piperidines and Liver-Diseases

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

Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).

Topics: Animals; Brain; Cocaine; Drug Discovery; Humans; Liver Diseases; Metabolic Diseases; Morpholines; Obesity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sulfonamides

Lapaquistat acetate is a squalene synthase inhibitor investigated for the treatment of hypercholesterolemia.. This report summarizes the phase 2 and 3 results from the lapaquistat clinical program, which was halted at an advanced stage as a result of potential hepatic safety issues. Efficacy and safety data were pooled from 12 studies (n=6151). These were 6- to 96-week randomized, double-blind, parallel, placebo- or active-controlled trials with lapaquistat monotherapy or coadministration with other lipid-altering drugs in dyslipidemic patients, including a large (n=2121) 96-week safety study. All studies included lapaquistat 100 mg daily; 5 included 50 mg; and 1 included 25 mg. The main outcome measures were the percent change in low-density lipoprotein cholesterol, secondary lipid/metabolic parameters, and overall safety. Lapaquistat 100 mg significantly decreased low-density lipoprotein cholesterol by 21.6% in monotherapy and by 18.0% in combination with a statin. It also reduced other cardiovascular risk markers, such as C-reactive protein. Total adverse events were higher for lapaquistat than placebo, although individual events were generally similar. At 100 mg, there was an increase in alanine aminotransferase value ≥3 times the upper limit of normal on ≥2 consecutive visits (2.0% versus 0.3% for placebo in the pooled efficacy studies; 2.7% versus 0.7% for low-dose atorvastatin in the long-term study). Two patients receiving lapaquistat 100 mg met the Hy Law criteria of alanine aminotransferase elevation plus increased total bilirubin.. Squalene synthase inhibition with lapaquistat acetate, alone or in combination with statins, effectively lowered low-density lipoprotein cholesterol in a dose-dependent manner. Elevations in alanine aminotransferase, combined with a rare increase in bilirubin, presented potential hepatic safety issues, resulting in termination of development. The lapaquistat experience illustrates the current challenges in lipid-altering drug development.. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00487994, NCT00143663, NCT00143676, NCT00864643, NCT00263081, NCT00286481, NCT00249899, NCT00249912, NCT00813527, NCT00256178, NCT00268697, and NCT00251680.

Topics: Adult; Aged; Anticholesteremic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Farnesyl-Diphosphate Farnesyltransferase; Female; Humans; Hypercholesterolemia; Liver Diseases; Male; Middle Aged; Oxazepines; Piperidines; Randomized Controlled Trials as Topic

Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease.. The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered.. Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function.. Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Endocannabinoids; Glycerides; Humans; Liver Diseases; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Remifentanil is a 4-anilidopiperidine mu-opioid analgesic which is rapidly metabolized by unspecific blood and tissue esterases. According to its unique pharmacokinetic profile, remifentanil-based anaesthesia combines high-dosage opioid analgesia intraoperatively with a rapid and predictable postoperative awakening. When compared with a standard fentanyl-based technique, the use of remifentanil has changed our present anaesthetic regimens. This includes the anaesthesia induction sequence, the choice and dosage of anaesthetics when used as adjuncts to remifentanil, and even more, the proper planning of postoperative pain management. The present paper was designed to review the current knowledge on remifentanil and all aspects of its use in anaesthesiology. In addition, present data on the use of remifentanil for analgesia and sedation of the critically ill patient are summarized.

Topics: Aging; Analgesics, Opioid; Anesthetics, Intravenous; Animals; Contraindications; Critical Care; Humans; Kidney Diseases; Liver Diseases; Pain, Postoperative; Piperidines; Remifentanil

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

Topics: Adult; Aged; Blood Glucose; Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Hypoglycemic Agents; Liver Diseases; Male; Piperidines; Renal Insufficiency; Rifampin

Rimegepant is a small-molecule calcitonin gene-related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75-mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open-label, single-dose, 4-group phase 1 study. Thirty-six subjects aged 41-71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0- and 3.9-fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration-time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment-emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment.

Topics: Adult; Area Under Curve; Humans; Liver Diseases; Piperidines

Cobimetinib is a kinase inhibitor indicated for use in combination with vemurafenib for treatment of unresectable/metastatic melanoma with specific BRAF mutations. Cobimetinib is extensively metabolized in liver; thus, patients with hepatic impairment (HI) might have increased cobimetinib exposure. In this study, we investigated the impact of HI on the pharmacokinetics (PK) and safety of cobimetinib. Subjects with normal hepatic function and mild to severe HI were enrolled. All subjects received a single oral dose of 10 mg cobimetinib, and serial blood samples were collected at specified times. Cobimetinib PK in subjects with mild and moderate HI was similar to that in those with normal liver function. However, subjects with severe HI, on average, showed ∼30% lower total AUC

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Azetidines; Female; Humans; Liver Diseases; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Severity of Illness Index

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; 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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

Atogepant is a selective oral calcitonin gene-related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single-dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open-label, parallel-group, single-dose phase 1 trial. Thirty-two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, ∼2 hours) with an apparent terminal elimination half-life of ∼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were -4%, -12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in participants with hepatic impairment compared with those with normal hepatic function, but these differences are not expected to be clinically relevant given the established safety profile of atogepant. Only 1 adverse event was reported: mild rhinorrhea in a participant with moderate hepatic impairment. Overall, atogepant was safe and not associated with any clinically relevant change in PK in participants with severe, moderate, or mild hepatic impairment.

