cGvHD) is a grave complication of allogeneic hematopoietic cell transplantation (alloHCT). Despite the use of prophylactic regimens for cGvHD, a significant proportion of patients develop cGvHD following alloHCT. The standard first-line therapy for cGvHD is high-dose corticosteroids. However, roughly 50% of patients will exhibit steroid-refractory or steroid-dependent cGvHD, which increases the risk of non-relapse mortality. Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) in August 2017 for the treatment of cGvHD after failure of one or more lines of systemic therapy. The approval was based on a study that demonstrated high rates of sustained responses and manageable toxicities in patients with steroid-refractory or -dependent cGvHD. In this review, we address the mechanisms of action of ibrutinib in cGvHD, as well as preclinical and clinical data supporting its use in patients with this important post-transplant complication.

Topics: Adenine; Animals; Chronic Disease; Drug Interactions; Graft vs Host Disease; Humans; Piperidines; Pyrazoles; Pyrimidines

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for a number of hematologic conditions, both malignant and nonmalignant. However, its success can be limited by the development of acute and chronic graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) is the most common long-term complication following allo-SCT, and patients who develop this condition have significantly higher morbidity and mortality and significantly lower quality of life than patients who do not. Until recently, there were no US Food and Drug Administration (FDA)-approved therapies for cGVHD treatment. In this review article, we describe how ibrutinib was identified as potential cGVHD therapy based on preclinical cGVHD models and clinical studies in B-cell malignancies and elucidation of its mechanisms of action in cGVHD. Results from a phase 2 clinical trial that was designed based on National Institutes of Health Criteria for the grading and staging of cGVHD culminated in the FDA-approval of ibrutinib as second line therapy of steroid-refractory or steroid-resistant cGVHD. Results of ibrutinib studies in phase 3 randomized studies, for cGVHD prophylaxis and as first -line testing along with steroids will be especially important in selecting the preferred indications for ibrutinib in patients at risk for or who have developed cGVHD.

Topics: Adenine; Animals; B-Lymphocytes; Chronic Disease; Drug Approval; Drug Resistance; Graft vs Host Disease; Humans; Neoplasms, Plasma Cell; Piperidines; Pyrazoles; Pyrimidines; Steroids; United States; United States Food and Drug Administration

The outlook for patients with psoriasis has improved significantly over the last 10 years with the introduction of targeted therapies. Cytokines exert their effects by activating intracellular signaling and transcription pathways, among which there are Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) pathways. JAKs are intracellular second messengers that are crucial for transmitting extracellular cytokine signals to the cell. JAK inhibition interrupts intracellular signaling and can suppress immune cell activation and inflammation in T-cell-mediated disorders, such as psoriasis. Consequently, JAKs are the subject of intensive research activity, since they represent possible therapeutic targets. Tofacitinib is an orally available compound belonging to a novel category of nonbiologic drugs, the "JAK inhibitors", which target JAKs. Recently, oral and topical formulations of tofacitinib have been demonstrated to be safe and effective for the treatment of plaque psoriasis in randomized clinical trials. In particular, a 10 mg bid dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly. Questions remain unresolved regarding the safety risk beyond the 5 mg bid dose. This review, assessing the available scientific literature, focuses on the profile of tofacitinib, as investigational compound in the treatment of plaque psoriasis. An overview of the efficacy and safety data from randomized clinical trials is provided. In addition, the authors highlight future potential applications of tofacitinib in other skin diseases, in particular alopecia areata and vitiligo.

Topics: Chronic Disease; Clinical Trials as Topic; Humans; Janus Kinase 3; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles

This chapter describes the potential use of flavopiridol, a CDK inhibitor with anti-inflammatory and anti-proliferative activities, in the treatment of various chronic diseases. Flavopiridol arrests cell cycle progression in the G1 or G2 phase by inhibiting the kinase activities of CDK1, CDK2, CDK4/6, and CDK7. Additionally, it binds tightly to CDK9, a component of the P-TEFb complex (CDK9/cyclin T), and interferes with RNA polymerase II activation and associated transcription. This in turn inhibits expression of several pro-survival and anti-apoptotic genes, and enhances cytotoxicity in transformed cells or differentiation in growth-arrested cells. Recent studies indicate that flavopiridol elicits anti-inflammatory activity via CDK9 and NFκB-dependent signaling. Overall, these effects of flavopiridol potentiate its ability to overcome aberrant cell cycle activation and/or inflammatory stimuli, which are mediators of various chronic diseases.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Antiviral Agents; Apoptosis; Cardiovascular Agents; Cell Cycle Checkpoints; Cell Proliferation; Chronic Disease; Disease Models, Animal; Drug Discovery; Flavonoids; Humans; Molecular Structure; Phytotherapy; Piperidines; Plants, Medicinal; Signal Transduction

To analyze lipid changes in patients with rheumatoid arthritis (RA) and patients with spondyloarthritis (SpA) treated with biologic agents or tofacitinib in randomized clinical trials (RCTs).. A systematic literature search was performed, using the Medline, Embase, Cochrane Library, and Web of Knowledge databases. Meta-analyses were performed using random-effects models to assess changes in the percentage of patients with abnormal lipid values or in the mean percentage of increase in the cholesterol and triglycerides levels.. Twenty-five of 4,527 identified articles met the inclusion criteria. Compared with RA patients treated with placebo, those treated with tocilizumab were more likely to have hypercholesterolemia (odds ratio [OR] 4.64; 95% confidence interval [95% CI] 2.71, 7.95 [P < 0.001]), increased levels of high-density lipoprotein (HDL) cholesterol (OR 2.25; 95% CI 1.14, 4.44 [P = 0.020]), and increased levels of low-density lipoprotein (LDL) cholesterol (OR 4.80; 95% CI 3.27, 7.05 [P < 0.001]); this was not observed in patients treated with tumor necrosis factor (TNF) antagonists (OR 1.54; 95% CI 0.90, 2.66 [P = 0.119]) or tofacitinib (OR 3.4; 95% CI 0.62, 18.55 [P = 0.158]). Among patients receiving tofacitinib 5 mg twice daily, the mean percentage of increases in the HDL cholesterol level (weighted mean difference [WMD] 13.00 mg/dl; 95% CI 12.08, 13.93 [P < 0.001]) and the LDL cholesterol level (WMD 11.20 mg/dl; 95% CI 10.08, 12.32 [P < 0.001]) were higher than those in the comparator groups. Among patients treated with tofacitinib 10 mg twice daily, the mean percentage of increases in the HDL cholesterol level (WMD 15.21 mg/dl; 95% CI 13.28, 17.14 [P < 0.001]) and the LDL cholesterol level (WMD 15.42 mg/dl; 95% CI 11.77, 19.06 [P < 0.001]) were also higher than those in the comparator groups. No data were available for RA treated with other biologic agents or for SpA.. In patients with RA treated with tocilizumab or tofacitinib but not with TNF antagonists, moderate changes in lipids are observed. Whether these changes pertain to the control of inflammation or to the mechanism of action of the biologic agents or tofacitinib remains undetermined.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Biological Products; Chronic Disease; Female; Humans; Lipids; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Spondylarthritis; Treatment Outcome

Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s, resulting in severe disability in some 150 to 200 million people per annum. In addition to mood and behavioural problems, cognition-particularly memory, attention and executive function-are commonly impaired by TBI. Cognitive problems following TBI are one of the most important factors in determining people's subjective well-being and their quality of life. Drugs are widely used in an attempt to improve cognitive functions. Whilst cholinergic agents in TBI have been reviewed, there has not yet been a systematic review or meta-analysis of the effect on chronic cognitive problems of all centrally acting pharmacological agents.. To assess the effects of centrally acting pharmacological agents for treatment of chronic cognitive impairment subsequent to traumatic brain injury in adults.. We searched ALOIS-the Cochrane Dementia and Cognitive Improvement Group's Specialised Register-on 16 November 2013, 23 February 2013, 20 January 2014, and 30 December 2014 using the terms: traumatic OR TBI OR "brain injury" OR "brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Supplementary searches were also performed in MEDLINE, EMBASE, PsycINFO, The Cochrane Library, CINAHL, LILACs, ClinicalTrials.gov, the World Health Organization (WHO) Portal (ICTRP) and Web of Science with conference proceedings.. We included randomised controlled trials (RCTs) assessing the effectiveness of any one centrally acting pharmacological agent that affects one or more of the main neurotransmitter systems in people with chronic traumatic brain injury; and there had to be a minimum of 12 months between the injury and entry into the trial.. Two review authors examined titles and abstracts of citations obtained from the search. Relevant articles were retrieved for further assessment. A bibliographic search of relevant papers was conducted. We extracted data using a standardised tool, which included data on the incidence of adverse effects. Where necessary we requested additional unpublished data from study authors. Risk of bias was assessed by a single author.. Only four studies met the criteria for inclusion, with a total of 274 participants. Four pharmacological agents were investigated: modafinil (51 participants); (-)-OSU6162, a monoamine stabiliser (12 participants of which six had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A meta-analysis could not be performed due to the small number and heterogeneity of the studies.All studies examined cognitive performance, with the majority of the psychometric sub-tests showing no difference between treatment and placebo (n = 274, very low quality evidence). For (-)-OSU6162 modest superiority over placebo was demonstrated on three measures, but markedly inferior performance on another. Rivastigmine was better than placebo on one primary measure, and a single cognitive outcome in a secondary analysis of a subgroup with more severe memory impairment at baseline. The study of modafinil assessed clinical global improvement (n = 51, low quality evidence), and did not find any difference between treatment and placebo. Safety, as measured by adverse events, was reported by all studies (n = 274, very low quality evidence), with significantly more nausea reported by participants who received rivastigmine compared to placebo. There were no other differences in safety between treatment and placebo. No studies reported any deaths.. There is insufficient evidence to determine whether pharmacological treatment is effective in chronic cognitive impairment in TBI. Whilst there is a positive finding for rivastigmine on one primary measure, all other primary measures were not better than placebo. The positive findings for (-)-OSU6162 are interpreted cautiously as the study was small (n = 6). For modafinil and atomoxetine no positive effects were found. All four drugs appear to be relatively well tolerated, although evidence is sparse.

Topics: Adolescent; Adult; Aged; Atomoxetine Hydrochloride; Benzhydryl Compounds; Brain Injuries; Chronic Disease; Cognition; Cognition Disorders; Humans; Middle Aged; Modafinil; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

The evaluation of quality of life (QoL) and its modification through therapeutic interventions has become a prioritary concern in recent years and a requirement on the part of regulatory agencies for the authorization of new drugs. In clinical studies of allergic disorders, particularly allergic rhinitis and urticaria, different types of generic questionnaires have been used - especially disease specific instruments such as the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) or skin disease specific tools such as the Dermatology Life Quality Index (DLQI). Throughout its clinical development, bilastine has been shown to be more effective than placebo and at least as effective as cetirizine, levocetirizine, fexofenadine or desloratadine in controlling the symptoms of seasonal allergic rhinitis and chronic urticaria. QoL has been studied as a secondary objective in three allergic rhinitis clinical trials, using the RQLQ, in a total of 2335 patients. Likewise, in chronic urticaria, QoL has been evaluated using the DLQI in a total of 525 patients, versus levocetirizine and placebo. The improvement in the QoL parameters in these studies (RQLQ or DLQI domains) at all times proved proportional to the symptoms improvement. In general, the data obtained relating to changes in QoL are concordant with the mean global visual analog scale (VAS in mm) values and their changes, from the beginning until the end of the treatment period, for all of the trials, for bilastine and all its comparators.

Topics: Benzimidazoles; Chronic Disease; Histamine H1 Antagonists; Humans; Piperidines; Quality of Life; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Urticaria

Histamine is a key mediator in the development of allergy symptoms, and oral H(1)-antihistamines are among the most widely used treatments for symptomatic relief in conditions such as allergic rhinitis and chronic urticaria. Ebastine is a second-generation antihistamine which has been shown to be an effective treatment for both seasonal and perennial allergic rhinitis. In controlled clinical trials in adult and adolescent patients with allergic rhinitis, ebastine 10 mg once-daily improved symptoms to a significantly greater extent than placebo and to a similar extent as loratadine 10 mg and cetirizine 10 mg (both once-daily), while ebastine 20 mg proved to be more effective than these two comparator antihistamines. In addition, ebastine was significantly more effective than placebo at relieving the symptoms of chronic idiopathic urticaria. Ebastine provides efficacy throughout the 24-h dosing interval with once-daily administration and clinical benefit is seen from the first day of treatment. Small studies have found beneficial effects for ebastine in patients with other disorders, including cold urticaria, dermographic urticaria, atopic asthma, mosquito bites and (in combination with pseudoephedrine) the common cold. In addition to the regular ebastine tablet, a fast-dissolving tablet (FDT) formulation, which disintegrates in the mouth without the aid of a drink, is also available. It has been shown to be bioequivalent to the regular tablet, and to be significantly more effective than desloratadine at reducing histamine-induced cutaneous wheals. A number of patient surveys demonstrated that the majority of individuals who tried the fast-dissolving formulation reported it to be convenient for use, fast-acting and preferred it to their previous antihistamine medication. Perhaps most importantly, a large proportion of patients indicated that they would prefer to use this new formulation in the future. Ebastine has a rapid onset of action and it can be administered once-daily, with or without food. Dose modifications are not needed in elderly patients, or in those with renal or mild to moderate hepatic impairment. Ebastine is generally well-tolerated, and clinical studies showed that at usual therapeutic doses of 10 and 20 mg once-daily, it had no clinically relevant adverse effects on cognitive function and psychomotor performance or on cardiovascular function. In conclusion, ebastine is an effective and generally well-tolerated treatment for allergic rhini

Topics: Animals; Butyrophenones; Chronic Disease; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Urticaria

Topics: Acetylcholine; Adrenergic alpha-2 Receptor Agonists; Amines; Analgesics; Animals; Brain-Derived Neurotrophic Factor; Chronic Disease; Clonidine; Cyclohexanecarboxylic Acids; Donepezil; Drug Therapy, Combination; Gabapentin; gamma-Aminobutyric Acid; Humans; Indans; Neuralgia; Norepinephrine; Piperidines; Posterior Horn Cells; Receptors, Adrenergic, alpha-2; Receptors, Muscarinic

Obesity is a chronic metabolic disorder that affects one third of American adults. Modest weight losses of just 5% to 10% of body weight, which are achievable with lifestyle modification and pharmacotherapy, can lead to remarkable improvements in many obesity-associated co-morbidities, including dyslipidemia, hypertension, and type 2 diabetes. In this review, the indications for pharmacotherapy and the goals of treatment are discussed, and current and future pharmacologic approaches to the treatment of obesity are examined. Current pharmacologic therapies for obesity are limited, but recent advances in our understanding of the complex and overlapping endocrine pathways that regulate body weight have led to new opportunities for antiobesity drug development. Important drug targets that are highlighted in this review include adipocyte-derived hormones, hypothalamic neuropeptides, and gastrointestinal hormones.

Topics: Amyloid; Anti-Obesity Agents; Appetite Depressants; Body Weight; Chronic Disease; Comorbidity; Cyclobutanes; Exenatide; Gastrointestinal Hormones; Humans; Islet Amyloid Polypeptide; Lactones; Leptin; Metformin; Obesity; Orlistat; Peptides; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Venoms

Topics: Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Humans; Nicergoline; Piperidines; Pyridines; Vasodilator Agents

The clinical use of an intravenous opioid testing can help to predict whether opioids will be beneficial. The determination of individual opioid responsiveness justifies subsequent long-term opioid treatment and is generally recommended. An overview over current testing procedures is given with particular regard to choice of opioid, maximum dose, determination of endpoints and duration of testing and recovery. Remifentanil testing is a new approch and is studied in a randomized placebo-controlled cross-over study in 24 patients suffering from severe non-cancer pain. An ascending infusion of remifentanil and placebo respectively was titrated against endpoints. The testing allowed a disctinction between 11 opioid-responders and 13 non-responders. Complete recovery after end of infusion was rapid with a reach of baseline conditions after 25 min in all patients. Thus the complete remifentanil testing procedure required at utmost 1 h. In conclusion, remifentanil testing offers a more rapid procedure allowing the routine use in an ambulatory setting.

Topics: Analgesics, Opioid; Chronic Disease; Dose-Response Relationship, Drug; Endpoint Determination; Humans; Infusions, Intravenous; Pain; Piperidines; Remifentanil; Treatment Outcome

The medical and social impact of cough is substantial. Current antitussive agents at effective doses have adverse events such as drowsiness, nausea and constipation that limit their use. There is also recent evidence that standard antitussive agents, such as codeine, may not reduce cough during upper respiratory infections. Therefore, there is a need for more effective and better-tolerated agents. The efficacy of levocloperastine, a novel antitussive, which acts both centrally on the cough center and on peripheral receptors in the tracheobronchial tree in treating chronic cough, was compared with that of other standard antitussive agents (codeine, levodropropizine and DL-cloperastine) in six open clinical trials. The studies enrolled patients of all ages with cough associated with various respiratory disorders including bronchitis, asthma, pneumonia and chronic obstructive pulmonary disease. Levocloperastine significantly improved cough symptoms (intensity and frequency of cough) in all trials, and improvements were observed after the first day of treatment. In children, levocloperastine reduced nighttime awakenings and irritability, and in adults it was effective in treating cough induced by angiotensin-converting enzyme inhibitors. When compared with other antitussive agents, levocloperastine had improved or comparable efficacy, with a more rapid onset of action. Importantly, no evidence of central adverse events was recorded with levocloperastine, whereas drowsiness was reported by a significant number of patients receiving codeine. Levocloperastine is an effective antitussive agent for the treatment of cough in patients of all ages. It has a more rapid onset of action than standard agents with an improved tolerability profile.

Topics: Adolescent; Adult; Aged; Antitussive Agents; Bronchitis; Chronic Disease; Clinical Trials as Topic; Codeine; Cough; Female; Humans; Lung Diseases; Male; Middle Aged; Patient Selection; Piperidines; Propylene Glycols; Stereoisomerism; Treatment Outcome

Dyspepsia affects one in four Australians; of those who present in general practice, the majority will have functional or non-ulcer dyspepsia, with no structural explanation for their symptoms. Older patients who present for the first time with dyspepsia, and those with 'alarm features' deserve immediate investigation (preferably by upper endoscopy), to exclude cancer, peptic ulcer or oesophagitis. Other patients may be given empiric therapy (for example, a prokinetic or H2 blocker) initially, but require investigation if this fails. The role of Helicobacter pylori infection in functional dyspepsia is uncertain.

Topics: Adult; Aged; Antacids; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Bismuth; Child; Cholelithiasis; Chronic Disease; Cisapride; Diagnosis, Differential; Domperidone; Dopamine Antagonists; Dyspepsia; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Metoclopramide; Peptic Ulcer; Piperidines; Stomach Neoplasms

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

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

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

Asthma is a chronic disease requiring long-term treatment, principally on an ambulant basis. A regimen is described involving all the measures which are practicable in ambulant use--elimination of allergens, hyposensitization and multiple drug treatment with corticosteroids, ACTH, beta-adrenergic agents, anticholinergics, theophylline, sodium cromoglicate and the new compound, ketotifen--taking into account both the aetiology and pathogenesis of the disease and synergistic effects of the available medicines. The immediate aim is to give the patient sustained freedom from symptoms. Once this has been achieved, multiple drug treatment can gradually give way to a protective/prophylactic regimen. Two-and-a-half years of experience with the oral antianaphylactic histamine-release inhibitor, ketotifen, have convinced us that this new drug is very suitable both as part of a multiple-drug regimen designed to bring the condition under control, and as a prophylactic for subsequent protection against further attacks. An additional advantage of ketotifen is the very low incidence of adverse reactions. Brief reference is also made to the treatment of infections and to the role of psychotherapy, breathing exercises and sport in asthma therapy.

Topics: Adrenergic beta-Agonists; Adrenocorticotropic Hormone; Allergens; Asthma; Chronic Disease; Cromolyn Sodium; Desensitization, Immunologic; Drug Therapy, Combination; Glucocorticoids; Humans; Parasympatholytics; Piperidines; Theophylline; Thiophenes

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

This single-arm, multicentre, phase I study is the first study of zanubrutinib, a potent, specific, irreversible Bruton tyrosine kinase (BTK) inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. The objectives were to evaluate safety and preliminary anti-tumour activity. Forty-four patients received zanubrutinib 320 mg once daily (QD) (n = 10) or 160 mg twice daily (BID) (n = 34) until disease progression or unacceptable toxicity. 29.5% of patients received zanubrutinib for at least two years. The most common adverse event (AE) and the most common grade 3 or higher AE was neutrophil count decreased (54.5% and 25.0% respectively). Two patients (4.5%) discontinued treatment due to AEs and one treatment-emergent AE led to death. All haemorrhagic events were grade 1-2 (except for one non-serious grade 3 purpura). No second primary malignancies, tumour lysis syndrome, or atrial fibrillation/flutter occurred. The overall response rate was 52.3% (complete response rate, 18.2%). Patients with all cancer subtypes benefited from treatment. BTK C481S/R or L528W mutations were found in zanubrutinib-progressive patients. The safety/efficacy profiles of patients treated with 320 mg QD and 160 mg BID were comparable and similar daily area under the curve (AUC) was achieved. Overall, zanubrutinib was well tolerated and either of these two regimens is clinically practical. Registered at ClinicalTrials.gov (NCT03189524, on 16 June 2017, https://clinicaltrials.gov/ct2/show/NCT03189524).

Topics: Agammaglobulinaemia Tyrosine Kinase; China; Chronic Disease; Humans; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

Topics: Adenine; Adolescent; Chronic Disease; Graft vs Host Disease; Humans; Japan; Piperidines; Pyrazoles; United States

Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough.. Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score.. All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated.. Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation.. EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu.

Topics: Aged; Antitussive Agents; Bridged Bicyclo Compounds, Heterocyclic; Chronic Disease; Cough; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurokinin-1 Receptor Antagonists; Pilot Projects; Piperidines; Quality of Life; Respiratory Function Tests; Severity of Illness Index; Surveys and Questionnaires

Treatment standards for chronic lymphocytic leukemia (CLL) have been transformed with the advent of effective inhibitors of B-cell receptor signaling such as ibrutinib - a first-in-class inhibitor of BTK. Off-target kinase inhibitions by ibrutinib are thought to contribute to its adverse events. Zanubrutinib is a next-generation BTK inhibitor with minimal off-target effects, sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes from patients with B-cell malignancies and promising responses in patients with CLL. Described here is a head-to-head Phase III study comparing the efficacy and safety of zanubrutinib with those of ibrutinib in patients with CLL/small lymphocytic lymphoma in the relapsed/refractory setting.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Chronic Disease; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Outcome Assessment, Health Care; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Safety

Chronic spontaneous urticaria (CSU) is a debilitating condition, adversely affecting the patient's quality of life. Bilastine is a recently introduced, non-sedative H1-antihistamine for its treatment. We wanted to compare the effectiveness, safety, and tolerability of bilastine 20 mg vs levocetirizine 5 mg in moderate-to-severe CSU. We conducted a double-blind, randomized controlled trial with two groups: bilastine 20 mg (n = 31) and levocetirizine 5 mg (n = 27), once daily for 42 days. We included patients (18-65 years), with moderate-to-severe CSU. UAS7, VAS, and DLQI were used to assess severity of urticaria, global urticaria-induced discomfort and quality of life, respectively. DLQI was assessed at baseline (D0) and end-of-treatment (D42), while UAS7 and VAS were noted at baseline and all follow-up visits. Assessment of UAS7 alteration was our primary objective, while changes in DLQI and VAS were the secondary outcomes. Safety was assessed by recording drug-related adverse events, biochemical investigations, and electrocardiogram, along with tolerability and compliance. Both drugs significantly improved UAS7, DLQI, and VAS at end-of-treatment (D42) compared with baseline (intra-group). At the end-of-treatment, all parameters showed greater improvement with bilastine, but only UAS7 reduction was significant (bilastine > levocetirizine, P = .03). In both the groups, UAS7 and VAS improved significantly D14 onwards, and was maintained throughout the study. Sedation was significantly less with bilastine (P = .04), while neither drug showed any serious adverse-effect. Tolerability of both drugs was similar. Therefore, bilastine was found to be a more effective and less-sedative novel therapy for CSU compared to levocetirizine, with similar effect on quality of life.

Topics: Benzimidazoles; Cetirizine; Chronic Disease; Chronic Urticaria; Double-Blind Method; Histamine H1 Antagonists, Non-Sedating; Humans; Piperidines; Quality of Life; Treatment Outcome; Urticaria

Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n = 6), fatigue (n = 5), and diarrhea (n = 4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n = 12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

Topics: Adenine; Chronic Disease; Female; Graft vs Host Disease; Humans; Male; Piperidines; Pyrazoles; Pyrimidines; Time Factors

Bilastine is a highly selective, non-sedating antihistamine, indicated for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Available data suggest that bilastine interferes neither with driving ability nor with flying-related performance. However, no data are available on the effect of bilastine on the driving ability in extreme conditions. Here we analyzed the effect of 7 days treatment with 20 mg bilastine in patients with allergic rhinitis and/or chronic urticaria, on psychophysical performance assessed by the Formula One (F1) high-speed simulator-driving test.. This study is a phase IV, interventional, prospective, mono-centric, single arm, open-label trial. Eighteen outpatients affected by allergic rhinitis and/or chronic urticaria, able to perform a preliminary driving test on F1 simulator were considered (V-1). First, the patients had a screening visit to assess their eligibility (V0). Visit 1 (V1), at the end of placebo before bilastine treatment and Visit 2 (V2), at the end of bilastine treatment. The primary variable parameter was the ability to maintain the vehicle in a central position at different speeds (50, 150, and 250 km/h).. Bilastine had a good safety profile and was well tolerated in terms of adverse events, laboratory parameters and vital signs. Bilastine did not have any negative effect on the ability to maintain the requested path, a constant speed as well as on attention and reactivity levels, even in extreme driving conditions.. This study is the first done in patients with allergic rhinitis and/or chronic urticaria using a F1-high speed simulator-driving test evaluating subjects' performance under bilastine treatment.

Topics: Adult; Attention; Automobile Driving; Benzimidazoles; Chronic Disease; Computer Simulation; Dizziness; Female; Histamine Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Piperidines; Prospective Studies; Rhinitis, Allergic; Urticaria; Young Adult

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.

Topics: Adenine; Adrenal Cortex Hormones; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Biomarkers; Chronic Disease; Demography; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Humans; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Severity of Illness Index; Treatment Failure; Young Adult

Bilastine, a novel non-sedating second-generation H. We conducted a multicenter, randomized, double-blind, placebo-controlled phase II/III study (trial registration No. JapicCTI-142574). Patients (age, 18-74 years) were randomly assigned to receive bilastine 20 mg, 10 mg or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline (Day -3 to 0) in total symptom score (TSS) at 2 weeks (Day 8-14), consisting of the itch and rash scores.. A total of 304 patients were randomly allocated to bilastine 20 mg (101 patients), bilastine 10 mg (100 patients), and placebo (103 patients). The changes in TSS at 2 weeks were significantly decreased by bilastine 20 mg than did placebo (p < 0.001), demonstrating the superiority of bilastine 20 mg. Bilastine 10 mg also showed a significant difference from placebo (p < 0.001). The TSS changes for the bilastine showed significant improvement from Day 1, and were maintained during the treatment period. The Dermatology Life Quality Index scores were also improved in bilastine than in placebo. The bilastine treatments were safe and well tolerated.. Two-week treatment with bilastine (20 or 10 mg) once daily was effective and tolerable in Japanese patients with CSU, demonstrating an early onset of action.

