piperidines and Drug-Related-Side-Effects-and-Adverse-Reactions

This study aimed at providing pooled estimates of the incidence of adverse drug reactions (ADRs) of ubrogepant and rimegepant and to use meta-regression to identify correlations between the occurrence of selected ADRs, socio-demographic, and clinical characteristics from data published in clinical studies.. Ovid MEDLINE (up to 03/02/2022) was searched along with the references listed in the reviews identified with the research query. Random intercept and slope logistic regression models were used to estimate the logit transformation of the pooled incidence. To examine how selected clinical and socio-demographic characteristics correlated with the pooled incidence rates, we performed random-effects meta-regression.. Significant heterogeneity of incidence estimates was observed in clinical studies along with correlations between ADRs and the sociodemographic and clinical characteristics of patients exposed to ubrogepant. In particular, we observed a correlation between ubrogepant dosage and muscle strain and between Body Mass Index (BMI) and liver function values. For rimegepant, significant correlations were observed between age and infections and having aura symptoms at baseline and nausea/dizziness/diarrhea/muscle strain.. This study provided pooled incidence estimates of ubrogepant and rimegepant's ADRs and highlighted new safety aspects of the pharmacological treatment with ubrogepants and rimigepants from correlations obtained from the meta-regression.

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Piperidines; Pyridines; Pyrroles

Several observational studies on Tofacitinib (TOFA) in ulcerative colitis (UC) have been published over the last 2 years.. To estimate effectiveness and safety of TOFA arising from real-world experience.. PubMed Central/Medline and Embase were systematically searched for real-world observational studies on TOFA for the treatment of UC through November 2020.. Seven studies comprising 759 patients met the inclusion criteria. The pooled estimate rates were 49% for clinical response, 40% for clinical remission, and 34% for corticosteroid-free clinical remission at induction, while the rates of endoscopic response and endoscopic remission were 37% and 19%, respectively. At maintenance, the pooled estimate rates of clinical response, clinical remission, and corticosteroid-free clinical remission were 36%, 35%, and 24%, respectively. The pooled estimate of incidence rate of adverse events was 53.0 per 100 person-years (PY), while the pooled estimate of incidence rate of withdrawal of TOFA due to adverse events was 9.3 per 100 PY, with a pooled rate of infections of 17.6 per 100 PY.. Cumulative analysis of data from real-world studies confirmed the good efficacy of TOFA in UC shown by randomized controlled trials for both induction and maintenance, while the safety profile was consistent with previous reports.

Topics: Adult; Colitis, Ulcerative; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Induction Chemotherapy; Janus Kinase Inhibitors; Maintenance Chemotherapy; Male; Middle Aged; Observational Studies as Topic; Piperidines; Pyrimidines; Treatment Outcome

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

Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy.. The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism.. Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.

Topics: Adenine; Aged; COVID-19; Disease Management; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors

Tofacitinib is an oral, small molecule JAK inhibitor that targets JAK1/JAK3. Tofacitinib has been approved by the FDA to be used in the treatments of rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and ulcerative colitis. Considering the important pathogenic role of the JAK/STAT pathway in autoimmune disease, tofacitinib could be, theoretically, effective in the treatments of other systemic rheumatic diseases. Here we reviewed the published literature to profile the perspectives about the off-label uses of tofacitinib, especially in those refractory cases with poor response to conventional therapies or biologic agents. Tofacitinib can be a new therapeutic option and help reducing hormone dependence and correlated adverse events.

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Janus Kinase 1; Janus Kinase 3; Off-Label Use; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Rheumatic Diseases

Ibrutinib is a first-in-class, highly potent Bruton tyrosine kinase inhibitor which has become standard of care for patients with chronic lymphocytic leukaemia and other lymphoproliferative disorders. It requires indefinite administration which places emphasis on toxicity and long-term tolerance.. Extensive use of ibrutinib in studies and clinical practice has better defined its full toxicity profile which has made its use more challenging than initially foreseen. In particular, dysrhythmias, bleeding, infections and constitutional symptoms have been reported and can result in dose reduction or discontinuation of ibrutinib. Herein, we review the common as well as rare but important toxicities and discuss approach and management on a practical level. We also highlight that patients should be regularly monitored for adverse events and proactively treated to minimise side effects and avoid disruption.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Piperidines; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Treatment Outcome

Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection.

Topics: Antiviral Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coinfection; Drug-Related Side Effects and Adverse Reactions; Hepatitis B, Chronic; Hepatitis D; Hepatitis Delta Virus; Humans; Interferon-alpha; Lipopeptides; Nucleic Acids; Piperidines; Polymers; Pyridines; Recurrence; Treatment Outcome

Bruton tyrosine kinase signaling (BTK) is critical step for B-cell development and immunoglobulin synthesis. Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib has been approved by FDA for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allogeneic stem cell transplantation. Ibrutinib is generally well tolerated drug with rapid and durable responses but has some side events. The most common side effects are diarrhea, upper respiratory tract infection, bleeding, fatigue and cardiac side effects. These events are generally mild (grade I-II). However atrial fibrillation (AF) and bleeding are important and may be grade III or higher side effects require strict monitoring. Here side effects of ibrutinib have been summarized and important considerations in the management of these adverse events have been reviewed.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Incidence; Leukemia; Lymphoma; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

New generations of small molecules are being developed for the treatment of ulcerative colitis. Among them, tofatinib (a Janus kinase (JAK) inhibitor) has demonstrated efficacy for inducing and maintaining remission and achieving mucosal healing with a reasonable safety profile. Oral administration is attractive for patients and lack of immunogenicity represents an advantage over biologic drugs. Areas covered: This review discusses the molecular aspects of the JAK-STAT pathway; the mechanism of action of tofacitinib pertinent to ulcerative colitis and the evidence on the efficacy of tofacitinib for achieving clinically relevant outcomes, including clinical remission, mucosal healing, and normalization of quality of life, as well as safety aspects with special attention to adverse events related to the mode of action of the drug. Expert commentary: Tofacitinib will be the first drug on the class of JAK inhibitors to be available for treatment of ulcerative colitis. The efficacy of the drug, with a rapid onset of action even in cases of severe colitis, oral administration, and possibility to use the drug intermittently without generating immunogenicity, will bring about a redesign of current treatment paradigms for ulcerative colitis.

Topics: Animals; Colitis, Ulcerative; Drug-Related Side Effects and Adverse Reactions; Expert Testimony; Humans; Janus Kinases; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Signal Transduction; STAT Transcription Factors; Treatment Outcome

Migraine is among the most disabling disorders worldwide, with a significant therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties. Further limitations include side effects, inconsistency in therapeutic action and possible non-response. Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid of vasoconstriction. Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan as a possible acute migraine treatment. We analyze all currently available results in Phase I to III studies. Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular for patients at cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate severity. The results of long-term Phase III studies will determine if these adverse events represent a limitation in clinical practice.

Topics: Benzamides; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk Factors; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Disease Management; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Severity of Illness Index

Vandetanib has recently demonstrated clinically meaningful benefits in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). Given the potential for long-term vandetanib therapy in this setting, in addition to treatment for disease-related symptoms, effective management of related adverse events (AEs) is vital to ensure patient compliance and maximize clinical benefit with vandetanib therapy.. This expert meeting-based review aims to summarize published data on AEs associated with vandetanib therapy and to provide clinicians with specific practical guidance on education, monitoring, and management of toxicities induced in patients treated with vandetanib in advanced and metastatic MTC. The content of this review is based on the expert discussions from a multidisciplinary meeting held in October 2012.. Characteristics, frequency, and risk data are outlined for a number of dermatological, cardiovascular, gastrointestinal, and general AEs related to vandetanib treatment. Preventive strategies, practical treatment suggestions, and points for clinical consideration are provided.. Good patient and team communication is necessary for the prevention, early detection, and management of AEs of vandetanib. Physicians, nurses, and other healthcare providers play a critical role in providing AE management and patient support to optimize outcomes with vandetanib in MTC.