Topics: Administration, Oral; Aged; Calcitonin Gene-Related Peptide Receptor Antagonists; Female; Half-Life; Humans; Liver Diseases; Male; Middle Aged; Piperidines; Pyridines; Pyrroles; Severity of Illness Index; Spiro Compounds

The pharmacokinetics and safety of single-dose zanubrutinib (80 mg) were assessed in subjects with mild, moderate, and severe hepatic impairment (

Topics: Area Under Curve; Humans; Liver Diseases; Piperidines; Pyrazoles; Pyrimidines

Imarikiren hydrochloride (TAK-272; SCO-272) is a novel direct renin inhibitor. The objective of this study was to determine the effects of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics and safety of imarikiren.. This phase I, open-label, parallel-group comparative study evaluated the pharmacokinetics and safety of a single 40 mg oral dose of imarikiren in RI [mild, moderate, severe, or end-stage renal disease (ESRD), and on hemodialysis] or HI (mild or moderate) subjects compared with subjects with normal renal or hepatic function.. Following administration of a single 40 mg oral imarikiren dose, the geometric mean imarikiren area under the plasma concentration-time curve from time zero to infinity (AUC. RI and HI are associated with limited changes in imarikiren pharmacokinetics. Imarikiren was safe and well-tolerated, regardless of the severity of RI or HI.. ClinicalTrials.gov Identifier: NCT02367872.

Topics: Adult; Aged; Area Under Curve; Benzimidazoles; Cardiovascular Agents; Enzyme Inhibitors; Female; Humans; Kidney; Kidney Failure, Chronic; Liver Diseases; Male; Middle Aged; Morpholines; Piperidines; Renal Dialysis

Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile.. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD).. Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT.. Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD.. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

Topics: Alanine Transaminase; Anti-Obesity Agents; Body Mass Index; Cannabinoid Receptor Antagonists; Case-Control Studies; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Insulin Resistance; Lactones; Liver Diseases; Metformin; Obesity; Orlistat; Pioglitazone; Piperidines; Polycystic Ovary Syndrome; Prognosis; Pyrazoles; Receptor, Cannabinoid, CB1; Retrospective Studies; Rimonabant; Thiazolidinediones; Weight Loss

This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUC

Topics: Adenine; Adult; Aged; Area Under Curve; Biomarkers; Drug Monitoring; Female; Humans; Incidence; Liver Diseases; Liver Function Tests; Male; Middle Aged; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Severity of Illness Index

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment.

Topics: Administration, Oral; Adult; Area Under Curve; Biotransformation; Cytochrome P-450 CYP2C19; Female; Florida; Genotype; Humans; Janus Kinase Inhibitors; Liver; Liver Diseases; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Piperidines; Pyrimidines; Pyrroles; Severity of Illness Index

Two studies were conducted in subjects with mild or moderate hepatic or renal impairment and subjects with normal organ function to evaluate the pharmacokinetics of casopitant and to assess its safety in these populations. A total of 26 subjects were enrolled in the hepatic impairment study and 18 subjects in the renal impairment study. All subjects received oral casopitant 100 mg once-daily for 5 days. Casopitant area under the concentration-time curve (AUC) increased 11% and 24% in subjects with mild or moderate hepatic impairment, respectively, on Day 1, compared with subjects with normal hepatic function; a similar increase was observed on Day 5. The AUC of the active major metabolite, GSK525060, was reduced 29% and 19% on Days 1 and 5, respectively, in subjects with moderate hepatic impairment, but not altered by mild hepatic impairment. Casopitant AUC increased 34% and 22% on Day 1 in subjects with mild or moderate renal impairment, respectively, and 28% and 11% on Day 5, respectively, compared with subjects with normal renal function. GSK525060 AUC was increased 17% and 24% on Days 1 and 5, respectively, in subjects with mild renal impairment; but did not significantly change in subjects with moderate renal impairment. Further age-adjusted analysis showed no meaningful effect of renal impairment on casopitant or GSK525060 AUC. Plasma protein binding of casopitant and GSK525060 was similar in all subjects. The pharmacokinetics of casopitant is not altered to a clinically significant extent in subjects with mild or moderate, hepatic or renal impairment. The impact of severe hepatic or renal impairment was not evaluated.

Topics: Administration, Oral; Adult; Analysis of Variance; Antiemetics; Area Under Curve; Biotransformation; Drug Administration Schedule; Female; Humans; Kidney Diseases; Least-Squares Analysis; Liver Diseases; Male; Middle Aged; Models, Biological; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Protein Binding; Severity of Illness Index; United States

To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine.. Open-label parallel-group study.. 24 patients with varying degrees of hepatic insufficiency, as categorised by the Child-Pugh classification, and 12 healthy volunteers.. Healthy subjects and patients with Child-Pugh class A (n = 8) or B (n = 8) received ebastine 20 mg once daily for 7 days. Patients with Child-Pugh class C (n = 8) [single or repeated dose] received ebastine 10 mg. Plasma concentrations of ebastine and carebastine were determined for 23.5 hours following the initial dose on day 1 and for 96 hours following the dose on day 7 by using a sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 microg/L for ebastine and 1.00 microg/L for carebastine. Hepatic function was assessed by blood clearance of indocyanine green 0.5 mg/kg administered intravenously on day 2. Cardiac and overall safety parameters were monitored.. Overall, the pharmacokinetics of ebastine were not modified by hepatic impairment. No correlation between ebastine pharmacokinetics and hepatic function, as expressed by indocyanine green clearance, was observed. Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences. Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients. Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters.. Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects. Nevertheless, the dosage used in severely impaired patients (10mg daily) was half that used in patients with mild to moderate impairment, and any comedication did not include drugs affecting liver function; in clinical practice, both these factors should be taken into account.