Topics: Adolescent; Adult; Aged; Benzimidazoles; Chronic Disease; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Phenotype; Piperidines; Quality of Life; Treatment Outcome; Urticaria; Young Adult

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. A Phase 3 withdrawal/re-treatment study (NCT01186744; OPT Retreatment) showed tofacitinib re-treatment was effective in patients with chronic plaque psoriasis.. To describe the effects of tofacitinib withdrawal/re-treatment on health-related quality of life (HRQoL) and disease symptoms measured by patient-reported outcomes (PROs).. The study was divided into initial treatment, treatment withdrawal, and re-treatment periods. Initial treatment: patients were randomized to receive tofacitinib 5 (n = 331) or 10 mg (n = 335) BID for 24 weeks. Treatment withdrawal: patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline and Physician's Global Assessment of 'clear'/'almost clear' at Week (W)24 received placebo (withdrawal) or the previous dose (continuous treatment). Re-treatment: at relapse (> 50% loss of W24 PASI response) or at W40, patients received their initial tofacitinib dose. PROs included: Dermatology Life Quality Index (DLQI), Itch Severity Item (ISI), Short Form-36 (SF-36) and Patient's Global Assessment (PtGA).. After initial treatment with tofacitinib 5 and 10 mg BID, substantial and significant improvements were reported for mean DLQI (baseline: 12.6 and 12.6; W24: 5.1 and 2.6) and ISI (baseline: 6.7 and 6.9; W24: 2.9 and 1.6). Patients continuously treated with tofacitinib 5 and 10 mg BID maintained those improvements through Week 56 (DLQI: 3.0 and 2.1; ISI: 2.3 and 1.4). By W40, patients withdrawn from tofacitinib 5 and 10 mg BID showed worsening in DLQI (5.0 and 6.2) and ISI (3.7 and 4.0) scores; improvements were regained upon re-treatment (W56, DLQI: 3.4 and 2.4; ISI: 2.2 and 1.6). Similar results were reported for PtGA and SF-36.. Continuous tofacitinib treatment provided sustained improvement in HRQoL and disease symptoms. Patients randomized to treatment withdrawal lost initial improvements. Upon re-treatment, improvements were recaptured to levels comparable to those seen with continuous treatment.

Topics: Chronic Disease; Dermatologic Agents; Double-Blind Method; Humans; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index

A number of second-generation non-sedating antihistamines are used in clinical practices over the world. However, long-term safety and efficacy have not been proved high level evidence based medicine. We have performed an open-label, multicenter, phase III study to evaluate the long-term safety and efficacy of bilastine, a novel non-sedating H

Topics: Adult; Benzimidazoles; Chronic Disease; Eczema; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Japan; Long Term Adverse Effects; Male; Middle Aged; Piperidines; Prurigo; Pruritus; Quality of Life; Severity of Illness Index; Treatment Outcome; Urticaria

Oxidative stress plays a key role in the development of chronic pulmonary complications of sulfur mustard (SM). Curcuminoids are polyphenols with documented safety and antioxidant activity. The present study aimed to investigate the efficacy of short-term supplementation with curcuminoids (co-administered with piperine to enhance the bioavailability of curcuminoids) in alleviating systemic oxidative stress and clinical symptoms, and improvement of health-related quality of life (HRQoL) in subjects suffering from chronic pulmonary complications due to SM exposure who are receiving standard respiratory treatments. Eighty-nine subjects were recruited to this randomized double-blind placebo-controlled trial, being randomly allocated to either curcuminoids (1500 mg/day) + piperine (15 mg/day) combination (n = 45) or placebo (n = 44) for a period of 4 weeks. High-resolution computed tomography suggested the diagnosis of bronchiolitis obliterans in all subjects. Efficacy measures were changes in serum levels of reduced glutathione (GSH) and malonedialdehyde (MDA). The severity and frequency of respiratory symptoms and HRQoL were also assessed using St. George respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) indices. Serum levels of GSH were increased whilst those of MDA decreased by the end of trial in both groups. Likewise, there were significant improvements in the total as well as subscale (symptoms, activity and impact) SGRQ and CAT scores in both groups. However, comparison of magnitude of changes revealed a greater effect of curcuminoids-piperine combination compared to placebo in elevating GSH, reducing MDA and improving CAT and SGRQ (total and subscale) scores (p < 0.001). Regarding the promising effects of curcuminoids on the measures of systemic oxidative stress, clinical symptoms and HRQoL, these phytochemicals may be used as safe adjuvants in patients suffering from chronic SM-induced pulmonary complications who are receiving standard treatments.

Topics: Adult; Alkaloids; Antioxidants; Benzodioxoles; Bronchiolitis; Chronic Disease; Curcuma; Curcumin; Double-Blind Method; Glutathione; Humans; Male; Malondialdehyde; Middle Aged; Mustard Gas; Oxidative Stress; Phytotherapy; Piper; Piperidines; Plant Extracts; Polyphenols; Polyunsaturated Alkamides; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests

Regulations on medicinal products for paediatric use require that pharmacokinetics and safety be characterized specifically in the paediatric population. A previous study established that a 10-mg dose of bilastine in children aged 2 to <12 years provided an equivalent systemic exposure as 20 mg in adults. The current study assessed the safety and tolerability of bilastine 10 mg in children with allergic rhinoconjunctivitis and chronic urticaria.. In this phase III, multicentre, double-blind study, children were randomized to once-daily treatment with bilastine 10-mg oral dispersible table (n = 260) or placebo (n = 249) for 12 weeks. Safety evaluations included treatment-emergent adverse events (TEAEs), laboratory tests, cardiac safety (ECG recordings) and somnolence/sedation using the Pediatric Sleep Questionnaire (PSQ).. The primary hypothesis of non-inferiority between bilastine 10 mg and placebo was demonstrated on the basis of a near-equivalent proportion of children in each treatment arm without TEAEs during 12 weeks' treatment (31.5 vs. 32.5%). No clinically relevant differences between bilastine 10 mg and placebo were observed from baseline to study end for TEAEs or related TEAEs, ECG parameters and PSQ scores. The majority of TEAEs were mild or moderate in intensity. TEAEs led to discontinuation of two patients treated with bilastine 10 mg and one patient treated with placebo.. Bilastine 10 mg had a safety and tolerability profile similar to that of placebo in children aged 2 to <12 years with allergic rhinoconjunctivitis or chronic urticaria.

Topics: Adolescent; Adult; Benzimidazoles; Child; Child, Preschool; Chronic Disease; Double-Blind Method; Female; Follow-Up Studies; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Piperidines; Rhinitis, Allergic, Perennial; Treatment Outcome; Urticaria

Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. Psoriasis impacts on physical and psychological well-being; improvements in health-related quality of life (HRQoL) with etanercept in psoriasis are well documented.. To evaluate HRQoL with tofacitinib, vs. placebo or etanercept, in the Phase 3, randomized, placebo-controlled, non-inferiority, Oral-treatment Psoriasis Trial (OPT) Compare Study (NCT01241591).. Adults with moderate to severe chronic plaque psoriasis were randomized 3:3:3:1 to tofacitinib 10 or 5 mg twice daily (BID), etanercept 50 mg twice weekly or placebo, for 12 weeks. Patient-reported outcomes (PROs) included Dermatology Life Quality Index (DLQI), Itch Severity Item and Patient Global Assessment of psoriasis.. At baseline, 83.4% (911/1092) of patients had a DLQI score ranging between 6 and 30, indicating a substantial burden of disease. By Week 12, 47.3%, 43.6% and 30.9% of patients in the tofacitinib 10 mg BID, etanercept and tofacitinib 5 mg BID groups, respectively, had a DLQI score of 0 or 1 (no effect of psoriasis on QoL) vs. 7.8% for placebo (all P < 0.0001). Tofacitinib significantly reduced itch vs. placebo (P < 0.05 both doses) and etanercept (P < 0.0001 both doses) within 1 day of starting treatment. Furthermore, reductions in itch were greater with tofacitinib 10 mg BID, vs. etanercept, at Weeks 2-12 (all time points P < 0.05). At Week 2, an Itch Severity Item score of 'little or no itch' was more frequent with tofacitinib 10 mg (68.6%) vs. etanercept (57.4%) and placebo (12.2%), and the PtGA response rate was significantly greater with tofacitinib 10 mg vs. placebo (P < 0.05).. Oral tofacitinib provided significant improvements across multiple PROs by Week 12. Improvements with tofacitinib 10 mg BID were comparable to etanercept, and improvements in itch were greater and more rapid with tofacitinib 10 mg BID.

Topics: Chronic Disease; Dermatologic Agents; Etanercept; Humans; Patient Satisfaction; Piperidines; Placebos; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis.. To compare outcomes following tofacitinib withdrawal with outcomes of continuation.. In this phase 3 study (NCT01186744), patients received tofacitinib 5 mg (n = 331) or 10 mg (n = 335) twice daily for 24 weeks. The patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) score from baseline and Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) received a placebo (withdrawal) or the previous dose. At relapse (> 50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose.. Initial treatment: 33·5% and 55·2% achieved both PASI 75 and PGA responses with tofacitinib 5 and 10 mg twice daily, respectively, making them eligible for the treatment-withdrawal period. Withdrawal: 56·2%, 62·3%, 23·3% and 26·1% maintained PASI 75 responses with tofacitinib 5, 10 mg, placebo (5 mg) and placebo (10 mg) twice daily, respectively; 49·9%, 63·9%, 22·9% and 18·0% maintained PGA responses; and 92·3%, 93·0%, 32·8% and 42·9% did not relapse. Elevations in low-density lipoprotein-cholesterol levels following initial treatment (mean increase: 8·71 mg dL(-1) with 5 mg twice daily, 10·26 mg dL(-1) with 10 mg twice daily) were reversed upon withdrawal. Retreatment: 36·8% and 61·0% of patients who relapsed achieved PASI 75 responses with tofacitinib 5 or 10 mg after 16 weeks; 44·8% and 57·1% regained PGA responses.. Patients who received continuous treatment maintained a response more effectively when compared with placebo recipients. Safety profiles were comparable in both the continuous treatment group and retreatment group. Of those patients who relapsed, up to 60% recaptured a response with tofacitinib.

Topics: Adolescent; Adult; Aged; Chronic Disease; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Outcome Assessment; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Retreatment; Treatment Outcome; Young Adult

New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population.. In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for ≥12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591.. Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39·5%) of 329 patients in the tofacitinib 5 mg group, 210 (63·6%) of 330 in the tofacitinib 10 mg group, 197 (58·8%) of 335 in the etanercept group, and six (5·6%) of 107 in the placebo group. A PGA response was achieved by 155 (47·1%) of 329 patients in the tofacitinib 5 mg group, 225 (68·2%) of 330 in the tofacitinib 10 mg group, 222 (66·3%) of 335 in the etanercept group, and 16 (15·0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events.. In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis.. Pfizer Inc.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Etanercept; Female; Humans; Immunoglobulin G; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Receptors, Tumor Necrosis Factor; Treatment Outcome

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. To determine the 16-week efficacy and safety of two oral tofacitinib doses vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.. Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of 'clear' or 'almost clear' (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75).. Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis.. Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate-to-severe psoriasis. Safety findings were consistent with prior studies.

Topics: Administration, Oral; Adolescent; Adult; Aged; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

The Janus kinase (JAK) inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210).. To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis.. Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up.. Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib.. Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

Topics: Adolescent; Adult; Aged; Basophils; Blood Cell Count; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Female; Hematocrit; Hemoglobins; Humans; Killer Cells, Natural; Leukocytes; Male; Middle Aged; Monocytes; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Young Adult

Tofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.. This phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.. Two tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm(2) treatment area containing a target plaque with or without one or more nontarget plaques and normal skin.. The primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) -54.4%] vs. vehicle 1 (LSM -41.5%), but not ointment 2 (LSM -24.2%) vs. vehicle 2 (LSM -17.2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.. Tofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

Topics: Administration, Cutaneous; Adult; Aged; Chronic Disease; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Ointments; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

The purpose of this study was to evaluate the effects of blonanserin, a novel antipsychotic, on cognitive function in first-episode schizophrenia.. Twenty-four antipsychotic-naïve patients with first-episode schizophrenia participated in the study. Blonanserin was given in an open-label design for 8 weeks. The Brief Assessment of Cognition in Schizophrenia-Japanese language version (BACS-J) was administered as the primary outcome measure at baseline and 8 weeks. Clinical evaluation included the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale-Japanese language version (SQLS-J), and the Clinical Global Impression-Severity of Illness Scale (CGI-S). To exclude the possibility of retest effects on the BACS-J, 10 age-matched patients with chronic schizophrenia treated with blonanserin were tested at baseline and after an 8-week interval.. Twenty first-episode patients completed the study. Repeated measures analysis of covariance revealed a significant group-by-time interaction effect on the letter fluency task due to better performance in the first-episode group, but not in the control group. Main effect of time or group-by-time interaction effect on the Tower of London task was not significant; however, the first-episode group, but not the control group, showed substantial improvement with a moderate effect size. All items on the PANSS, SQLS-J, and CGI-S significantly improved after 8 weeks of treatment.. These results suggest that blonanserin improves some types of cognitive function associated with prefrontal cortical function.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Female; Humans; Male; Piperazines; Piperidines; Prospective Studies; Psychiatric Status Rating Scales; Quality of Life; Schizophrenia; Severity of Illness Index; Single-Blind Method; Treatment Outcome; Young Adult

Thoracotomy is one of the most painful surgical incisions. Little is known, however, about the effect of type of anaesthesia on chronic post-thoracotomy pain syndrome (CPTS). We therefore compared the incidence of CPTS after total intravenous anaesthesia (TIVA) and inhalation anaesthesia.. Patients (n = 366) were prospectively randomized into two groups: Group I (n = 173) received TIVA (propofol + remifentanil) and Group II (n = 170) received inhalation anaesthesia with sevoflurane. We assessed acute pain on postoperative days 1, 3 and 5, and the prevalence of CPTS at 3 and 6 months using a numerical rating scale (NRS).. The prevalence of CPTS was significantly lower in patients receiving TIVA than in those receiving inhalation anaesthesia at 3 months (38.2% versus 56.5%, P = 0.001) and at 6 months (33.5% versus 50.6%, P = 0.002), respectively. Moreover, allodynia-like pain was significantly less common in the TIVA group at 3 (P = 0.021) and 6 months (P = 0.032). NRS score of acute pain, however, did not differ significantly between the two groups.. TIVA with propofol and remifentanil may reduce the incidence of CPTS at 3 and 6 months.

Topics: Acute Pain; Adolescent; Adult; Aged; Analgesics; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Chronic Disease; Drug Administration Schedule; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Methyl Ethers; Middle Aged; Pain Measurement; Pain, Postoperative; Piperidines; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Thoracotomy; Young Adult

Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.. This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.. One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.. At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed.. Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.

Topics: Administration, Oral; Adult; Chronic Disease; Dermatologic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Janus Kinase 3; Male; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Treatment Outcome

Bilastine is a novel nonsedative H(1)-receptor antagonist, which may be used for the symptomatic treatment of chronic idiopathic urticaria (CU). The aim of this study was to compare the clinical efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg and placebo in CU patients with moderate-to-severe symptoms.. Overall 525 male and female subjects aged 18-70 years were randomized to receive bilastine 20 mg, levocetirizine 5 mg or placebo, once daily for 28 days, in double-blind manner, in 46 centres across Europe and Argentina. Patients rated symptoms of pruritus, number of wheals, and maximum size of wheals (on predefined scales) as reflective (over past 12 h) symptoms twice daily, for assessment of change from baseline in the total symptoms scores (TSS) over 28 days as the primary efficacy measure. Changes in reflective and instantaneous symptoms scores, Dermatology Life Quality Index (DLQI), and CU-associated discomfort and sleep disturbance were assessed as secondary outcomes. Safety was assessed according to adverse events, laboratory tests and electrocardiograms.. Bilastine reduced patients' mean reflective and instantaneous TSS from baseline to a significantly greater degree than placebo (P < 0.001); from day 2 onwards of treatment. The DLQI, general discomfort, and sleep disruption were also improved significantly in bilastine-treated patients as compared with placebo-treated patients (P < 0.001 for all parameters). Comparison with levocetirizine indicated both treatments to be equally efficacious as well as equally safe and well tolerated as compared with placebo.. Bilastine 20 mg is a novel effective and safe treatment option for the management of CU.

Topics: Adolescent; Adult; Aged; Area Under Curve; Benzimidazoles; Cetirizine; Chronic Disease; Double-Blind Method; Female; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Piperidines; Quality of Life; Urticaria; Young Adult

To investigate the relationships between 2 anesthetic techniques, or the extent of allodynia around the surgical wound, and the occurrence of chronic post-thoracotomy pain.. Prospective, randomized study.. A single-institution, university hospital.. Thirty-eight patients who underwent elective thoracotomy under general anesthesia.. High-dose remifentanil (average effect-site concentration 5.61 +/- 0.84 ng/mL) with epidural analgesia started and at the end of surgery or low-dose remifentanil (average effect site concentration 1.99 +/- 0.02 ng/mL) with epidural analgesia with 0.5% ropivacaine started at the beginning of anesthesia.. Pain intensity and the extent of allodynia around the wound were measured during the hospital stay. The presence and intensity of residual pain were assessed 1, 3, and 6 months after surgery and at the end of the study (6-13 months, average 9 months). A DN4 neuropathic pain diagnostic questionnaire was conducted at the same times. In the high-dose group, the area with allodynia was three times larger than the area in the low-dose group. The increased allodynia was associated with a higher incidence of chronic pain (RR: 2.7-4.2) 3 and 6 months after surgery and at the end of the study (median follow-up: 9.5 months).. High-dose remifentanil (0.14-0.26 microg/kg/min) without epidural analgesia during surgery is associated with a large area of allodynia around the wound. These patients develop a much higher incidence of chronic pain than those receiving low-dose remifentanil with epidural analgesia during surgery.

Topics: Aged; Analgesia, Epidural; Anesthetics; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Pain Measurement; Pain, Postoperative; Piperidines; Preoperative Care; Prospective Studies; Remifentanil; Thoracotomy

There is considerable incentive to develop new treatment strategies that effectively target cognitive deficits in schizophrenia. One of the theoretically promising novel treatment candidates is acetylcholinesterase inhibitors that increase the synaptic levels of cholinergic, nicotinic, and muscarinic receptor activity. The purpose of this study was to assess the efficacy of donepezil as an adjuvant agent in the treatment of chronic schizophrenia in particular for cognitive impairments. This investigation was a 12-week, double-blind study of parallel groups of patients with stable chronic schizophrenia. Thirty patients were recruited from inpatient and outpatient departments, age ranging from 22 to 44 years. All participants met DSM-IV-TR. diagnostic criteria for schizophrenia. To be eligible, patients were required to have been treated with a stable dose of risperidone as their primary antipsychotic treatment for a minimum period of 8 weeks. The subjects were randomized to receive donepezil (10 mg/day) or placebo, in addition to risperidone (4-6 mg/day). Clinical psychopathology was assessed with Positive and Negative Syndrome Scale (PANSS). Cognition was measured by a cognitive battery. Patients were assessed by a psychiatrist at baseline and after 8, and 12 weeks after the medication started. The PANSS scores and cognitive performance were used as the outcome measures. The donepezil group had significantly greater improvement in the negative symptoms over the 12-week trial. There were no differences between the donepezil and placebo groups on any neurocognitive assessments at endpoint (week 12). The present study indicates donepezil as a potential adjunctive treatment strategy for negative symptoms of chronic schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Mental Status Schedule; Neuropsychological Tests; Nootropic Agents; Piperidines; Prospective Studies; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

To study the effects of acetylcholinesterase inhibitors (AChEIs) in the management of cognitive impairments in patients with schizophrenia, we investigated the effects of 12 weeks of adjunctive therapy with donepezil on their cognitive impairments. Twenty-four subjects stabilized on haloperidol treatment (5-30 mg/day) for a minimum of 3 months were entered into a double-blind, placebo-controlled trial of donepezil as an adjunctive treatment. Subjects were randomly assigned under double-blind conditions to receive either 5 mg/day donepezil (N = 12) or pLacebo (N = 12) for 12 weeks. The subjects were evaluated at baseline, and after 4, 8, and 12 weeks using the Korean version of Mini Mental State Examination (K-MMSE), Brief Psychiatric Rating Scale (BPRS), and standard neuropsychological assessment. The K-MMSE scores improved significantly (p < 0.05) but the BPRS scores did not improve significantly in patients given donepezil; subjects showed slight improvement in several cognitive measures. At the end of the study, the difference in the mean K-MMSE scores between the donepezil and placebo groups approached statistical significance (p = 0.056). Of the several domains of cognitive functions assessed, verbal recognition and visual recall memory improved significantly (p < 0.05). But donepezil did not affect scores in the executive function tests. Our findings support a potential positive effect of AChEIs in the management of cognitive impairments in patients with chronic schizophrenia. Further studies with large subjects are needed to confirm our findings.

Topics: Adult; Antipsychotic Agents; Cholinesterase Inhibitors; Chronic Disease; Cognition Disorders; Donepezil; Double-Blind Method; Drug Therapy, Combination; Haloperidol; Humans; Indans; Piperidines; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The aim was to investigate the efficacy of a combination of low-dose remifentanil (REMI) and ketamine (KET) compared to the single drugs and placebo (P) on whiplash associated pain (WAD) in a double-blind, randomized, placebo-controlled, cross-over study. Twenty patients with chronic (>1 year) WAD were included. Four different drug combinations were tested in four sessions: placebo/placebo (P/P), placebo/remifentanil (P/REMI), ketamine/placebo (KET/P) and ketamine/remifentanil (KET/REMI). Target concentrations were 1 and 2ng/ml (stepwise) for remifentanil and 100ng/ml for ketamine. Habitual pain intensity was assessed on a visual analogue scale (VAS). Experimental pain was assessed with electrical stimulation (single and repeated) of tibialis anterior (TA) muscle, pressure pain algometry applied over infraspinatus (IS) and TA muscles and VAS scores after intramuscular hypertonic saline infusion in TA. KET/REMI significantly reduced habitual pain. KET/REMI infused at low REMI target concentration (1ng/ml) significantly elevated electrical intramuscular pain thresholds (single and repeated). Pain thresholds to electrical stimulation were similarly increased by both P/REMI and KET/REMI at 2ng/ml target concentration. Pressure pain thresholds were increased by both KET/REMI and P/REMI. VAS-scores after intramuscular saline were also similarly decreased by both REMI combinations. Seven out of 20 subjects were non-responders (<50% pain relief). No correlation was found between effects on spontaneous pain and experimental pain. KET/REMI showed an analgesic effect on habitual pain. Experimental pain was attenuated by both combinations containing the opioid, however, KET seemed to enhance the effect of REMI on electrical pain thresholds when a low REMI target concentration was used.

Topics: Adult; Analgesics, Opioid; Chronic Disease; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Electric Stimulation; Excitatory Amino Acid Antagonists; Female; Humans; Ketamine; Male; Middle Aged; Multivariate Analysis; Neck Pain; Pain Measurement; Pain Threshold; Piperidines; Pressure; Reaction Time; Receptors, N-Methyl-D-Aspartate; Remifentanil; Sodium Chloride; Whiplash Injuries

Evidence suggests that urinary excretion of endothelin-1 (ET-1) reflects renal ET-1 production and is independent of systemic ET-1 activity. The influence of ET receptors on urinary ET-1 excretion has not been studied in humans, yet peritubular ETB receptors are abundant within the kidney. We have studied the effects of acute ETA and ETB receptor blockade with BQ-123 and BQ-788, respectively, on urinary ET-1 excretion in a randomized, placebo-controlled, double-blind study in 16 subjects with a wide range of GFRs (15-152 ml/min). Plasma ET-1 concentrations (pET-1) and urinary ET-1 excretion rate (uET-1) at baseline correlated inversely with GFR (R2 = 0.18 and 0.36, respectively, P < 0.01). However, changes in pET-1 after ET receptor antagonism were not related to changes in uET-1 (R2 = 0.007, P = 0.18). pET-1 increased only after BQ-788, alone or in combination with BQ-123, consistent with ETB receptor-mediated clearance of ET-1 from the circulation. uET-1 was reduced only after BQ-788 alone [-4.7 pg/min (SD 5.5), P < 0.01]. Because BQ-788 also reduced GFR, fractional excretion of ET-1 (FeET-1) was calculated. FeET-1 fell after BQ-788 alone [-41% (SD 26%), P < 0.01] or in combination with BQ-123 [-40% (SD 29%), P < 0.01]. FeET-1 was not altered by placebo or BQ-123 alone. In conclusion, urinary ET-1 excretion does not appear to relate to the pool of plasma ET-1. Because of the short duration of this study, it is unlikely that ET receptor blockade had significant effects on renal ET-1 production. Therefore, the reduction in FeET-1 after ETB blockade appears to indicate that renal excretion of ET-1 is at least partly facilitated by ETB receptor activation.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Drug Combinations; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Oligopeptides; Osmolar Concentration; Peptides, Cyclic; Piperidines

There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients.. Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.

Topics: Administration, Oral; Adolescent; Adult; Aged; Analgesics, Opioid; Chronic Disease; Drug Administration Schedule; Drug Tolerance; Follow-Up Studies; Humans; Hyperalgesia; Infusions, Intravenous; Low Back Pain; Middle Aged; Morphine; Pain Threshold; Piperidines; Prospective Studies; Remifentanil

Cognitive impairment and negative signs are common in patients with schizophrenia. Up to 35% of elderly patients with schizophrenia fulfill the diagnostic criteria of dementia. Donepezil inhibits cholinesterase, thus enhancing cholinergic neurotransmission. We tested the efficacy of donepezil in elderly patients with chronic schizophrenia and severe cognitive impairment.. Following baseline assessment, patients were randomly assigned to receive either donepezil or placebo. The dose was 5 mg daily for the first week and 10 mg for an additional 11 weeks. The procedure was repeated using the crossover compound. The Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI) and Alzheimer Disease Assessment Scale - Cognitive subscale (ADAS-Cog) were used to assess the severity of symptoms, cognitive status and intervention effects.. Twenty subjects were enrolled (15 females, five males), mean age 70.2 years (SD 6.5) and mean duration of disease 38.5 years (SD 9.3). A modest treatment effect was found for both placebo and donepezil treatment periods. No crossover effect was found. No statistical differences were demonstrated between the two treatment groups (CGI p = 0.37, PANSS p = 0.71, ADAS-Cog p = 0.86). Two patients died during the study period due to unrelated causes and one patient discontinued participation due to increased agitation.. Donepezil does not seem to improve negative signs and cognitive impairment in elderly patients with chronic schizophrenia.

Topics: Aged; Alzheimer Disease; Antipsychotic Agents; Chronic Disease; Cognition Disorders; Comorbidity; Cross-Over Studies; Dementia; Depressive Disorder; Donepezil; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

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

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

To determine preliminarily whether donepezil will improve memory, behavior, and global function after chronic traumatic brain injury (TBI).. Sixteen-week open-label study.. Outpatient TBI rehabilitation program.. Four patients with chronic, severe TBI.. Donepezil 5mg daily for 8 weeks followed by 10mg daily for 4 weeks.. Memory measures included the Rey Auditory Verbal Learning Test (RAVLT), the Complex Figure Test (CFT), items from the Rivermead Behavioural Memory Test (RBMT), and a semantic fluency task. The Neuropsychiatric Inventory (NPI) evaluated behavior and affect. Function was assessed by using the FIM instrument and a clinical global impression of change.. On the RAVLT, the mean scores for learning and short- and long-term recall improved by 0.4, 1.04, and.83 standard deviations (SDs) above baseline, respectively. On the CFT, the mean scores for short-term recall and long-term recall improved by 1.56 and 1.38 SDs above baseline, respectively. A positive trend was observed on the RBMT and on the NPI subscales.. Donepezil may improve some aspects of memory and behavior in persons with chronic TBI. Randomized clinical trials are required to support these preliminary findings.

Topics: Adult; Brain Injuries; Chronic Disease; Donepezil; Humans; Indans; Male; Memory Disorders; Mental Disorders; Neuropsychological Tests; Nootropic Agents; Piperidines; Treatment Outcome

Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel-group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group.

Topics: Adult; Blood Glucose; Blood Proteins; Caffeine; Carbamates; Chronic Disease; Humans; Hypoglycemic Agents; Liver Diseases; Male; Middle Aged; Piperidines; Protein Binding

The ultrastructure of the nasal mucosa following the use of intranasal levocabastine was studied in 20 patients suffering from perennial allergic rhinitis. The patients received twice daily 0.05 per cent levocabastine spray with a treatment duration of four weeks. At the end of the treatment period regression of the allergic process was evidenced by progressive reappearance of normal cilia and microvilli on the columnar cells, decrease of intercellular oedema and cytoplasmic vacuoles, increased number of mucous acinar cells, gradual decrease of vascular congestion, as well as diminished oedema fluid formation. The drug, however, had no effect on mast cell degranulation nor on eosinophilic infiltration. Normalization of the ultrastructural features correlated well with clinical improvement. Considering the results of the present study, levocabastine nasal spray appears to be an effective treatment for perennial allergic rhinitis and can be used with, or as an alternative to, other anti-allergic medications.