Topics: Carcinoma, Neuroendocrine; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Piperidines; Prognosis; Quinazolines; Risk Assessment; Thyroid Neoplasms; Treatment Outcome

In India, Ayurveda has made a major contribution to the drug discovery process with new means of identifying active compounds. Recent advancement in bioavailability enhancement of drugs by compounds of herbal origin has produced a revolutionary shift in the way of therapeutics. Thus, bibliographic investigation was carried out by analyzing classical text books and peer-reviewed papers, consulting worldwide-accepted scientific databases from last 30 years. Herbal bioenhancers have been shown to enhance bioavailability and bioefficacy of different classes of drugs, such as antibiotics, antituberculosis, antiviral, antifungal, and anticancerous drugs at low doses. They have also improved oral absorption of nutraceuticals like vitamins, minerals, amino acids, and certain herbal compounds. Their mechanism of action is mainly through absorption process, drug metabolism, and action on drug target. This paper clearly indicates that scientific researchers and pharmaceutical industries have to give emphasis on experimental studies to find out novel active principles from such a vast array of unexploited plants having a role as a bioavailability and bioefficacy enhancer. Also, the mechanisms of action by which bioenhancer compounds exert bioenhancing effects remain to be explored.

Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Benzodioxoles; Biological Availability; Curcumin; Databases, Factual; Dietary Supplements; Drug Compounding; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Herb-Drug Interactions; Humans; Phenytoin; Piperidines; Plant Preparations; Plants, Medicinal; Polyunsaturated Alkamides

Timely and important studies are reviewed and commentaries provided by leading palliative care clinicians. Symptoms, interventions, and treatment-related adverse events addressed in this issue are management of Alzheimer's agitation with donepezil; needle-free lidocaine powder for minor painful procedures; psychostimulants in depression; anticoagulation for cancer-related venous thromboembolism; effect of waiting for acute pain treatment on risk of chronic pain; and an update on severe cutaneous reactions associated with medications.

Topics: Alzheimer Disease; Amphetamines; Anesthetics, Local; Anticoagulants; Antidepressive Agents; Depression; Donepezil; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Indans; Lidocaine; Nootropic Agents; Pain; Palliative Care; Phlebotomy; Piperidines; Prescription Drugs; Psychomotor Agitation; Randomized Controlled Trials as Topic; Sertraline; Stevens-Johnson Syndrome; Thromboembolism

Topics: Animals; Antidepressive Agents, Second-Generation; Cognition Disorders; Dopamine D2 Receptor Antagonists; Double-Blind Method; Drug Discovery; Drug-Related Side Effects and Adverse Reactions; Humans; Piperazines; Piperidines; Randomized Controlled Trials as Topic; Schizophrenia; Serotonin 5-HT2 Receptor Antagonists; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to a combination of insulin resistance and impaired insulin secretion. The hyperglycemia is associated with an increased risk for micro- and macrovascular complications, and lowering fasting and postprandial hyperglycemia may be protective against these complications. Repaglinide is an insulin secretagogue that lowers blood glucose levels in patients with T2DM. We review the effects of repaglinide in patients with T2DM, its impact on glycemia and its non-glycemic effects, and its effects when used in special situations or patient populations. Results from randomized controlled trials, observational studies, and safety reports involving humans and published in the English-language through 1 May 2007 identified by a search in PubMed/MEDLINE were evaluated. Present knowledge indicates that repaglinide reduces fasting and postprandial hyperglycemia and the level of glycosylated hemoglobin (HbA1c) in patients with T2DM. It is at least as effective in reducing HbA1c and fasting plasma glucose as sulphonylureas, metformin, or the glitazones and in combination therapy with other drugs, repaglinide is as effective as any other combination. Some studies show a better effect of repaglinide on postprandial glycemia than the comparators. Its propensity to induce hypoglycemia is similar to or a little less than that of sulphonylureas. Repaglinide is associated with less weight gain than sulphonylureas and the glitazones. Repaglinide has primarily a role in the treatment of T2DM when metformin cannot be used due to adverse effects, when metformin fails to adequately control blood glucose levels, when there is a need for flexible dosing (i.e. the elderly or during Ramadan fasting), or when there is a specific wish to lower postprandial glucose. Repaglinide may also have an advantage when an oral agent is needed in diabetic patients with renal impairment. Because of its short duration of action, repaglinide should be taken before each meal, usually at least three times a day. Although no study has investigated whether repaglinide lowers total mortality or cardiovascular endpoints, several studies indicate beneficial effects on cardiovascular surrogate endpoints, such as carotid intima-media thickening, markers of inflammation, platelet activation, lipid parameters, endothelial function, adiponectin, and oxidative stress. In conclusion, repaglinide is a compound that can be used in both mono- and combina

Topics: Carbamates; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemic Agents; Piperidines

Topics: Animals; Anti-Arrhythmia Agents; Biological Transport; Carbohydrate Metabolism; Cations; Chemical Phenomena; Chemistry, Physical; Drug-Related Side Effects and Adverse Reactions; Organelles; Pharmaceutical Preparations; Phospholipids; Piperidines

Topics: Anemia, Pernicious; Anorexia Nervosa; Cisapride; Connective Tissue Diseases; Diabetes Complications; Domperidone; Drug-Related Side Effects and Adverse Reactions; Gastric Emptying; Gastroesophageal Reflux; Gastrointestinal Motility; Humans; Intestinal Pseudo-Obstruction; Metoclopramide; Piperidines; Postgastrectomy Syndromes; Stomach Diseases

Topics: Adolescent; Adult; Aged; Basal Ganglia Diseases; Benzamides; Butyrophenones; Child; Drug-Related Side Effects and Adverse Reactions; Dystonia; Extrapyramidal Tracts; Female; Humans; Male; Middle Aged; Muscle Hypertonia; Muscle Rigidity; Parkinson Disease, Secondary; Phenothiazines; Piperazines; Piperidines; Reserpine; Thioxanthenes

Topics: Adrenergic beta-Antagonists; Allopurinol; Amphetamine; Animals; Anti-Bacterial Agents; Contraceptives, Oral; Digitalis Glycosides; Drug and Narcotic Control; Drug-Related Side Effects and Adverse Reactions; Ephedrine; Gonanes; Humans; Immunosuppressive Agents; Italy; Legislation, Drug; Methyldopa; Morpholines; Piperidines; Sympatholytics

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

For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC.. To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC.. We evaluated data (November 2017 data cut-off) from OCTAVE Open, an ongoing, open-label, long-term extension study. The dose de-escalation group comprised 66 tofacitinib induction responders in remission following 52 weeks' tofacitinib 10 mg b.d. maintenance therapy, subsequently de-escalated to 5 mg b.d. in OCTAVE Open. The dose escalation group comprised 57 tofacitinib induction responders who experienced treatment failure while receiving 5 mg b.d. maintenance therapy, subsequently escalated to 10 mg b.d. in OCTAVE Open.. After tofacitinib de-escalation, 92.4% (61/66) and 84.1% (53/63) of patients maintained clinical response and 80.3% (53/66) and 74.6% (47/63) maintained remission, at months 2 and 12, respectively. After dose escalation, 57.9% (33/57) and 64.9% (37/57) of patients recaptured clinical response and 35.1% (20/57) and 49.1% (28/57) were in remission, at months 2 and 12, respectively. The incidence rate of herpes zoster with dose escalation (7.6 patients with events/100 patient-years) was numerically higher than in the overall tofacitinib UC programme.. Following tofacitinib de-escalation in patients already in remission on 10 mg b.d., most maintained remission, although 25.4% lost remission, at month 12. For induction responders who dose-escalated following treatment failure on 5 mg b.d. maintenance therapy, 49.1% achieved remission by month 12. (ClinicalTrials.gov number: NCT01470612).

Topics: Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Maintenance Chemotherapy; Male; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Treatment Outcome

If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice.. The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group.. A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute.. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Squamous Cell; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lung Injury; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sulfones; Survival Rate

Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine.. The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs).. This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks.. The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal.. Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.

Topics: Administration, Oral; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines

P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across different prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Immune-related effects are the main reason for treatment suspension, thus affecting survival benefit. Nevertheless, the correct management of adverse events, eventually including dose modification, allows patients to remain on treatment. In conclusion, duvelisib represents a promising treatment in chronic lymphocytic leukemia and a salvage therapy after ibrutinib.

Topics: Adenine; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Class I Phosphatidylinositol 3-Kinases; Drug Evaluation; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Salvage Therapy

Topics: B-Lymphocytes; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines

Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported.. To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis.. Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75).. Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54.. In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

Topics: Administration, Oral; Adult; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Janus Kinase 3; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Severity of Illness Index; Time Factors; Treatment Outcome

In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study.. Patients were randomly assigned 1:1 to receive vemurafenib (960 mg twice a day) and either cobimetinib (60 mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations.. Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade ≥3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade ≥3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation.. These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care.. NCT01689519.