Topics: Adult; Area Under Curve; Butyrophenones; Case-Control Studies; Female; Half-Life; Histamine H1 Antagonists; Humans; Intestinal Absorption; Liver Diseases; Male; Metabolic Clearance Rate; Middle Aged; Piperidines

To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of donepezil HCl 5 mg following oral doses for 1 and 24 days in hepatically impaired patients compared with healthy controls under steady-state, multiple-dose conditions.. In this single-centre, multiple-dose, open-label study, patients with impaired hepatic function (Child-Pugh grade A or B) and healthy controls (matched by gender, age and weight to the hepatically impaired patients) received a single 5 mg dose of donepezil on day 1 and then donepezil HCl 5 mg once daily from days 6 to 29. PK and PD (determination of erythrocyte acetylcholinesterase inhibition) parameters were evaluated on days 1 and 29. Treatment-emergent adverse events (AEs), vital signs, physical examination and clinical laboratory test parameters were monitored throughout the study.. A total of 35 subjects (18 patients with hepatic impairment and 17 healthy controls) were enrolled and 32 subjects (16 in each group) completed the study. On day 1 (following a single dose) hepatically impaired patients showed a significant decrease in T(max), while t((1/2)) and AUC(0-infinity) were significantly increased compared with the healthy controls. On day 29 (following multiple doses), AUC(0-24 h), C(max), t((1/2)), C(SS), and R(A) were significantly increased in hepatically impaired patients compared with healthy controls. AUC(0-24 h) increased by 47.6% in the patients with hepatic impairment compared with the healthy controls. There were no significant differences in PD between the groups, although at steady state, the mean AChE inhibition was 16.2% higher in the hepatically impaired patients. No serious AEs were reported and no subject withdrew from the study due to AEs. The most common AEs in both groups were headache and diarrhoea. No clinically significant changes from baseline were observed in vital signs, physical examination findings or electrocardiograms. There was a significant difference in the number of hepatically impaired subjects with abnormalities in serum glucose compared with healthy subjects. However, these elevations were not associated with AEs.. The results of this study suggest that patients with AD and mild to moderate hepatic impairment (Child-Pugh grade A or B) can be safely given donepezil 5 mg once daily and that this dose is associated with a nonsignificantly higher AChE inhibition than age-matched volunteers.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Humans; Indans; Liver Diseases; Male; Middle Aged; Piperidines

The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction.. The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX capsules).. The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 +/- 11.5 h; 17.5 +/- 10.2 h (mean +/- s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 +/- 200 ng ml(-1) h vs 331 +/- 282 ng ml(-1) h). There was a significant correlation between the AUC(0,infinity) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers.. These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.

Topics: Adult; Antitussive Agents; Cytochrome P-450 CYP2D6; Dextromethorphan; Humans; Liver; Liver Diseases; Male; Middle Aged; Oxidation-Reduction; Piperidines; Thiazoles

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

Remifentanil, a new mu-opioid agonist with an extremely short duration of action, is metabolized by circulating and tissue esterases; therefore, its clearance should be relatively unaffected by changes in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmacodynamics of remifentanil.. Ten volunteers with chronic, stable, severe hepatic disease and awaiting liver transplantation and ten matched controls were enrolled. Each subject was given a 4-h infusion of remifentanil. The first five pairs received 0.0125 microgram x kg(-1) x min(-1) for 1 h followed by 0.025 microgram x kg(-1) x min(-1) for 3 h; the second five pairs received double these infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyses, and the ventilatory response to a hypercarbic challenge was assessed. Simultaneous pharmacokinetic and pharmacodynamic analyses were performed. The pharmacokinetics were described using a one-compartment intravenous infusion model, and ventilatory depression was modelled using the inhibitory E(max) model. The pharmacokinetics of the metabolite GR90291 were determined using noncompartmental methods.. There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups. The subjects with liver disease were more sensitive to the ventilatory depressant effects of remifentanil. The EC(50) values (the remifentanil concentrations determined from simultaneous pharmacokinetic/pharmacodynamic analyses to depress carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml (95% confidence interval 2.07-2.97 ng/ml) and 1.56 ng/ml (95% confidence interval 1.37-1.76 ng/ml), respectively.. The pharmacokinetics of remifentanil and GR90291 are unchanged in persons with severe, chronic liver disease. Such patients may be more sensitive to the ventilatory depressant effects of remifentanil, a finding of uncertain clinical significance, considering the extremely short duration of action of the drug.

Topics: Adult; Analgesics, Opioid; Female; Humans; Liver Diseases; Male; Middle Aged; Piperidines; Remifentanil

The tolerance and efficacy of ethyl (Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (piprozoline, Gö 919, Problin) were investigated in open and controlled clinical trials involving a total of 1545 patients and 1807 courses of therapy. The objective of this paper is to compare the experimental findings, some of which have already been published, with the results of the extensive clinical investigations. Despite the well-known problems associated with obtaining precise data on upper abdominal disorders, the evaluation of the available comprehensive clinical data has shown that probiline possesses definite therapeutic benefits confirming the experimental findings. Individual complaints such as bloating, upper abdominal pressure, meteorism and flatulence, nausea and vomiting, constipation, anorexia, and fat intolerance improved significantly under probiline therapy. Taking all the criteria into consideration, the overall results of the studies with probiline versus placebo in patients with gall-bladder diseases and intestinal disorders have proved that this choleretic substance is of therapeutic benefit. Serum bilirubin and alkaline phosphatase showed a significantly greater tendency to return to normal levels under probiline therapy than with placebo. The majority of conditions treated were of biliary origin. Aside from establishing the drug's therapeutic profile, the data published also show that the rate of side-effects was insignificant.