Topics: Administration, Intranasal; Adult; Chronic Disease; Female; Histamine H1 Antagonists; Humans; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Nasal Mucosa; Piperidines; Rhinitis, Allergic, Perennial; Treatment Outcome

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

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

To assess the efficacy of a prokinetic agent in the long-term treatment of chronic intestinal dysmotility and the influence of extrinsic denervation.. We assessed symptoms, compliance and untoward effects in an open, 1-year trial of cisapride, 20 mg t.d.s., in 37 patients with neuropathic forms of chronic intestinal dysmotility. Patients' autonomic function had previously been characterized; effects of cisapride at 12 weeks in a placebo-controlled trial were previously reported.. Seventeen patients had idiopathic dysmotility, 11 had diabetes mellitus with autonomic dysfunction, five had had previous gastric surgery and four had neurological syndromes. Median medication compliance was 98.9% for the study period completed by each individual. Median duration of follow-up was 9.5 months; 20 patients completed 1 year of treatment, and 27 of 37 at least 6 months of treatment; seven dropped out because of lack of benefit. Mean total symptom score was significantly reduced at the last observation relative to the entry into the trial; this was particularly the case in those patients without abdominal vagal dysfunction. One patient withdrew because of aggravation of abdominal pain.. During an open, long-term trial, cisapride, 20 mg t.d.s., provided continued symptomatic relief to patients with chronic intestinal dysmotility, particularly those without vagal neuropathy.

Topics: Adult; Aged; Anti-Ulcer Agents; Autonomic Nervous System Diseases; Chronic Disease; Cisapride; Female; Follow-Up Studies; Gastrointestinal Motility; Humans; Intestinal Diseases; Male; Middle Aged; Patient Compliance; Piperidines; Regression Analysis

Ebastine is a new second generation histamine H1 receptor antagonist that has shown clinical efficacy in the treatment of seasonal and perennial allergic rhinitis and chronic urticaria after once-daily administration. This double-blind multicentre randomised placebo-controlled study has investigated the long term efficacy of ebastine 10mg once daily in the treatment of chronic urticaria compared with that of terfenadine 60mg twice daily. At the end of a 3-month treatment period, ebastine was significantly superior to placebo in improving symptoms of chronic urticaria (including severity of itching, number of wheals per day), and its efficacy was similar to that of terfenadine. In a global assessment of efficacy, investigators considered chronic urticaria to have improved in 73% of ebastine recipients compared with 68% and 52% of patients treated with terfenadine or placebo, respectively. The patients' assessments of efficacy were similar to those of the investigators. Ebastine was well tolerated, the incidence and nature of adverse events with this agent being similar to those reported in patients treated with terfenadine or placebo. The most common adverse events were headache and dry mouth. Thus, these results, which show ebastine to be an effective and well tolerated agent, indicated that the drug should be considered for the first-line therapy of chronic urticaria.

Topics: Adult; Anti-Allergic Agents; Butyrophenones; Chronic Disease; Double-Blind Method; Histamine H1 Antagonists; Humans; Piperidines; Terfenadine; Urticaria

A clinical trial was carried out to determine the effect of cisapride on rate of passage of digesta and clinical parameters in horses with chronic grass sickness. Sixteen horses were given intramuscular cisapride (0.1 mg kg-1 three times daily) (group I), and 15 received oral cisapride (0.8 mg kg-1 three times daily) (group O). A liquid-phase marker (cobalt-EDTA) and a solid-phase marker (polystyrene pellets) were given by stomach tube at the beginning of each of three consecutive 7 day periods, i.e., before, during and after cisapride therapy. Seven horses in each group completed the rate of passage trial; the remainder provided clinical data only. The rate of passage was found to be significantly faster after cisapride therapy than before. Comparison with data from 20 normal animals showed a trend towards normal rates of passage after therapy. In cases that died during the trial, the caecum and large colon were the main sites of pellet retention. Dry matter intake was significantly higher after therapy than before in group O and dry matter output was higher after treatment than before in both groups. Gut auscultation score increased in both groups in the periods during and after cisapride administration but heart rate was unaffected. Diarrhoea and colic occurred in each group but its occurrence was not associated with cisapride therapy. The results suggest that by increasing gut motility, cisapride is of benefit in the management of selected cases of chronic grass sickness.

Topics: Animals; Anti-Ulcer Agents; Autonomic Nervous System Diseases; Chronic Disease; Cisapride; Female; Gastrointestinal Diseases; Gastrointestinal Motility; Horse Diseases; Horses; Male; Piperidines; Poaceae

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2 = 0.50-0.51, p < 0.001). Only depressive symptoms did not contribute significantly to these results (p > 0.10). Path analysis showed that the greater mean change (p < 0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

This study was performed in order to evaluate the short-term efficacy and safety of fixed risperidone doses compared to haloperidol.. In a multi-national, parallel-group, double-blind study, patients with chronic schizophrenia (DSM-III-R) were randomly assigned to risperidone 1, 4, 8, 12 or 16 mg or haloperidol 10 mg daily for 8 weeks. Efficacy was assessed by the Positive and Negative Syndrome Scale for schizophrenia (PANSS) and clinical global impression (CGI), and safety primarily by the Extrapyramidal Symptom Rating Scale (ESRS).. One thousand three hundred and sixty-two patients were evaluated. The optimum risperidone doses were 4 mg and 8 mg, with response rates of 63.4% (56.8%; 69.7%) and 65.8% (59.2%; 71.9%) respectively. Response rate in haloperidol-treated patients was 58.7% (52.0%; 65.3%); the 95% confidence intervals (CI) of the differences between risperidone 4 mg or 8 mg and haloperidol were (- 4.3%; 13.7%) and (- 1.9%; 16.0%) respectively. There were no significant differences in CGI scores at endpoint between risperidone 4 mg, 8 mg, 12 mg and 16 mg and haloperidol (3.0, 3.0, 3.2, 3.1 and 3.1 respectively); the 95% CI of the differences between risperidone 4 mg or 8 mg and haloperidol were ( - 0.4; 0.1) and ( - 0.3; 0.2) respectively. Mean shifts to the maximum total ESRS scores versus baseline (mean (confidence interval)) were significantly greater in haloperidol-treated patients (5.1 (4.0; 6.2)) than in the risperidone 1, 4, 8 and 12 mg groups (1.1 (0.3; 1.9); 1.8 (0.9; 2.7); 2.7 (1.8; 3.6) and 3.2 (2.3; 4.1) respectively (P < 0.05)).. Risperidone is an effective antipsychotic for the treatment of chronic schizophrenia; doses of 4 and 8 mg seem to be optimal and have a lower incidence of side-effects than haloperidol.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Humans; Isoxazoles; Male; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

Authors report results on a comparative multicenter double blind trial carried out to assess the efficacy of Ifenprodil tartrate (*) (60 mg a.d.) versus placebo in symptomatic treatment of stable peripheral arterial occlusive disease (Fontaine stage II). Ninety four patients were included in this six months, two parallel group study (2 homogeneous groups) which shows a statistically significant functional improvement in the treatment group versus the placebo group. After six months of treatment, the maximum walking distance (MWD)--main assessment criteria--was 126.0 +/- 18.5 meters in the Ifenprodil group versus 46.4 +/- 20.2 meters in the placebo group (p = 0.005). This represents an improvement of 62.1% in the Ifenprodil group versus 21.0% in the placebo group. An improvement of at least 50% in MWD was observed in 41.3% of patients treated by Ifenprodil and in only 12.5% of patients receiving placebo (p = 0.002). The evolution of ankle/brachial systolic post exercise index from JO to J180 was not significantly different in the two groups. Clinical and biological tolerance of Ifenprodil tartrate was excellent.

Topics: Aged; Arterial Occlusive Diseases; Chronic Disease; Double-Blind Method; Female; Humans; Leg; Male; Middle Aged; Piperidines; Placebos; Vasodilator Agents

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

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

Dopaminergic hyperactivity mediated via D2 receptors is implicated in the etiology of positive symptoms of schizophrenia, but selective D2 antagonists provide imperfect therapy. This article describes a subanalysis of a trial of risperidone, a combined 5-HT2A/D2 antagonist, in 513 patients with DSM-III-R chronic schizophrenia. Risperidone at 2, 6, 10, and 16 mg/day was compared with placebo and haloperidol 20 mg/day. All doses of risperidone and the 20-mg dose of haloperidol were superior to placebo (mean change from baseline on the PANSS positive and general psychopathology subscales). The 6-mg dose of risperidone also produced significantly more improvement than haloperidol 20 mg. We conclude that risperidone is an effective drug for patients with positive features of schizophrenia.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Piperidines; Receptors, Dopamine D2; Receptors, Serotonin; Risperidone; Schizophrenia; Treatment Outcome

In a randomized, crossover study, 24 schizophrenic patients received a single 4-mg dose of risperidone in caplet or tablet form. Each of the two study periods lasted 5 days. Blood samples to determine (by radioimmunoassay) plasma levels of risperidone and its major metabolite, 9-hydroxy-risperidone (9-OH-risperidone), were obtained each day. The two formulations of risperidone were bioequivalent. Following are the mean pharmacokinetics of risperidone and risperidone + 9-OH-risperidone: area under the plasma concentration curve (AUC) from 0 to 96 hours; 278.0 and 716.9 ng.hr/mL; AUC from 0 to infinity, 291.9 and 762.4 ng.hr/mL; peak plasma concentration, 33.0 and 44.5 ng/mL; time to peak concentration, 1.39 and 1.78 hours; and elimination half-life, 14.93 and 23.04 hours. These results demonstrate that the active moiety (risperidone plus 9-OH-risperidone) has a half-life of 23 hours and reveal a pool of risperidone (terminal half-life, 14.9 hours) that may allow twice-daily or even once-daily dosing.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Cross-Over Studies; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Therapeutic Equivalency

Reasons for the variable efficacy of prokinetic agents in the treatment of chronic intestinal motility disorders are unclear. The aim of this study was to assess the influence of extrinsic autonomic neuropathy and motility patterns on the symptom response to cisapride in 42 such patients.. A randomized, double-blind, placebo-controlled, two-dose (10 and 20 mg, three times daily), 12-week study included (1) measurement of autonomic (including abdominal vagal) function; (2) standardized 5-hour upper gastrointestinal manometry; and (3) assessment of symptoms based on visual analog scale at baseline and 6 and 12 weeks. Statistical analysis compared symptom response among treatment and autonomic dysfunction groups and assessed the influence of absence of migrating motor complexes and presence of postprandial antral hypomotility on symptomatic responses to cisapride.. There was no significant overall effect of cisapride in the entire group of 42 patients. Generalized sympathetic and vagal dysfunctions influence the response of patients with neuropathic chronic intestinal motility disorder to two doses of cisapride.. Idiopathic intestinal motility disorder, unassociated with abdominal vagal dysfunction, is more likely to respond to cisapride. Detailed characterization of patient subgroups is crucial to designing treatment trials in patients with small bowel motility disorders.

Topics: Adult; Autonomic Nervous System; Autonomic Nervous System Diseases; Chronic Disease; Cisapride; Double-Blind Method; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Myoelectric Complex, Migrating; Piperidines; Vagus Nerve

In a double-blind study, 135 inpatients with a diagnosis of chronic schizophrenia were randomly assigned to 8 weeks of treatment with one of six parallel treatments: risperidone (a new central 5-hydroxytryptamine2 and dopamine D2 antagonist), 2, 6, 10, 16 mg/day; haloperidol, 20 mg/day; or placebo, after a single-blind placebo washout period. Doses were increased in fixed increments up to a fixed maintenance dose reached after 1 week. On the Clinical Global Impression-Severity of Illness and Improvement, all active medications were superior to placebo except for risperidone (2 mg) on the Clinical Global Impression-Improvement. On the total Positive and Negative Syndrome Scale (PANSS) score and positive subscale, superiority to placebo was observed for all treatment groups except for haloperidol and risperidone (2 mg), which tended to be superior to placebo on total PANSS and the positive subscale, respectively. On the PANSS negative subscale, only risperidone (6 mg/day) was significantly better than placebo. Risperidone (6 mg) was superior to haloperidol on the total PANSS, General Psychopathology, and Brief Psychiatric Rating Scale subscales. Although there was a linear increase in parkinsonism with increasing risperidone dosage, there were no statistically significant differences between risperidone (2, 6, and 16 mg/day) and placebo. At doses of 6 to 16 mg, risperidone displayed a marked antidyskinetic effect compared with placebo. This effect was more pronounced in patients with severe dyskinesia. By contrast, haloperidol produced significantly more parkinsonism than placebo and risperidone (2, 6 and 16 mg), with no effect on tardive dyskinesia. These data suggest that risperidone, at the optimal therapeutic dose of 6 mg/day, produced significant improvement in both positive and negative symptoms without an increase in drug-induced parkinsonian symptoms and with a significant beneficial effect on tardive dyskinesia.

Topics: Adult; Aged; Antipsychotic Agents; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Dyskinesia, Drug-Induced; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Neurologic Examination; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology

A parallel group double-blind comparative trial was conducted to study the efficacy and safety of risperidone compared with haloperidol. After a one-week wash-out, 35 chronic schizophrenic patients (17 males, 18 females) were randomly assigned to one of two groups for eight weeks of double-blind treatment. The patients' psychopathology was assessed by means of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinical Global Impression (CGI). Safety assessments included the Extrapyramidal Symptom Rating Scale (ESRS), the UKU Side Effect Rating Scale, vital signs, body weight, ECG and laboratory screening. Thirty-two patients completed the trial: there were 3 dropouts in the risperidone group. The results on the PANSS and CGI indicate that the mean changes from baseline on the total PANSS score and on the total BPRS score were comparable in both treatment groups. The number of patients where a clinical improvement at least 20% reduction in baseline score was also similar in both treatment groups. Risperidone caused less extrapyramidal symptoms and less side effects in UKU scale than haloperidol. No significant ECG changes were induced, no relevant changes in blood pressure or clinical laboratory parameters were observed. This study has demonstrated that the combined serotonin 5-HT2 and dopamine-D2 antagonist risperidone is an antipsychotic as potent as haloperidol. Risperidone causes less extrapyramidal symptoms, and is better tolerated than haloperidol.

Topics: Adolescent; Adult; Chronic Disease; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia

We assessed upper gastrointestinal anatomy and function with contrast radiology and antroduodenal manometry in 51 children with chronic intestinal pseudo-obstruction (CIP) prior to entering these patients into an open-label outpatient trial of cisapride. The diagnosis of CIP was based on characteristic symptoms requiring special nutritional support (parenteral in 30, tube feeding in 12) or interfering with daily activities (documented by diary in nine). At a time the subjects were not acutely ill, antroduodenal pressures were recorded for > 4 h fasting and > 1 h after a complex liquid meal. Results were categorized by the most prominent manometric abnormality as myopathy (n = 6), absent migrating motor complex (MMC) (n = 27), failure to induce fed pattern (n = 7), MMC plus discrete abnormalities (n = 7), and postprandial duodenal hypomotility (n = 4). Patients in the first two categories did not have effective MMCs, but those in the last three categories did. Compared to children without MMCs, those with MMCs rarely required parenteral nutrition (p < 0.001). All children were treated with oral cisapride 0.2 mg/kg/dose t.i.d., and evaluated every 2 months for up to 1 yr. Of 49 evaluable subjects, the final global assessment was unchanged in 25, fair (improved symptom score) in 17, or excellent (change from TPN to tube feeding or tube feeding to oral feeding) in seven. Children with MMCs (13 of 18) responded more often to cisapride than those without MMCs (11 of 31), p < 0.02. All four subjects with postprandial duodenal hypomotility had excellent responses. Children with normal diameter bowel responded more often than those with dilated bowel, p < 0.004. To summarize, in children with CIP, absence of the MMC was associated with need for greater intensity of nutritional support and decreased response rate to cisapride. The response to cisapride was highly variable within the study group, but often could be predicted by the presence or absence of bowel dilation and MMCs.

Topics: Child, Preschool; Chronic Disease; Cisapride; Enteral Nutrition; Female; Humans; Intestinal Pseudo-Obstruction; Linear Models; Male; Manometry; Myoelectric Complex, Migrating; Parenteral Nutrition, Total; Piperidines; Serotonin Antagonists

The efficacy and tolerability of cisapride in chronic dyspepsia was evaluated in a randomized, double-blind, placebo-controlled study. After 4 weeks' treatment with oral cisapride 10 mg three times daily (n = 14), bloating and epigastric discomfort were significantly reduced compared with placebo (n = 15; p < 0.05). Moreover, the global response to treatment was excellent or good in 71.4% of patients in the cisapride group versus 20.0% with placebo. No significant side effects were observed. It is concluded that cisapride is an effective and well-tolerated treatment for chronic dyspepsia.

Topics: Adolescent; Adult; Chronic Disease; Cisapride; Double-Blind Method; Dyspepsia; Female; Gastrointestinal Motility; Humans; Male; Piperidines; Severity of Illness Index; Treatment Outcome

A double-blind, placebo-controlled trial was performed to determine the therapeutic efficacy of cisapride in patients with refractory functional dyspepsia. A total of 147 patients with functional dyspepsia characterized by prominent epigastric pain or discomfort were randomized to 2 weeks' treatment with metoclopramide or domperidone (both 30 mg/day); of these, 53 patients unresponsive to dopamine antagonist treatment were randomized to cisapride 30 mg/day or placebo for an additional 2 weeks. Metoclopramide and domperidone produced comparable alleviation of epigastric symptoms; global efficacy was good or excellent in 62% and 57% of patients, respectively. In refractory patients, cisapride tended to display greater efficacy than placebo against epigastric pain, particularly at night. Global assessments of efficacy significantly favored cisapride over placebo, with good or excellent ratings in 65% and 32% of patients, respectively. Cisapride was well tolerated. Thus, cisapride appears to be an effective agent in functional dyspepsia unresponsive to other gastrokinetic agents.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cisapride; Domperidone; Double-Blind Method; Dyspepsia; Female; Gastrointestinal Motility; Humans; Male; Metoclopramide; Middle Aged; Piperidines; Treatment Outcome

This trial included patients from general practice with endoscopy-negative chronic dyspepsia and epigastric pain or discomfort. Eleven eligible patients with sufficiently severe dyspeptic symptoms after a 2-week placebo run-in period were entered into a 4-week, parallel group, double-blind randomized comparison of 10 mg cisapride three times daily and matched placebo, and were subsequently evaluable. Symptoms were comparable in the two treatment groups at the start of double-blind treatment. The cisapride group had a significantly greater reduction in the frequency of daytime epigastric pain/discomfort and the frequency and severity of nocturnal pain/discomfort after 2 weeks. After 2 weeks, all six cisapride recipients were free of nocturnal pain, compared with only one of five placebo recipients. After 4 weeks of double-blind therapy, improvements in the placebo group had reduced between-treatment differences, with five of six cisapride recipients and three of five placebo recipients being free of nocturnal pain. Cisapride was well tolerated.

Topics: Abdominal Pain; Adult; Aged; Chronic Disease; Cisapride; Double-Blind Method; Dyspepsia; Family Practice; Female; Gastrointestinal Motility; Humans; Male; Middle Aged; Piperidines

The Positive and Negative Syndrome Scale (PANSS) has been translated into Swedish and tested in 88 chronic schizophrenic patients. All 4 subscales exhibited a roughly normal distribution. The overall alpha for the positive, negative and general psychopathology subscales were 0.81, 0.58 and 0.63, respectively. The correlation between the positive and negative subscales was -0.17 (NS). The interrater reliability was 0.73-0.75 for the positive, 0.65-0.74 for the negative and 0.75-0.77 for the general psychopathology subscales. The intraclass coefficients were 0.75-0.77 for the positive, 0.27-0.46 for the negative, 0.56-0.72 for the general psychopathology subscales and 0.66-0.71 for the total scale. Thus, the validity and reliability of the PANSS (Swedish version) are quite satisfactory.

Topics: Antipsychotic Agents; Chronic Disease; Cross-Cultural Comparison; Double-Blind Method; Haloperidol; Humans; Isoxazoles; Observer Variation; Piperidines; Psychiatric Status Rating Scales; Psychometrics; Reproducibility of Results; Risperidone; Schizophrenia; Schizophrenic Psychology; Sweden

Forty-four chronic schizophrenic inpatients participated in this multicentre 12-week parallel-group double-blind trial. After a run-in period of 2 weeks and a single-blind placebo wash-out of 1 week, they were randomly assigned to treatment with either the serotonin2 and dopamine-D2 antagonist risperidone or haloperidol. Two patients were excluded from the efficacy analysis. Five patients dropped out in the haloperidol group and 1 in the risperidone group. At the end of the trial, the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol. The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia, the Schedule for Affective Disorders and Schizophrenia-change version, and the Nurses' Observation Scale for Inpatient Evaluation. The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double-blind treatment. The consumption of antiparkinsonian medication was 10 times lower with risperidone. Both drugs were well tolerated and the laboratory, endocrinological and cardiovascular safety parameters were comparable. This study suggests that risperidone is comparable to haloperidol as an antipsychotic, but that it has a safer EPS profile.

Topics: Adult; Aged; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Female; Haloperidol; Hospitalization; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology

The ventricle-brain ratio (VBR) of 42 chronic schizophrenic patients was compared with that of 42 age-matched medical controls. For the schizophrenics, the relationship of various clinical parameters to the VBR was assessed, and the outcome of 12 weeks of double-blind treatment with either risperidone or haloperidol. The results confirm that schizophrenic patients have slightly enlarged lateral ventricles compared with medical controls. Only for schizophrenics, an effect of age, but not of duration of illness, was noticed. This study does not support the validity of a clinical subdivision of chronic schizophrenic patients on the basis of the VBR. Neither negative, positive nor general psychopathological symptoms, as measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), were related to the VBR, nor were abnormal involuntary movements or extrapyramidal symptoms. No association between season of birth or a family history of major mental disorder and VBR could be demonstrated. Treatment response was predicted by the total PANSS score and the PANSS general psychopathology subscale score at baseline. There was a trend for patients with higher VBR to have a more or haloperidol). or haloperidol).

Topics: Adult; Aged; Antipsychotic Agents; Brain; Cerebral Ventricles; Chronic Disease; Dilatation, Pathologic; Double-Blind Method; Female; Haloperidol; Humans; Isoxazoles; Male; Middle Aged; Piperidines; Risperidone; Schizophrenia; Schizophrenic Psychology; Tomography, X-Ray Computed

This multicenter trial indicates that risperidone is an effective treatment for the positive and negative symptoms of schizophrenia. The most effective dose appears to be about 6 mg of risperidone daily. This dose was more effective than 20 mg of haloperidol. In addition, this dose was associated with very low rates of extrapyramidal side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Chronic Disease; Double-Blind Method; Humans; Isoxazoles; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

The effects on gastric emptying and gastrointestinal symptoms of treatment with cisapride alone and in combination with domperidone were investigated in 25 patients with chronic idiopathic dyspepsia. In a double-blind study, 9 patients were randomly assigned to receive cisapride 2.5 mg three times daily, and 8 patients to receive placebo. After 7 days of treatment, gastric emptying was significantly accelerated and the score of gastrointestinal symptoms was significantly reduced in patients treated with cisapride. Placebo treatment had no significant effect. A randomized, double-blind crossover study of 8 patients compared the effects of combined treatment with cisapride 2.5 mg plus domperidone 10 mg three times daily for 7 days against the effects of cisapride plus placebo. Administration of cisapride plus domperidone gave significantly higher gastric emptying and lower gastrointestinal symptoms than cisapride plus placebo.

Topics: Chronic Disease; Cisapride; Domperidone; Double-Blind Method; Drug Therapy, Combination; Dyspepsia; Female; Gastric Emptying; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists

The clinical efficacy and the safety of chronic oral administration of cisapride, a new gastrointestinal prokinetic agent, (10 mg tid) and clebopride (0.5 mg tid) was assayed in 48 outpatients affected with functional dyspepsia, in a randomized double-blind study. Each of the drugs induced a significant reduction in dyspeptic symptoms after 2 and 4 weeks (p less than 0.001). Two patients, given clebopride, dropped out of the study because of severe side effects during the first week of treatment. Mild adverse reactions were reported in 6 out of 23 cisapride-treated patients and in 10 out of 20 clebopride-treated patients who completed the study. The most common side effect of cisapride was diarrhoea and that of clebopride was drowsiness. Cisapride appears to be as effective as clebopride in reducing dyspeptic symptoms and seems to induce less severe side effects.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antiemetics; Benzamides; Chronic Disease; Cisapride; Double-Blind Method; Dyspepsia; Female; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists

We conducted a 12-month trial of cisapride (10 mg three times a day) in 21 patients with gastric stasis due to clinically and manometrically diagnosed gastroparesis (N = 9; seven due to diabetes) or chronic intestinal pseudo-obstruction (N = 12). Radionuclide solid-liquid gastric emptying tests were performed at baseline and at the end of the 12-month period. Symptoms were assessed monthly by diary and every three months by the investigators; frequency and severity of symptoms were scored in a standardized manner. For the whole group of 21 patients, gastric emptying of both solids and liquids improved significantly after one year of cisapride (P less than 0.05). Among chronic intestinal pseudoobstruction patients, there was predominantly an improvement in gastric emptying of solids; in contrast, patients with gastroparesis had a greater improvement in liquid emptying. Total symptom score improved significantly in the gastroparesis group (median score: 8 at baseline vs 6 at one year, P less than 0.05) but not in the chronic intestinal pseudoobstruction patients (median score at baseline 10 vs 9 at one year). Similarly, body weight showed a trend towards improvement in the gastroparesis group. No significant side effects were noted. We conclude that during a 12-month open trial, cisapride was effective in improving gastric emptying in patients with gastric stasis and consistently improved symptoms in those with gastroparesis.

Topics: Administration, Oral; Adult; Body Weight; Chronic Disease; Cisapride; Double-Blind Method; Female; Gastric Emptying; Humans; Intestinal Pseudo-Obstruction; Male; Piperidines; Serotonin Antagonists; Stomach Diseases

The exact relationship between depression and chronic headache remains unclear. Considerable clinical and pharmacological evidence suggests the existence of a common biological terrain. Many antidepressant drugs are effective in the treatment of migraine and chronic headache disorders. Ritanserin, a new very selective serotonin-2 (5-HT2) antagonist, has recently shown both analgesic and antidepressant properties. The present study compares in a double-blind design, the effectiveness of ritanserin and amitriptyline, a well-known antidepressant extensively used in migraine prophylaxis. Thirty-eight patients (30 females and 8 males ranging in age from 20 to 50 yrs) were classified according to the International Headache Society criteria as: patients with chronic tension-type headache (CTH) (11 cases) and patients with coexisting migraine and CTH (MCTH) (27 cases). Only patients with a score equal to or higher than 18 on the Hamilton Rating Scale for Depression (HRSD) were included. Ritanserin was highly effective in reducing Pain Total Index and analgesic consumption in chronic headache, and its activity was similar to that observed during amitriptyline treatment. A significant improvement of HRSD and HRSA (Hamilton Rating Scale for Anxiety) scores was observed during both treatments. The main results of our study concern the demonstration of antiheadache and antidepressive properties of ritanserin. To better define the profile of the patients and their clinical responsiveness to the treatment, dexamethasone suppression test, clonidine test and nociceptive flexion reflex were investigated in our patients. Our data confirm the usefulness of these methods as markers of chronic headache with depression.

