piperidines and Pneumonia

We aimed to evaluate the risk of PARP inhibitors (PARPis) causing pneumonitis in randomized controlled trials (RCTs) and in the real-world practice.. First, a systematic review based on meta-analysis was conducted. RCTs with available data reporting pneumonitis events for PARPis were eligible for analysis. Second, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the main features of PARPi-related pneumonitis.. PARPis increased the risk of pneumonitis that can result in serious outcomes and tend to occur early. Early recognition and management of PARPi-pneumonitis is of vital importance in clinical practice. The mechanisms and risk factors should be studied further to improve clinical understanding and innovative treatment strategies for these diseases.

Topics: Adverse Drug Reaction Reporting Systems; Humans; Incidence; Indazoles; Neoplasms; Phthalazines; Piperazines; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic; Time Factors

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

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

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

The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date.. Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL.. With up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Piperidines; Pneumonia; Progression-Free Survival; Remission Induction; Survival Rate

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

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

Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling, resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with 560 mg ibrutinib orally once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed overall response rate (ORR) by 2007 International Working Group criteria. Among 63 enrolled patients, median age was 66 years (range, 30-92). Median number of prior systemic therapies was 2 (range, 1-9), and 63% received ≥1 prior chemoimmunotherapy. In 60 evaluable patients, ORR was 48% (95% confidence interval [CI], 35-62). With median follow-up of 19.4 months, median duration of response was not reached (95% CI, 16.7 to not estimable), and median progression-free survival was 14.2 months (95% CI, 8.3 to not estimable). Grade ≥3 adverse events (AEs; >5%) included anemia, pneumonia, and fatigue. Serious AEs of any grade occurred in 44%, with grade 3-4 pneumonia being the most common (8%). Rates of discontinuation and dose reductions due to AEs were 17% and 10%, respectively. Single-agent ibrutinib induced durable responses with a favorable benefit-risk profile in patients with previously treated MZL, confirming the role of BCR signaling in this malignancy. As the only approved therapy, ibrutinib provides a treatment option without chemotherapy for MZL. This study is registered at www.clinicaltrials.gov as #NCT01980628.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; B-Lymphocytes; Disease-Free Survival; Drug Administration Schedule; Fatigue; Female; Humans; Immunotherapy; Lymphoma, B-Cell, Marginal Zone; Male; Middle Aged; Piperidines; Pneumonia; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

To determine the effects of propofol and sevoflurane on cytokine levels in children with community-acquired pneumonia undergoing flexible fibreoptic bronchoscopy (FFB).. Children with community-acquired pneumonia were randomly assigned to receive 3-5 mg/kg propofol i.v. or 8% inhaled sevoflurane. Haemodynamic variables, stress hormone responses and serum cytokines were compared between the two groups.. Out of 50 children aged 2-12 years (propofol, n = 25; sevoflurane, n = 25), there were no significant between-group differences in haemodynamic variables and stress hormones. Interleukin (IL)-6 and IL-10 decreased significantly following FFB in both groups. IL-6 levels were significantly lower in the sevoflurane group than propofol group at 4 h and 1 d following FFB (61.3 ± 11.9 versus 82.6 ± 19.7 pg/ml; 52.8 ± 9.7 versus 75.4 ± 13.6 pg/ml, respectively). IL-10 levels in the sevoflurane group were significantly lower than in the propofol group at 1 d following FFB.. In children with community-acquired pneumonia, use of sevoflurane was associated with lower circulating IL-6 and IL-10 levels compared with propofol, following FFB. Pneumonia severity is reflected by higher blood cytokine levels, thus, sevoflurane may be more beneficial to recovery from community-acquired pneumonia than propofol, however further studies are required to test this hypothesis.

Topics: Anesthetics; Bronchoscopy; Child; Child, Preschool; Community-Acquired Infections; Cytokines; Demography; Female; Fiber Optic Technology; Hemodynamics; Humans; Male; Methyl Ethers; Piperidines; Pneumonia; Propofol; Remifentanil; Sevoflurane