Topics: Adolescent; Adult; Aged; Biliary Tract Diseases; Cholagogues and Choleretics; Clinical Trials as Topic; Drug Evaluation; Female; Gastrointestinal Diseases; Hepatomegaly; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Piperidines; Thiazoles

Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Carbazoles; Fasting; Female; Humans; Liver Diseases; Male; Middle Aged; Models, Biological; Neoplasms; Nitriles; Panobinostat; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Renal Insufficiency

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

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. It is eliminated via multiple pathways including oxidative metabolism (∼70%) and renal excretion (29%). This study aimed to predict the impact of drug-drug interactions and renal or hepatic impairment on tofacitinib pharmacokinetics using a physiologically based pharmacokinetic (PBPK) model. The model was developed using Simcyp based on the physicochemical properties and in vitro and in vivo pharmacokinetics data for tofacitinib. The model was verified by comparing the predicted pharmacokinetic profiles with those observed in available clinical studies after single or multiple doses of tofacitinib, as well as with tofacitinib as a victim of drug-drug interactions (because of inhibition of cytochrome P450 [CYP450] 3A4, CYP450 2C19, or CYP450 induction). In general, good agreement was observed between Simcyp predictions and clinical data. The results from this study provide confidence in using the PBPK modeling and simulation approach to predict the pharmacokinetics of tofacitinib under intrinsic (eg, renal or hepatic impairment) or extrinsic (eg, inhibition of CYP450 enzymes and/or renal transporters) conditions. This approach may also be useful in predicting pharmacokinetics under untested or complex situations (eg, when a combination of intrinsic and extrinsic factors may impact pharmacokinetics) when conducting clinical studies may be difficult, in response to health authority questions regarding dosing in special populations, or for labeling discussions.

Topics: Administration, Oral; Adult; Computer Simulation; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; Humans; Infusions, Intravenous; Liver Diseases; Male; Middle Aged; Models, Biological; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Renal Insufficiency; Young Adult

Alectinib is approved and recommended as the preferred first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open-label study (NCT02621047) investigated a single 300-mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child-Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration-time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7-196) and 176% (90%CI 98.4-315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic-impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.

Topics: Adult; Area Under Curve; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Female; Half-Life; Humans; Liver; Liver Diseases; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

In absence of liver protective drugs, a large number of hepatopathies may arise during drug administration. This study was executed to investigate the possible new pathways underlying the hepatoprotective effect of Tempol (4-hydroxy-2,2,6,6- tetramethylpiperidine-1-oxyl), following oral administration of carbon tetrachloride in mice.. Thirty albino mice were randomized into 3 equal groups. The duration of study was 28 days. The groups were classified as follows: Group I (healthy control): received saline, in the same volume of CCl4 dose, daily, orally, for 14 days, then sacrificed. Group II: received CCl4, as a single oral dose only, of 1 ml/kg body weight, dissolved in olive oil (1:1 v/v), the animals of this group were sacrificed 14 days after CCl4 single dose intoxication. Group III (protective Tempol treated): received a single dose of Tempol, 20mg/kg, orally, daily for 14 days. Two hours after the last Tempol dose, animals of group III received a single oral dose of CCl4. Fourteen days later, animals were scarified to collect blood and liver tissues for analysis. Tempol pretreatment significantly captured elevated levels of ALT and AST activities, lipid peroxidation, total bilirubin and increased total thiol and catalase contents. Notably, it significantly reduced the expression of tumor necrosis factor-alpha (TNF-α), Caspase-3 and endoplasmic reticulum (ER) inositol-requiring enzyme 1(IRE1) mRNAs, which is an ER trans membrane sensor that activates the unfolded protein response (UPR) to maintain the ER and cellular function.. Pretreatment with Tempol has potential hepatoprotective effects against acute liver injury, induced by CCl4, through antioxidant and anti-inflammatory activities.