Topics: Adult; Amitriptyline; Chronic Disease; Depression; Double-Blind Method; Female; Headache; Humans; Male; Piperidines; Ritanserin

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

Topics: Adolescent; Adult; Chronic Disease; Cisapride; Cystic Fibrosis; Double-Blind Method; Female; Humans; Intestinal Obstruction; Male; Piperidines; Recurrence; Serotonin Antagonists; Syndrome

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

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

Twenty-eight patients with chronic idiopathic dyspepsia defined by the presence of chronic unexplained symptoms suggestive of gastric stasis and directly related to food ingestion were included in this prospective study. Gastric emptying of the liquid and solid phases of a meal was quantified by a dual-isotope method, and symptoms were evaluated by a diary and a visual analog scale. Delay in gastric emptying was evidenced in 59% of the dyspeptic patients; it occurred with liquids in more cases than solids. Quantitative and qualitative evaluation of symptoms was of no practical value in predicting the presence of objective stasis. The dyspeptic patients were included in a double-blind randomized controlled trial of cisapride, a new gastrokinetic drug devoid of central antiemetic effects. After six weeks of cisapride treatment, all patients with initially abnormal gastric emptying rates for liquids, and all but one for solids returned to normal ranges, and significant differences between cisapride and placebo groups were observed for half emptying times of both solids (136 +/- 16 min vs 227 +/- 32 min; P less than 0.02) and liquids (61 +/- 4 min vs 132 +/- 37 min; P less than 0.01). Cisapride also significantly improved dyspeptic symptom scores at weeks 3 and 6 of treatment as compared to those measured before treatment. Nevertheless, the decrease in global diary score was significantly higher than that seen with placebo at week 3 (-16 +/- 6 vs -1 +/- 9; P less than 0.05), but not at week 6 (-18 +/- 5 vs -10 +/- 8).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Chronic Disease; Cisapride; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Gastric Emptying; Humans; Male; Middle Aged; Patient Compliance; Piperidines; Placebos; Radionuclide Imaging; Random Allocation; Serotonin Antagonists; Time Factors

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

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

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

The effects of cisapride, a nondopaminolytic motility-enhancing agent, were studied in 56 patients with chronic functional dyspepsia; all had symptoms suggestive of delayed gastric emptying. The patients received 4 mg or 8 mg of cisapride or placebo orally three times daily for two successive three-week periods according to a randomized, double-blind, crossover study design. Although there was a high placebo response (55% showed good or excellent results), the global response to treatment was significantly (P = 0.024) in favor of cisapride (75% had good or excellent results). The drug was particularly superior to placebo (P = 0.03) in the improvement of a cluster of symptoms typical of postprandial discomfort, including early satiety and nausea. Side effects were minimal.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cisapride; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Dyspepsia; Female; Gastric Emptying; Humans; Male; Middle Aged; Piperidines; Random Allocation

Thirty patients with frequent (greater than or equal to 30/hr) and repetitive ventricular premature beats (VPBs) unassociated with acute infarction were randomized to intravenous lorcainide (LOR) or lidocaine (LID). Following at least 2 hours of baseline Holter monitoring, patients received LOR, 2 mg/kg then 200 mg/24hr, or LID, 1 mg/kg then 2 mg/min, with rebolus if needed. Nonresponders detected by bedside telemetry were crossed over. Clinical response was 6 of 25 (24%) including two of nine crossovers with LOR and 8 of 26 (31%) including 3 of 12 crossovers with LID (p = NS). By computer analysis of 24-hour Holter monitors and asymptotic regression of success rates at hourly intervals, it was projected that greater than or equal to 80% reduction in VPBs occurred in 28% of LOR and in 25% of LID (p = NS), and complete suppression of repetitive VPBs occurred in 102% of LOR and in 92% of LID (p = NS). The mean drug levels were 405 ng/ml (range 371 to 463) with LOR and 3.4 micrograms/ml (range 2.1 to 3.6) with LID. Side effects were similar, occurring in 8 of 25 LOR trials and in 11 of 26 LID trials (p = NS). Thus, LOR and LID effectively suppress repetitive VPBs and to a lesser extent VPB frequency. However, neither drug is superior and each may be an effective alternative when resistance to the other is encountered.

Topics: Aged; Arrhythmias, Cardiac; Benzeneacetamides; Chronic Disease; Electrocardiography; Female; Humans; Infusions, Parenteral; Kinetics; Lidocaine; Male; Middle Aged; Monitoring, Physiologic; Myocardial Infarction; Piperidines; Random Allocation

Topics: Alcoholism; Blood Pressure; Chronic Disease; Female; Humans; Hypertension; Ketanserin; Male; Piperidines

Ketanserin ia a quinazoline derivative which acts selectively on serotonin (S2) receptors. The compound has been shown to possess antihypertensive properties. BP and HR were measured blindly on 14 patients with essential hypertension during one year. Ketanserin 40 mg, once or twice daily, reduced BP (and HR to a slight extent) largely unchanged from 14 days after initiation of therapy. Response rate varied from 57-77% at the regular control visits. During the one year follow up period the reduction in supine SBP was 9 +/- 3% (p less than 0.001) and DBP was 12 +/- 1% (p less than 0.001). The only side effect was a slight sedation that passed with time. It is concluded that ketanserin is effective in the chronic treatment of hypertension and may offer a new alternative to existing pharmacotherapy.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Placebos; Serotonin Antagonists

Topics: Brief Psychiatric Rating Scale; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Piperidines; Placebos; Schizophrenia

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

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

Oral domperidone (30 mg/day) or placebo tablets were given to 41 patients presenting with symptoms of chronic post-prandial dyspepsia, in a double blind study. The tablets were taken three times a day before meals. The first part of the study lasted four weeks and was followed by a second four week period in which domperidone was given on an open basis to all subjects. At the end of the double-blind phase all indices but one (bitter regurgitation) as well as the gastro-oesophageal reflux cluster had significantly improved on domperidone treatment while none had done so on placebo. During the subsequent open four weeks of domperidone all items improved in both study groups. No side effects were seen in any of the participants in the study.

Topics: Adult; Aged; Antiemetics; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Food; Humans; Male; Middle Aged; Piperidines; Placebos

A doubld-blind crossover study of oral domperidone (10 mg t.d.s.) involving 48 patients suffering from chronic postprandial dyspepsia, showed a significant relief of symptoms on active treatment compared to placebo. The trial lasted eight weeks, the crossover in medication taking place at four weeks. Side effects were rare and mild and it is concluded that domperidone could be a very useful drug for the symptomatic treatment of upper gastrointestinal distress.

Topics: Adolescent; Adult; Antiemetics; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Food; Humans; Male; Middle Aged; Piperidines

Forty patients who were suffering from chronic dyspepsia, diagnosed clinically and radiologically as being related to delayed gastric emptying, were treated with either domperidone or placebo in a double-blind trial. The trial lasted four weeks and the dose of domperidone was 10 mg orally t.d.s. before meals. The results showed that the drug markedly improved symptoms and that side effects were few, being recorded in one patient only, on active treatment. It is concluded that domperidone is a useful agent for the treatment of dyspepsia with retarded gastric emptying.

Topics: Adult; Aged; Antiemetics; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Gastric Emptying; Humans; Male; Middle Aged; Piperidines; Placebos

Forty patients with postprandial nausea and vomiting from a variety of underlying causes, were given either domperidone 20 mg t.d.s. or placebo in a double-blind study lasting two weeks. The tablets were taken before meals and no other anti-emetics were used. Nausea and vomiting were reduced in those patients given the active therapy, the results being recorded as excellent in 62% in the domperidone group and 18% of controls.

Topics: Adult; Aged; Antiemetics; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Dyspepsia; Female; Food; Humans; Male; Middle Aged; Nausea; Piperidines; Vomiting

Forty-seven infants and children suffering from chronic vomiting or regurgitation, participated in a two-week double-blind trial comparing 1% drops of domperidone, 1% metoclopramide drops or placebo. The dose was 0.3 mg/kg given t.d.s. before meals. Both active medicaments were significantly more effective than placebo in controlling the symptoms and domperidone was also significantly superior to metoclopramide. It is concluded, in view of the good safety margin with domperidone, that this drug could become the treatment of choice in such cases.

Topics: Antiemetics; Benzimidazoles; Child; Child, Preschool; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Gastroesophageal Reflux; Humans; Infant; Infant, Newborn; Male; Metoclopramide; Nausea; Piperidines; Vomiting

Domperidone, at a dosage of 20 mg t.d.s before meals, in a double-blind, crossover, placebo-controlled trial reduced the level of the symptoms of dyspepsia by 76% compared to a 16% reduction with placebo. This difference was statistically significant (p less than 0.001). Thirteen of the fourteen patients in the study preferred domperidone to placebo. Four patients in the active treatment period and one in the placebo complained of mild side-effects.

Topics: Adult; Aged; Benzimidazoles; Chronic Disease; Double-Blind Method; Drug Evaluation; Dyspepsia; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Piperidines; Placebos

32 patients with chronic postprandial dyspepsia were selected for a 4-week controlled double-blind trial of domperidone and a placebo. The patients received either domperidone or a placebo at a dose rate of two 10-mg tablets t.i.d. before meals. A questionnaire was completed at the start of the study, and after 2 and 4 weeks of treatment. Excellent or good improvement was obtained in 71% of the domperidone-treated patients compared to only 13% of the placebo-treated cases. Domperidone was also significantly superior to the placebo when both drugs were compared to previously used medications. Side effects were not reported. It is concluded that domperidone has a beneficial effect on chronic postprandial dyspepsia.

Topics: Adult; Aged; Antiemetics; Benzimidazoles; Chronic Disease; Double-Blind Method; Drug Evaluation; Dyspepsia; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Piperidines; Placebos

1. The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol, 375 mg oral theophylline and both drugs in combination were compared in a randomized, placebo-controlled, double-blind trial in eight patients with chronic, partially reversible airways obstruction. 2. The four treatments were (i) oral theophylline, placebo aerosol (TP); (ii) oral placebo, rimiterol aerosol (PR); (iii) oral theophylline, rimiterol aerosol (TR) and; (iv) oral placebo, placebo aerosol (PP). The aerosol was administered 2 h after the oral treatment. 3. Significant bronchodilatation (% FEV1 change from control) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min, whereas with PR only for 45 min (P less than 0.05). 4. The mean, peak % FEV1 increases from control were 51.8% at 125 min, 31.7% at 125 min, 26.1% at 210 min and 0.9% at 30 min for TR, PR, TP and PP respectively. 5. At 125 min (5 min after aerosol inhalation) the mean % FEV1 change from control with TR (51.8%) Was significantly greater than with PR (31.7%), TP (22.2%) (P less than 0.05) and PP (-2.4%) (P less than 0.01). 6. The mean, peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively. Theophylline half-life ranged between 4.3 and 12.5 h (mean +/- s.e. mean, 8.0 +/- 0.8 h). 7. Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved.

Topics: Administration, Oral; Adult; Aerosols; Aged; Airway Obstruction; Bronchodilator Agents; Catechols; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Piperidines; Theophylline

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

This investigation is a 52-week double-blind study comparing the efficacy and safety of penfluridol and trifluoperazine in 25 chronic schizophrenic outpatients. Penfluridol was administered once weekly and trifluoperazine daily. Measurements were made at baseline, various fixed intervals during the study period and termination. The data reveals that both agents were similarly effective in maintaining control of the symptoms of chronic schizophrenic patients at a level commensurate with or better than that provided by their previous medication. Besides being effective, medications were also well tolerated. The side effects were characteristic of marketed neuroleptics. Akathisia was more common with penfluridol but readily controlled with anti-parkinsonian medication. Other side effects were similar in severity and occurrence between study-drug groups. Both agents had low autonomic liability, and neither agent was depressogenic.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Female; Humans; Interpersonal Relations; Male; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Trifluoperazine

Penfluridol, a diphenylbutylpiperidene derivative, is a new long acting neuroleptic, administered orally, once weekly. It is marketed in several European countries and has been used successfully in the treatment of various acute psychoses, for severely ill chronic schizophrenic patients, and as maintenance therapy for chronic schizophrenic patients. The present study was designed to compare, in a double-blind fashion, the efficacy of penfluridol and fluphenazine decanoate in the maintenance therapy of schizophrenic outpatients.

Topics: Adult; Ambulatory Care; Chronic Disease; Double-Blind Method; Drug Evaluation; Female; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

In a double-blind long-term study, regular inhalations of a short-acting selective beta2-stimulator, rimiterol, was compared with a long-acting one, terbutaline. The trial comprised 60 patients with chronic obstructive lung disease, all patients were on a small dose of an oral beta2-stimulator. Both drugs were regularly given in aerosol form with a minimum dose of three inhalations three times daily. The main purpose was to study subjective and objective side effects. Haematological, hepatic and renal functions were screened for toxicity. Consumption of spray was recorded. No side effects occurred. There was no evidence of development of isoprenaline resistance. The consumption of spray was the same in both groups. In this study, regular inhalation treatment of rimiterol seemed to be as effective as terbutaline in long-term bronchodilator therapy.

Topics: Aerosols; Asthma; Bronchitis; Catechols; Chronic Disease; Drug Evaluation; Female; Humans; Isoproterenol; Lung Diseases, Obstructive; Male; Piperidines; Pulmonary Emphysema; Terbutaline

Topics: Administration, Oral; Adult; Chronic Disease; Clinical Trials as Topic; Drug Administration Schedule; Female; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia

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

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

Plasma levels of penfluridol and thiothixene were studied after 4 weeks treatment in a double-blind controlled trial of 47 patients suffering from chronic schizophrenic syndromes. There was found a tenfold variation in plasma levels for penfluridol, and about a twentyfold variation for thiothixene. For penfluridol, a significant correlation between dosage and plasma level and also between dosage and changes in psychopathology as regards factor 5 in the Märtens & Jonsson S scale which comprises the items most characteristic of a schizophrenic syndrome, was found. For thiothixene, a significant correlation between plasma levels and changes in factor 5 was found. A gas-chromatographic method for penfluridol is also described.

Topics: Adult; Chromatography, Gas; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Thiothixene

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Electroencephalography; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Sleep; Sleep Stages; Sleep, REM; Time Factors

The new antihistamine, HC20-511 (Sandoz), was compared with Dimetinden (Fenistil retard) in a single-blind comparative study in 42 patients with dermatoses, 28 of whom suffered from chronic urticaria. HC20-511 had a better effect, especially in chronic urticaria, where pruritus, erythema and papules quickly disappeared. The effect appeared somewhat faster than and lasted as long as that of Dimetinden, although HC20-511 is not a retard-preparation unlike the Dimetinden preparation used for comparison. HC20-511 also caused less side effects.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Dimethindene; Drug Therapy, Combination; Female; Fumarates; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Pruritus; Skin Diseases; Thiophenes; Urticaria; Vomiting

Topics: Acute Disease; Adult; Aged; Antitussive Agents; Benzhydryl Compounds; Chronic Disease; Clinical Trials as Topic; Codeine; Cough; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines; Propanolamines

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Penfluridol; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Time Factors

Topics: Administration, Oral; Chronic Disease; Clinical Trials as Topic; Humans; Penfluridol; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia

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: Adult; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Female; Hospitalization; Hospitals, Psychiatric; Humans; Male; Mental Disorders; Phenothiazines; Piperidines; Schizophrenia

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: Aggression; Analysis of Variance; Arrhythmias, Cardiac; Basal Ganglia Diseases; Benzoates; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Handwriting; Humans; Male; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Statistics as Topic; Tranquilizing Agents; Tremor

Topics: Adult; Analysis of Variance; Basal Ganglia Diseases; Body Weight; Chlorpromazine; Chronic Disease; Clinical Trials as Topic; Electrocardiography; Electroencephalography; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Social Behavior; Substance Withdrawal Syndrome; Thioridazine; Toluene; Tranquilizing Agents; Vision Tests

Topics: Analysis of Variance; Antitussive Agents; Bronchitis; Chronic Disease; Cough; Densitometry; Humans; Oxazines; Piperidines; Placebos; Sputum; Viscosity

Topics: Adult; Behavior; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Paranoid Disorders; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Paranoid

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Dibenzazepines; Drug Evaluation; Enuresis; Female; Humans; Intellectual Disability; Middle Aged; Neurasthenia; Piperidines; Psychotropic Drugs; Schizophrenia

Topics: Adult; Caproates; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Drug Evaluation; Female; Fluorobenzenes; Fluphenazine; Humans; Hypnotics and Sedatives; Male; Middle Aged; Paranoid Disorders; Piperidines; Psychiatric Status Rating Scales; Psychological Tests; Schizophrenia; Spiro Compounds; Time Factors

Topics: Adult; Aged; Antiparkinson Agents; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Haloperidol; Hospitalization; Humans; Hydrocarbons, Halogenated; Interview, Psychological; Middle Aged; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Surveys and Questionnaires; Time Factors; Toluene; Tranquilizing Agents

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: Adult; Aged; Antipsychotic Agents; Basal Ganglia Diseases; Chronic Disease; Clinical Trials as Topic; Esters; Female; Humans; Male; Methotrimeprazine; Middle Aged; Piperidines; Schizophrenia; Sulfonamides; Time Factors; Undecylenic Acids

Topics: Adult; Age Factors; Aged; Antidepressive Agents; Antiparkinson Agents; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Female; Humans; Hypnotics and Sedatives; Injections; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Time Factors

Topics: Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Fluphenazine; Humans; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides; Undecylenic Acids

Topics: Angina Pectoris; Chronic Disease; Clinical Trials as Topic; Humans; Middle Aged; Perhexiline; Piperidines; Statistics as Topic; Vasodilator Agents

Topics: Adult; Attention; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Fluorobenzenes; Galvanic Skin Response; Humans; Memory; Motor Skills; Occupational Therapy; Perception; Piperidines; Placebos; Schizophrenia; Spiro Compounds; Tranquilizing Agents; Word Association Tests

Topics: Basal Ganglia Diseases; Blood Pressure; Chronic Disease; Clinical Trials as Topic; Female; Fluorobenzenes; Fluphenazine; Heart Rate; Humans; Injections, Intramuscular; Male; Parkinson Disease, Secondary; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds; Time Factors; Tranquilizing Agents

Topics: 1-Propanol; Adult; Antiparkinson Agents; Basal Ganglia Diseases; Benztropine; Biperiden; Chronic Disease; Clinical Trials as Topic; Drug Combinations; Evaluation Studies as Topic; Humans; Male; Middle Aged; Movement Disorders; Parasympatholytics; Piperidines; Procyclidine; Pyrrolidines; Schizophrenia; Tranquilizing Agents; Trihexyphenidyl; Tropanes

Topics: Adult; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Movement Disorders; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Tranquilizing Agents; Trifluoperazine

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Evaluation Studies as Topic; Female; Humans; Injections, Intramuscular; Interview, Psychological; Length of Stay; Middle Aged; Occupational Therapy; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Surveys and Questionnaires; Tranquilizing Agents

Topics: Administration, Oral; Aged; Analgesics; Animals; Chemistry, Organic; Chronic Disease; Dogs; Humans; Male; Middle Aged; Organic Chemistry Phenomena; Pain; Piperidines; Placebos; Rats; Rats, Inbred Strains

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Nitriles; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Psychotic Disorders; Thioridazine; Tranquilizing Agents

Topics: Adolescent; Adult; Child; Child, Preschool; Chronic Disease; Delayed-Action Preparations; Dermatitis; Female; Follow-Up Studies; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Placebos; Pruritus; Tablets; Time Factors; Urticaria

Topics: Adult; Benzimidazoles; Chronic Disease; Clinical Trials as Topic; Electroencephalography; Evaluation Studies as Topic; Humans; Male; Piperidines; Placebos; Schizophrenia; Tranquilizing Agents

Topics: Acute Disease; Adolescent; Adult; Aged; Antidepressive Agents; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Community Mental Health Services; Female; Fluorine; Humans; Male; Middle Aged; Piperidines; Schizophrenia; Trifluperidol

Topics: Adult; Age Factors; Antidepressive Agents; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Female; Fluorine; Hospitalization; Humans; Middle Aged; Piperidines; Placebos; Schizophrenia; Trifluperidol

Topics: Adult; Antidepressive Agents; Butyrophenones; Chlorpromazine; Chronic Disease; Clinical Trials as Topic; Female; Fluorine; Humans; Middle Aged; Piperidines; Placebos; Schizophrenia; Trifluperidol

Topics: Chronic Disease; Humans; Osteomyelitis; Piperidines; Pyrimidines; Recurrence

Topics: B-Lymphocytes; Bronchiolitis Obliterans Syndrome; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Piperidines; Steroids

The second-generation antihistamines at licensed doses are first-line treatment in urticaria and up-dosing is recommended as second-line treatment. To assess the efficacy and safety of escalated doses of ebastine in patients with chronic urticaria (CU), we designed this study. Recruited patients with CU were treated with increasing doses of ebstine. Treatment started at the daily dose of 10 mg. The symptom is assessed weekly, and if there is no significant improvement, the dose is increased from 10 mg to 20 mg, and if still no significant improvement, up to 40 mg. Pruritus, number, diameter, duration and frequency of wheals, and adverse reactions were assessed. One hundred and forty (76.50%) patients achieved marked effect with ebastine 10 mg/day, 27 (14.75%) patients with ebastine 20 mg/day and 13 (7.10%) patients with ebastine 40 mg/day, while 3(1.64%) patients did not get marked effect. There was no significant difference of effect between factitious urticaria, CSU, cholinergic urticaria and CSU with factitious urticaria in different dose (all p > 0.05). Common adverse reactions of ebstine treatment, included dry mouth, somnolence, tiredness and headache, were mild or moderate. There was no significant difference between the degree score of dry mouth with different doses of ebastine, and the same to somnolence, tiredness and headache (all p > 0.05). Doses escalation of ebastine should be effective in treatment of factitious urticaria, CSU and cholinergic urticaria with poorly treated by standard of double doses. Increasing ebastine dose did not increase the incidence of adverse reactions.

Topics: Butyrophenones; Cholinergic Agents; Chronic Disease; Chronic Urticaria; Headache; Histamine H1 Antagonists; Humans; Piperidines; Prospective Studies; Sleepiness; Urticaria; Xerostomia

Topics: Chronic Disease; Humans; Photosensitivity Disorders; Piperidines; Pyrimidines

The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway play a key role in immune modulation, especially in the polarization of T helper cells. JAK inhibitors reduce inflammation by inhibiting the phosphorylation of STAT. We investigated whether a JAK inhibitor, tofacitinib, can reduce inflammation in a mouse model of chronic rhinosinusitis with nasal polyps (CRSwNP).. An eosinophilic CRSwNP model was induced using 4-week-old BALB/c mice. The therapeutic effects of topical tofacitinib were compared with the effects of triamcinolone acetonide (TAC). Polyp formation and eosinophilic infiltration were assessed by histology. Levels of phosphorylated STAT (pSTAT), eosinophil cationic protein, and eotaxin were measured by immunohistochemistry. Gene expression levels of GATA-3 was measured using quantitative PCR. The production of cytokines in sinonasal tissues, including interleukin IL-4, IL-5, IL-12, and interferon-γ, were measured using enzyme-linked immunosorbent assays (ELISA).. Topical tofacitinib administration significantly reduced the number of polyp-like lesions and the degree of eosinophilic infiltration, with an efficacy comparable with that of systemic TAC administration. Similarly, the levels of pSTAT6, eosinophil cationic protein, and eotaxin decreased with tofacitinib treatment. Tofacitinib decreased the gene expression level of GATA-3. Lastly, tofacitinib significantly decreased IL-4 and IL-5 production to a similar extent as that by systemic or topical TAC administration. Tofacitinib, but not TAC, significantly increased the production of interferon-γ.. Topical tofacitinib administration may be an effective treatment for eosinophilic CRSwNP by inhibiting phosphorylation of STATs.. N/A. Laryngoscope, 131:E1400-E1407, 2021.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Animals; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Eosinophils; Humans; Janus Kinases; Male; Mice; Nasal Mucosa; Nasal Polyps; Piperidines; Pyrimidines; Rhinitis; Signal Transduction; Sinusitis; STAT Transcription Factors; Triamcinolone Acetonide

Topics: Benzimidazoles; Cetirizine; Chronic Disease; Chronic Urticaria; Humans; India; Piperidines; Urticaria

The Janus kinases (JAKs) are intracellular tyrosine kinases involved in a broad variety of inflammatory cascades participating in the pathogenesis of systemic lupus erythematosus (SLE). Diffuse non-scarring alopecia is one of the most frequent cutaneous manifestations in SLE, resulting in devastating psychosocial consequences. Although recent studies have shown promising outcomes of the JAK inhibitors in SLE treatment, the efficacy of tofacitinib in diffuse non-scarring alopecia due to SLE has never been reported. Here we present a 29-year-old SLE patient with a 10-year history of refractory severe diffuse non-scarring alopecia who experienced dramatic hair regrowth with tofacitinib. Furthermore, we have made a systematic review regarding the potential effectiveness of tofacitinib in systemic and cutaneous lupus erythematosus. To the best of our knowledge, this is the first case study depicting an SLE patient with refractory alopecia who experienced impressive hair regrowth with the JAK1/3 inhibitor tofacitinib therapy, which contributes to expanding the field of possible uses of tofacitinib in SLE patients with difficult-to-treat cutaneous involvement, including severe alopecia.

Topics: Adult; Alopecia Areata; Chronic Disease; Female; Humans; Lupus Erythematosus, Systemic; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Treatment Outcome

Topics: Adenine; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Mycoses; Piperidines; Pyrazoles; Steroids

The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs.. The antidepressant-like and procognitive effects of the "biased agonists" F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT. Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds' activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined.. F15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4-16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels.. Our studies showed that 5-HT

Topics: Aminopyridines; Animals; Antidepressive Agents; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Locomotion; Male; Mice; Piperidines; Pyrimidines; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Single-Blind Method; Stress, Psychological

Topics: Animals; Cannabidiol; Chronic Disease; Cobalt; Depression; Limbic System; Microinjections; Neuralgia; Piperazines; Piperidines; Prefrontal Cortex; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1A; Sciatica; Serotonin 5-HT1 Receptor Antagonists; Swimming; Synapses

Stress contributes to major depressive disorder (MDD) and chronic pain, which affect a significant portion of the global population, but researchers have not clearly determined how these conditions are initiated or amplified by stress. The chronic social defeat stress (CSDS) model is a mouse model of psychosocial stress that exhibits depressive-like behavior and chronic pain. We hypothesized that metabotropic glutamate receptor 5 (mGluR5) expressed in the nucleus accumbens (NAc) normalizes the depressive-like behaviors and pain following CSDS. Here, we show that CSDS induced both pain and social avoidance and that the level of mGluR5 decreased in susceptible mice. Overexpression of mGluR5 in the NAc shell and core prevented the development of depressive-like behaviors and pain in susceptible mice, respectively. Conversely, depression-like behaviors and pain were exacerbated in mice with mGluR5 knockdown in the NAc shell and core, respectively, compared to control mice subjected to 3 days of social defeat stress. Furthermore, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, reversed the reduction in the level of the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the NAc of susceptible mice, an effect that was blocked by 3-((2-methyl-1, 3-thiazol-4-yl) ethynyl) pyridine hydrochloride (MTEP), an mGluR5 antagonist. In addition, the injection of CHPG into the NAc shell and core normalized depressive-like behaviors and pain, respectively, and these effects were inhibited by AM251, a cannabinoid type 1 receptor (CB1R) antagonist. Based on these results, mGluR5-mediated eCB production in the NAc relieves stress-induced depressive-like behaviors and pain.

Topics: Animals; Cannabinoid Receptor Antagonists; Chronic Disease; Depressive Disorder, Major; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Microinjections; Nucleus Accumbens; Pain; Piperidines; Pyrazoles; Pyridines; Receptor, Metabotropic Glutamate 5; Signal Transduction; Social Defeat; Stress, Psychological; Thiazoles

Topics: Adult; Chronic Disease; Female; Fibrosis; Global Burden of Disease; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Incidence; Interferon-alpha; Lipopeptides; Liver Diseases; Male; Middle Aged; Piperidines; Prevalence; Pyridines; Risk Factors; Superinfection; Uzbekistan

Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL

Topics: Aged; Alkaloids; alpha-Tocopherol; Benzodioxoles; Biomarkers; C-Reactive Protein; Chronic Disease; Dietary Supplements; Female; Ferritins; Humans; Inflammation; Luminescent Measurements; Male; Metabolic Syndrome; Middle Aged; Neutrophils; Oxidative Stress; Oxygen Consumption; Piperidines; Polyunsaturated Alkamides; Resveratrol; Time Factors

Topics: Aged; Arthritis, Rheumatoid; Chronic Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pruritus; Pyrimidines; Severity of Illness Index; Treatment Outcome

Although existing psoriasis treatments are effective and well tolerated in many patients, there is still a need for new effective targeted treatment options. Tofacitinib is an oral Janus kinase inhibitor that has been investigated in patients with moderate-to-severe chronic plaque psoriasis.. To consider the benefits and risks of tofacitinib in patients with moderate-to-severe psoriasis.. Data were pooled from one phase II, four phase III and one long-term extension study comprising 5204 patient-years of tofacitinib treatment. Efficacy end points included patients achieving Physician's Global Assessments of 'clear' or 'almost clear', ≥ 75% and ≥ 90% reduction in Psoriasis Area and Severity Index (coprimary end points) and improvements in Dermatology Life Quality Index score, Hospital Anxiety and Depression Scale depression score and Itch Severity Item score, at weeks 16 and 52. Safety data were summarized for 3 years of tofacitinib exposure.. Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients' quality of life and was well tolerated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID.. Tofacitinib has a benefit-risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Young Adult

Topics: Adenine; Aged; Alemtuzumab; Antineoplastic Agents, Immunological; Antiviral Agents; Chronic Disease; Disease Progression; Hepatitis E; Hepatitis E virus; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Ribavirin

Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeated 7 questions on first-line treatment and 3 questions on second-line scenarios followed by an updated survey on all current systemic treatment options known and applied, with 29 of 66 centers (43%) responding. In summary, the results show a large overlap of first-line treatment practice between centers and the 2 surveys because of a lack of new data that changes practice, except significant heterogeneity of treatment of cGVHD progressive onset type, which can be explained by the lack of trials focusing on this high-risk entity. In contrast, treatment options applied to second-line therapy vary considerably, with new agents like ibrutinib and ruxolitinib entering clinical practice. Moreover, treatment of bronchiolitis obliterans syndrome demonstrates heterogeneity in applied therapeutic options and sequence because of a lack of controlled data and different conclusions from already existing evidence. In summary, the survey results demonstrate an increasing number of treatment options applied to cGVHD accompanied by a significant heterogeneity in second-line treatment and underline the urgent need for clinical trials and registry analyses on rare entities with high mortality like progressive onset type and lung involvement of cGVHD.