Topics: Aged; Azetidines; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Vemurafenib

Analyze clinical use of dexmedetomidine to relieve prognosis of remifentanil anesthesia recovery and analyze intervention effect.. Choose 3600 cases of cerebral functional area operation patients treated in different hospitals during June 2011 and December 2015 for general analysis, group the patients by considering relevant parting of anesthesia recovery by American Society of Anesthesiologists, and divide the patients into dexmedetomidine group and control group according to different use of drugs. The two groups of patients are anesthetized, patients' anesthesia wake-up time and wake-up success rate are recorded, and effect of two types of anesthesia wake-up way are compared.. There exists no significant statistical difference in wake-up success rate of the two groups of patients, wake-up time has small difference, but anesthesia recovery quality of dexmedetomidine group is higher, which is conducive to physical rehabilitation of patients and minimize the effects of anesthetics on patients.. In clinical surgery, after use of remifentanil anesthesia on patients, use of dexmedetomidine for anesthesia recovery can minimize adverse effects of drugs on patients and thus is worthy to be effectively promoted in clinics.

Topics: Adult; Aged; Anesthesia, General; Atracurium; Dexmedetomidine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hyperalgesia; Hypnotics and Sedatives; Intraoperative Care; Male; Middle Aged; Neuromuscular Blocking Agents; Piperidines; Preoperative Care; Remifentanil; Treatment Outcome

Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's).. Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States.. Four memory care practices within four healthcare systems in the greater Indianapolis area.. Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs.. Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks.. Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event.. 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant.. This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management.. Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686).

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Costs; Drug-Related Side Effects and Adverse Reactions; Ethnicity; Female; Galantamine; Humans; Indans; Indiana; Male; Medication Adherence; Piperidines; Rivastigmine

Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR).. Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed.. 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs).. Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations.. (NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385).

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Methotrexate; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Observation (watch and wait) is the standard of care for patients with asymptomatic Binet stage A chronic lymphocytic leukemia (CLL). However, the clinical course of these patients is very heterogeneous with some patients requiring treatment rather soon and others not progressing for ages. The clinical staging does not reflect this high variability of the clinical course of CLL. Published data demonstrate that the comprehensive use of several risk factors dramatically improves the accuracy of prognostication independent of clinical stage. The treatment of CLL underwent considerable changes with the introduction of kinase-inhibitors, including ibrutinib, an orally administered, well-tolerated and potent inhibitor of Bruton's tyrosine kinase. This is the first prospective, multicenter, placebo-controlled, double-blind, Phase III study to compare efficacy and safety of ibrutinib to a watch-and-wait approach in Binet stage A CLL with risk of disease progression defined by the comprehensive CLL score.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Staging; Piperidines; Pyrazoles; Pyrimidines; Risk

Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis.. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585.. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups.. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV.. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

Topics: Administration, Oral; Adult; Antiviral Agents; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis D, Chronic; Hepatitis Delta Virus; Humans; Male; Middle Aged; Piperidines; Placebos; Plasma; Prenylation; Pyridines; RNA, Viral; Treatment Outcome; Viral Load

Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.. We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.. Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.. Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

Topics: Adolescent; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Gene Expression Regulation, Neoplastic; Germ-Line Mutation; Humans; Multiple Endocrine Neoplasia Type 2b; Neoplasm Metastasis; Neoplasm Recurrence, Local; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms

To evaluate the long-term efficacy of monotherapy with the dipeptidase-4 inhibitor alogliptin benzoate in hemodialysis (HD) patients with type 2 diabetes.. Sixteen diabetic HD patients with inadequate glycemic control (hemoglobin A1c (HbA1c) level >6.5% and glycated albumin (GA) level >20%) on diet and exercise participated in the study. No patients were taking other oral antidiabetic drugs or receiving insulin therapy. Alogliptin 6.25 mg was administered to patients once daily. HbA1c, GA levels were obtained before and after 2 years of treatment. Body weight and active glucagon-like peptide-1, blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels were also examined before and after treatment.. Both HbA1c and GA levels decreased after starting alogliptin administration. As compared to the pretreatment levels, HbA1c and GA levels significantly decreased at 3 and 18 months, respectively, after starting alogliptin administration. HbA1c and GA levels decreased from 7.1 ± 0.2 to 5.8 ± 1.6% and from 22.5 ± 0.7 to 19.6 ± 0.6%, respectively, 24 months after beginning treatment. Glucagon-like peptide-1 levels (8.9 ± 5.7 pmol/l before treatment) doubled after treatment. Body weight and blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels did not change with treatment. Only one significant adverse effect, a drug-related rash, was seen in 1 patient.. Long-term (2-year) effects of alogliptin benzoate monotherapy suggest its efficacy as a new treatment strategy in diabetic HD patients.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoglycemic Agents; Japan; Longitudinal Studies; Male; Middle Aged; Piperidines; Prevalence; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome; Uracil

Lasmiditan (COL-144) is a novel, centrally acting, highly selective 5-HT(1F) receptor agonist without vasoconstrictor activity that seemed effective when given as an intravenous infusion in a proof-of-concept migraine study. We aimed to assess the efficacy and safety of oral lasmiditan for the acute treatment of migraine.. In this multicentre, double-blind, parallel-group, dose-ranging study in 43 headache centres in five European countries, patients with migraine with and without aura and who were not using prophylaxis were randomly assigned (1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg, 200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied in identical numbered tablet packs. The randomisation code was generated by an independent statistician. Patients and investigators were masked to treatment allocation. The primary endpoint was dose response for headache relief (moderate or severe becoming mild or none) at 2 h. The primary analysis was done in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00883051.. Between July 8 2009, and Feb 18, 2010, 512 patients were randomly assigned to treatment, 391 of whom received treatment. 86 patients received placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis). There was a linear association between headache response rate at 2 h and lasmiditan dose (Cochran-Armitage test p<0·0001). Every lasmiditan treatment dose significantly improved headache response at 2 h compared with placebo (lasmiditan 50 mg: difference 17·9%, 95% CI 3·9-32·1, p=0·022; 100 mg: 38·2%, 24·1-52·4, p<0·0001; 200 mg: 28·8%, 9·6-39·9, p=0·0018; 400 mg: 38·7%, 23·9-53·6, p<0·0001). The proportion of patients with treatment-emergent adverse events increased with increasing doses (53/82 [65%], 59/82 [72%], 61/71 [86%], and 59/70 [84%] for lasmiditan 50, 100, 200, and 400 mg, respectively vs 19/86 [22%] for placebo). Most adverse events were mild or moderate in intensity, with 16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse event compared with five of 86 (6%) on placebo. The most common adverse events were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and somnolence.. Oral lasmiditan seems to be safe and effective in the acute treatment of migraine. Further assessment in larger placebo-controlled and triptan-controlled trials are needed to assess the potential role of lasmiditan in acute migraine therapy.. CoLucid Pharmaceuticals.

Topics: Administration, Oral; Adult; Aged; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Young Adult

This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0-4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22 % ended therapy for toxicity. Of the 20 response-evaluable patients, 10 % demonstrated partial response and 15 % stable disease ≥24 weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200 mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.

Topics: Administration, Metronomic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Blood Platelets; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Drug-Related Side Effects and Adverse Reactions; Female; Gene Expression Regulation, Neoplastic; Humans; Methotrexate; Middle Aged; Neoplasm Staging; Neovascularization, Pathologic; Piperidines; Platelet Factor 4; Proteomics; Quinazolines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR.. This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (ε4-positive, ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+).. At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%).. No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.