Topics: Acute Disease; Animals; Carbon Tetrachloride; Caspase 3; Catalase; Cyclic N-Oxides; Gene Expression Regulation; Glutathione; Liver; Liver Diseases; Male; Membrane Proteins; Mice; Piperidines; Protective Agents; Protein Serine-Threonine Kinases; RNA, Messenger; Signal Transduction; Spin Labels; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Rho kinase (ROCK) inhibition has been reported to improve various inflammatory diseases including endotoxemia. Mitochondrial dysfunction might be the key to the pathophysiology of sepsis-induced organ failure. Therefore, this study aimed to explore whether ROCK inhibition protects against the liver injury by regulating mitochondrial function in endotoxemia model mice. The mice were randomly divided into four groups (N=6-8 per group): control, LPS, LPS+Y-27632 (LPS+Y), and LPS+Mito-TEMPO (LPS+M). For induction of endotoxin-induced acute liver injury, the mice were intraperitoneally administered lipopolysaccharide (LPS, 20mg/kg). The ROCK inhibitor Y-27632 (or mitochondrial antioxidant Mito-TEMPO) was intraperitoneally administered at 18 and 1h before injection of LPS. The mice were euthanized 8h after LPS administration. The liver and blood samples were taken and preserved for analysis. Results of this study showed that pretreatment with Y-27632 or Mito-TEMPO significantly attenuated the liver injury as compared to the LPS group. This was confirmed by decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and by reduced hepatocellular apoptosis and histologic damage. Pretreatment with Y-27632 or Mito-TEMPO markedly reduced the LPS-induced inflammatory response and oxidative stress the in liver. Furthermore, it showed similar protective effects on the hepatic mitochondrial function, including an increased activity of complexes I and IV and mitochondrial superoxide dismutase (MnSOD), and an upregulated expression of mtDNA-encoded genes. Taken together, these data demonstrate that Mito-TEMPO can potently inhibit the endotoxin-induced mitochondrial and hepatic abnormalities and indicate that mitochondrial dysfunction might play a key role in the endotoxemia-induced acute liver injury. Moreover, our study shows that ROCK inhibition protects against the endotoxemia-induced liver injury by improving the mitochondrial function.

Topics: Alanine Transaminase; Amides; Animals; Antioxidants; Apoptosis; Aspartate Aminotransferases; Cyclooxygenase 2; DNA-Binding Proteins; Endotoxemia; Female; Hepatocytes; High Mobility Group Proteins; Lipopolysaccharides; Liver; Liver Diseases; Male; Malondialdehyde; Mice, Inbred C57BL; Mitochondria; Organophosphorus Compounds; Peroxidase; Piperidines; Protein Kinase Inhibitors; Pyridines; rho-Associated Kinases; Superoxide Dismutase

Remifentanil has a rapid onset and short duration of action, predictable pharmacokinetic/pharmacodynamic profile, and unlike fentanyl, does not accumulate with repeated or prolonged administration. This study evaluated predictors of remifentanil use in surgical patients with renal or hepatic impairment, or obesity in the United States who received remifentanil, fentanyl, or the combination.. Data (2010) from the US Healthcare National Inpatient Database, State Inpatient Database, State Ambulatory Surgery Database, and private hospital and Medicaid databases were used in this analysis. Patients included had presence of hepatic or renal disease, and/or obesity and were >5 and ≤80 years of age.. In 2010, 9,274 patients with renal impairment, 1,896 with hepatic impairment, and 6,278 with obesity were identified. The percentage of surgical patients diagnosed with renal disease, hepatic disease, or obesity who received remifentanil was 41, 28, and 35%, respectively; 29, 17, and 22% received both remifentanil and fentanyl, and 30, 55, and 43% received fentanyl alone, respectively. In patients with renal or hepatic disease the probability of remifentanil use was greater for persons aged >50 years, with Medicare as primary payer, or who were diagnosed with obesity (p < 0.05 all comparisons). In obese patients, the probability of remifentanil use was greater for persons aged >50 years or female (both p < 0.05). For all 3 disease states, the probability of remifentanil use was lower for those receiving epidural anesthesia or with Medicaid as primary payer (p < 0.05 all comparisons).. Remifentanil in combination with fentanyl is used less than fentanyl in surgical patients with hepatic impairment or obesity. This is inconsistent with the fact that the pharmacokinetic/pharmacodynamic features of remifentanil suggest it is the preferred intraoperative opioid in these patients. Predictors of remifentanil use in patients with renal or hepatic impairment, or obesity include older age, obesity, and Medicare as primary payer. Remifentanil in combination with fentanyl was significantly less utilized than fentanyl in persons with Medicaid as primary payer even though there was a disproportionate enrollment of beneficiaries with renal or hepatic disease, or obesity in state Medicaid programs.

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Drug Therapy, Combination; Female; Fentanyl; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Obesity; Pain, Postoperative; Piperidines; Predictive Value of Tests; Remifentanil; Retrospective Studies; United States

Ronald de Vries graduated in Organic and Analytical Chemistry at the Free University of Amsterdam, The Netherlands. After working in a Contract Laboratory (CRO) for 7 years, he joined Janssen R&D in 1998. At Janssen R&D, Belgium, Ronald worked in the bioanalytical department that supports both clinical and nonclinical bioanalysis. In this department he had several roles, such as providing the bioanalytical support for various drug development programs and leading the method establishment group. He has done numerous global assay transfers to/from Janssen from/to other laboratories and plays an important role in the introduction and application of new technologies and applied innovation in the department. In 2014 he started in the drug metabolism and pharmacokinetics department of Janssen R&D, where his main tasks are in vivo and in vitro metabolite identification using high resolution MS and Radiodetection.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Bile Acids and Salts; Blood Chemical Analysis; Calibration; Chromatography, High Pressure Liquid; Humans; Liver Diseases; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Quality Control; Tandem Mass Spectrometry; Taurocholic Acid

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

The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults.. We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll(-/-) mice, fatty acid amide hydrolase(-/-) mice, and in cannabinoid receptor type 1(-/-) (CB1-/-) and cannabinoid receptor type 2(-/-) (CB2-/-). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses.. Wild-type mice given JZL184 and Mgll(-/-) mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB2 and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl4.. MAGL modulates hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat conditions that expose the liver to oxidative stress and inflammatory damage.