Topics: Adenine; Adult; Austria; Bronchiolitis Obliterans; Chronic Disease; Female; Germany; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Male; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Switzerland

Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation.. Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated.. AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial-mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts.. These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

Topics: Allografts; Animals; Chronic Disease; Disease Models, Animal; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Interleukin-6; Janus Kinases; Kidney Transplantation; Piperidines; Pyrroles; Rats; Rats, Inbred Lew; Tacrolimus

This study investigated the effect of rimonabant, a cannabinoid receptor type 1 antagonist, on calcium/calmodulin- dependent protein kinase II and cannabinoid receptor type 1 in chronic intermittent hypoxia.. Healthy male rats were divided into control group, intermittent hypoxia group for 4 or 6 weeks, hypoxic intervention group that received rimonabant (1 mg/kg/d) before exposure to hypoxia for 4 or 6 weeks (n = 10/group). Morphological changes and expressions of the two indexes in the cerebral hippocampus cells were determined by haematoxylin-eosin staining and immunohistochemistry, respectively.. In the intermittent hypoxia group at 4 weeks, the hippocampal cells were damaged with sparse cytoplasm and unclear boundaries, which are even worse at 6 weeks. In contrast, the hippocampal cells of the hypoxic intervention group were neatly arranged at 4 weeks. At 6 weeks, cells were larger with scarce cytoplasm and nuclear changes indicative of cell death. Calcium/calmodulin-dependent protein kinase II and cannabinoid receptor type 1 expression in the cerebral hippocampus was elevated in the intermittent hypoxia group at 4 weeks with even greater at 6 weeks. Cannabinoid receptor type 1 expression was reduced in the hypoxic intervention group compared to the intermittent hypoxia group. Correlation analysis revealed significant positive correlation of them in the intermittent hypoxia group.. Chronic intermittent hypoxia induced structural damage in the hippocampus and increased cannabinoid receptor type 1 and calcium/calmodulin-dependent protein kinase II expression, which may mediate cognitive impairment associated with chronic intermittent hypoxia. Rimonabant had a protective effect against chronic intermittent hypoxia.

Topics: Animals; Brain Injuries; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cannabinoid Receptor Antagonists; Chronic Disease; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Hypoxia; Male; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant

Tofacitinib is a targeted inhibitor of janus kinase (JAK), currently approved for the treatment of rheumatoid arthritis. We present a patient on treatment withtofacitinib who had an episode of classic dermatomal herpes zoster followed months later by atypical chronic cutaneous ulcers also caused by herpes zoster.

Topics: Arthritis, Rheumatoid; Chronic Disease; Female; Herpes Zoster; Humans; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin; Skin Ulcer

The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation.. Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks.. Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma.. Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions.

Topics: Animals; Chronic Disease; Complement C4b; Disease Models, Animal; Disease Progression; Graft Rejection; Graft Survival; Humans; Immunity, Cellular; Immunity, Humoral; Immunosuppressive Agents; Janus Kinase 3; Kidney; Kidney Transplantation; Male; Peptide Fragments; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Inbred F344; Rats, Inbred Lew; Signal Transduction; Treatment Outcome

Topics: Benzimidazoles; Chronic Disease; Humans; Piperidines; Treatment Outcome; Urticaria

We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.

Topics: Animals; Anti-Arrhythmia Agents; Atrioventricular Block; Chronic Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Humans; Infusions, Intravenous; Piperidines; Pyridines; Torsades de Pointes

Vesicular acetylcholine transporter (VAChT) is a rate-limiting factor for synaptic acetylcholine transport. Our study focused on whether [. Morris water maze test was used to evaluate learning and memory deficits in pilocarpine-induced chronic epilepsy rats 12 weeks after status epilepticus. Interictal [. Epileptic rats exhibited significant memory deficits in Morris water maze test. [. [

Topics: Acholeplasmataceae; Animals; Brain; Chronic Disease; Disease Models, Animal; Epilepsy; Fluorodeoxyglucose F18; Male; Maze Learning; Memory Disorders; Muscarinic Agonists; Naphthols; Pilocarpine; Piperidines; Positron-Emission Tomography; Rats; Rats, Sprague-Dawley; Vesicular Acetylcholine Transport Proteins

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Biological Availability; Chronic Disease; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Male; Mice, Inbred Strains; Neurogenic Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; Stress, Psychological

Topics: Anti-Allergic Agents; Benzimidazoles; Chronic Disease; Drug Therapy, Combination; Female; Hepatitis B, Chronic; Humans; Middle Aged; Omalizumab; Piperidines; Prednisone; Urticaria; Viral Load; Viremia

Topics: Animals; Body Weight; Cardiomegaly; Cell Line; Chronic Disease; Electrocardiography; Heart; Heart Failure; Hemodynamics; Humans; Male; Mice; Myocardium; Organ Size; Piperidines; Pressure; Rats; Receptors, G-Protein-Coupled; Substrate Specificity; Thiophenes

Increasing evidence suggests that interleukin (IL)-17A plays an important role in chronic lung allograft dysfunction (CLAD), characterized by airway and lung parenchymal fibrosis, after lung transplantation. Halofuginone is a plant derivative that has been shown to inhibit Th17 differentiation. The purpose of this study was to examine the effect of halofuginone on CLAD development using a minor alloantigen‒mismatched mouse orthotopic lung transplant model.. C57BL/6 recipient mice received an orthotopic left lung transplant from C57BL/10 donors, mismatched for minor antigens. Lung transplant recipients received daily intraperitoneal injections of 2.5 μg halofuginone or vehicle alone. Lung grafts were assessed on Days 7, 14, and 28 post-transplant.. Compared with control mice, on Day 28 post-transplant, lung grafts of mice treated with halofuginone showed a significant reduction in the percentage of obliterated airways (6.8 ± 4.7% vs 52.5 ± 13.8%, p < 0.01), as well as significantly reduced parenchymal fibrosis (5.5 ± 2.3% vs 35.9 ± 10.9%, p < 0.05). Immunofluorescent staining for IL-17A demonstrated a decreased number and frequency of IL-17A‒positive cells in halofuginone-treated lung grafts on Day 28, as compared with controls. Halofuginone treatment also decreased IL-17A and IL-22 transcripts at Day 14, transforming growth factor-β1 and matrix metalloproteinase-2 transcripts at Days 14 and 28.. The beneficial effect of halofuginone on development of airway and lung parenchymal fibrosis in the mouse lung transplant model highlights the important role of IL-17A in CLAD and merits further pre-clinical and clinical studies.

Topics: Animals; Chronic Disease; Disease Models, Animal; Graft Rejection; Interleukin-17; Lung Transplantation; Male; Mice; Mice, Inbred C57BL; Piperidines; Protein Synthesis Inhibitors; Quinazolinones; Th17 Cells; Transplantation, Homologous

Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis.. We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis.. Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID.. At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure.. There was no dose comparison beyond week 52.. Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

Topics: Administration, Oral; Adult; Aged; Chronic Disease; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Janus Kinases; Male; Middle Aged; Patient Safety; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD). In the brain, NAMPT is primarily expressed in neurons and can prevent neuronal degeneration. NAMPT is also highly expressed in inflammatory cells, and is responsible for their activation. Since inflammation following traumatic brain injury enhances neuronal damage, we assessed the effects of nicotinamide mononucleotide (NMN), the direct NAMPT metabolite, and FK866, a potent NAMPT inhibitor, on brain injury in a cryoinjury mouse model. Twenty-four hours after brain cryoinjury, the density of neuron and the level of NAD decreased. Both NMN and FK866 alleviated the neuronal loss and decreased the lesion volume. NMN prevented the cryoinjury-induced decrease of NAD level, and FK866 decreased it further. On day 14 after cryoinjury, further neuronal loss occurred, astrocytes and Iba1-positive macrophage/microglia activated, and the NAD level increased. At this time-point, NAMPT expression was strongly induced in Iba1-positive macrophages/microglia in the lesion core. NMN and FK866 also alleviated the neuronal loss and decreased the lesion volume. In addition, FK866 significantly attenuated the activation of astrocytes and Iba1-positive macrophages/microglia, and decreased the NAD, while NMN had no such effects. Taken together, both FK866 and NMN attenuate traumatic brain injury. However, FK866 acts via the inhibition of the NAMPT activity in inflammatory cells resulting in the inhibition of inflammation, whereas NMN is effective via replenishing NAD.

Topics: Acrylamides; Acute Disease; Animals; Astrocytes; Brain; Brain Injuries; Calcium-Binding Proteins; Cell Count; Chronic Disease; Cold Temperature; Cytokines; Disease Models, Animal; Macrophages; Male; Mice, Inbred BALB C; Microfilament Proteins; Microglia; NAD; Neurons; Neuroprotective Agents; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Piperidines

Allogeneic stem-cell transplantation (SCT) induces long-term remission in a fraction of patients with high-risk chronic lymphocytic leukemia (CLL) or Richter's transformation (RT). Our purpose was to determine the outcomes of patients whose disease progressed after allogeneic SCT.. We retrospectively analyzed the outcomes of 72 patients (52 with CLL and 20 with RT) who underwent allogeneic SCT between 1998 and 2011 and had documented progression after transplantation. Twenty-two (31%) never had a response, and 50 (69%) had a response but experienced relapse after a median of 7 months (range, 2 to 85 months). Forty-eight patients who were receiving or were candidates to receive post-SCT cell-based therapies were not included in this analysis.. The median age at time of transplantation was 58 years (range, 30 to 72 years). Sixty-two patients (86%) received more than two treatment regimens and 37 (51%) received more than three treatment regimens before SCT. Sixty-six patients (92%) had active disease at the time of transplantation. The 2- and 5-year survival rates were 67% and 38% (patients with CLL) and 36% and 0% (patients with RT). The patients who developed acute or chronic graft-versus-host disease had a longer overall survival (OS; P = .05). In a multivariable analysis, RT or low hemoglobin at the time of SCT predicted shorter OS. Chronic graft-versus-host disease and an initial response to SCT predicted longer OS.. Patients with CLL in whom allogeneic SCT fails may have a response to and benefit from salvage therapies, and their prognosis is relatively good.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Chronic Disease; Disease Progression; Factor Analysis, Statistical; Female; Graft vs Host Disease; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Retrospective Studies; Risk Factors; Salvage Therapy; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous; Treatment Failure; Treatment Outcome

To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ETB receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats.. Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV + SB202190, LEV + BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2h of recording per day at the same time of day. We also performed western blot after EEG analysis.. Compared to control animals, PGP, ETB receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ETB receptor expression was enhanced in the hippocampus of non-responders.. To the best of our knowledge, these findings are the first indications of the role of ETB receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ETB receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.

Topics: Animals; Anticonvulsants; Brain; Chronic Disease; Disease Models, Animal; Endothelin B Receptor Antagonists; Enzyme Inhibitors; Epilepsy; Imidazoles; Levetiracetam; Male; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Piperidines; Piracetam; Pyridines; Rats, Sprague-Dawley; Receptor, Endothelin B; Seizures; Treatment Outcome

Pain per se may increase anxiety and conversely, anxiety may increase pain. Therefore, a positive feedback loop between anxiety and pain possibly contributes to pain and suffering in some pathophysiological pain conditions, such as that induced by peripheral nerve injury. Recent results indicate that transient receptor channels 4 and 5 (TRPC4/C5) in the amygdala have anxiogenic effects in rodents, while their role in chronic pain conditions is not known. Here, we studied whether the amygdaloid TRPC4/C5 that are known to have anxiogenic properties contribute to the maintenance of sensory or affective aspects of pain in an experimental model of peripheral neuropathy. Rats with a spared nerve injury (SNI) model of neuropathy in the left hind limb had a chronic cannula for microinjections of drugs into the right amygdala or the internal capsule (a control site). Sensory pain was assessed by determining mechanical hypersensitivity with calibrated monofilaments and affective pain by determining aversive place-conditioning. Amygdaloid treatment with ML-204, a TRPC4/C5 antagonist, produced a dose-related (5-10 μg) antihypersensitivity effect, without obvious side-effects. Additionally, amygdaloid administration of ML-204 reduced affective-like pain behavior. In the internal capsule, ML-204 had no effect on hypersensitivity or affective-like pain in SNI animals. In healthy controls, amygdaloid administration of ML-204 failed to influence pain behavior induced by mechanical stimulation or noxious heat. The results indicate that the amygdaloid TRPC4/C5 contribute to maintenance of pain hypersensitivity and pain affect in neuropathy.

Topics: Affect; Amygdala; Animals; Chronic Disease; Hyperalgesia; Indoles; Male; Microinjections; Neuralgia; Physical Stimulation; Piperidines; Rats; Touch; TRPC Cation Channels

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair. This study aimed to investigate the role of brain-derived neurotrophic factor (BDNF) signalling in the antidepressant-like effect of piperine in mice exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. It was also found that BDNF protein expression in the hippocampus and frontal cortex were significantly decreased in CUMS-treated mice. Chronic treatment of piperine at the dose of 10mg/kg significantly ameliorated behavioural deficits of CUMS-treated mice in the sucrose preference test and forced swim test. Piperine treatment also significantly decreased immobility time in the forced swim test in naive mice. In parallel, chronic piperine treatment significantly increased BDNF protein expression in the hippocampus and frontal cortex of both naive and CUMS-treated mice. In addition, inhibition of BDNF signalling by injection of K252a, an inhibitor of the BDNF receptor TrkB, significantly blocked the antidepressant-like effect of piperine in the sucrose preference test and forced swim test of CUMS-treated mice. Taken together, this study suggests that BDNF signalling is an essential mediator for the antidepressant-like effect of piperine.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Carbazoles; Chronic Disease; Disease Models, Animal; Enzyme Inhibitors; Food Preferences; Indole Alkaloids; Male; Mice; Mice, Inbred ICR; Piperidines; Polyunsaturated Alkamides; Signal Transduction; Stress, Psychological; Sucrose; Sweetening Agents; Time Factors

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair, which was related to the serotonergic system. The present study aimed to examine the behavioral and biochemical effects of piperine in rats exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. In addition, it was found that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) contents in the hippocampus and frontal cortex were significantly decreased in CUMS-treated rats. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by CUMS. The results suggest that piperine produces an antidepressant-like effect in CUMS-treated rats, which is possibly mediated by increasing 5-HT and BDNF contents in selective brain tissues.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Chronic Disease; Male; Piperidines; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Sprague-Dawley; Serotonin; Stress, Psychological

The studies reported herein are the first to document the effect of the in vivo administration of a JAK3 inhibitor for defining the potential role of NK cells during acute SIV infection of a group of 15 rhesus macaques (RM). An additional group of 16 MHC/KIR typed RM was included as controls. The previously optimized in vivo dose regimen (20 mg/kg daily for 35 days) led to a marked depletion of each of the major NK cell subsets both in the blood and gastro-intestinal tissues (GIT) during acute infection. While such depletion had no detectable effects on plasma viral loads during acute infection, there was a significant sustained increase in plasma viral loads during chronic infection. While the potential mechanisms that lead to such increased plasma viral loads during chronic infection remain unclear, several correlates were documented. Thus, during acute infection, the administration of the JAK3 inhibitor besides depleting all NK cell subsets also decreased some CD8⁺ T cells and inhibited the mobilization of the plasmacytoid dendritic cells in the blood and their localization to the GIT. Of interest is the finding that the administration of the JAK3 inhibitor during acute infection also resulted in the sustained maintenance during chronic infection of a high number of naïve and central memory CD4⁺ T cells, increases in B cells in the blood, but decreases in the frequencies and function of NKG2a⁺ NK cells within the GIT and blood, respectively. These data identify a unique role for JAK3 inhibitor sensitive cells, that includes NK cells during acute infection that in concert lead to high viral loads in SIV infected RM during chronic infection without affecting detectable changes in antiviral humoral/cellular responses. Identifying the precise mechanisms by which JAK3 sensitive cells exert their influence is critical with important implications for vaccine design against lentiviruses.

Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Disease; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Janus Kinase 3; Killer Cells, Natural; Macaca mulatta; Piperidines; Pyrimidines; Pyrroles; Simian Acquired Immunodeficiency Syndrome; Viral Load

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chronic Disease; Drug Approval; Humans; Inflammation; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rheumatic Diseases; Switzerland

Chronic intermittent hypoxia-hypercapnia (CIHH) exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs) can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B)-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2) signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII), synapse-associated protein 102 (SAP102) and Ras GTPase-activating protein (SynGAP) have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor) have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway.. Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9 ∼ 11%O2, 5.5 ∼ 6.5%CO2) for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist) administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) activation, which is responsible for neuroprotection.. These findings suggest that the ameliorative cognitive deficits caused by lovastatin are due to the downregulation of excessive NR2B expression accompanied by increased expression of ERK signaling cascade. The effect of NR2B in upregulating pERK1/2 maybe due, at least in part, to inactivation of CaMKII/SAP102/SynGAP signaling cascade.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Chronic Disease; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gene Expression Regulation; GTPase-Activating Proteins; Hippocampus; Hypercapnia; Hypoxia; Learning Disabilities; Lovastatin; Male; MAP Kinase Signaling System; Maze Learning; Membrane Microdomains; Memory Disorders; Neuropeptides; Nootropic Agents; Piperidines; Pulmonary Disease, Chronic Obstructive; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spatial Learning; Synaptosomes

DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.

Topics: Acute Disease; Administration, Oral; Animals; Antitubercular Agents; Bacterial Proteins; Biological Availability; Chronic Disease; DNA Gyrase; Drug Resistance, Bacterial; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Fluoroquinolones; Humans; Macrophages; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Docking Simulation; Mutation; Mycobacterium tuberculosis; Piperidines; Protein Subunits; Rats; Stereoisomerism; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tuberculosis, Pulmonary

Intracranial implants elicit neurodegeneration via the foreign body response (FBR) that includes BBB leakage, macrophage/microglia accumulation, and reactive astrogliosis, in addition to neuronal degradation that limit their useful lifespan. Previously, monocyte chemoattractant protein 1 (MCP-1, also CCL2), which plays an important role in monocyte recruitment and propagation of inflammation, was shown to be critical for various aspects of the FBR in a tissue-specific manner. However, participation of MCP-1 in the brain FBR has not been evaluated. Here we examined the FBR to intracortical silicon implants in MCP-1 KO mice at 1, 2, and 8 weeks after implantation. MCP-1 KO mice had a diminished FBR compared to WT mice, characterized by reductions in BBB leakage, macrophage/microglia accumulation, and astrogliosis, and an increased neuronal density. Moreover, pharmacological inhibition of MCP-1 in implant-bearing WT mice maintained the increased neuronal density. To elucidate the relative contribution of microglia and macrophages, bone marrow chimeras were generated between MCP-1 KO and WT mice. Increased neuronal density was observed only in MCP-1 knockout mice transplanted with MCP-1 knockout marrow, which indicates that resident cells in the brain are major contributors. We hypothesized that these improvements are the result of a phenotypic switch of the macrophages/microglia polarization state, which we confirmed using PCR for common activation markers. Our observations suggest that MCP-1 influences neuronal loss, which is integral to the progression of neurological disorders like Alzheimer's and Parkinson disease, via BBB leakage and macrophage polarization.

Topics: Animals; Benzoxazines; Blood-Brain Barrier; Brain; Cell Survival; Chemokine CCL2; Chronic Disease; Foreign-Body Reaction; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurodegenerative Diseases; Neurons; Piperidines; Prostheses and Implants; Receptors, CCR2; Tissue Engineering

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chronic Disease; Humans; Leukemia, Lymphoid; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Modulation of vagal tone using electrical vagal nerve stimulation or pharmacological acetylcholinesterase inhibition by donepezil exerts beneficial effects in an animal model of chronic heart failure (CHF). Considering different treatment mechanisms underlying renin-angiotensin system (RAS) suppression and parasympathetic activation, we hypothesized that parasympathetic activation together with RAS inhibition could attenuate CHF progression. To test this hypothesis, we investigated the therapeutic effects of a combination of donepezil and losartan in CHF rats with extensive myocardial infarction (MI).. Rats (n = 85) that had survived extensive MI were implanted with a blood pressure transmitter and were randomly assigned to receive either a combination of donepezil and losartan (DLT group) or losartan alone (LT group). Compared with the LT group, the DLT group showed a significantly lower heart rate without hypotension. DLT therapy further improved 280-day overall survival relative to the LT group (31% vs. 8%, P = 0.022) by preventing cardiac dysfunction (LV dP/dtmax , 4064 ± 170 vs. 3430 ± 117 mmHg/s, P < 0.01; LV end-diastolic pressure, 17 ± 2 vs. 22 ± 2 mmHg, P < 0.05). DLT therapy was also associated with lower plasma BNP and catecholamine levels, lower cardiac angiotensin II concentrations, and higher capillary density in the peri-infarct region.. Combined treatment with donepezil and losartan prevented the progression of cardiac dysfunction and improved the long-term survival of CHF rats with extensive MI, suggesting that this combination could be a novel pharmacotherapy for severe CHF.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Cholinesterase Inhibitors; Chronic Disease; Disease Models, Animal; Disease Progression; Donepezil; Drug Synergism; Drug Therapy, Combination; Heart Failure; Indans; Losartan; Myocardial Infarction; Piperidines; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vagus Nerve

We conducted a retrospective cohort study evaluating the efficacy and usefulness of the addition of lafutidine, a novel histamine H2-receptor antagonist, in treatment of patients with idiopathic chronic urticaria whose disease was not well controlled with histamine H1-receptor antagonists. Based on the assessment of global improvement, moderate or better improvement was achieved in 39 of 46 patients (85%) after 1-3 weeks of additional administration of lafutidine and 35 patients (76%) after 3 months. No incidence of drug-related adverse reactions was reported in any patient. Lafutidine was rated as useful or better in 34 patients (74%) after 3 months of treatment. The usefulness of the drug was not affected by differences in background factors, such as disease duration, previous treatment duration and the number of concomitant H1-receptor antagonists. Lafutidine appears to be a promising addition to histamine H1-receptor antagonist therapy for the treatment of chronic urticaria resistant to treatment with H1-receptor antagonists alone.

Topics: Acetamides; Adolescent; Adult; Aged; Chronic Disease; Drug Therapy, Combination; Female; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Male; Middle Aged; Piperidines; Pyridines; Retrospective Studies; Urticaria; Young Adult

A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.

Topics: Adenosine A2 Receptor Agonists; Animals; Cells, Cultured; Chronic Disease; Constriction, Pathologic; Cyclic AMP-Dependent Protein Kinases; Hyperalgesia; Inflammation; Injections, Spinal; Ligation; Male; Piperidines; Protein Kinase C; Random Allocation; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Signal Transduction

Vagal activation by electrical stimulation has been shown to improve the long-term survival of rats with chronic heart failure (CHF) after extensive myocardial infarction (MI). Acetylcholinesterase inhibition increases synaptic acetylcholine, and can disproportionately increase vagal tone. To develop an alternative therapy for CHF using a clinically available drug, the present study investigated whether oral donepezil, an acetylcholinesterase inhitor, could reproduce the beneficial effects of electrical vagal stimulation in rats.. At 2 weeks after ligation of the proximal left coronary artery, resulting in extensive MI, surviving rats were randomly assigned to donepezil-treated and untreated groups. Donepezil treatment started 14 days after MI significantly decreased the heart rate (325 ± 6 vs. 355 ± 10 beats/min, P<0.05) and improved 140-day survival (29% to 54%, P=0.03) by preventing pump failure (cardiac index: +29%, P<0.001; left ventricular+dp/dtmax: +18%, P<0.01; left ventricular end-diastolic pressue: -26%, P<0.01) and cardiac remodeling (biventricular weight: 2.73 ± 0.04 vs. 3.06 ± 0.08 g/kg, P<0.001). In addition, donepezil treatment lowered the levels of plasma arginine vasopressin, brain natriuretic peptide, catecholamine, and tissue pro-inflammation markers.. Oral donepezil markedly improved the long-term survival of CHF rats by preventing pump failure and cardiac remodeling, indicating that donepezil may be a new alternative therapy for CHF. 

Topics: Animals; Cholinesterase Inhibitors; Chronic Disease; Donepezil; Heart Failure; Indans; Male; Myocardial Infarction; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

Topics: Adult; Antipsychotic Agents; Chronic Disease; Female; Follow-Up Studies; Humans; Hyperprolactinemia; Male; Middle Aged; Piperazines; Piperidines; Prolactin; Schizophrenia

Endocannabinoids (eCBs) are involved in the stress response and alterations in eCB signaling may contribute to the etiology of mood disorders. Exposure to chronic mild stress (CMS), a model of depression, produces downregulation of the cannabinoid 1 (CB1) receptor in the hippocampus of male rats. However, it is unknown how this stress-induced change in CB1 levels affects eCB-mediated neurotransmission. In vitro, field potential recordings from CMS-exposed (21-days) rats were performed to assess the effects of stress on eCB-regulated glutamatergic neurotransmission in/on hippocampal area CA1. We observed that application of the CB1 agonist, WIN 55,212-5 (1 μM), in stress animals resulted in a ∼135% increase in excitatory neurotransmission, whereas CB1 activation in non-stress animals leads to a ∼30% decrease. However, during blockade of GABA(A) neurotransmission with picrotoxin, CB1 activation yielded a ∼35% decrease in stress animals. These findings indicate that CMS does not directly affect glutamatergic neurotransmission. Rather, CMS sensitizes CB1 function on GABAergic terminals, leading to less inhibition and an increase in excitatory neurotransmission. This finding is reinforced in that induction of weak long-term-potentiation (LTP) is enhanced in CMS-exposed animals compared to controls and this enhancement is CB1-dependent. Lastly, we observed that the LTP-blocking property of WIN 55,212-5 shifts from being glutamate-dependent in non-stress animals to being GABA-dependent in stress animals. These results effectively demonstrate that CMS significantly alters hippocampal eCB-mediated neurotransmission and synaptic plasticity.

Topics: Animals; Benzoxazines; Chronic Disease; Disease Models, Animal; Excitatory Postsynaptic Potentials; GABA Antagonists; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Male; Morpholines; Naphthalenes; Neuronal Plasticity; Picrotoxin; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Stress, Psychological; Synaptic Transmission

The purpose of this study was to investigate the influence of chronic virus- related liver disease severity on propofol requirements.. In this study, 48 male patients with chronic hepatitis B infection were divided into three groups according to Child-Turcotte-Pugh classification of liver function (groups A, B, and C with mild, moderate and severe liver disease, respectively). After intubation, propofol concentration was adjusted by ± 0.3 μg/mL increments to maintain bispectral index in the range of 40-60. Target propofol concentrations at anesthesia initiation, pre-intubation and pre-incision were recorded.. The initial concentration used in group C was significantly lower than that used in group A or B (p<0.05), whereas no difference was observed between groups A and B. At pre-intubation, the actual required concentration of propofol increased significantly (3.2 μg/mL) in group A (p<0.05), which lead to significant differences between the groups (p<0.05). At pre-incision, the requirements for propofol decreased significantly in both groups A and B (3.0 μg/mL and 2.7 μg/mL, respectively) compared with those at pre-intubation (p<0.05), and were significantly different for all three groups (p<0.05), with group C demonstrating the lowest requirement (2.2 μg/mL). The required concentrations of propofol at pre-incision were similar to those at induction.. In this study, propofol requirements administered by target-controlled infusion to maintain similar depths of hypnosis were shown to depend on the severity of chronic virus-related liver dysfunction. In other words, patients with the most severe liver dysfunction required the least amount of propofol.