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

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

Ertapenem has proven to be an effective antimicrobial; however, increasing enzyme-mediated resistance has been noted. Combination with zidebactam, a β-lactam enhancer, is restorative. Human-simulated regimens (HSRs) of ertapenem and zidebactam alone and in combination (WCK 6777; 2 g/2 g q24h) were assessed for efficacy against carbapenemase-producing Klebsiella pneumoniae (CP-KP) in the pneumonia model.. Infected ICR mice were rendered neutropenic and exposed to various doses of ertapenem and zidebactam alone and in combination to develop the HSRs that were subsequently confirmed in additional pharmacokinetic studies. Twenty-one CP-KP (KPC or OXA-48-like producers) with WCK 6777 MICs of 1-8 mg/L were utilized. Mice were treated for 24 h with saline or HSRs of ertapenem, zidebactam and WCK 6777. Efficacy was defined as change in mean lung bacterial density relative to 0 h.. Confirmatory pharmacokinetic analysis showed agreement between predicted human exposures (%fT>MIC) and those achieved in vivo for all three HSRs. The 0 h bacterial density across all isolates was 6.69 ± 0.31 log10 cfu/lungs. At 24 h, densities increased by 2.57 ± 0.50, 2.2 ± 0.60 and 2.05 ± 0.71 log10 cfu/lungs in the 24 h control, ertapenem HSR and zidebactam HSR groups, respectively. Overall, 18/21 of the isolates exposed to the WCK 6777 HSR displayed a killing profile that exceeded the translational benchmark for efficacy of a 1 log10 cfu reduction. Among the remaining three isolates, two displayed ∼0.5 log10 kill and stasis was observed in the third.. Human-simulated exposures of WCK 6777 demonstrated potent in vivo activity against CP-KP, including those with WCK 6777 MICs up to 8 mg/L.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Cyclooctanes; Ertapenem; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Piperidines; Pneumonia

The targeted agents capmatinib and tepotinib provide a new treatment for patients with non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutation (METex14). However, drug-induced pneumonitis is an uncommon but threatening adverse effect found in patients treated with both capmatinib and tepotinib. The safety of treating a patient with a MET inhibitor after drug-induced pneumonitis by another MET inhibitor remains unclear. Here, we present a case of a patient with NSCLC harboring a METex14 who was treated with a standard dose of tepotinib after advanced capmatinib-induced pneumonitis and did not present pneumonitis relapse. Tepotinib may be a safe option when medical professionals consider switching MET inhibitors after patients experience pneumonitis.

Topics: Benzamides; Carcinoma, Non-Small-Cell Lung; Exons; Humans; Imidazoles; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Piperidines; Pneumonia; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines; Triazines

Piperine (PIP) is a major phytoconstituent in black pepper which is responsible for various pharmacological actions such as anti-inflammatory, antioxidant, and antitumor activity. To investigate the effects and mechanisms of PIP on cigarette smoke (CS)-induced lung pathology using both in-vitro and in-vivo models. BEAS-2B and A549 cells were exposed to CS extract (CSE) for 48 h; BALB/c mice were exposed to CS (9 cigarettes/day, 4 days) to induce features of airway disease. PIP at doses of (0.25, 1.25, and 6.25 µM, in vitro; 1 and 10 mg/kg, in vivo, i.n) and DEX (1 µM, in vitro; 1 mg/kg, in vivo, i.n) were used to assess cytotoxicity, oxidative stress, epithelial−mesenchymal transition (EMT), Sirtuin1 (SIRT1), inflammation-related cellular signaling, and lung function. PIP treatment protects cells from CSE-induced lung epithelial cell death. PIP treatment restores the epithelial marker (p < 0.05) and decreases the mesenchymal, inflammatory markers (p < 0.05) in both in vitro and in vivo models. The PIP treatment improves the altered lung function (p < 0.05) in mice induced by CS exposure. Mechanistically, PIP treatment modulates SIRT1 thereby reducing the inflammatory markers such as IL-1β, IL-6 and TNF-α (p < 0.05) and enhancing the epigenetic marker HDAC2 (p < 0.05) and antioxidant marker Nrf2 (p < 0.05) expressions. Thus, PIP alleviates pulmonary inflammation by modulating the SIRT1-mediated inflammatory cascade, inhibits EMT, and activates Nrf2 signaling.

Topics: Animals; Antioxidants; Epithelial-Mesenchymal Transition; Lung; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; Nicotiana; Oxidative Stress; Piperidines; Pneumonia; Sirtuin 1; Smoke

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Methotrexate; Piperidines; Pneumonia; Pyrimidines; Pyrroles; Treatment Outcome

Topics: Aged; Colitis, Ulcerative; Female; Humans; Piperidines; Pneumonia; Protein Kinase Inhibitors; Pyrimidines

Organising pneumonia (OP) complicated by rheumatoid arthritis (RA), a rare type of interstitial lung disease, is sometimes refractory and resistant to immunosuppressive therapy. We report for the first time two cases of refractory OP with RA for which tofacitinib, an inhibitor of Janus kinase, was highly effective. Two women, aged 84 and 65 years, developed refractory OP during treatment for RA with biologics, certolizumab pegol, and etanercept. A moderate amount of prednisolone was effective in both cases; however, recurrences were observed with reduced glucocorticoid dosage. When tofacitinib was administered, OP and RA were well controlled. Thus, the glucocorticoid dosage was successfully tapered low enough until no side effects were observed. Tofacitinib therapy may be a treatment option for refractory OP.