Topics: Animals; Benzodioxoles; Disease Models, Animal; Eicosanoids; Endocannabinoids; Immunohistochemistry; Inflammation Mediators; Liver Diseases; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Oxidative Stress; Piperidines; Random Allocation; Reactive Oxygen Species; Reference Values; Signal Transduction

Opioid preconditioning against ischemia reperfusion injury has been well studied in myocardial and neuronal tissues. The objective of this study was to determine whether remifentanil could attenuate hepatic injury and to investigate the mechanisms.. A rat model of hepatic ischemia reperfusion injury and a hepatocyte hypoxia reoxygenation (HR) injury model were used, respectively, in two series of experiments. Remifentanil was administered before ischemia or hypoxia and the experiments were repeated with previous administration of naloxone, L-arginine and N-ω-nitro-L-arginine methyl ester, a nonselective opioid receptor antagonist, a nitric oxide donor, and nitric oxide synthase (NOS) inhibitor, respectively. Serum aminotransferase, cytokines, and hepatic lipid peroxidation were measured. Histopathology examination and apoptotic cell detection were assessed. For the in vitro study, cell viability, intracellular nitric oxide, apoptosis, and NOS expression were evaluated.. Remifentanil and L-arginine pretreatment reduced concentrations of serum aminotransferases and cytokines, decreased the concentrations of hepatic malondialdehyde and myeloperoxidase activity, and increased superoxide dismutase, nitric oxide, and inducible NOS expression in vivo. Decreased histologic damage and apoptosis were also seen in these two groups. These changes were prevented by previous administration of N-ω-nitro-L-arginine methyl ester but not naloxone. There was an increase in inducible NOS protein expression but not endogenous NOS in remifentanil and L-arginine pretreated groups compared with control, naloxone, and N-ω-nitro-L-arginine methyl ester groups.. Pretreatment with remifentanil can attenuate liver injury both in vivo and in vitro. Inducible NOS but not opioid receptors partly mediate this effect by exhausting reactive oxygen species and attenuating the inflammatory response.

Topics: Analgesics, Opioid; Animals; Arginine; Blotting, Western; Cell Survival; Cytokines; Disease Models, Animal; Ischemic Preconditioning; Lipid Peroxidation; Liver; Liver Diseases; Male; Naloxone; Narcotic Antagonists; Nitric Oxide Synthase; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Reperfusion Injury; Transaminases

Small-for-size grafts are prone to mechanical injury and a series of chemical injuries that are related to hemodynamic force. Hepatic stellate cells activate and trans-differentiate into contractile myofibroblast-like cells during liver injury. However, the role of hepatic stellate cells on sinusoidal microcirculation is unknown with small-for-size grafts.. Thirty-five percent of small-for-size liver transplantation was performed with rats as donors and recipients. Endothelin-1 levels as well as hepatic stellate cells activation-related protein expression, endothelin-1 receptors, and ultrastructural changes were examined. The cellular localizations of two types of endothelin-1 receptors were detected. Furthermore, liver function and sinusoidal microcirculation were analyzed using two different selective antagonists of endothelin-1 receptor.. Intragraft expression of hepatic stellate cells activation-related protein such as desmin, crystallin-B and smooth muscle α-actin was upregulated as well as serum endothelin-1 levels and intragraft expression of the two endothelin receptors. The antagonist to endothelin-1 A receptor not to the endothelin-1 B receptor could attenuate microcirculatory disturbance and improve liver function.. Small-for-size liver transplantation displayed increased hepatic stellate cells activation and high level of endothelin-1 binding to upregulation of endothelin-1 A receptor on hepatic stellate cells, which contracted hepatic sinusoid inducing graft injury manifested as reduction of sinusoidal perfusion rate and elevation of sinusoidal blood flow.

Topics: Actins; Animals; Blotting, Western; Crystallins; Desmin; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Gene Expression Regulation; Hepatic Stellate Cells; Liver; Liver Circulation; Liver Diseases; Liver Transplantation; Male; Microcirculation; Oligopeptides; Organ Size; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred Lew; Receptor, Endothelin A; Receptor, Endothelin B; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