Topics: Adult; Anesthesia; Anesthetics, Intravenous; Chronic Disease; Electroencephalography; Hepatitis B, Chronic; Humans; Liver Diseases; Male; Middle Aged; Piperidines; Propofol; Remifentanil; Virus Diseases

Chronic stress is a risk factor for depression, and chronic stress can induce cognitive impairments associated with prefrontal cortical dysfunction, which are also major components of depression. We have previously shown that 5 wk chronic intermittent cold (CIC) stress induced a reversal-learning deficit in rats, associated with reduced serotonergic transmission in the orbitofrontal cortex (OFC) that was restored by chronic treatment with a selective serotonin reuptake inhibitor (SSRI). However, the mechanisms underlying the beneficial cognitive effects of chronic SSRI treatment are currently unknown. Thus, the purpose of this study was to investigate the potential modulatory influence specifically of 5-HT2A receptors (5-HT2ARs) in the OFC on reversal learning, and their potential contribution to the beneficial cognitive effects of chronic SSRI treatment. Bilateral microinjections of the selective 5-HT2AR antagonist, MDL 100,907 into OFC (0.02-2.0 nmol) had a dose-dependent detrimental effect on a reversal-learning task, suggesting a facilitatory influence of 5-HT2ARs in the OFC. In the next experiment, rats were exposed to 5 wk CIC stress, which compromised reversal learning, and treated chronically with the SSRI, citalopram (20 mg/kg.d) during the final 3 wk of chronic stress. Chronic citalopram treatment improved reversal learning in the CIC-stressed rats, and bilateral microinjection of MDL 100,907 (0.20 nmol, the optimal dose from the preceding experiment) into OFC once again had a detrimental effect on reversal learning, opposing the beneficial effect of citalopram. We conclude that 5-HT2ARs in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Attention; beta-Cyclodextrins; Chronic Disease; Citalopram; Cognition; Fluorobenzenes; Male; Microinjections; Pharmaceutical Vehicles; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Reversal Learning; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Set, Psychology; Stress, Psychological

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co-administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.

Topics: Area Under Curve; Carbamates; Chronic Disease; Computer Simulation; Drug Interactions; Humans; Ketolides; Kidney Diseases; Models, Biological; Piperazines; Piperidines; Purines; Sildenafil Citrate; Sulfones

Blockade of tyrosine kinase signaling by masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, can modulate allergic airway inflammation, but effects on lung mechanics have not been well characterized. We hypothesized masitinib would decrease airway eosinophilia and consequently improve pulmonary mechanics in a feline allergic asthma model.. Asthma was induced in 12 cats using Bermuda grass allergen (BGA). Cats received 50 mg/day oral masitinib or placebo. Bronchoalveolar lavage fluid (BALF) was analyzed for eosinophils, total protein (TP) and BGA-specific IgE. Ventilator-acquired mechanics after methacholine (MCh) challenge determined MCh concentration needed to increase baseline airway resistance by 200% (EC(200)R(aw)), positive end expiratory occlusion pressure (PEEP) and end inspiratory breath hold pressure (P(plat)). An inverse correlate of respiratory system compliance P(plat)-PEEP was also calculated. Data were analyzed using the Wilcoxon test, with one-tailed significance set at p < 0.1.. After 4 weeks, percent eosinophils in BALF was lower in masitinib-treated cats (7 ± 9%) versus controls (30 ± 27%, p = 0.023). BALF TP significantly differed (p = 0.047) between groups, decreasing with masitinib and increasing with placebo. BALF BGA-specific IgE was unaffected by masitinib. Both groups showed an improvement in EC(200)R(aw) (masitinib, p = 0.015; control, p = 0.078) but no significant change in PEEP after 4 weeks. Masitinib-treated cats demonstrated decreased P(plat) (p = 0.033) and P(plat)-PEEP (p = 0.075) at week 4, suggesting an improvement in respiratory compliance.. Masitinib reduced BALF eosinophilia and TP, indicating improved airway inflammation and edema, and improved P(plat) and P(plat)-PEEP, suggesting benefit to respiratory compliance influenced by airway inflammation/edema. Masitinib deserves further study in humans with chronic allergic asthma.

Topics: Allergens; Animals; Anti-Asthmatic Agents; Asthma; Benzamides; Bronchoalveolar Lavage Fluid; Cats; Chronic Disease; Cynodon; Eosinophils; Immunoglobulin E; Inflammation; Lung; Male; Methacholine Chloride; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Thiazoles

Halofuginone, isolated from Dichroa febreifuga, is a potent inhibitor of skin collagen in chronic graft-versus-host disease (GVHD). To evaluate the effect of halofuginone on the development of cutaneous GVHD, we developed a murine model based on BALB/c (H-2d) as recipients with transplantation of C57BL/6(H-2b) bone marrow plus splenocytes. Halofuginone or its vehicle dimethyl sulfoxide (DMSO) was given introperitoneally at a dose of 5 ug/mouse daily from one day before transplantation until 20 days post-transplantation. Halofuginone-treated recipients showed only very mild appearance of cutaneous GVHD, whereas DMSO-treated recipients rapidly showed manifestation of severe cutaneous GVHD, indicating a protective effect of halofuginone in cutaneous GVHD. After injected with halofuginone, we observed a decrease in the number of CD4(+) interleukin (IL)-17(+) cells and a parallel increase in that of CD4(+) interferon (IFN)-gamma(+) cells in peripheral blood. This shift between CD4(+) IL-17(+) cells and CD4(+) IFN-gamma(+) cells developed through modulation of cytokine profile indicated by a marked increase in the levels of IFN-gamma, tumor necrosis factor (TNF)-alpha, and IL-6. The level of IL-10 was not changed obviously. Mechanistically, we demonstrate that severe tissue damage was associated with the production of IL-17 and expansion of CD4(+)IL-17(+) cells during this disorder. Specific inhibition of Th17 differentiation by halofuginone reduced disease severity. Our results indicate a significant role of halofuginone in suppressing cutaneous GVHD, apparently through effect on inhibition of Th17 cells differentiation.

Topics: Angiogenesis Inhibitors; Animals; Bone Marrow Transplantation; Cell Differentiation; Chronic Disease; Cytokines; Female; Graft vs Host Disease; Male; Mice; Mice, Inbred BALB C; Piperidines; Quinazolinones; Skin Diseases; Th17 Cells; Time Factors; Transplantation, Homologous

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Agents; Chronic Disease; Disease Management; Drug Administration Schedule; Humans; Lymphoma, Non-Hodgkin; Oligonucleotides; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Rituximab; Standard of Care

Life event stressors are the major vulnerability factors for the development of cognitive disorders. A vital therapeutic for stress related disorders is curcumin, derived from curry spice turmeric. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co-administration with piperine against chronic unpredictable stress (CUS)-induced cognitive impairment and oxidative stress in mice. Male Laca mice were subjected to undergo a battery of stressors for a period of 28 days. Vehicle/drugs were administered daily 30mins before CUS procedure. Chronic stress significantly impaired memory performance (delayed latency time to reach platform in Morris water maze as well as to reach closed arm in elevated plus maze test) and decreased locomotor activity along with sucrose consumption. Further, there was a significant impairment in oxidative parameters (elevated malondialdehyde, nitrite concentration and decreased reduced glutathione, catalase levels) and mitochondrial enzyme complex activities, along with raised acetylcholinesterase and serum corticosterone levels. Chronic treatment with curcumin (200 and 400mg/kg, p.o.) significantly improved these behavioral and biochemical alterations, restored mitochondrial enzyme complex activities and attenuated increased acetylcholinesterase and serum corticosterone levels. In addition, co-administration of piperine (20mg/kg; p.o.) with curcumin (100 and 200mg/kg, p.o.) significantly elevated the protective effect as compared to their effects alone. The results clearly suggest that piperine enhanced the bioavailability of curcumin and potentiated its protective effects against CUS induced cognitive impairment and associated oxidative damage in mice.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzodioxoles; Chronic Disease; Cognition Disorders; Corticosterone; Curcumin; Cytochrome P-450 Enzyme Inhibitors; Dietary Sucrose; Drug Synergism; Food Preferences; Male; Maze Learning; Mice; Mice, Inbred Strains; Mitochondria; Motor Activity; Neuroprotective Agents; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Stress, Psychological; Uncertainty

At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists.. Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days.. All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect.. The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

Topics: Acute Disease; Analgesics; Animals; Chronic Disease; Cold Temperature; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Foot Injuries; Hyperalgesia; Infrared Rays; Ketamine; Motor Activity; Neuralgia; Pain; Pain Measurement; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

A Bayesian nonlinear longitudinal Emax model for a binary endpoint was used to characterize the dose-response relationship for a new treatment of rheumatoid arthritis. The model includes prespecified parametric functions for the dependence of response on dose level and time. It was selected based on pharmacometric input about likely dose and time trends. The longitudinal model was useful for combining data collected at different doses and times from two different studies. The example illustrates the utility of more substantive parametric models to guide selection of doses outside the initial dosing range when designing an additional phase 2 study and for extrapolating shorter-term phase 2 dose response to longer-term phase 3 studies, as is often required for dosing decisions in drug development for chronic diseases. Comparison of the estimated dose response from the longitudinal model with a corresponding logistic regression model applied at a single time point also demonstrated improved precision. Specification of an informative prior distribution based on numerous sources of prior information is described. This was the most difficult step in the analysis and one that has limited the use of Bayesian methods in similar applications. Model fit was evaluated and the potential impact of some model deficiencies on the dosing decision was assessed. Analyses of the combined studies identified doses likely to achieve a targeted effect in larger and longer confirmatory trials.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Chronic Disease; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Humans; Longitudinal Studies; Nonlinear Dynamics; Piperidines; Pyrimidines; Pyrroles

Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures. Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks. The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain.

Topics: Acoustic Stimulation; Acute Disease; Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Reflex; Kindling, Neurologic; Limbic System; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Seizures

Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.

Topics: Adaptation, Psychological; Amygdala; Animals; Anxiety Disorders; Arachidonic Acids; Benzodioxoles; Cannabinoid Receptor Modulators; Chronic Disease; Disease Models, Animal; Endocannabinoids; Glycerides; Male; Mice; Mice, Inbred ICR; Monoacylglycerol Lipases; Organ Culture Techniques; Piperidines; Stress, Psychological

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Chronic Disease; Enzyme Inhibitors; Fibroblasts; Gene Expression; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Joints; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteoclasts; Piperidines; Pyrimidines; Pyrroles; RANK Ligand; Signal Transduction; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

This study investigates the actions of KMUP-1 on RhoA/Rho-kinase (ROCK)-dependent Ca(2+) sensitization and the K(+)-channel in chronic pulmonary arterial hypertension (PAH) rats.. Sprague-Dawley rats were divided into control, monocrotaline (MCT), and MCT+KMUP-1 groups. PAH was induced by a single intraperitoneal injection (i.p.) of MCT (60 mg/kg). KMUP-1 (5 mg/kg, i.p.) was administered once daily for 21 days to prevent MCT-induced PAH. All rats were sacrificed on day 22.. MCT-induced increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were prevented by KMUP-1. In myograph experiments, KCl (80 mM), phenylephrine (10 microM) and K(+) channel inhibitors (TEA, 10 mM; paxilline, 10 microM; 4-AP, 5 mM) induced weak PA contractions in MCT-treated rats compared to controls, but the PA reactivity was restored in MCT+KMUP-1-treated rats. By contrast, in beta-escin- or alpha-toxin-permeabilized PAs, CaCl(2)-induced (1.25 mM, pCa 5.1) contractions were stronger in MCT-treated rats, and this action was suppressed in MCT+KMUP-1-treated rats. PA relaxation in response to the ROCK inhibitor Y27632 (0.1 microM) was much higher in MCT-treated rats than in control rats. In Western blot analysis, the expression of Ca(2+)-activated K(+) (BK(Ca)) and voltage-gated K(+) channels (Kv2.1 and Kv1.5), and ROCK II proteins was elevated in MCT-treated rats and suppressed in MCT+KMUP-1-treated rats. We suggest that MCT-treated rats upregulate K(+)-channel proteins to adapt to chronic PAH.. KMUP-1 protects against PAH and restores PA vessel tone in MCT-treated rats, attributed to alteration of Ca(2+) sensitivity and K(+)-channel function.

Topics: Animals; Blotting, Western; Calcium; Chronic Disease; Female; Hypertension, Pulmonary; Monocrotaline; Muscle Contraction; Muscle, Smooth, Vascular; Myography; Piperidines; Potassium Channels, Calcium-Activated; Potassium Channels, Voltage-Gated; Pulmonary Artery; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Up-Regulation; Xanthines

Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders.

Topics: Alkaloids; Animals; Antidepressive Agents; Behavior, Animal; Benzodioxoles; Biogenic Amines; Biological Availability; Biomarkers; Brain Chemistry; Chronic Disease; Cold Temperature; Curcumin; Depressive Disorder; Female; Light; Monoamine Oxidase; Motor Activity; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar; Stress, Psychological; Swimming

The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain.

Topics: Afferent Pathways; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chronic Disease; Disease Models, Animal; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Freund's Adjuvant; Glutamic Acid; Inflammation; Male; Mice; Mice, Inbred C57BL; Nociceptors; Organ Culture Techniques; Pain Measurement; Pain, Intractable; Patch-Clamp Techniques; Periaqueductal Gray; Phenols; Piperidines; Quercetin; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Up-Regulation

Exposure to stressful events has a myriad of consequences in animals and in humans, and triggers synaptic adaptations in many brain areas. Stress might also alter cannabinoid-receptor-mediated transmission in the brain, but no physiological study has addressed this issue so far. In the present study, we found that social defeat stress, induced in mice by exposure to aggression, altered cannabinoid CB(1)-receptor-mediated control of synaptic transmission in the striatum. In fact, the presynaptic inhibition of GABAergic IPSCs induced by the cannabinoid CB(1) receptor agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol] was reduced after a single stressful episode and fully abolished after 3 and 7 d of stress exposure. Repeated psychoemotional stress also impaired the sensitivity of GABA synapses to endocannabinoids mobilized by group I metabotropic glutamate receptor stimulation, whereas the cannabinoid CB(1)-mediated control of glutamate transmission was unaffected by repeated exposure to an aggressor. Corticosteroids released in response to the activation of the hypothalamic-pituitary-adrenal axis played a major role in the synaptic defects observed in stressed animals, because these alterations were fully prevented by pharmacological blockade of glucocorticoid receptors and were mimicked by corticosterone injections. The recovery of stress-induced synaptic defects was favored when stressed mice were given access to a running wheel or to sucrose consumption, which function as potent natural rewards. A similar rescuing effect was obtained by a single injection of cocaine, a psychostimulant with strong rewarding properties. Targeting cannabinoid CB(1) receptors or endocannabinoid metabolism might be a valuable option to treat stress-associated neuropsychiatric conditions.

Topics: Animals; Chronic Disease; Corpus Striatum; Dronabinol; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; gamma-Aminobutyric Acid; Glutamates; Male; Mice; Mice, Inbred C57BL; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, Glucocorticoid; Social Environment; Stress, Psychological; Synaptic Transmission

In this report, we present the case of a patient with a relapse of schizophrenia following an episode of depression and increased anxiety after antiobesity treatment with rimonabant, a cannabinoid type 1 receptor antagonist.. After 4 weeks of treatment the patient developed psychiatric symptoms, i.e. depressed mood and elevated anxiety. Four months after the discontinuation of rimonabant, the patient presented with psychotic symptoms fulfilling ICD-10 criteria of paranoid schizophrenia. Antipsychotic treatment with quetiapine was initialized. A stable recovery took further 4 weeks in which combined treatment with quetiapine and ziprasidone was given.. The course of the illness suggests that the continuous affective symptoms, which were most likely a side effect of rimonabant, may have triggered the psychosis analogous to the stress-diathesis model of schizophrenia. As a consequence, rimonabant may not be the first choice in obese patients with a history of schizophrenia due to a potentially increased risk of a relapse via an indirect mechanism.

Topics: Adult; Anti-Obesity Agents; Chronic Disease; Female; Humans; Obesity; Piperidines; Pyrazoles; Recurrence; Rimonabant; Schizophrenia, Paranoid

Chronic ethanol consumption produces painful neuropathy for which there is no reliably successful therapy, largely due to a lack of understanding of the central mechanisms that underlie the development of the neuropathic pain-like state induced by chronic ethanol treatment. The aim of this study was to investigate what mechanisms contribute to the neuropathic pain-like state induced by chronic ethanol treatment in rats. Mechanical hyperalgesia was clearly observed during ethanol consumption and even after ethanol withdrawal, and lasted for 14 weeks. This hyperalgesia was significantly attenuated by repeated i.p. injection of ifenprodil, a selective NR2B subunit-containing NMDA receptor antagonist. Under these conditions, mRNA and protein levels of NR1, NR2A and NR2B subunits did not change in the spinal cord of chronic ethanol-fed rats. Interestingly, phosphorylated-Ser-1303 NR2B (p-Ser1303-NR2B) subunit was significantly increased in the spinal cord of chronic ethanol-fed rats, whereas p-Tyr1472-NR2B was not affected in the superficial spinal dorsal horn of ethanol-fed rats. These findings suggest that spinal p-Ser1303-NR2B plays a significant role in the development of the ethanol-dependent neuropathic pain-like state in rats.

Topics: Alcohol Drinking; Animals; Chronic Disease; Disease Models, Animal; Ethanol; Hyperalgesia; Immunoblotting; Immunohistochemistry; Male; Pain Threshold; Piperidines; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome

N-Phenyl-2-[1-[3-(2-pyridinylethynyl)benzoyl]-4-piperidine]acetamide (JNJ-5234801) is a structurally novel atypical anxiolytic with an overall in vivo profile in animals suggestive of the potential to show anxiolytic efficacy in humans at doses that will not cause CNS-related side effects. Furthermore, unlike the benzodiazepines, JNJ-5234801 does not have an adverse interaction with ethanol even at doses 20 to 40 times the minimal effective dose in the rat elevated plus maze (MED=1.0 mg/kg, p.o.).. In the present study, JNJ-5234801 was evaluated for potential efficacy in reducing alcohol intake in alcohol-preferring rats. Alcohol-preferring P rats were allowed to drink water or alcohol (10%, v/v) in a 2-bottle choice procedure. Once stable baselines were established, the acute effects of JNJ-5234801 [(10-40 mg/kg, intraperitoneally (i.p.)] were assessed. In a separate study, chronic treatment with JNJ-5234801 (40 mg/kg once daily, i.p.) for 12 consecutive days was compared with naltrexone (20 mg/kg, twice daily, i.p.).. There was a selective dose-dependent reduction in alcohol intake in the alcohol-preferring (P) rats after acute administration of JNJ-5234801 (10-40 mg/kg, i.p.). There were no significant effects on food or water intake. When administered subchronically, both JNJ-5234801 (40 mg/kg once daily, i.p.) and naltrexone (20 mg/kg, twice daily, i.p.) considerably reduced alcohol intake, but tolerance to the alcohol-suppressing effects appeared to occur sooner in the naltrexone-treated group. While both compounds slightly but significantly reduced food intake at the beginning, only JNJ-5234801 increased water intake and decreased alcohol preference.. The novel atypical anxiolytic JNJ-5234801 has a favorable profile effects on alcohol intake and related measures compared with naltrexone, which is recommended for the treatment of alcoholism.

Topics: Acute Disease; Alcohol Drinking; Animals; Anti-Anxiety Agents; Chronic Disease; Dose-Response Relationship, Drug; Drinking; Drug Tolerance; Injections, Intraperitoneal; Male; Naltrexone; Narcotic Antagonists; Piperidines; Pyridines; Rats

In this study, we investigated the antidepressant-like effect of piperine in mice exposed to chronic mild stress (CMS) procedure. Repeated administration of piperine for 14 days at the doses of 2.5, 5 and 10 mg/kg reversed the CMS-induced changes in sucrose consumption, plasma corticosterone level and open field activity. Furthermore, the decreased proliferation of hippocampal progenitor cells was ameliorated and the level of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS stressed mice was up-regulated by piperine treatment in the same time course. In addition, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactic dehydrogenase (LDH) assays showed that piperine (6.25-25 microM) or fluoxetine (FLU, 1 microM) dose-dependently protected primary cultured hippocampal neurons from the lesion induced by 10 microM corticosterone (CORT). Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the messenger ribonucleic acid (mRNA) level of BDNF in cultured neurons. Treatment with piperine (6.25-25 microM) for 72 h reversed the CORT-induced reduction of BDNF mRNA expression in cultured hippocampal neurons. In summary, up-regulation of the progenitor cell proliferation of hippocampus and cytoprotective activity might be mechanisms involved in the antidepressant-like effect of piperine, which may be closely related to the elevation of hippocampal BDNF level.

Topics: Alkaloids; Animals; Antidepressive Agents; Benzodioxoles; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Corticosterone; Depression; Hippocampus; Immunohistochemistry; L-Lactate Dehydrogenase; Male; Mice; Neurons; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Stress, Psychological; Tetrazolium Salts; Thiazoles; Weight Gain

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Modulators; Cannabinoids; Chronic Disease; Disease Models, Animal; Disease Progression; Endocannabinoids; Fatty Liver; Glycolysis; Hepatitis C, Chronic; Hepatocytes; Humans; Hypertension, Portal; Lipogenesis; Liver; Liver Cirrhosis; Liver Diseases; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

Tinnitus, the perception of sound in the absence of external acoustic stimulation, is a common and devastating pathology. It is often a consequence of acoustic trauma or drug toxicity. The neuronal mechanisms of tinnitus are neither yet fully understood nor are effective treatments available. Using a novel behavioral paradigm for measuring tinnitus in the rat based on tone-guided navigation, we show here that the development of long-term noise-induced tinnitus, the most prevalent and clinically important form of human tinnitus, can be abated by local administration of the NMDA antagonist "ifenprodil" into the cochlea in the first 4 days following the noise insult but not afterwards. This suggests that long-term tinnitus undergoes a consolidation-like process, resembling the ontogeny of items in long-term memory. Furthermore, this finding paves the way to potential therapeutic strategies for the prevention of chronic tinnitus once the noise insult had taken place.

Topics: Acoustic Stimulation; Animals; Audiometry; Chronic Disease; Cochlea; Excitatory Amino Acid Antagonists; Hair Cells, Auditory; Hearing; Male; Neuronal Plasticity; Piperidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Time Factors; Tinnitus; Treatment Outcome

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.

Topics: Animals; Arthritis; Chronic Disease; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Freund's Adjuvant; Lactones; Male; Nitric Oxide Synthase Type II; Pain; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Stifle; Sulfides; Sulfones; Time Factors; Weight-Bearing

We have shown previously that when postsynaptic NMDA receptors are blocked, the frequency, but not amplitude, of spontaneous EPSCs (sEPSCs) at synapses in the entorhinal cortex is reduced by NMDA receptor antagonists, demonstrating that glutamate release is tonically facilitated by presynaptic NMDA autoreceptors. In the present study, we recorded sEPSCs using whole-cell voltage clamp in neurons in layer V in slices of the rat entorhinal cortex. Using specific antagonists for NR2A [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid] and NR2B [(alphaR, betaS)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro 25-6981)] subunit-containing receptors, we confirmed that in slices from juvenile rats (4-6 weeks of age), the autoreceptor is predominantly of the NR1-NR2B subtype. In older (4-6 months of age) control animals, the effect of the NR2B antagonist was less marked, suggesting a decline in autoreceptor function with development. In slices from rats (aged 4-6 months) exhibiting spontaneous recurrent seizures induced with a lithium-pilocarpine protocol, Ro 25-6981 again robustly reduced sEPSC frequency. The effect was equal to or greater than that seen in the juvenile slices and much more pronounced than that seen in the age-matched control animals. In all three groups, the NR2A antagonist was without effect on sEPSCs. These results suggest that there is a developmental decrease in NMDA autoreceptor function, which is reversed in a chronic epileptic condition. The enhanced autoreceptor function may contribute to seizure susceptibility and epileptogenesis in temporal lobe structures.

Topics: Age Factors; Animals; Autoreceptors; Chronic Disease; Entorhinal Cortex; Epilepsy, Generalized; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Membrane Potentials; Neurons; Patch-Clamp Techniques; Phenols; Pilocarpine; Piperidines; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Status Epilepticus

Substance P (SP) is a modulatory, pro-inflammatory neuropeptide. We investigated the role of the SP receptor, neurokinin-1 (NK-1), in EAE. Our data show that in the chronic phase, mice lacking NK-1 have improved mobility and decreased numbers of LFA-1 high CD4+ T cells and MOG-specific, IFN-gamma producing CD4+ T cells. SR140333, an NK-1 antagonist, administered alone during the chronic phase of EAE was not sufficient to ameliorate symptoms. These results indicate that SP, through NK-1, contributes to maintenance of CNS inflammation, and combining NK-1 antagonists with conventional anti-inflammatory treatments may enhance the success of treatments for diseases like multiple sclerosis.

Topics: Animals; Anti-Inflammatory Agents; CD4-Positive T-Lymphocytes; Chronic Disease; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Female; Immunity, Cellular; Immunosuppression Therapy; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neuroimmunomodulation; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Substance P

Acetylcholinesterase inhibitors (AChEIs), commonly prescribed in Alzheimer's disease, may trigger complications of chronic airways disorders. The aim of this study was to determine whether initiation of therapy with AChEIs contributes to complications of chronic airways disorders in an elderly population.. Sequence-symmetry analysis was used to assess two cohorts of patients, both with a history of chronic airways disorders. Both cohorts comprised Medicare beneficiaries who received drug coverage through the Pennsylvania Pharmaceutical Assistance Contract for the Elderly, between 1997 and 2002. One cohort of 922 patients initiated treatment with an AChEI; the other cohort of 2819 patients initiated treatment with a beta-adrenoceptor antagonist (beta-blocker), a comparator drug also contraindicated in chronic airways disorders. The occurrence of the following four outcomes in claims data was assessed: (i) emergency room visits for complications of chronic airways disorders; (ii) hospitalisations for complications of chronic airways disorders; (iii) physician visits for complications of chronic airways disorders; and (iv) dispensing of an antibacterial and an oral corticosteroid on the same day. Rate ratios (RRs) were adjusted for age, sex, race, nursing home residence, cognitive status, severity of chronic airways disorders, comorbid illnesses and all other patient characteristics that can be assumed to remain constant over the study period.. Initiators of AChEIs had no detectable increased rate of complications of chronic airways disorders. Adjusted RRs of the four outcomes ranged from 1.00 (95% CI 0.61, 1.62; p = 0.99) for physician visits to 1.64 (95% CI 0.55, 4.89; p = 0.37) for emergency room visits, none reaching statistical significance. In contrast, beta-blocker initiators had significantly increased rates of all four outcomes after treatment, with adjusted RRs ranging from 1.97 (95% CI 1.18, 3.29; p = 0.009) for emergency room visits to 2.76 (95% CI 1.71, 4.45; p < 0.0001) for dispensing of an antibacterial and oral corticosteroid on the same day.. These results suggest that, in current clinical practice, physicians can prescribe AChEIs safely to elderly patients with chronic airways disorders, while beta-blocker prescribing continues to result in adverse health outcomes.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Chronic Disease; Cross-Over Studies; Donepezil; Female; Galantamine; Humans; Indans; Logistic Models; Male; Phenylcarbamates; Piperidines; Respiratory Tract Diseases; Rivastigmine

The purpose of the study was to compare three types of general anesthesia for functional endoscopic sinus surgery (ESS) with controlled hypotension measuring the quality of visibility of the surgical field and the blood loss during the operation. Seventy-one patients underwent endoscopic ethmoidectomy bilaterally for nasal polyposis and/or chronic sinusitis. The patients were divided into three groups according to the type of anesthesia they had: group A (sufentanil/sevoflurane), group B (remifentanil/propofol), and group C (fentanyl/isoflurane). The mean estimated blood loss for group A was 117.83 ml, for group B it was 100.5 ml and for group C it was 198.89 ml. The average quality of visibility of the surgical field was 1.57 for group A, 1.3 for group B and 2.79 for group C. The quantity of blood loss (p < 0.01) and the visibility of the surgical field (p < 0.001) demonstrated a difference among the three groups. Remifentanil and sufentanil during functional ESS enable controlled hypotension and a general improvement in surgical conditions.