Topics: Aged; Aged, 80 and over; Alleles; Alzheimer Disease; Apolipoproteins E; Cholinesterase Inhibitors; Donepezil; Drug-Related Side Effects and Adverse Reactions; Edema; Female; Genotype; Humans; Hypoglycemic Agents; Indans; Intelligence Tests; Interview, Psychological; Male; Middle Aged; Nasopharyngitis; Piperidines; PPAR gamma; Rosiglitazone; Thiazolidinediones; Treatment Outcome

Treatment options for patients suffering from indolent forms of mastocytosis remain inadequate with the hyperactivation of mast cells responsible for many of the disease's systemic manifestations. Masitinib is a potent and highly selective oral tyrosine kinase inhibitor. A combined inhibition of c-Kit and Lyn make it particularly efficient in controlling the activity of mast cells and therefore, of potential therapeutic benefit in mastocytosis. Masitinib was administered to 25 patients diagnosed as having systemic or cutaneous mastocytosis with related handicap (i.e., disabilities associated with flushes, depression, pruritus and quality-of-life) at the initial dose levels of 3 or 6 mg/kg/day over 12 weeks. In accordance with the AFIRMM study, response was based upon change of clinical symptoms associated with patient handicap at week 12 relative to baseline, regardless of disease subtype. Improvement was observed in all primary endpoints at week 12 including a reduction of flushes, Hamilton rating, and pruritus as compared with baseline by 64% (P = 0.0005), 43% (P = 0.0049), and 36% (P = 0.0077), respectively. An overall clinical response was observed in 14/25 patients (56%; [95%CI = 37%-75%]), with sustainable improvement observed throughout an extension phase (>60 weeks). Common adverse events were edema (44%), nausea (44%), muscle spasms (28%), and rash (28%), the majority of which were of mild or moderate severity with a significant decline in frequency observed after 12 weeks of treatment. One patient experienced a serious adverse event of reversible agranulocytosis. Masitinib is a promising treatment for indolent forms of mastocytosis with handicap and indicates acceptable tolerability for long-term treatment regimens.

Topics: Adult; Benzamides; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Mastocytosis, Cutaneous; Mastocytosis, Systemic; Middle Aged; Mutation, Missense; Piperidines; Pyridines; Thiazoles; Treatment Outcome

Bilastine is a novel, nonsedating H(1)-antihistamine developed for symptomatic treatment of Allergic Rhinitis and Chronic Idiopathic Urticaria. The objective of this study was to compare the efficacy and safety of bilastine 20 mg vs placebo and desloratadine 5 mg in subjects with seasonal allergic rhinitis (SAR).. This randomized, double blind, placebo-controlled, parallel-group multicentre study evaluated the effect of 2 weeks' treatment with bilastine 20 mg, desloratadine 5 mg or matched placebo once daily, in 12-70 years old symptomatic SAR patients. All subjects assessed the severity of nasal (obstruction, rhinorrhoea, itching, and sneezing) and nonnasal (ocular itching, tearing, ocular redness, itching of ears and/or palate) symptoms on a predetermined scale to provide a total symptom score (TSS), composed of nasal and nonnasal symptom scores (NSS and NNSS, respectively). The primary efficacy measure was the area under the curve (AUC) for the TSS over the entire treatment period.. Bilastine 20 mg significantly reduced the AUC of TSS to a greater degree from baseline compared to placebo (98.4 with bilastine vs 118.4 with placebo; P < 0.001), but not compared to desloratadine 5 mg (100.5). Bilastine 20 mg was not different from desloratadine 5 mg but significantly more effective than placebo in improving the NSS, NNSS, and rhinitis-associated discomfort scores (P < 0.05), and rhinoconjunctivitis quality of life questionnaire total (P < 0.005) and four out of seven individual domain (P < 0.05) scores. The incidence of treatment emergent adverse events was similar for bilastine (20.6%), desloratadine (19.8%), and placebo (18.8%).. Bilastine 20 mg once daily was efficacious, safe and not different from desloratadine 5 mg once daily in the treatment of SAR symptoms.

Topics: Adolescent; Adult; Aged; Area Under Curve; Benzimidazoles; Child; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Loratadine; Male; Middle Aged; Piperidines; Quality of Life; Rhinitis, Allergic, Seasonal; Treatment Outcome; Young Adult

Pharmacokinetic interactions between casopitant (a substrate and weak to moderate inhibitor of CYP3A), dexamethasone (a substrate and weak inducer of CYP3A), and ondansetron (a mixed CYP substrate) were evaluated in a two-part, three-period, single-sequence study in two groups of healthy subjects.. Part 1: subjects received oral casopitant (regimen A); oral dexamethasone and IV ondansetron (regimen B); and oral casopitant, a reduced dose of oral dexamethasone, and IV ondansetron (regimen C). Part 2: subjects received oral casopitant (regimen D); IV dexamethasone and oral ondansetron (regimen E); and oral casopitant, IV dexamethasone, and oral ondansetron (regimen F). Each regimen was separated by 14 days.. Casopitant AUC in regimen C was increased 28% on day 1 but decreased 34% on day 3 compared to casopitant alone in regimen A. When given with casopitant and ondansetron in regimen C, dexamethasone AUC was 17% lower on day 1, but similar on day 3, compared to regimen B (representing dose-normalized increases in exposure of 39% and 108%, respectively). Ondansetron exposure was equivalent in regimens B and C. Casopitant AUC in regimen F was similar to regimen D on days 1 and 3. Dexamethasone AUC increased 21% when given with oral casopitant and oral ondansetron (regimen F compared to regimen E). Ondansetron exposure was equivalent in regimens E and F.. When repeat-dose oral dexamethasone is to be coadministered with oral casopitant, a reduction in dexamethasone dose may be considered; however, no change in casopitant dose is required. Ondansetron exposure was not affected by coadministration with casopitant.

Topics: Adolescent; Adult; Antiemetics; Dexamethasone; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nausea; Neurokinin-1 Receptor Antagonists; Ondansetron; Piperazines; Piperidines; Vomiting; Young Adult

The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron.. In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort.. The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%).. None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.

Topics: Adolescent; Adult; Antiemetics; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Granisetron; Humans; Indoles; Male; Middle Aged; Nausea; Piperazines; Piperidines; Quinolizines; Vomiting; Young Adult

The efficacy and safety of the new drug, BGP-15, were compared with placebo in insulin-resistant patients in a 28-day dose-ranging study. Forty-seven nondiabetic patients with impaired glucose tolerance were randomly assigned to 4 weeks of treatment with 200 or 400 mg of BGP-15 or placebo. Insulin resistance was determined by hyperinsulinemic euglycemic clamp technique and homeostasis model assessment method, and beta-cell function was measured by intravenous glucose tolerance test. Each BGP-15 dose significantly increased whole body insulin sensitivity (M-1, p=0.032), total body glucose utilization (M-2, p=0.035), muscle tissue glucose utilization (M-3, p=0.040), and fat-free body mass glucose utilization (M-4, p=0.038) compared to baseline and placebo. No adverse drug effects were observed during treatment. BGP-15 at 200 or 400 mg significantly improved insulin sensitivity in insulin-resistant, nondiabetic patients during treatment compared to placebo and was safe and well-tolerated. This was the first clinical study demonstrating the insulin-sensitizing effect of a molecule, which is considered as a co-inducer of heat shock proteins.

Topics: Adult; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Glucose; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Middle Aged; Oximes; Piperidines; Placebos; Young Adult

Despite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200x10(9)/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Flavonoids; Humans; Infusions, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocyte Count; Male; Middle Aged; Piperidines; Recurrence; Risk Factors; Treatment Outcome

Topics: Adverse Drug Reaction Reporting Systems; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance; Piperidines; World Health Organization

Adverse drug events (ADEs) rates associated with anti-dementia acetylcholinesterase inhibitors are estimated to be 5%-20% and show a wide range of symptoms. No report has examined whether there is a difference in the anti-dementia drugs' ADEs profile. This study aimed to establish whether anti-dementia drugs' ADEs profile differed. Data was based on the Japanese Adverse Drug Event Report (JADER) database. The reporting odds ratios (RORs) was used to analyze data for ADEs from April 2004-October 2021. The target drugs were donepezil, rivastigmine, galantamine, and memantine. The top ten most frequently occurring adverse events were selected. The association between the RORs and antidementia drug ADEs was evaluated, and compared the distribution rate of expression age related to ADEs and each ADEs' timing of onset due to anti-dementia drugs. The primary outcome was RORs. Secondary outcome were expression age and time-to-onset of ADE associated with anti-dementia drugs. A total of 705,294 reports were analyzed. The adverse events incidence differed. Bradycardia, loss of consciousness, falls, and syncope incidence were significantly diverse. The Kaplan-Meier curve results for the cumulative ADEs incidence showed that donepezil had the slowest onset, while galantamine, rivastigmine, and memantine had approximately the same timing of onset.

Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Donepezil; Drug-Related Side Effects and Adverse Reactions; Galantamine; Humans; Indans; Memantine; Piperidines; Rivastigmine

This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan-Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.

Topics: Age Factors; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Janus Kinase Inhibitors; Japan; Male; Middle Aged; Piperidines; Purines; Pyrazoles; Pyrimidines; Registries; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors; Sulfonamides; Time Factors; Treatment Outcome

Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, although 4 next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant's failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all 5 compounds and thus to compare the 4 next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically based pharmacokinetic models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the 4 next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the 4 compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant, and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and nonhepatotoxic molecules within the same class.

Topics: Azepines; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Chemical and Drug Induced Liver Injury; Computer Simulation; Drug-Related Side Effects and Adverse Reactions; Humans; Imidazoles; Piperidines; Pyridines; Pyrroles; Spiro Compounds

We describe a case vision-threatening sclerouveitis as a probable adverse drug reaction to ibrutinib.. Case report.. Ibrutinib is an inhibitor of Bruton's kinase which has shown success in the treatment of hematological malignancies such as chronic lymphocytic leukemia. Despite being generally well tolerated, recent studies have implicated ibrutinib in several adverse events affecting organs such as the heart, intestines, and the eyes. We present the case of a patient who developed severe sclerouveitis after approximately one year of ibrutinib therapy, and suggest this is a probable adverse drug reaction associated with ibrutinib in accordance with the Naranjo algorithm, highlighting the importance of prompt management of ocular symptoms in these patients.

Topics: Adenine; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Uveitis

The tyrosine kinase inhibitors (TKI) vandetanib and cabozantinib are approved as targeted therapies in advanced medullary thyroid carcinoma (MTC) with symptoms or high tumour burden. Only recently, toxicity in long-time TKI usage was analysed. However, little is known about the impact of TKI discontinuation on MTC disease course after longer-term therapy. Here, we report our experience in a series of 7 MTC patients with vandetanib treatment of up to 87 months followed by discontinuation for concerns of toxicity or due to side-effects. The discontinuation of TKI therapy is a relevant clinical scenario. To our knowledge we present the largest single center series on an important aspect of TKI management.. Retrospective analysis of MTC patients with continued discontinuation of vandetanib treatment in a tertiary referral endocrine tumour centre. Analysis included a review of patients' records for TKI indication, and treatment response as well indications for continued TKI discontinuation and follow-up by clinical assessment, calcitonin and CEA doubling times as well as imaging (ultrasound, CT).. Seven MTC patients [6 sporadic MTC, 1 Multiple Endocrine Neplasie Type 2a (MEN2a)] with previous vandetanib treatment (median: 41 months; range 7-87 months) and continued TKI discontinuation were identified out of 161 analysed MTC files. TKI treatment was initiated due to high tumour burden and symptoms or RECIST (Response Evaluation Criteria In Solid Tumors) progression in all patients. Two patients (29%) remained stable after discontinuation of vandetanib until now (follow-up of 47 and 61 months). Both patients had been on TKI therapy for 73 and 58 months. Five patients (71%) developed progressive disease after TKI discontinuation. In 2 patients, vandetanib was restarted after 45 and 52 months resulting again in disease control. One patient was enrolled in a new RET kinase inhibitor trial after 45 months of vandetanib discontinuation. Two patients declined restart of treatment due to mental health issues leading to discontinuation of vandetanib in the first place (after 7 and 38 months of treatment) and both patients died of rapidly progressive disease. At time points of tumour progression, calcitonin-doubling time (CDT) was < 2 years in all patients.. This case series suggests that discontinuation of long-term vandetanib treatment with documented stable disease does not automatically result in rapid disease progression but may be followed by prolonged "TKI free" stable disease in individual patients. Analysis of calcitonin and CDT during discontinuation is indicated as it will unmask tumour progression earlier than imaging. Restart with the same TKI is possible in case of progression.

Topics: Adult; Carcinoma, Neuroendocrine; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Quinazolines; Retrospective Studies; Thyroid Neoplasms; Withholding Treatment; Young Adult

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Cell Cycle Proteins; Drug-Related Side Effects and Adverse Reactions; Female; Granuloma; Humans; Lactams; Microtubule-Associated Proteins; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Sarcoidosis; Serine Endopeptidases; Skin; Withholding Treatment

Topics: Adenine; Aged; Arm; Drug-Related Side Effects and Adverse Reactions; Humans; Lymphedema; Male; Piperidines; Skin

We sought to describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis.. Retrospective chart review.. Among 6871 patients and 17 EGFR or FGFR inhibitors, 1161 patients (16.9%) referred for ophthalmologic examination. In total, 1145 patients had disease-related or unrelated ocular complications. Among 16 patients with treatment-related ocular complications, three patients had treatment-related radiation retinopathy and one patient showed treatment-related corneal ulcer. Finally the authors identified that, in 12 patients, three EGFR inhibitors and two FGFR inhibitors caused corneal epithelial lesions. Vandetanib, Osimertinib, and ABT-414 caused vortex keratopathy in nine patients, while ASP-5878 and FPA-144 caused epithelial changes resembling corneal dysmaturation in three patients. The mean interval until symptoms appeared was 246 days with vandetanib, 196 days with osimertinib, 30 days with ABT-414, 55 days with ASP-5878, and 70 days with FPA-144. The mean of the lowest logarithm of minimal angle of resolution visual acuity results of the right and left eyes after chemotherapy were 0.338 and 0.413. The incidence rates of epithelial changes were 15.79% with vandetanib, 0.5% with osimertinib, 100% with ABT-414, 50.0% with ASP-5878, and 18.2% with FPA-144. After excluding deceased patients and those who were lost to follow-up or still undergoing treatment, we confirmed the reversibility of corneal lesions after the discontinuation of each agent. Seven patients showed full recovery of their vision and corneal epithelium, while three achieved a partial level of recovery. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy.. EGFR and FGFR inhibitors are chemotherapy agents that could make corneal epithelial changes. Contrary to the low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed a high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with these agents that decreased visual acuity could develop due to corneal epithelial changes and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops.. This study was approved by the institutional review board (IRB) of Samsung Medical Center (IRB no. 2019-04-027) and was conducted according to the principles expressed in the Declaration of Helsinki.

Topics: Acrylamides; Adult; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Corneal Diseases; Drug-Related Side Effects and Adverse Reactions; Epithelium, Corneal; ErbB Receptors; Female; Humans; Immunoconjugates; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Retrospective Studies; Therapies, Investigational; Vision Disorders; Visual Acuity

We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.. Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT. This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial.. For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72-86% (26% severe), while in phase 3 was 36-43% (2% severe). The most common AEs in all studies were CNS-related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3.. This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials.

Topics: Adult; Benzamides; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Female; Forms as Topic; Humans; Informed Consent; Male; Middle Aged; Migraine Disorders; Patient Reported Outcome Measures; Piperidines; Pyridines; Serotonin Receptor Agonists; Translating

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA).. Our objective was to compare the incidence rates (IRs) of adverse events in tofacitinib clinical trials and real-world observational data for alternative treatments.. The tofacitinib "dose-comparison cohort" included months 0-12 of two phase III studies (tofacitinib 5 [n = 238] and 10 [n = 236] mg twice daily [BID]); the "all-tofacitinib comparison cohort" (n = 783) included two phase III and one ongoing long-term extension study (data cutoff May 2016). An "observational comparison cohort" (n = 5799) comprised patients initiating a conventional synthetic disease-modifying antirheumatic drug (DMARD), biologic DMARD, or apremilast in the US Truven MarketScan database from 2010 to 2015. IRs for serious infections (SIEs; requiring hospitalization), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, and major adverse cardiovascular events (MACE) across cohorts were qualitatively compared.. IRs (patients with events/100 patient-years) for SIEs were similar between the tofacitinib dose-comparison cohort (5 mg BID: 1.3; 10 mg BID: 2.0) and the observational comparison cohort (1.1-7.9; treatment dependent). The tofacitinib dose-comparison cohort had a higher rate of HZ (5 mg BID: 2.0; 10 mg BID: 2.7) than did the observational comparison cohort (0.8-2.0). IRs for NMSC were generally lower in the all-tofacitinib comparison cohort (0.5) than in the observational comparison cohort (0.4-6.0). IRs for MACE, malignancies excluding NMSC, and NMSC were similar between cohorts.. In patients with PsA, tofacitinib had a safety profile similar to that of other systemic therapies in real-world settings, except for the risk of HZ, a known risk of tofacitinib.. ClinicalTrials.gov: NCT01877668; NCT01882439; NCT01976364.