Vandetanib, an oncology drug being evaluated in phase III clinical trials, undergoes significant renal and hepatic excretion. The objective of these two studies was to investigate the single-dose pharmacokinetics of vandetanib in subjects with renal or hepatic impairment in comparison with healthy subjects.. Two open-label, parallel-group studies were conducted at a single centre in Germany. Subjects aged 18-75 years with a body mass index of 18-32 kg/m2 were eligible. The renal impairment study recruited subjects with normal renal function and mild, moderate and severe renal impairment according to creatinine clearance calculated from a 24-hour urine collection pre-dose. The hepatic impairment study recruited subjects with normal hepatic function and mild, moderate and severe hepatic impairment according to the Child-Pugh classification. All subjects received a single 800 mg oral vandetanib dose. Blood samples for measurement of vandetanib, N-desmethylvandetanib and vandetanib N-oxide were collected before and at various timepoints after vandetanib administration for up to 63 days. Pharmacokinetic parameters were determined using noncompartmental methods.. Thirty-two subjects were recruited for the renal impairment study (ten with normal renal function and six, ten and six with mild, moderate and severe impairment, respectively). Thirty subjects were recruited for the hepatic impairment study (eight with normal hepatic function and eight, eight and six with mild, moderate and severe impairment, respectively). The area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) values of free vandetanib increased by approximately 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. These increases were statistically significant, with the increase in the severe renal impairment group having the possibility of being double the value observed in subjects with normal renal function (geometric least squares [GLS] mean ratio [renal impairment : normal renal function] of 1.79; 90% CI 1.39, 2.31). Peak plasma concentrations of free vandetanib increased slightly by approximately 7%, 9% and 11% in subjects with mild, moderate and severe renal impairment, respectively. Total plasma clearance of free vandetanib decreased with all degrees of renal dysfunction. Hepatic impairment did not have a statistically significant effect on the AUC(infinity) of total vandetanib. Peak plasma concentrations of total vandetanib were reduced in subjects with all classifications of hepatic impairment compared with normal hepatic function, with a statistically significant effect in the severe hepatic impairment group (GLS mean ratio 0.71; 90% CI 0.53, 0.96). Increased exposure to both metabolites was seen in subjects with renal impairment. Exposure to N-desmethylvandetanib was reduced in subjects with hepatic impairment, while exposure to vandetanib N-oxide was increased in subjects with severe hepatic impairment. Vandetanib was well tolerated and had a similar tolerability profile in subjects with renal or hepatic impairment compared with healthy subjects.. Exposure to vandetanib was increased by about 46%, 62% and 79% in subjects with mild, moderate and severe renal impairment, respectively. A doubling in exposure could be ruled out in subjects with mild or moderate renal impairment but not for those with severe renal impairment. The possibility of dose reductions in patients with severe renal impairment will need to be assessed when the safety and tolerability profile is fully defined. Exposure to vandetanib was not altered in subjects with hepatic impairment, and no dose adjustment would be expected in patients with hepatic impairment.

Topics: Adult; Aged; Angiogenesis Inhibitors; Area Under Curve; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Piperidines; Quinazolines

The methanolic extract from the fruit of Piper chaba (Piperaceae) was found to have a hepatoprotective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. From the ethyl acetate-soluble fraction, a new amide constituent named piperchabamide E together with twenty known amide constituents (e.g., piperine, piperchabamides A-D, and piperanine) and two aromatic constituents were isolated as the hepatoprotective constituents. With regard to structure-activity relationships, the amide moiety and the 1,9-decadiene structure between the benzene ring and amide moiety were suggested to be important for strong inhibition of D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes. Furthermore, a principal amide constituent, piperine, dose-dependently inhibited increase in serum GPT and GOT levels at doses of 2.5-10 mg/kg (p.o.) in D-GalN/LPS-treated mice, and this inhibitory effect was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

Topics: Alanine Transaminase; Alkaloids; Amides; Animals; Aspartate Aminotransferases; Benzodioxoles; Cell Death; Chromatography, High Pressure Liquid; Fruit; Galactosamine; Hepatocytes; Lipopolysaccharides; Liver; Liver Diseases; Male; Mice; Mice, Mutant Strains; Molecular Structure; Piperaceae; Piperidines; Plant Extracts; Polyunsaturated Alkamides; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

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

We report a patient who presented with multiple small submucosal nodules with granulomatous inflammation in the minor salivary glands of the oral cavity. A 43-year-old woman presented with a 1-week history of multiple small submucosal nodules in her oral cavity after having taken medicine for abdominal pain. The patient did not have a history of fever, rectal bleeding, skin lesions or arthritis, but did have a history of drug allergy and bronchial asthma. Histopathological examination of the submucosal nodules showed sialadenitis with marked infiltration of lymphocytes, eosinophilic cells, macrophages and Langhans-type or foreign-body-type multinucleate giant cells. The macrophages tended to be aggregated and appeared to have caused immature granuloma formation without caseous necrosis. Degranulated eosinophilic cells were numerous. Sarcoidosis, Crohn's disease, tuberculosis and atypical mycobacterial infection were not identified by medical examination. Three weeks after discontinuing the medication the patient was seen again at a follow-up visit. Multiple submucosal small nodules and other symptoms were not evident at that time. This case report may represent a new entity of salivary gland disease that we tentatively refer to as 'allergic granulomatous sialadenitis'.

Topics: Abdominal Pain; Adult; Anti-Ulcer Agents; Diagnosis, Differential; Enzymes; Female; Granuloma; Humans; Hypersensitivity; Inflammation; Liver Diseases; Piperidines; Ranitidine; Salivary Glands, Minor; Sialadenitis

Previously, we have shown that primary afferent sensory neurons are necessary for disease activity in T cell-mediated immune hepatitis in mice. In the present study, we analyzed the possible role of substance P (SP), an important proinflammatory neuropeptide of these nerve fibers, in an in vivo mouse model of liver inflammation. Liver injury was induced by bacterial lipopolysaccharide (LPS) in D-galactosamine (GalN)-sensitized mice. Depletion of primary afferent nerve fibers by neonatal capsaicin treatment down-regulated circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) and protected mice from GalN/LPS-induced liver injury. Likewise, pretreatment of mice with antagonists of the SP-specific neurokinin-1 receptor (NK-1R), i.e., (2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)-methyl)-1-azabicyclo(2.2.2.)-octan-3-amine (CP-96,345) and (2S,3S)3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine (L-733,060), dose dependently protected mice from GalN/LPS-induced liver injury. The presence of the NK-1R in the murine liver was demonstrated by reverse transcription-polymerase chain reaction, sequence analysis, and immunocytochemistry. NK-1R blockade reduced inflammatory liver damage, i.e., edema formation, neutrophil infiltration, hepatocyte apoptosis, and necrosis. To get further insight into the mechanism by which receptor blockade attenuated GalN/LPS-induced liver damage, we analyzed plasma levels and intrahepatic expression of TNFalpha, IFNgamma, interleukin (IL)-6, and IL-10. NK-1R blockade clearly inhibited GalN/LPS-induced production of TNFalpha and IFNgamma, whereas synthesis of the hepatoprotective cytokines IL-6 and IL-10 was increased. NK-1 receptor antagonists might be potent drugs for treatment of inflammatory liver disease, most likely by inhibiting SP effects.