Topics: Adjuvants, Anesthesia; Adult; Anesthetics, Intravenous; Chronic Disease; Endoscopy; Female; Humans; Male; Middle Aged; Monitoring, Intraoperative; Nasal Polyps; Otorhinolaryngologic Surgical Procedures; Piperidines; Remifentanil; Retrospective Studies; Sinusitis; Sufentanil; Tampons, Surgical

Cytotoxic nitric oxide (NO) is produced during ischemia-reperfusion injury and acute and chronic rejection in allografts by expression of inducible (i) NO synthase (NOS). Therefore, continuous inhibition of iNOS may prevent early graft dysfunction and immune injury (rejection) and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity that works by preventing iNOS monomers from dimerization. In this study, the authors evaluated the effect of FR260330 in prevention of chronic rejection in a model of rat aortic allografts.. Male Lewis (LEW, RT1l) rats received male ACI (RT1a) aorta allografts or LEW aorta isografts. Fourteen groups (n > or = 6) were involved in this study. FR260330, tacrolimus, or both were administered orally for 14 or 90 days, according to protocol. The degree of intimal proliferation of graft aorta was determined by a computerized image system.. Both low and high doses of FR260330- or tacrolimus-treated grafts showed significantly decreased intima/(intima+media) ratios at day 90 compared with placebo controls. Combination therapy of low-dose FR260330 with low-dose tacrolimus produced a significant decrease of intima/(intima+media) ratios with intact endothelium compared with placebo controls. Anti-alpha-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation is related to migration of vascular smooth muscle cells.. A selective inhibitor of NOS, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combination therapy of low-dose FR260330 with tacrolimus produces significant protection of immune injury and may serve to improve long-term graft survival and function.

Topics: Actins; Animals; Aorta; Body Weight; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Graft Rejection; Graft Survival; Hyperplasia; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Piperidines; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous; Tunica Intima; Tunica Media

CC chemokine receptor 1 (CCR1) represents a promising target in chronic airway inflammation and remodeling due to fungus-associated allergic asthma. The present study addressed the therapeutic effect of a nonpeptide CCR1 antagonist, BX-471, in a model of chronic fungal asthma induced by Aspergillus fumigatus conidia. BX-471 treatment of isolated macrophages inhibited CCL22 and TNF-alpha and promoted IL-10 release. BX-471 also increased toll like receptor-9 (TLR9) and decreased TLR2 and TLR6 expression in these cells. When administered daily by intraperitoneal injection, from days 15 to 30 after the initiation of chronic fungal asthma, BX-471 (3, 10, or 30 mg kg(-1)) dose-dependently reduced airway inflammation, hyper-responsiveness, and remodeling at day 30 after conidia challenge. The maximal therapeutic effect was observed at the 10 mg kg(-1) dose. In summary, the therapeutic administration of BX-471 significantly attenuated experimental fungal asthma via its effects on both innate and adaptive immune processes.

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Asthma; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Immunity, Innate; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Phenylurea Compounds; Piperidines; Receptors, CCR1; Receptors, Chemokine

Topics: Analgesics, Opioid; Anesthesia, General; Anesthetics, Intravenous; Chronic Disease; Dermatologic Surgical Procedures; Female; Fentanyl; Humans; Intubation, Intratracheal; Leg; Lymphedema; Midazolam; Middle Aged; Morphine; Piperidines; Propofol; Remifentanil; Subcutaneous Tissue

1. We describe here the alterations in the nociceptive sensitivity of Swiss CD1 mice receiving an intraplantar (i.pl.) administration of XC Rous sarcoma-virus-transformed rat fibroblasts (XC cells). 2. Histological studies reveal that XC cells remain at the injection site 2-3 weeks after implantation, a time at which an inflammatory reaction is also detected. No tumoral growth was found and 5 weeks after inoculation neither XC cells nor inflammatory reaction were observed. 3. Measures to different types of noxious stimuli were performed. At week 1 after XC cell inoculation, hyperalgesia to thermal, but not mechanical, stimuli as well as to capsaicin injection is present in the implanted paw. At week 5 after XC cell implantation, only thermal hyperalgesia is present, and this enhanced reactivity persisted for even 25 weeks after the disappearance of XC tumoral cells. 4. Pharmacological studies on thermal hyperalgesia were conducted at two different stages, week 1 and week 5 after XC cell inoculation. The systemic administration of morphine (1-10 mg/kg i.p. (intraperitoneal); 30 min before testing) prevents this thermal hyperalgesic reaction both at week 1 and week 5. The endothelin type A (ETA) receptor antagonist BQ-123 (10 nmol; i.pl.; 90 min before testing) abolishes both the early (week 1) and the late (week 5) thermal hyperalgesia. In contrast, the selective endothelin type B (ETB) receptor antagonist, BQ-788 (10 nmol; i.pl.; 90 min before) abolishes thermal hyperalgesia only at week 1, but not at week 5 after XC cell inoculation. 5. It might be concluded that endothelins are probably involved in this type of long-term thermal hyperalgesia produced by the transitory presence of the XC tumoral cell line.

Topics: Animals; Avian Sarcoma Viruses; Capsaicin; Cell Line, Transformed; Cell Line, Tumor; Chronic Disease; Endothelin Receptor Antagonists; Endothelins; Fibroblasts; Genetic Vectors; Hindlimb; Hyperalgesia; Inflammation; Male; Mice; Morphine; Neoplasm Regression, Spontaneous; Neoplasm Transplantation; Nociceptors; Oligopeptides; Pain Measurement; Peptides, Cyclic; Piperidines; Rats; Reaction Time; Receptors, Endothelin

To investigate the mechanisms of histamine on chronic epilepsy induced by pentylenetetrazole (PTZ).. To induce chemical kindling, a subconvulsive dose (35mg/kg) of PTZ was ip injected every 48 h in rats. Behavior changes were observed for 30 min after every injection of PTZ.. Ip injection of histidine or icv injection of clobenpropit inhibited the development of kindling induced by PTZ, presenting prolonged latency for myoclonic jerks and clonic generalized seizures and depressed seizure stages in a dose-dependent manner. H(3)receptor agonist, immepip, and histidine decarboxylase, alpha-fluoromethylhistidine reversed the ameliorating effect of clobenpropit on seizure development in a dose-dependent manner.. Brain histamine plays an important role in protection against myoclonic jerks and clonic generalized clonic seizures and its action may be via H(3)receptor.

Topics: Animals; Brain; Chronic Disease; Dose-Response Relationship, Drug; Epilepsy; Histamine; Histidine; Imidazoles; Male; Pentylenetetrazole; Piperidines; Rats; Rats, Sprague-Dawley; Thiourea

Topics: Adult; Aged; Aphasia; Cholinesterase Inhibitors; Chronic Disease; Donepezil; Female; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Pilot Projects; Piperidines; Severity of Illness Index; Stroke; Treatment Outcome

To investigate the effectiveness of donepezil hydrochloride (Aricept) in treating persistent memory deficits in people with traumatic brain injury.. Single subject ABAC design was used so that each participant could serve as their own control.. Seven TBI survivors with persistent memory dysfunction, at least 1.5 years post-injury, underwent two 6-month trials of Aricept. The following tests were used to assess memory and cognition: Brief Visual Memory Test-Revised (BVMT-R), Hopkins Verbal Learning Test, Digit Span and Letter Number Sequence sub-test of the Wechsler Adult Intelligence Scale-III, Controlled Oral Word Association Test and Memory Functioning Questionnaire.. During the first treatment phase, participants received 5 mg/day of Aricept for 1 month, increasing to 10 mg/day of Aricept for an additional 5 months. During the second treatment phase, participants received 5 mg/day of Aricept for the entire 6 months.. A repeated measures analysis of variance indicated significant improvement on immediate and delayed memory portions of the BVMT-R when taking 10 mg/day of Aricept.. Findings contribute to the growing body of research into the use of Aricept in treating memory deficits in TBI survivors and support the need for further research.

Topics: Adult; Analysis of Variance; Brain Injuries; Cholinesterase Inhibitors; Chronic Disease; Donepezil; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Pilot Projects; Piperidines; Psychiatric Status Rating Scales

A case is reported of a 54-year-old female patient with schizophrenia and cognitive impairment. Her memory dysfunction improved following the addition of donepezil to quetiapine. The possible implications for future studies are reviewed.

Topics: Antipsychotic Agents; Chronic Disease; Dibenzothiazepines; Donepezil; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Indans; Mental Recall; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Quetiapine Fumarate; Retention, Psychology; Schizophrenia; Schizophrenic Psychology

We previously demonstrated that the pulmonary vascular response to substance P (SP) increased in chronically hypoxic rats. This study explored the temporal increase in reactivity of the pulmonary vascular response to SP and its underlying mechanisms. First, young female Wistar rats were exposed to sea level (SL) or simulated high altitude (HA) for 15 h/day for 3 days, 1 wk, 2 wk, and 4 wk. Lungs were isolated and perfused with 4% bovine serum albumin in Krebs-Henseleit buffer solution. SP (1.5 x 10(-4) M) induced significant increases in pulmonary arterial pressure (P(pa)), venous pressure (P(v)), capillary pressure (P(c)), arterial resistance (R(a)), and filtration coefficient (K(fc)) in SL lungs. Increases in P(pa) and R(a) were significantly augmented in HA lungs, with a temporal increase trend peaking at 2 wk of HA exposure. The selective neurokinin (NK) type 1 (NK1) receptor antagonist SR-14033 significantly attenuated SP-induced increases in P(pa), P(v), P(c), R(a), and K(fc) in SL lungs. In lungs exposed to HA for 2 wk, SR-14033 suppressed the effect of SP on P(pa). Also, chronic hypoxia induced significant increases in NK1 receptors and NK1 receptor mRNA, with a temporal trend. We conclude that chronic hypoxia temporally augments SP-induced vascular responses, which are closely associated with increases in NK1 receptors and gene expression.

Topics: Altitude; Animals; Blood Pressure; Blood Vessels; Capillaries; Chronic Disease; Female; Hypoxia; In Vitro Techniques; Piperidines; Pulmonary Circulation; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; RNA, Messenger; Substance P; Time Factors

Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were compared in large (LPA) and small pulmonary artery (SPA) rings from normoxic and chronically hypoxic (CH) rats. In addition, the effects of a selective phosphodiesterase (PDE) 5 inhibitor, E-4021, on ACh-induced relaxation were evaluated. Chronic hypoxia markedly decreased both ACh- and SNP-induced relaxations in LPA but not in SPA rings. Pretreatment with E-4021 caused a much greater leftward shift of the concentration-response curve for ACh in hypoxic than in normoxic LPA rings, eliminating the difference in response to ACh between these two vessels. These results suggest that cGMP-dependent relaxation is impaired in the proximal but not in the distal pulmonary artery of CH rats and that increased PDE5 activity could be a mechanism responsible for this impaired responsiveness.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Animals; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Hypertension; Hypoxia; In Vitro Techniques; Male; Nitroprusside; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents

Patients with liver disease are prone to develop peptic ulceration and often receive H(2)-receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H(2)-receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H(2)-receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease.. Blood samples were obtained from 11 patients with chronic hepatitis, 11 patients with cirrhosis and six healthy subjects. Under fasting conditions, 75 mg of roxatidine acetate was administered orally, and plasma roxatidine levels were determined sequentially from 3 to 12 h. Relationships between pharmacokinetic variables and each parameter related to hepatic functions were also investigated.. There was no difference in the pharmacokinetic variables and serum levels of roxatidine between chronic hepatitis and healthy controls. In contrast, in cirrhosis, serum roxatidine levels were significantly higher than those in chronic hepatitis and normal control. Half-life, the area under the plasma concentration-time curve and clearance in cirrhosis were also significantly longer, bigger and smaller than those in chronic hepatitis and healthy controls, respectively. The half-life became longer and the clearance became smaller in parallel with the progression of liver disease. Serum levels of hyaluronate and gamma-glutamyl transpeptidase showed a good correlation with half-life, clearance and elimination rate. A good correlation between creatinine clearance and elimination rate was found.. Pharmacokinetics of roxatidine acetate is affected by hepatic function, and the dosage of roxatidine acetate for patients with liver disease, especially cirrhosis, should be modified.

Topics: Administration, Oral; Adult; Aged; Area Under Curve; Chronic Disease; Creatinine; Half-Life; Hepatitis C, Chronic; Histamine H2 Antagonists; Humans; Liver Cirrhosis; Liver Function Tests; Metabolic Clearance Rate; Middle Aged; Peptic Ulcer; Piperidines

The chronic mild stress (CMS) model of depression was used to study the potential antidepressant-like activity of NKP608, a non-peptidic, specific, potent and orally active NK1 receptor antagonist. In this model, a substantial decrease in consumption of a 1% sucrose solution is observed in rats continously subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic, oral treatment with NKP608 (once daily for 5 weeks) gradually reversed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipramine (10 mg/kg). The time-course of action of NKP608 in the CMS model was dose-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of the CMS-induced deficit in sucrose consumption after 4 weeks of treatment (comparable to 5 weeks required for imipramine), while only 1 week of treatment was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective. These results suggest that NKP608 has antidepressant-like properties in the CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antidepressant imipramine.

Topics: Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Chronic Disease; Depression; Electroshock; Imipramine; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinolines; Rats; Rats, Wistar; Stress, Psychological

The functional interactions between the endogenous cannabinoid and opioid systems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Delta9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observed in the effects induced on body temperature, locomotion, or ring catalepsy. During a chronic treatment with Delta9-tetrahydrocannabinol, the development of tolerance to the analgesic responses induced by this compound was slower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndrome, precipitated in Delta9-tetrahydrocannabinol-dependent mice by the injection of SR141716A, was significantly attenuated in mutant mice. These results indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Delta9-tetrahydrocannabinol and participates in the expression of cannabinoid abstinence.

Topics: Acute Disease; Analysis of Variance; Animals; Autoradiography; Behavior, Animal; Body Temperature; Body Weight; Brain; Chronic Disease; Dronabinol; Drug Tolerance; Enkephalins; Hyperalgesia; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Protein Precursors; Psychotropic Drugs; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Substance Withdrawal Syndrome

In our previous study, we demonstrated that chronic ethanol (EtOH) exposure down-regulated the cannabinoid receptors (CB1) in mouse brain synaptic plasma membrane (SPM) (Basavarajappa et al., Brain Res. 793 (1998) 212-218). In the present study, we investigated the effect of chronic EtOH (4-day inhalation) on the CB1 agonist stimulated guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTP gamma S) binding in SPM from mouse. Our results indicate that the net CP55,940 stimulated [35S]GTP gamma S binding was increased with increasing concentrations of CP55,940 and GDP. This net CP55,940 (1.5 microM) stimulated [35S]GTP gamma S binding was reduced significantly (-25%) in SPM from chronic EtOH group (175 +/- 5.25%, control; 150 +/- 8.14%, EtOH; P < 0.05). This effect occurs without any significant changes on basal [35S]GTP gamma S binding (152.1 +/- 10.7 for control, 147.4 +/- 5.0 fmol/mg protein for chronic EtOH group, P > 0.05). Non-linear regression analysis of net CP55,940 stimulated [35S]GTP gamma S binding in SPM showed that the Bmax of cannabinoid stimulated binding was significantly reduced in chronic EtOH exposed mouse (Bmax = 7.58 +/- 0.22 for control; 6.42 +/- 0.20 pmol/mg protein for EtOH group; P < 0.05) without any significant changes in the G-protein affinity (Kd = 2.68 +/- 0.24 for control; 3.42 +/- 0.31 nM for EtOH group; P > 0.05). The pharmacological specificity of CP55,940 stimulated [35S]GTP gamma S binding in SPM was examined with CB1 receptor antagonist, SR141716A and these studies indicated that CP55,940 stimulated [35S]GTP gamma S binding was blocked by SR141716A with a decrease (P < 0.05) in the IC50 values in the SPM from chronic EtOH group. These results suggest that the observed down-regulation of CB1 receptors by chronic EtOH has a profound effect on desensitization of cannabinoid-activated signal transduction and possible involvement of CB1 receptors in EtOH tolerance and dependence.

Topics: Analgesics; Animals; Binding, Competitive; Brain Chemistry; Central Nervous System Depressants; Chronic Disease; Cyclohexanols; Dose-Response Relationship, Drug; Down-Regulation; Ethanol; Guanosine 5'-O-(3-Thiotriphosphate); Kinetics; Male; Mice; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Sulfur Radioisotopes; Synaptic Membranes

Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K(+) (K(v)) channels and release of intracellular Ca(2+), were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K(+) current [I(K(v))], with maximum inhibition of 12-18% seen at a concentration of 0.1-1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I(K(v)) inhibition, a switch in coupling between ET-1 and I(K(v)) from ET(B) to ET(A) receptors occurred. This switch in receptor coupling, combined with reduced I(K(v)) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ET(A)-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.

Topics: Animals; Antihypertensive Agents; Calcium; Chronic Disease; Electrophysiology; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Channel Blockers; Potassium Channels; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin

To test whether a potent cGMP-specific phosphodiesterase inhibitor, E 4021, is a selective pulmonary vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects in conscious, chronically hypoxic pulmonary hypertensive rats. Chronically hypoxic pulmonary hypertension was induced by keeping adult Sprague-Dawley rats in a hypobaric chamber for 3 weeks. Two days after catheterization. E 4021 was injected intravenously at doses of 3, 10, 30, 100, 300, and 1,000 micrograms/kg at 10-min intervals. E 4021 caused significant decreases in mean pulmonary arterial pressure of 11 +/- 5, 12 +/- 6, and 18 +/- 5% at doses of 100, 300, and 1,000 micrograms/kg, respectively. In contrast to its depressor effect on mean pulmonary arterial pressure, E 4021 decreased mean systemic arterial pressure significantly (by 9 +/- 2%) at a dose of 1,000 micrograms/kg only. Heart rate and cardiac output were unchanged after the administration of E 4021. Tissue cGMP-specific phosphodiesterase activity was markedly higher in lung than in aorta. These results indicate that E 4021 is a relatively selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats. We conclude E 4021 may be useful for the treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Chronic Disease; Hypertension, Pulmonary; Hypoxia; Lung; Male; Phosphodiesterase Inhibitors; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilator Agents

We describe a 73-yr-old woman anaesthetized for a laminectomy. She suffered from hepatic failure with mild encephalopathy complicated by several exacerbations associated with sedative and opioid therapy. The challenge for anaesthesia management was to provide adequate analgesia and avoid causing hepatic encephalopathy during and after the surgery. We used remifentanil to provide intraoperative and postoperative analgesia, because it has a short duration of action and does not require hepatic metabolism. We closely monitored the respiratory and the neurological status throughout the administration and conclude that remifentanil can provide perioperative analgesia in patients at risk of developing hepatic encephalopathy.

Topics: Aged; Analgesia; Analgesics, Opioid; Arachnoid Cysts; Chronic Disease; Contraindications; Female; Humans; Laminectomy; Liver Failure; Pain, Postoperative; Piperidines; Remifentanil

Oral administration of an ammonia solution (0.01%) or a sodium taurocholate solution (TCA solution, 5 mM) as drinking water for 4 weeks or 13 weeks, respectively, resulted in gastric mucosal thinning and decreased parietal cell numbers. Oral administration of TCA solution also caused cell infiltration in the lamina propria of the mucosa and mucosal fibrosis. When lafutidine (3, 10 mg/kg) was administered orally once daily for one week after the withdrawal of ammonia or TCA solution, the recovery of the mucosal thickness in the fundic gland area and the parietal cell number were significantly accelerated, and the recovery of mucosal thickness in the pyloric gland area also tended to be accelerated. Lafutidine at 10 mg/kg for 1 week had no influence on normal mucosal thickness and parietal cell numbers. At the doses that produce equal or greater acid antisecretory effect than lafutidine, oral administration of cimetidine (30 mg/kg) and famotidine (1 mg/kg) had no effect on either of these atrophy indexes. These results demonstrate that lafutidine, unlike cimetidine and famotidine, can accelerate the healing of mucosal injuries in ammonia- and TCA-induced chronic gastritis models.

Topics: Acetamides; Ammonia; Animals; Anti-Ulcer Agents; Cell Count; Chronic Disease; Cimetidine; Famotidine; Gastric Mucosa; Gastritis; Humans; Male; Parietal Cells, Gastric; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Taurocholic Acid

The influence of KU-1257 on the recurrence and relapse of acetic acid ulcers in rats was investigated grossly and histologically in comparison with that of cimetidine. The ulcer was induced by topical application of glacial acetic acid at the junction of the corpus and antrum on the anterior wall of the stomach. The drug was administered from the 5th to the 153rd day after the ulcer induction and then discontinued to the 238th day. The healing rates of the control groups (control) rose until the 119th day after the ulcer induction, followed by ups and downs. The quality of healing in the regenerated mucosa and the granulation tissue of the healed ulcer was poor, resulting in the recurrence and relapse of ulcers. The recurrence and relapse of ulcers also occurred in the cimetidine groups (CIM). On the other hand, the KU-1257 groups (KU-1257) showed much lower recurrence and relapse rates of ulcers than the control and CIM groups. Moreover, KU-1257, unlike CIM, improved the quality of ulcer healing throughout the period of its administration and even after it was discontinued. These results suggest that KU-1257 improves the quality of ulcer healing, and this may contribute to the low recurrence and relapse rates of ulcers.

Topics: Acetates; Acetic Acid; Animals; Chronic Disease; Cimetidine; Histamine H2 Antagonists; Male; Phenylurea Compounds; Piperidines; Rats; Rats, Wistar; Recurrence; Stomach Ulcer; Time Factors

Tiscornia and Dreiling (Physiopathogenic Hypothesis of Alcoholic Pancreatitis: Supranormal Ecbolic Stimulation of the "Pancreon" Units Secondary to the Loss of the Negative Component of Pancreas Innervation. Pancreas 1987;2:604-612.) proposed that hypertonicity of intrapancreatic cholinergic neurons provoked by chronic alcoholism may contribute to the pathogenesis of chronic pancreatitis (CP). In the present study, the validity of this hypothesis was investigated in humans by studying the effects of atropine, cisapride, and ethanol on the meal-stimulated secretion of pancreatic polypeptide (PP) and cholecystokinin (CCK) in healthy volunteers, heavy drinkers, and CP patients. In healthy volunteers, the early phase PP response (0-40 min) to a test meal was completely blocked by atropine, whereas it was augmented by cisapride, an enhancer of acetylcholine release from cholinergic nerves. The early phase PP response to a test meal was inhibited by ethanol in healthy volunteers, whereas, in heavy drinkers, the response was augmented and the inhibition by ethanol was abrogated. In CP patients, ethanol tended to enhance the early phase PP response. Ethanol did not affect the early phase CCK response to a test meal in any group, but it significantly enhanced the late phase CCK response (40-120 min) in CP patients. These results suggest that: (i) oral ethanol may inhibit the postprandial activation of the cholinergic neural pathway to the pancreas in healthy subjects, (ii) in heavy drinkers, postprandial cholinergic tone may be augmented and become resistant to the inhibition by ethanol, and (iii) the ethanol-induced increase in the postprandial CCK response in CP patients may play some role in the pathophysiology of this disease.

Topics: Adult; Alcoholism; Analysis of Variance; Atropine; Cholecystokinin; Chronic Disease; Cisapride; Ethanol; Humans; Male; Middle Aged; Pancreatic Polypeptide; Pancreatitis; Parasympathomimetics; Piperidines; Postprandial Period; Radioimmunoassay

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

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

Case of an infant with chronic cough is reported. The most frequent causes of chronic cough were ruled out. Twenty-four hour oesophageal pH-monitoring showed a close correlation between gastro-oesophageal reflux episodes and cough attacks. The patient was successfully treated with cisapride (0.3 mg/kg t.i.d.). These findings show that irritable oesophagus syndrome can cause chronic cough.

Topics: Chronic Disease; Cisapride; Cough; Esophagitis, Peptic; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Infant; Male; Piperidines; Sympathomimetics; Syndrome

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Chronic Disease; Female; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia, Paranoid

Chronic hiccup is a rare but potentially severe condition, that can be symptomatic of a variety of diseases, or idiopathic. Many therapeutic interventions have been reported, most often as case reports. Among other drugs, baclofen has been suggested as a therapy for chronic hiccup. In a large series of patients, we have evaluated its therapeutic position. In patients with chronic hiccup, defined as hiccup spell or recurring hiccup attacks lasting more than 7 days, investigation of the upper gastro-oesophageal tract (fibroscopy, manometry, and pH monitoring) was systematically performed. Most patients had tried numerous drugs in the past, without success. Baclofen was used as a first treatment in patients without evidence of any gastro-oesophageal disease (n = 17), and was undertaken only after full treatment of such disease (n = 55) had failed to solve the hiccup problem (n = 20). Baclofen has, therefore, been administered to 37 patients with chronic hiccup (average duration 4.6 yrs). Baclofen produced a long-term complete resolution (18 cases) or a considerable decrease (10 cases) of hiccups in 28 of the 37 patients. There was no significant difference between patients with or without gastro-oesophageal disease. We conclude that so-called idiopathic chronic hiccup often results from gastro-oesophageal abnormalities. Also, if controlled studies confirm our encouraging results, baclofen can be a major element in the treatment of chronic hiccup that is idiopathic, or that cannot be helped by treatment of gastro-oesophageal diseases.

Topics: Anti-Ulcer Agents; Baclofen; Chronic Disease; Cisapride; Dose-Response Relationship, Drug; Female; Gastroesophageal Reflux; Hiccup; Humans; Male; Middle Aged; Omeprazole; Piperidines; Treatment Outcome

Gastro-oesophageal reflux (GOR) has been implicated in such clinical phenomena as aspiration pneumonia, bronchospasm or wheezing, apnea, stridor, and hoarseness. Various tests have been used as an aid to diagnosing patients with chronic respiratory disease where GOR is a causal factor. Different forms of conservative treatment have been tried for GOR, including cisapride. Several studies have evaluated its effect on the pH profile and respiratory symptoms in patients with chronic respiratory disease and have demonstrated improvement of nocturnal wheezing, cough, and irritability. Our experience with cisapride is positive in children with GOR. Patients refractory to medical treatment have been surgically treated with good results.

Topics: Anti-Ulcer Agents; Asthma; Child; Child, Preschool; Chronic Disease; Cisapride; Gastroesophageal Reflux; Humans; Infant; Piperidines; Pneumonia, Aspiration; Respiratory Sounds; Respiratory Tract Diseases

The outcome for 35 horses with chronic dysautonomia which were kept in the hospital at the Royal (Dick) School of Veterinary Studies and subsequently returned to their owners is recorded. They constituted 42.7 per cent of the 82 chronic cases seen between 1991 and 1994; the other 47 horses were euthanased while in hospital. Of the 35 animals returned to their owners four died and 27 were available for follow up; of these 27, 12 were working competitively and six were being trained for future competitive work. It takes at least a year before it is clear whether a horse can compete successfully again but all the surviving animals were capable of being ridden. Some of the horses suffered excessive sweating, had difficulty in swallowing some foodstuffs, or had coat changes for long periods after returning to a normal weight.