Topics: Arthritis, Psoriatic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Janus Kinase 3; Male; Middle Aged; Observational Studies as Topic; Piperidines; Protein Kinase Inhibitors; Pyrimidines

There are limited data on treatment patterns, adverse events (AEs), and economic burden in younger, commercially insured patients treated for mantle cell lymphoma (MCL).. Adults with ≥1 treatment for MCL between 1 November 2013-31 December 2017 were identified from IQVIA Real-World Data Adjudicated Claims-US; index date was first treatment. Patients carried ≥1 MCL diagnosis, were newly treated, and were enrolled continuously for ≥12 months prior to and ≥30 days following index. Patients receiving the four most common MCL regimens were included. Measures included frequency of incident AEs, resource use, and costs overall and by number of AEs. Adjusted logistic regression and generalized linear modeling evaluated risk of hospitalization and all-cause costs per patient per month (PPPM).. Two thousand five hundred and nine treated patients had a drug-specific code and were classified to a specific treatment regimen. Of those patients, 1785 patients received at least one of the four most commonly used MCL regimens (R-CHOP, rituximab monotherapy, B-R, and ibrutinib) at some point over follow-up (median 23 months). R-CHOP was the most common regimen observed in the first line (26%), followed by rituximab monotherapy (19%), B-R (15%), and ibrutinib (5%). The median age was 57 years; median Charlson Comorbidity Index was 0. Among patients receiving the four most common regimens, 63% of patients experienced ≥1 incident AE (R-CHOP 77%, B-R 58%, and ibrutinib 52%). An increasing number of incident AEs was associated with increased hospitalization risk (odds ratio = 2.4; 95% Confidence Interval [CI] 2.1-2.7) and increased mean costs PPPM (cost ratio = 1.1; 95% CI 1.1-1.2).. This is the largest study describing treatment patterns and clinical and economic impact of MCL treatment. The most common regimens were R-CHOP, rituximab monotherapy, B-R, and ibrutinib. The majority of treated patients experienced at least one incident AE, with hospitalization risk and all-cause costs increasing as the number of AEs increased.

Topics: Adenine; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Cyclophosphamide; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Health Care Costs; Health Care Rationing; Hospitalization; Humans; Incidence; Insurance, Health; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Practice Patterns, Physicians'; Prednisone; Pyrazoles; Pyrimidines; Retrospective Studies; Rituximab; Treatment Outcome; United States; Vincristine; Young Adult

A 38-year-old man with a diagnosis of BRAF-mutated metastatic melanoma was referred to our clinic. He had been under treatment with 60-mg oral cobimetinib daily for 21 days/7 day off in combination with 960 mg vemurafenib twice daily. The patient had symptoms of blurred vision and photophobia in his right eye. A slit-lamp examination revealed bilateral central corneal stromal opacity and epithelial microcystic edema Involvement was more severe in the right eye compared with the left eye. Fourteen days after the first visit, the patient's symptoms and slit-lamp findings were largely resolved. We suggest that endothelium pump failure was involved in this acute corneal decompensation case similar to the mechanism in retinal pigment epithelium.

Topics: Acute Disease; Administration, Oral; Adult; Azetidines; Corneal Edema; Drug-Related Side Effects and Adverse Reactions; Humans; Male; MAP Kinase Kinase 1; Melanoma; Piperidines; Skin Neoplasms; Vision Disorders

Topics: Acute Disease; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis; Humans; Liver; Lung Neoplasms; Piperidines

The signal is defined as "reported information on a possible causal relationship between an adverse event and a drug, of which the relationship is unknown or incompletely documented previously".. To detect novel adverse events of iloperidone by disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs).. The US FAERS database consists of 1028 iloperidone associated Drug Event Combinations (DECs) which were reported from 2010 Q1 to 2016 Q3. We consider DECs for disproportionality analysis only if a minimum of ten reports are present in database for the given adverse event and which were not detected earlier (in clinical trials). Two data mining algorithms, namely, Reporting Odds Ratio (ROR) and Information Component (IC) were applied retrospectively in the aforementioned time period. A value of ROR-1.96SE>1 and IC- 2SD>0 were considered as the threshold for positive signal.. The mean age of the patients of iloperidone associated events was found to be 44years [95% CI: 36-51], nevertheless age was not mentioned in twenty-one reports. The data mining algorithms exhibited positive signal for akathisia (ROR-1.96SE=43.15, IC-2SD=2.99), dyskinesia (21.24, 3.06), peripheral oedema (6.67,1.08), priapism (425.7,9.09) and sexual dysfunction (26.6-1.5) upon analysis as those were well above the pre-set threshold.. Iloperidone associated five potential signals were generated by data mining in the FDA AERS database. The result requires an integration of further clinical surveillance for the quantification and validation of possible risks for the adverse events reported of iloperidone.

Topics: Adverse Drug Reaction Reporting Systems; Akathisia, Drug-Induced; Antipsychotic Agents; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Isoxazoles; Piperidines; United States; United States Food and Drug Administration

Vandetanib is effective for treating symptomatic or progressive medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease, but its toxicity such as photosensitivity reactions should be considered. It is a rare adverse effect of this drug but might cause severe morbidity and even mortality.. A 26-year man with MTC developed phototoxic rashes on the sun-exposed areas of his shin after 15 days from the initiation of vandetanib treatment. Grade II skin toxicity was evaluated based on the Common Terminology Criteria for Adverse Events standard.. Drug-induced phototoxic rash.. The vandetanib dose was reduced by 30%, and the application of topical steroids and sunscreen was adopted.. After dose reduction of vandetanib, the symptoms of vandetanib-induced phototoxic rash resolved, although residual pigmentation was observed.. Close attention should be paid to the adverse effect of vandetanib, phototoxic rash, and patients should be advised on the prevention and treatment measures.

Topics: Adult; Antineoplastic Agents; Dermatitis, Phototoxic; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

　The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD.

Topics: Adverse Drug Reaction Reporting Systems; Afatinib; Bortezomib; Carbazoles; Cluster Analysis; Crizotinib; Dasatinib; Databases as Topic; Datasets as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Japan; Lung Diseases, Interstitial; Molecular Targeted Therapy; Particle Size; Piperidines; Pyrazoles; Pyridines; Quinazolines; Time Factors

Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58

Topics: Adenine; Adult; Aged; Aged, 80 and over; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Survival Rate

Bilastine is an H1-antihistamine approved for symptomatic treatment of patients with allergic rhinoconjunctivitis or urticaria. The safety profile of bilastine in clinical trials of allergic rhinoconjunctivitis or urticaria, assessed by type and frequency of adverse events (AE), was similar to that of placebo.. As part of the risk management plan for bilastine, the safety profile of bilastine in the elderly was assessed.. A prospective, multicenter, observational, open-label, 3-month follow-up study was performed to assess the safety profile of bilastine 20 mg in patients aged ≥65 years with allergic rhinoconjunctivitis and/or urticaria.. A total of 74 of 146 patients (50.7%) reported 129 treatment-emergent AEs (TEAE) during the study period. The incidence of TEAEs was low, with monthly and quarterly rates of 0.29 (95% confidence intervals [CI], 0.229-0.367) and 0.88 (95% CI, 0.688-1.100), respectively. Monthly and quarterly incidence rates were 0.04 (95% CI, 0.016-0.082) and 0.12 (95% CI, 0.048-0.246), respectively, for related TEAEs (eight TEAEs in seven patients) and were 0.02 (95% CI, 0.003-0.048) and 0.05 (95% CI, 0.010-0.143), respectively, for serious TEAEs (five TEAES in three patients). All serious TEAEs were considered to be unrelated to bilastine.. Bilastine 20 mg showed a favorable safety profile with a low incidence of TEAEs in patients aged ≥65 years. The results were in accordance with the known safety profile of bilastine 20 mg and incidence of AEs reported in previous studies and described in the approved summary of product characteristics.