Topics: Animals; Base Sequence; Biphenyl Compounds; Capsaicin; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Gene Expression; Lipopolysaccharides; Liver Diseases; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Piperidines; RNA, Messenger; Sequence Homology, Nucleic Acid; Time Factors; Transcriptional Activation

Topics: Analgesics, Opioid; Case-Control Studies; Humans; Kidney Failure, Chronic; Liver Diseases; Piperidines; Remifentanil

The plasma protein binding of the new antipsychotic risperidone and of its active metabolite 9-hydroxy-risperidone was studied in vitro by equilibrium dialysis. Risperidone was 90.0% bound in human plasma, 88.2% in rat plasma and 91.7% in dog plasma. The protein binding of 9-hydroxy-risperidone was lower and averaged 77.4% in human plasma, 74.7% in rat plasma and 79.7% in dog plasma. In human plasma, the protein binding of risperidone was independent of the drug concentration up to 200 ng/ml. The binding of risperidone increased at higher pH values. Risperidone was bound to both albumin and alpha 1-acid glycoprotein. The plasma protein binding of risperidone and 9-hydroxy-risperidone in the elderly was not significantly different from that in young subjects. Plasma protein binding differences between patients with hepatic or renal impairment and healthy subjects were either not significant or rather small. The blood to plasma concentration ratio of risperidone averaged 0.67 in man, 0.51 in dogs and 0.78 in rats. Displacement interactions of risperidone and 9-hydroxy-risperidone with other drugs were minimal.

Topics: Adult; Aged; Animals; Antipsychotic Agents; Blood Cells; Blood Proteins; Dogs; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Isoxazoles; Kidney Diseases; Liver Diseases; Male; Middle Aged; Orosomucoid; Paliperidone Palmitate; Piperidines; Protein Binding; Pyrimidines; Rats; Rats, Wistar; Risperidone; Serum Albumin

This paper reports a case of fatal perhexiline maleate liver injury. A 62-year-old man had received perhexiline maleate for 18 months before death. Hepatic failure developed after a routine surgical procedure. The clinical course and histological findings are presented.

Topics: Angina Pectoris; Chemical and Drug Induced Liver Injury; Humans; Liver; Liver Cirrhosis, Alcoholic; Liver Diseases; Male; Middle Aged; Osteoarthritis; Perhexiline; Piperidines; Postoperative Complications; Transaminases

Topics: Angina Pectoris; Body Weight; Humans; Liver Diseases; Neuromuscular Diseases; Perhexiline; Piperidines

Perhexiline maleate is an anti-anginal drug believed to cause liver damage. The possibility that this effect could be potentiated by alcohol has been investigated. Rats fed both the drug and alcohol did not show more severe liver damage than those fed alcohol alone. Livers from rats fed perhexiline alone did not differ from controls. There is no evidence from this study that alcohol potentiates the effect of perhexiline in rat liver. These results may have a bearing in perhexiline-induced liver damage in humans, but clinical studies are required.

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Synergism; Ethanol; Liver; Liver Diseases; Male; Microscopy, Electron; Perhexiline; Piperidines; Rats

Two middle-aged men, who had received perhexiline in recommended dosage, showed clinical and histological evidence of severe hepatic damage, and one of them died. Histological study of the livers showed a striking resemblance to alcoholic hepatitis.

Topics: Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Hepatitis, Alcoholic; Humans; Liver; Liver Diseases; Male; Middle Aged; Perhexiline; Piperidines

Topics: Acetals; Alcohols; Alkanes; Amines; Animals; Biological Assay; Diet; Ketones; Liver Diseases; Morpholines; Necrosis; Piperidines; Rats; Selenium; Structure-Activity Relationship

Topics: Adolescent; Adult; Analgesics; Anesthesia; Child; Haloperidol; Humans; Liver Diseases; Middle Aged; Nitrous Oxide; Piperidines

Topics: Acetylcholine; Adolescent; Adult; Aged; Androstanes; Anesthesia, General; Asthma; Bromides; Bronchi; Bronchitis; Child; Child, Preschool; Cholinesterases; Female; Humans; Liver Diseases; Male; Middle Aged; Neuromuscular Nondepolarizing Agents; Piperidines; Spirometry

Topics: Aged; Amides; Ammonia; Aspartic Acid; Chlorothiazide; Clopamide; Depression, Chemical; Diuretics; Female; Furosemide; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Liver Diseases; Magnesium; Male; Middle Aged; Piperidines; Potassium; Pulmonary Heart Disease; Stimulation, Chemical

Topics: Amides; Diuretics; Edema; Heart Failure; Humans; Kidney Diseases; Liver Diseases; Nutrition Disorders; Peritonitis, Tuberculous; Piperidines

Topics: Adult; Aged; Bile; Biliary Dyskinesia; Cholelithiasis; Female; Humans; Liver Diseases; Male; Middle Aged; Migraine Disorders; Piperidines