Topics: Animals; Autonomic Nervous System Diseases; Chronic Disease; Cisapride; Female; Follow-Up Studies; Gastrointestinal Diseases; Horse Diseases; Horses; Hospitals, Animal; Male; Piperidines; Serotonin Antagonists; Treatment Outcome

Topics: Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Humans; Isoxazoles; Piperidines; Risperidone; Schizophrenia

Topics: Antipsychotic Agents; Chronic Disease; Drug Therapy, Combination; Humans; Isoxazoles; Lithium Carbonate; Lorazepam; Male; Middle Aged; Piperidines; Priapism; Risperidone; Schizophrenia, Paranoid

To determine if NIP-121, a new antihypertensive agent with K+ channel-opening activity, would be an effective vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects under normoxic conditions in conscious chronically hypoxic pulmonary hypertensive rats and in control pulmonary normotensive rats. In contrast to no pulmonary vasodilation by NIP-121 in control rats, the K+ channel activator (10-100 mg/kg i.v.) decreased both mean pulmonary arterial pressure (from 42 +/- 2 to 33 +/- 2 mmHg; P < 0.05) and total pulmonary resistance (from 278 +/- 30 to 213 +/- 32 mmHg.l-1 x min; P < 0.05) in hypertensive rats. NIP-121 produced similar dose-related decreases in mean systemic arterial pressure and total systemic resistance in both groups of rats. Both the pulmonary and the systemic vasodilations to NIP-121 were inhibited by pretreatment with the blocker of ATP-sensitive K+ channels, glibenclamide (20 mg/kg), but not with the inhibitor of endothelium-derived relaxing factor synthesis, nitro-L-arginine (10 mg/kg). The L-type voltage-gated Ca2+ channel blocker, nifedipine (10-1,000 mg/kg i.v.), failed to cause pulmonary vasodilation in normoxic hypertensive rats, although there was dose-related systemic vasodilation. These results show that in contrast to the Ca2+ channel blocker, nifedipine, the K+ channel activator, NIP-121, is a potent vasodilator of chronic hypoxia-induced pulmonary hypertension in the rat. The mechanism of its hypotensive action in the hypertensive pulmonary vasculature might be more than simply membrane hyperpolarization and indirect inhibition of the L-type voltage-gated Ca2+ channel.

Topics: Altitude; Animals; Chronic Disease; Glyburide; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Male; Nifedipine; Oxadiazoles; Piperidines; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasodilation

Topics: Child; Chronic Disease; Cisapride; Electromyography; Gastrointestinal Motility; Gastrointestinal Transit; Humans; Intestinal Pseudo-Obstruction; Manometry; Myoelectric Complex, Migrating; Piperidines; Serotonin Antagonists

We examined the anti-ulcer effects of FRG-8813, a new-type histamine H2-receptor antagonist, in chronic ulcer models of rats and mice (W/WV). FRG-8813, given orally twice a day for 7 days, accelerated the healing of gastric or duodenal ulcer induced by acetic acid injection or application at the non-antisecretory doses (0.3 approximately 3 mg/kg). Administration of FRG-8813 to rats with ulcers increased the amounts of mucus in the gastric mucosa. These actions of FRG-8813 were more potent than those of famotidine or cimetidine. In W/WV mice, several ulcers spontaneously developed on gastric mucosa during the 8 weeks after the birth. The ulcers were aggravated by several unknown factors after the ulcer generation in W/WV mice. The aggravation of ulcers was inhibited by the 4-week administration of FRG-8813 with diet at the dose of 1 or 10 mg/kg/day, but was not inhibited by cimetidine at the dose of 100 mg/kg/day. From these results, we suggest that FRG-8813 is able to accelerate the healing of ulcers by antisecretory plus increasing actions on the integrity of the gastric mucosal defense mechanisms; therefore FRG-8813 is expected to be a useful drug for the treatment of gastric or duodenal ulcers in humans.

Topics: Acetamides; Animals; Chronic Disease; Disease Models, Animal; Duodenal Ulcer; Gastric Acid; Histamine H2 Antagonists; Male; Mice; Piperidines; Pyridines; Rats; Rats, Wistar; Stomach Ulcer

A 43-year-old man with chronic intestinal pseudo-obstruction is presented. He had undergone two laparotomies in an attempt to eliminate the cause of repeated episodes suggestive of obstruction. Gastrointestinal manometry showed severe abnormalities compatible with the diagnosis of chronic intestinal pseudo-obstruction. Laboratory tests indicated the presence of intestinal malabsorption and villous atrophy. A gluten-free diet accompanied by 10 days of treatment with tetracycline and 2 short periods of treatment with cisapride led to gradual, but apparently complete, resolution of the pseudo-obstructive syndrome. Repeated manometric studies showed progressive normalization of both the fasting and postprandial upper gastrointestinal motor pattern.

Topics: Adult; Chronic Disease; Cisapride; Fasting; Gastrointestinal Motility; Humans; Intestinal Pseudo-Obstruction; Male; Manometry; Piperidines; Tetracycline

Risperidone is a new benzisoxazole derivative displaying a very potent serotonin antagonism and a potent dopamine antagonism in pharmacological studies. These properties suggest the hypothesis that risperidone may exert antipsychotic effects and be superior to classic neuroleptics in its beneficial effects on negative and affective symptoms and its low extrapyramidal side-effect propensity. In an open pilot study 13 patients suffering from acute schizophrenic psychosis were treated with risperidone within an individually adapted dose range from 1 to 10 mg per day. A good antipsychotic efficacy could be demonstrated in 6 of the 8 patients who completed the trial. Risperidone was very well tolerated. The substance possesses a low EPS-inducing profile. Future research has to test the suggested advantage of risperidone over other neuroleptic drugs and its performance in the treatment of chronic schizophrenic patients.

Topics: Acute Disease; Adult; Antipsychotic Agents; Chronic Disease; Female; Humans; Isoxazoles; Male; Middle Aged; Pilot Projects; Piperidines; Psychiatric Status Rating Scales; Risperidone; Schizophrenia

The advent of histamine H2 receptor antagonists (H2-RA) has allowed the treatment of reflux esophagitis (RE) to be controlled over a relatively long term. The authors have experienced some cases resistant to H2-RA, but it was revealed that these cases can be successfully treated with proton pump inhibitors. It has been suggested that esophagogastric dysmotility can lead to RE. RE has been treated for many years by using GI-prokinetic agents, which theoretically inhibit acid reflux and improve esophageal acid clearance. In order to compare the effects on acid reflux of an H2-RA (famotidine), a proton pump inhibitor (omeprazole) and a GI-prokinetic agent (cisapride), we measured the 24-hour pH in the esophagus and stomach simultaneously, before and after treatment in 17 patients with RE. It was found that the proton pump inhibitor was the most effective drug for inhibiting esophageal acidification, followed by famotidine and then cisapride. Furthermore, we found that cisapride often actually exacerbated acid reflux. The differences in inhibitory effects on acidification allowed us to draw conclusions regarding the treatment of RE. It was concluded that the stronger the inhibitory effect of a drug on acid secretion, the more useful it was in the treatment of RE. The GI-prokinetic drug did not inhibit acid reflux as much as we had expected.

Topics: Adult; Aged; Chronic Disease; Cisapride; Esophagitis, Peptic; Esophagus; Famotidine; Female; Humans; Hydrogen-Ion Concentration; Male; Monitoring, Physiologic; Omeprazole; Piperidines; Serotonin Antagonists; Stomach

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

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

This is a case report of a previously asymptomatic 11-year-old boy who developed chronic intestinal pseudo-obstruction. Barium studies revealed grossly disordered motility of the proximal small bowel, and ganglion cells in a gastric biopsy were mildly abnormal. Treatment with conventional prokinetic agents and gastrojejunostomy were ineffective. Intravenous cisapride induced an immediate remission, which has been maintained subsequently by rectal administration of the drug.

Topics: Administration, Rectal; Child; Chronic Disease; Cisapride; Humans; Injections, Intravenous; Intestinal Pseudo-Obstruction; Intestine, Small; Male; Piperidines

Topics: Adolescent; Adult; Chronic Disease; Cluster Headache; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Piperidines; Vascular Headaches

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

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

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

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

In the treatment of chronic ectopic atrial tachycardia, standard antiarrhythmic therapy has been shown to be ineffective in the majority of patients. The intravenous and oral effects of two class IC antiarrhythmic drugs, encainide and flecainide, in five patients with chronic ectopic atrial tachycardia were studied using exercise testing, 24 hour long-term electrocardiography and programmed electrical stimulation. All patients had been treated unsuccessfully with at least four antiarrhythmic drugs. In two patients tachycardia was persistent, and in three patients tachycardia occurred intermittently for more than 12 hours/day. Intravenous encainide and flecainide at doses ranging from 0.3 to 2.0 mg/kg and from 0.5 to 1.5 mg/kg body weight, respectively, terminated atrial ectopic tachycardia in all patients. Oral encainide, 150 to 225 mg/day, completely suppressed ectopic atrial activity in four patients during a mean follow-up period of 8 +/- 3 months. In the remaining patient encainide markedly reduced the number of episodes of tachycardia. In three patients encainide had to be withdrawn because of intolerable side effects. These patients were well controlled with oral flecainide, 200 to 300 mg/day, without side effects. On the basis of these results, the efficacy of encainide and flecainide in the treatment of chronic ectopic atrial tachycardia appears to be not drug-specific but rather a general class IC property.

Topics: Adult; Anilides; Chronic Disease; Electrophysiology; Encainide; Female; Flecainide; Heart Atria; Humans; Male; Middle Aged; Piperidines; Tachycardia

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

Topics: Adult; Chronic Disease; Drug Evaluation; Humans; Male; Penfluridol; Piperidines; Schizophrenia, Paranoid; Time Factors

The objective of this study was to evaluate the haemodynamic and antiarrhythmic effects of flecainide acetate in patients with heart failure. Flecainide acetate, a class Ic antiarrhythmic agent, was given intravenously to 9 patients with congestive heart failure and frequent ventricular arrhythmias with nonsustained ventricular tachycardia. The drug (2 mg/kg) was infused slowly over 60 minutes. The maximum plasma level achieved was 218 (range 142-350) ng/ml. Six of the 9 patients experienced a 90% suppression of their arrhythmias for an average of 6.5 (range 2-15) hours. Pre-ejection period control (PEPc, 148.8 +/- 3.6 msec) increased to 157 msec and pre-ejection period/ejection time (PEP/ET) [control 0.449 +/- 0.027] to 0.516 (p less than 0.005), while the ejection time index (ETI) did not change. Cardiac index (control 2.4 +/- 0.36 L/min/m2) decreased by 11% (p less than 0.02), and pulmonary wedge pressure (control 13.4 +/- 2.4mm Hg) increased by 23% (p less than 0.05). Stroke work index, arterial pressure and vascular resistance did not change significantly. The parameters returned to control values on completion of the infusion. Flecainide acetate can be safely administered at the usual dose of 2 mg/kg to patients with congestive heart failure, provided that the infusion time is doubled. Antiarrhythmic efficacy under these conditions is good even at lower plasma concentrations.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Electrocardiography; Flecainide; Heart Failure; Hemodynamics; Humans; Piperidines

The efficacy of the new class Ic anti-arrhythmic (aa) drug, Flecainide, has been evaluated in patients (pts) affected by frequent and/or severe chronic ventricular arrhythmias (VA), as assessed by 24 hours Holter monitoring and maximal exercise stress testing. The protocol consisted in a preliminary screening with multiple aa drugs (average 6.0 per pt) using the acute oral drug testing. The most effective drug was then given for 72 hours and 24 hours Holter monitoring and exercise stress testing repeated; if the efficacy was confirmed, chronic treatment was initiated and control visits were repeated after 3, 6 and 12 months. The study population consisted of 27 pts; 22 (81%) were in Lown class 4A (18%) or 4B (63%). Eight pts (30%) had a previous (greater than 1 year) myocardial infarction, while in 14 (52%) no evidence of cardiac disease was found. During acute oral drug testing a positive response (reduction of PVC's greater than 90% and abolition of grades 4A and 4B) was obtained with Flecainide, 200 mg, in 20 pts (74%). In 6 pts (22%) no effect was observed, while a possible proarrhythmic effect was observed in 1 pt (4%). Eighteen pts entered the second phase of the study with an average dose of Flecainide of 175 mg b.i.d. In 83% of the pts there was a positive concordance between the acute oral testing and the 72 hours treatment, as in 15 out of 18 pts grades 4A and 4B were totally abolished and the mean frequency of PVC's was reduced by 99%. In 3 pts (17%) no response was observed. Flecainide increased significantly PR (37 msec), QRS (20 msec) and QTc (28 msec). The plasma levels attained with chronic therapy (846 ng/ml) were higher than those achieved with the acute oral testing (372 ng/ml). Mild side effects (dizziness, tremor and headache) were observed in 33% of the pts and were all eliminated by a 100 mg reduction in Flecainide dose. Fifteen pts entered the third phase (long term treatment): in this group there was a 93.3% correlation with phase two, as in 14 out of 15 pts there was a complete abolition of grade 4B arrhythmias, a 98.8% reduction of couplets and a reduction in the number of PVC's greater than 85%. This study shows that Flecainide is a quite powerful aa drug with modest side effects. Its efficacy against chronic VA is high, also when compared to the most effective and available aa drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Chronic Disease; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines

Topics: Arrhythmias, Cardiac; Chronic Disease; Flecainide; Heart Ventricles; Humans; Piperidines

Bronchial lability was measured in 10 normal subjects, 33 typical asthmatics, and 23 smokers with ventilatory defect, by three different methods in the course of a week. There was little difference between exercise/bronchodilator lability index, spontaneous diurnal variation, and histamine challenge in detecting bronchial lability. It was possible that histamine challenge was more sensitive and more specific to asthma. It is recommended that this test is used first in studies to detect bronchial lability but those apparently normal should also be tested by the other methods. There was no correlation between the numerical value of these indices of broncholability in abnormal subjects. The asthmatic and bronchitic subjects were not separated by any of the three methods.

Topics: Adult; Airway Resistance; Asthma; Bronchial Provocation Tests; Bronchitis; Chronic Disease; Circadian Rhythm; Exercise Test; Forced Expiratory Volume; Humans; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Smoking

Topics: Adolescent; Adult; Alkaloids; Anemia, Aplastic; Azepines; Central Nervous System Stimulants; Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Middle Aged; Piperidines; Stanozolol

During a one-week short-term in-hospital period, 60 patients with chronic ventricular arrhythmias were treated with 200 mg flecainide twice a day. Flecainide reduced premature ventricular complexes (PVCs) by more than 85% without causing important side-effects in 47 patients, who entered a one-year follow-up period and were followed with bimonthly 24-h ECGs. Median PVC-frequency remained reduced by more than 99% during the follow-up period. Repetitive ventricular beats and ventricular tachycardia were present in 83% and 42% of patients, respectively, before flecainide. During follow-up, these arrhythmias were seen in less than 32% and less than 10% of patients, respectively, at each 24-h ECG. Furthermore, the mean number of hours with repetitive ventricular beats and ventricular tachycardia remained reduced by more than 76% and more than 79%, respectively, throughout the follow-up period. Ventricular arrhythmias remained suppressed despite a gradual reduction in flecainide dosages (to a median of 300 mg day-1) and flecainide plasma levels. In nine out of 47 patients, an increase in ventricular arrhythmias above baseline values on one or more occasions was observed. During a flecainide withdrawal period, a 65-fold increase in median PVC-frequency was observed and ventricular tachycardia reappeared in 18 patients. Subjective side-effects were acceptable except for two patients. During the follow-up period, one patient developed reversible heart failure and sinus node dysfunction. During the total study period, four patients, with either severe coronary artery disease (2) or cardiomyopathy (2) developed lethal arrhythmias (3) or ischaemic events (1). We conclude that prolonged flecainide treatment is effective in a high proportion of patients with chronic ventricular arrhythmias. In some patients an arrhythmogenic effect may occur.

Topics: Adult; Aged; Arrhythmias, Cardiac; Chronic Disease; Dizziness; Drug Evaluation; Electrocardiography; Female; Flecainide; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Time Factors

The efficacy and safety of oral flecainide for treatment of ventricular arrhythmias were assessed during a 3-day period in patients with various cardiac diseases. Of 11 patients who received a low dose of flecainide (median daily dose 240 mg), only 4 responded with 90% or greater reduction in premature ventricular complex frequency. Ventricular tachycardia could not be suppressed. During treatment no electrocardiographic changes occurred. 14 of the 19 patients who received a high dose of flecainide (median daily dose 480 mg), demonstrated a 90% or greater reduction in premature ventricular complexes, and ventricular tachycardia did not recur during treatment in 7 out of 9 patients. However, PQ, QRS, and QTc intervals were significantly increased. In general, flecainide was well tolerated and drug administration did not have to be discontinued because of side effects. Flecainide acetate treatment, with a median dose of 480 mg daily, appears to be highly effective for suppressing complex ventricular arrhythmias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Drug Evaluation; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia

Topics: Adolescent; Adult; Aged; Alkaloids; Anemia, Aplastic; Azepines; Central Nervous System Stimulants; Child; Chronic Disease; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Middle Aged; Piperidines

Gamma scintigraphy plays an important role in the topographic diagnosis of focalized cerebrovascular insufficiency. Furthermore, sequential imaging allows a comparative study of arterial distribution while studying the "transit time" of the radioactive tracer. In this work, the authors attempted to quantify transit time in patients with chronic cerebrovascular insufficiency while comparing the radioactivity in the hemispheres with that of the various arterial territories. The study of the arca and slope of the various arterial territories. The study of the area and slope of the tracer profile indirectly gives information about the cerebro-correlation between cerebrovascular resistance and the clinical state, there was, however, an interesting relation during vasodilator treatment (ifenprodil tartrate) in which promising clinical results were preceded by an increase in the arterial inflow component of the radioactivity curve.

Topics: Adult; Aged; Cerebral Arterial Diseases; Chronic Disease; Female; Gamma Rays; Humans; Male; Middle Aged; Piperidines; Radionuclide Imaging; Technetium; Vasodilator Agents

Six infants with severe life-threatening protracted diarrhoea were treated with loperamide. Steady-state perfusion studies of the jejunum showed that in 2 of them the small intestine was in a net secretory state with respect to water, and in the others this was inferred from the fact that the diarrhoea persisted despite nothing by mouth. Loperamide resulted in a prompt and impressive improvement in the condition of each infant. We conclude that this drug has an important role in the management of protracted diarrhoeal states in some infants who are unresponsive to current treatments, and that its effect is related to its antisecretory action.

Topics: Child, Preschool; Chronic Disease; Diarrhea, Infantile; Female; Humans; Infant; Jejunum; Loperamide; Male; Perfusion; Piperidines; Water

After an initial pilot study in five patients, the effect of flecainide on chronic ventricular arrhythmias was tested during 48-hour oral administration of 250 mg twice a day in nine further patients with previously drug-resistant chronic, stable ventricular arrhythmias. Mean age was 45.9 +/- 14.9 years; seven patients were male. Three patients had coronary artery disease, whereas the diagnoses in the remaining patients were congestive cardiomyopathy, aortic stenosis or no apparent heart disease. Continuous Holter monitoring with quantitative evaluation was performed in all patients for 24 hours before and during a two days' period of treatment. The mean number of ventricular ectopic beats decreased from 20.3 +/- 6.4 beats/min during hour six of treatment and further to 3.1 +/- 7.7 beats/min during hour 25 to 48 after onset of treatment. In either of nine patients, the mean decrease in ventricular ectopic rate was 97.5%. In only one patient, therapy was ineffective, Ventricular couplets were completely suppressed in six of eight cases. Looking at the spontaneous variability of ventricular ectopic beats during the control period, eight of nine patients showed a decrease which considerably exceeded the statistically necessary one. Headache of moderate degree was reported in one case in the pilot study. Therapy had to be stopped after the first dose because of QRS widening in another patient. In conclusion, this short-term study suggests that flecainide may be an effective drug for the management of ventricular arrhythmias.

Topics: Adult; Anti-Arrhythmia Agents; Aortic Valve Stenosis; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; 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: Analgesics, Opioid; Animals; Arthritis, Experimental; Benzimidazoles; Chronic Disease; Drug Tolerance; Male; Morphine; Mycobacterium; Pain; Piperidines; Rats

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: Adult; Chronic Disease; Colitis, Ulcerative; Humans; Loperamide; Male; Megacolon, Toxic; Peristalsis; Piperidines

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Chronic Disease; Drug Tolerance; Morphine; Naloxone; Pain; Piperidines; Rats; Reaction Time; Time Factors

Topics: Benzimidazoles; Chemical Phenomena; Chemistry; Chronic Disease; Dyspepsia; Gastrointestinal Motility; Humans; Piperidines

Twenty patients were treated with penfluridol and 21 with fluphenazine for a period of up to 1 year. Penfluridol, an oral neuroleptic administered weekly was as efficacious as fluphenazine administered twice daily and appeared to be superior to fluphenazine in improving emotional withdrawal and anergia. The low incidence of side effects and other signs of toxicity, coupled with an effective prophylactic activity, suggests that penfluridol is an important addition to our therapeutic armamentarium for the treatment of chronic schizophrenia.

Topics: Adult; Ambulatory Care; Chronic Disease; Female; Fluphenazine; Humans; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Electrocardiography; Exercise Test; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos; Verapamil

Topics: Adolescent; Adult; Antitussive Agents; Chronic Disease; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines; Respiratory Tract Diseases

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

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Drug Tolerance; Female; Humans; Male; Maleates; Middle Aged; Palliative Care; Perhexiline; Piperidines

In a controlled trial of penfluridol and thiothixene as maintenance drugs in patients with chronic schizophrenic syndromes, some improvement over previous neuroleptics was seen with both drugs. This improvement was mainly evident in variables concerned with participation in social activities as assessed with the S-scale and by ward behaviour. The drug dosages necessary were very low and gave few and easily manageable side-effects. There was no significant difference between penfluridol and thiothixene. Penfluridol has the clear practical advantage of being the only long-acting drug for oral administration so far available.

Topics: Adolescent; Adult; Aged; Biperiden; Chlorpromazine; Chronic Disease; Drug Evaluation; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Penfluridol; Piperidines; Schizophrenia; Thiothixene

Topics: Acute Disease; Antipsychotic Agents; Basal Ganglia Diseases; Bipolar Disorder; Child; Chronic Disease; Delayed-Action Preparations; Dibenzazepines; Dibenzothiepins; Dosage Forms; Drug Therapy, Combination; Fluphenazine; Humans; Paranoid Disorders; Perphenazine; Pimozide; Piperazines; Piperidines; Schizophrenia; Structure-Activity Relationship; Thioridazine; Thioxanthenes; Tranquilizing Agents

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Cyclohexanes; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines; Prenylamine

An open trial of Carpipramine which chemically is a synthesis of a tricyclic antidepressant and the side chain of a butyrophrenone has been performed in 75 acute and chronic schizophrenics over a period of 30 days. The daily dose was 400-800 mg exeeding the recommendations of the manufacturer. The psychopathological changes were documented and evaluated by means of the AMP and the AMPAS-system. In 50 of the patients the trial could be completed. Only the productive symptoms and disturbance of sleep showed a significantly decreased frequency before day 10. It seems remarkable that the symptom of somatic hallucinations responded very rapidly under treatment with Carpipramine. Significant sedative or extrapyramidal side-effects were not observed; anticholinergic effects were moderate. There seems to be evidence of a slight centrally stimulating component. The substance cnnot be classified as a typical neuroleptic nor as an antidepressant drug. A differential action depending on the initial syndrome constellation is discussed.

Topics: Acute Disease; Antidepressive Agents, Tricyclic; Chronic Disease; Dibenzazepines; Drug Evaluation; Humans; Piperidines; Schizophrenia

Topics: Adult; Ambulatory Care; Antipsychotic Agents; Chronic Disease; Delayed-Action Preparations; Depression; Electrocardiography; Female; Follicle Stimulating Hormone; Humans; Injections, Intramuscular; Male; Middle Aged; Movement Disorders; Outpatient Clinics, Hospital; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Self-Assessment; Spermatogenesis; Sulfonamides

Topics: Acute Disease; Amides; Analgesics; Chronic Disease; Drug Combinations; Drug Evaluation; Female; Fumarates; Humans; Male; Nerve Compression Syndromes; Neuralgia; Pain; Piperidines; Propionates; Pyridines

Topics: Acidosis, Respiratory; Acute Disease; Adult; Aged; Alkalosis, Respiratory; Aminophylline; Anti-Bacterial Agents; Chronic Disease; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Oxygen Inhalation Therapy; Partial Pressure; Piperidines; Prednisone; Prognosis; Respiratory Insufficiency; Spirometry

Topics: Administration, Oral; Adult; Chronic Disease; Female; Humans; Hydrocarbons, Halogenated; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Time Factors; Toluene; Tranquilizing Agents

Topics: Adult; Chemical Phenomena; Chemistry; Chronic Disease; Female; Fluphenazine; Humans; Male; Middle Aged; Palmitic Acids; Phenothiazines; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Sulfonamides

Topics: Adult; Chronic Disease; Evaluation Studies as Topic; Female; Fluorobenzenes; Humans; Injections, Intramuscular; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Social Adjustment; Spiro Compounds; Tranquilizing Agents

Topics: Adolescent; Adult; Aged; Analgesics; Benperidol; Benzimidazoles; Child; Chronic Disease; Cough; Drug Synergism; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Pain; Palliative Care; Piperidines; Psychology; Substance-Related Disorders

Topics: Alcoholism; Antipsychotic Agents; Chronic Disease; Delayed-Action Preparations; Female; Fluphenazine; Hallucinations; Humans; Male; Palmitic Acids; Paranoid Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Sulfonamides

Topics: Adult; Chronic Disease; Female; Hallucinations; Humans; Hydrocarbons, Halogenated; Male; Motor Skills; Paranoid Disorders; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds; Thinking; Tranquilizing Agents

Topics: Acute Disease; Anesthesia, Epidural; Arterial Occlusive Diseases; Carboxylic Acids; Chronic Disease; Embolism; Gangrene; Humans; Piperidines; Sympatholytics; Thromboangiitis Obliterans; Thrombosis; Vasodilator Agents

Topics: Adult; Attention; Benzimidazoles; Chronic Disease; Haloperidol; Humans; Hydrocarbons, Halogenated; Ketones; Male; Memory; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Social Behavior; Time Factors; Tranquilizing Agents

Topics: Anxiety; Benzimidazoles; Chronic Disease; Hallucinations; Humans; Ketones; Mental Disorders; Piperidines; Psychotic Disorders; Schizophrenia; Schizophrenia, Disorganized; Tranquilizing Agents

Topics: Adult; Analysis of Variance; Benzimidazoles; Chronic Disease; Electroencephalography; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Piperidines; Psychiatric Status Rating Scales; Schizophrenia; Social Adjustment; Statistics as Topic; Tranquilizing Agents

Topics: Adult; Chronic Disease; Electroencephalography; Humans; Male; Phenothiazines; Piperidines; Schizophrenia

Topics: Benzimidazoles; Chronic Disease; Delayed-Action Preparations; Humans; Ketones; Mental Disorders; Piperidines; Schizophrenia; Tranquilizing Agents

Topics: Acute Disease; Adolescent; Adult; Chronic Disease; Delayed-Action Preparations; Drug Tolerance; Esters; Humans; Middle Aged; Phenothiazines; Piperidines; Psychotic Disorders; Undecylenic Acids

Topics: Acute Disease; Administration, Oral; Animals; Atrophy; Body Weight; Chronic Disease; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Organ Size; Piperidines; Rats; Rifampin; Sex Factors; Testis

Topics: Acute Disease; Calcium; Chronic Disease; Humans; Laryngeal Edema; Piperidines; Rhinitis, Allergic, Seasonal

Topics: Bronchitis; Chronic Disease; Humans; Injections, Intravenous; Khellin; Lung Diseases; Lung Diseases, Obstructive; Phenothiazines; Piperidines; Posture; Quaternary Ammonium Compounds; Respiratory Tract Diseases; Theophylline

Topics: Antitussive Agents; Bronchitis; Bronchoscopy; Chronic Disease; Cough; Humans; Piperidines; Tuberculosis; Xanthenes

Topics: Acetazolamide; Amides; Chronic Disease; Clopamide; Diuretics; Humans; Hydrogen-Ion Concentration; Lung Diseases; Piperidines; Respiratory Insufficiency

Topics: Adolescent; Adult; Aged; Amygdala; Astrocytoma; Brain Neoplasms; Central Nervous System Diseases; Cerebral Cortex; Chronic Disease; Electroencephalography; Electrophysiology; Epilepsy, Temporal Lobe; Female; Humans; Male; Mental Disorders; Middle Aged; Parasympatholytics; Piperidines; Temporal Lobe

Topics: Adult; Chronic Disease; Colitis; Enterocolitis, Pseudomembranous; Female; Humans; Intestinal Diseases, Parasitic; Male; Middle Aged; Piperidines

Topics: Chronic Disease; Digitalis; Digitalis Glycosides; Humans; Hypertension, Pulmonary; Piperidines; Plant Extracts; Promethazine; Pulmonary Heart Disease

Topics: Chronic Disease; Hallucinations; Humans; Mental Disorders; Piperidines; Psychopharmacology; Syndrome

Topics: Aged; Anticonvulsants; Chronic Disease; Disease; Hypnotics and Sedatives; Piperidines; Sleep Wake Disorders