Topics: Aged; Aged, 80 and over; Benzimidazoles; Conjunctivitis, Allergic; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Histamine H1 Antagonists; Humans; Incidence; Male; Piperidines; Prospective Studies; Rhinitis, Allergic; Spain; Urticaria

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline

Topics: Aged; BRCA1 Protein; BRCA2 Protein; Clinical Trials as Topic; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Female; Germ-Line Mutation; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Progression-Free Survival; Risk Assessment

Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown.. This multicenter, retrospective analysis evaluated the significance of comorbidities, as assessed by the Cumulative Illness Rating Scale (CIRS), among patients with CLL treated with ibrutinib.. One hundred forty-five patients received ibrutinib (80% in a relapsed/refractory setting). A high burden of comorbidities (CIRS score ≥ 7) was associated with inferior median event-free survival (EFS; 24 vs 37 months; P = .003) and 2-year overall survival (OS; 79% vs 100%; P = .005). In an adjusted Cox model, both EFS and OS worsened with an incremental increase in the CIRS score. Furthermore, comorbidities were associated with an increased risk of ibrutinib dose reduction and therapy discontinuation. CIRS was predictive in both frontline and relapsed CLL, regardless of patient age.. Comorbidities portend a poor prognosis among patients with CLL treated with ibrutinib. Prospective studies are needed to optimize the treatment of patients with CLL who have comorbidities. Cancer 2018. © 2018 American Cancer Society.

Topics: Adenine; Aged; Aged, 80 and over; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Electronic Health Records; Female; Humans; Immunotherapy; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Treatment Outcome

Parkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs.. A retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs.. Forty-five iPD patients (mean age of onset: 62.67 ± 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 ± 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs.. This study was limited by its retrospective study design and small sample size and with likely selection bias.. The prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Olanzapine; Outcome and Process Assessment, Health Care; Parkinson Disease; Piperidines; Psychological Techniques; Psychotic Disorders; Quality of Life; Retrospective Studies; Urea

Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by joint destruction. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. This post hoc analysis assessed the safety of tofacitinib in Latin American (LA) patients with RA versus the Rest of World (RoW) population.. Data were pooled from 14 clinical studies of tofacitinib: six Phase 2, six Phase 3 and two long-term extension studies. Incidence rates (IRs; patients with events/100 patient-years of treatment exposure) were calculated for safety events of special interest combined across tofacitinib doses. 95% confidence intervals (CI) for IRs were calculated using the maximum likelihood method. Descriptive comparisons were made between LA and RoW (excluding LA) populations.. This analysis included data from 984 LA patients and 4687 RoW patients. IRs for safety events of special interest were generally similar between LA and RoW populations, with overlapping 95% CIs. IRs for discontinuation due to adverse events, serious infections, tuberculosis, all herpes zoster (HZ), serious HZ, malignancies (excluding non-melanoma skin cancer) and major adverse cardiovascular events were numerically lower for LA versus RoW patients; IR for mortality was numerically higher. No lymphoma was reported in the LA population versus eight cases in the RoW population. Exposure (extent and length) was lower in the LA population (2148.33 patient-years [mean = 2.18 years]) versus RoW (10515.68 patient-years [mean = 2.24 years]).. This analysis of pooled data from clinical studies of tofacitinib in patients with RA demonstrates that tofacitinib has a consistent safety profile across LA and RoW patient populations.

Topics: Adult; Aged; Arthritis, Rheumatoid; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Janus Kinase Inhibitors; Latin America; Long Term Adverse Effects; Male; Middle Aged; Patient Safety; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Ibrutinib is a Bruton tyrosine kinase inhibitor and is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) in frontline and relapsed/refractory settings. The authors previously reported poor outcomes for patients who discontinued ibrutinib; however, long-term outcomes were not reported.. Data from 320 patients who received ibrutinib on clinical studies between 2010 and 2015 at The University of Texas MD Anderson Cancer Center were retrospectively analyzed.. Long-term outcomes among patients with CLL after they discontinued ibrutinib were analyzed. Ninety of 320 patients (28%) who were treated on ibrutinib-based regimens discontinued ibrutinib. Of these, 80 had relapsed/refractory disease, and 10 were treatment-naive. The median time to discontinuation was 15 months (range, 1.2-54 months). After a median follow-up of 38 months after starting ibrutinib, 40 patients (44%) remained alive. Major reasons for ibrutinib discontinuation were intolerance (n = 29; 32%), miscellaneous (n = 28; 31%), progression (n = 19; 21%), and Richter transformation (RT) (n = 9; 10%). The median survival according to the reason for discontinuation was 33 months for ibrutinib intolerance, 11 months for miscellaneous causes, 16 months for progressive CLL, and 2 months for RT. Among the 19 patients who had progressive CLL, 42% responded to subsequent therapy.. Ibrutinib discontinuation was observed during therapy. Patients with CLL who had disease transformation had especially poor outcomes, whereas those who developed progressive disease during ibrutinib therapy had a median survival of <1.5 years. Survival was associated with the reason for discontinuation; patients who had progressive CLL had better survival compared with those who had disease transformation. Effective salvage strategies for patients with CLL who progress on ibrutinib therapy is of critical importance. Cancer 2017;123:2268-2273. © 2017 American Cancer Society.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Deprescriptions; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retrospective Studies; Survival Rate

The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

Topics: Adverse Drug Reaction Reporting Systems; Androstenes; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Germany; Humans; Male; Piperidines; Prostatic Neoplasms; Quinazolines; Survival Rate; Thyroid Neoplasms

While low toxicity is reported, there are sparse data on the safety of acute picaridin (icaridin) exposures in humans.. The purpose of this study was to review National Poison Data System (NPDS) data regarding ingestion of insect repellents containing picaridin and compare those to insect repellents containing DEET and other insect repellents not containing DEET.. NPDS was queried for single agent human insect repellent ingestions reported between 1 January 2000 and 31 May 2015 using the American Association of Poison Control Center generic categories 201048 (Insect Repellents with DEET) and 201049 (Insect Repellents without DEET). Picaridin-containing product exposures were assessed using Poisindex(®) product ID 6744589. Insect repellents of unknown type were not included.. 68,429 exposures occurred; 24% were non-DEET-containing products, of which 2% were picaridin-containing products. Among picaridin exposures, 92.9% were managed outside of a health-care facility; there were no reported cases of major effect or death, and only one case of moderate effect. Primary symptoms across all insect repellent exposures included ocular irritation/pain, vomiting, red eye/conjunctivitis, and oral irritation. Treatment primarily included dilution/irrigation/wash.. Unintentional ingestion of picaridin-containing and other insect repellents was associated only with minor toxicity and was generally managed outside of a health-care facility.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Insect Repellents; Male; Middle Aged; Piperidines; Poison Control Centers; United States; Young Adult

No worldwide pharmacovigilance study evaluating the spectrum of adverse drug reactions (ADRs) induced by cholinesterase inhibitors (ChEI) in Alzheimer's disease has been conducted since their emergence on the market.. To describe ChEI related ADRs in Alzheimer's disease (donepezil, rivastigmine, and galantamine) and characterize their seriousness as reported by national pharmacovigilance systems to VigiBase, a World Health Organization International Drug Monitoring Program database, between 1998 and 2013.. All ChEI RELATED REPORTS: , submitted to VigiBase between 1998 and 2013 from THE FIVE CONTINENTS: were extracted. Analyses were carried out for general, serious, and nonserious ADRs.. A total of 18 955 reports (43 753 ADRs) FROM 58 COUNTRIES: were reported: 60.1% in women; mean age 77.4 ± 9.1 years. Most reports originated from Europe (47.6%) and North America (40.4%). Rivastigmine and donepezil were involved in MOST: reports (41.4% each). The most frequently reported ADRs were neuropsychiatric (31.4%), gastrointestinal (15.9%), general (11.9%), and cardiovascular (11.7%) disorders. During the 2006-2013 period, serious ADRs remained more often reported than nonserious ones; the most serious were neuropsychiatric (34.0%), general (14.0%), cardiovascular (12.1%), and gastrointestinal (11.6%) disorders. Medication errors were reported in 2.0% of serious cases. Death occurred in 2.3% of the reports.. This international pharmacovigilance study highlights the ADR pattern induced by ChEIs. Neuropsychiatric events were the most frequently reported ADRs. Serious cardiovascular events were frequently reported, suggesting that their significance has probably been previously underestimated. Given the frailty of the patients and the frequent comedications, caution is advised before introducing a ChEI.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Galantamine; Humans; Indans; Male; Medication Errors; North America; Pharmacovigilance; Piperidines; Rivastigmine; World Health Organization

We have recently introduced the use of mammalian cardiac tissue slices for in vitro drug testing purposes. Here we show how this method can be applied for long-term studies in safety pharmacology.. In freshly prepared cardiac slices from guinea-pig or rat ventricle, extracellular field potentials (FP) and intracellular action potentials (AP) were recorded in response to electrical stimulation using the 4-channel heart slice screening system 'Synchroslice'. To assess viability of the slices on consecutive days after preparation, drug effects on FP/AP parameters, like duration and latency, were monitored.. In the presence of the potassium channel blocker E4031 (1 μM), FP and AP duration (FPD and APD) were significantly increased (FPD, 39.0%; APD, 28.1%) in guinea-pig ventricular slices. Similar changes were observed 24-28 h after slice preparation (FPD, 48.6%; APD, 25.4%). Furthermore, AP duration was reduced in the presence of the calcium channel blocker nifedipine (10 μM) on the day of preparation (40.5%) and 24-28 h later (38.7%). In contrast, in the presence of the potassium channel blocker 4-aminopyridine (30 mM) AP duration was prolonged 4.95 and 4.19-fold, 2-8 h and 24-28 h after preparation, respectively. Finally, FP propagation was repeatedly slowed down by the gap junction blocker carbenoxolone (30 μM), as revealed from FP onset latency increases observed on three consecutive days (2-8 h after preparation, 93.0%; 24-28 h, 76.8%, 48-56 h, 61.7%).. Freshly isolated cardiac slices reproduced established physiological and pharmacological responses for more than 24 h after preparation. Thus, cardiac slices can be used for several days after preparation which makes them a robust model for electrophysiological studies. We propose that cardiac slices can become a versatile tool in heart research and risk assessment of drugs.

Topics: 4-Aminopyridine; Action Potentials; Animal Testing Alternatives; Animals; Animals, Laboratory; Anti-Arrhythmia Agents; Calcium Channel Blockers; Carbenoxolone; Disease Models, Animal; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Guinea Pigs; Heart Ventricles; In Vitro Techniques; Male; Nifedipine; Piperidines; Potassium Channel Blockers; Pyridines; Rats; Rats, Wistar; Risk Assessment; Toxicity Tests

There is an on-going need to identify medications suitable for the long-term treatment of canine atopic dermatitis (CAD). Masitinib mesilate is a potent and selective tyrosine kinase inhibitor of the c-KIT receptor. A strong relationship exists between the SCF/c-KIT pathway and pathogenesis of CAD, suggesting that masitinib may potentially fulfil the above role. This study reports on an uncontrolled pilot study of masitinib in CAD. Masitinib was administered orally to 11 dogs at a mean dose of 11.0 +/- 1.83 mg/kg/day (free base) for 28 days. Treatment response was assessed by evolution of clinical appearance according to a modified version of the Canine Atopic Dermatitis Extent and Severity Index (mCADESI), pruritus scale and surface area of lesions. Masitinib improved CAD with a mean reduction in mCADESI of 50.7 +/- 29.8% (95% C.I. = 29.4-72.0; p = 0.0004) at day 28 relative to baseline, with 8/10, 8/10 and 4/10 dogs showing improvement of >or=33%, >or=40% and >or=50%, respectively. Improvement was further evidenced by a decrease in pruritus score and the surface area of lesions. No serious or severe adverse events occurred during this trial, although 6/11 dogs presented with mild to moderate treatment related adverse events. There is sufficient compelling evidence to warrant further investigation.

Topics: Animals; Benzamides; Dermatitis, Atopic; Dog Diseases; Dogs; Drug-Related Side Effects and Adverse Reactions; Pilot Projects; Piperidines; Pruritus; Pyridines; Severity of Illness Index; Skin; Thiazoles; Treatment Outcome

Pharmacovigilance has revealed hundreds of reports of neuropsychiatric disorders and several deaths by suicide.

Topics: Cannabinoid Receptor Antagonists; Clinical Trials as Topic; Depression; Drug-Related Side Effects and Adverse Reactions; Europe; Humans; Movement Disorders; Piperidines; Psychotic Disorders; Pyrazoles; Suicide

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.

Topics: Albuterol; Animals; Bronchoconstrictor Agents; Bronchodilator Agents; Dogs; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hyperventilation; Hypoventilation; Macaca fascicularis; Male; Methacholine Chloride; Pharmaceutical Preparations; Piperidines; Rats; Remifentanil; Respiration; Respiratory Function Tests; Respiratory Insufficiency; Species Specificity

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Female; Haplorhini; Infusions, Intravenous; Male; Membrane Transport Proteins; Microbial Sensitivity Tests; Molecular Structure; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Solubility; Stereoisomerism

Topics: Analgesics, Opioid; Anesthetics, Intravenous; Child; Clinical Trials as Topic; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Piperidines; Remifentanil; Sumatriptan; Vasoconstrictor Agents

We describe herein an evaluation of trypanocidal effects of the natural alkaloid piperine and twelve synthetic derivatives against epimastigote and amastigote forms of the protozoan parasite Trypanosoma cruzi, the causative agent of the incurable human disease, Chagas' disease. The results obtained point to piperine as a suitable template for the development of new drugs with trypanocidal activity.

Topics: Alkaloids; Animals; Benzodioxoles; Cells, Cultured; Chagas Disease; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Humans; Inhibitory Concentration 50; Parasitic Sensitivity Tests; Piperidines; Polyunsaturated Alkamides; Trypanocidal Agents; Trypanosoma cruzi

Patients routinely cite the media, after physicians and pharmacists, as a key source of information on new drugs, but there has been little research on the quality of drug information presented. We assessed newspaper descriptions of drug benefits and harms, the nature of the effects described and the presence or absence of other important information that can add context and balance to a report about a new drug.. We looked at newspaper coverage in the year 2000 of 5 prescription drugs launched in Canada between 1996 and 2001 that received a high degree of media attention: atorvastatin, celecoxib, donepezil, oseltamivir and raloxifene. We searched 24 of Canada's largest daily newspapers for articles reporting at least one benefit or harm of any of these 5 drugs. We recorded the benefits and harms reported and analyzed how such information was presented; we also determined whether clinical or surrogate outcomes were mentioned; if and how drug effects were quantified; whether contraindications, other treatment options and costs were mentioned; and whether any information on affiliations of quoted interviewees and potential conflicts of interest was presented.. Our search yielded 193 articles reporting at least one benefit or harm for 1 of the 5 drugs. All of the articles mentioned at least one benefit, but 68% (132/193) made no mention of possible side effects or harms. Only 24% (120/510) of mentions of drug benefits and harms presented quantitative information. In 26% (31/120) of cases in which drug benefits and harms were quantified, the magnitude was presented only in relative terms, which can be misleading. Overall, 62% (119/193) of the articles gave no quantification of the benefits or harms. Thirty-seven (19%) of the 193 articles reported only surrogate benefits. Other information needed for informed drug-related decisions was often lacking: only 7 (4%) of the articles mentioned contraindications, 61 (32%) mentioned drug costs, 89 (46%) mentioned drug alternatives, and 30 (16%) mentioned nondrug treatment options (such as exercise or diet). Sixty-two percent (120/193) of the articles quoted at least one interviewee. After exclusion of industry and government spokespeople, for only 3% (5/164) of interviewees was there any mention of potential financial conflicts of interest. Twenty-six percent (15/57) of the articles discussing a study included information on study funding.. Our results raise concerns about the completeness and quality of media reporting about new medications.

Topics: Acetamides; Advertising; Anti-Inflammatory Agents, Non-Steroidal; Anticholesteremic Agents; Antiviral Agents; Atorvastatin; Bibliometrics; Canada; Celecoxib; Cholinesterase Inhibitors; Consumer Product Safety; Disclosure; Donepezil; Drug Industry; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Estrogen Antagonists; Heptanoic Acids; Humans; Indans; Newspapers as Topic; Oseltamivir; Patient Education as Topic; Piperidines; Pyrazoles; Pyrroles; Raloxifene Hydrochloride; Sulfonamides

Topics: Butyrophenones; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Piperazines; Piperidines; Professional-Patient Relations; Psychotherapy; Schizophrenia; Thioxanthenes

Topics: Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Glutethimide; Humans; Piperidines; Poisoning; Suicide

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Meperidine; Piperidines