Topics: Aged; Aged, 80 and over; Arthritis, Rheumatoid; Female; Humans; Piperidines; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome

This was a comparative assessment of WCK 5222 (cefepime/zidebactam 2/1 g as a 1 h infusion every 8 h) efficacy using human-simulated plasma and ELF exposures against serine-carbapenemase-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model.. Ten clinical isolates were utilized: eight were serine-carbapenemase-producing (KPC, n = 4; OXA-48-like, n = 4) Enterobacterales with WCK 5222 MICs (1:1) ranging from 1 to 4 mg/L; and two were previously studied MDR isolates serving as quality controls. Lungs of mice were inoculated with 50 μL of 107 cfu/mL. Treatment mice received human-simulated regimens of cefepime, zidebactam or WCK 5222 derived from plasma or epithelial lining fluid (ELF) profiles obtained from healthy subjects. Lung bacterial densities resulting from the humanized exposures in plasma and ELF were compared.. Initial lung bacterial densities ranged from 6.06 to 6.87 log10 cfu/lungs, with a mean bacterial burden increase to 9.06 ± 0.42 after 24 h. Human-simulated plasma and ELF exposures of cefepime and zidebactam monotherapy had no activity. Human-simulated WCK 5222 plasma exposures resulted in a >1 log10 cfu/lungs reduction in bacterial burden for all isolates. Humanized WCK 5222 ELF exposures achieved a >1 log10 cfu/lungs reduction for all isolates. While statistically significant differences in bacterial burden reduction were observed between the plasma and ELF exposures for WCK 5222 in 5/8 isolates, all treatments achieved the translational kill target of a >1 log10 cfu reduction.. Clinically achievable WCK 5222 plasma and ELF exposures produced in vivo killing of carbapenem-resistant Enterobacterales in the neutropenic murine pneumonia model that is predictive of efficacy in humans.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Cefepime; Cephalosporins; Cyclooctanes; Humans; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Piperidines; Pneumonia

Cannabinoids and the endocannabinoid system significantly contributes to the airway inflammation. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are two main enzymes responsible for the metabolism of the endocannabinoids anandamide (AEA) and 2-arachydonoyl glycerol (2-AG), respectively. In the present study, we aimed to investigate the effects of local and systemic FAAH and MAGL inhibitor treatments in experimental airway inflammation and tracheal hyperreactivity in mice. Airway inflammation was induced by intranasal (i.n.) lipopolysaccharide (LPS) application (60 μl; 0,1 mg/ml in PBS) to mice and the control group received PBS. Systemic (intraperitoneal (i.p.)) or local (i.n.) FAAH inhibitor URB597 and MAGL inhibitor JZL184 treatments were administered 1h before LPS/PBS application. Fourty 8 h after LPS/PBS application, tracheas were removed to assess airway reactivity, and the lungs and bronchoalveolar lavage (BAL) fluids were isolated for histopathological evaluation, cytokine and endocannabinoid measurements. LPS application lead to an increase in 5-hydroxytryptamine (5-HT) contractions in isolated tracheal rings while carbachol contractions remained unchanged. The increased 5-HT contractions were prevented by both systemic and local URB597 and JZL184 treatments. Systemic treatment with URB597 and JZL184, and local treatment with JZL184 reduced peribronchial and paranchymal inflammation in the LPS group while i.n. application of URB597 worsened the inflammation in the lungs. Systemic URB597 treatment increased lung AEA level whereas it had no effect on 2-AG level. However, JZL184 treatment increased 2-AG level by either systemic or local application, and also elevated AEA level. Inflammation-induced increase in neutrophil numbers was only prevented by systemic URB597 treatment. However, both URB597 and JZL184 treatments abolished the increased TNF-α level either they are administered systemically or locally. These results indicate that FAAH and MAGL inhibition may have a protective effect in airway inflammation and airway hyperreactivity, and therefore their therapeutic potential for airway diseases should be further investigated.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Carbamates; Cytokines; Endocannabinoids; Glycerides; Inflammation; Lipopolysaccharides; Lung; Male; Mice; Monoacylglycerol Lipases; Piperidines; Pneumonia; Polyunsaturated Alkamides; Respiratory Hypersensitivity

Interstitial pneumonitis is a rare drug adverse effect. We report two cases of cobimetinib-induced and vemurafenib-induced reversible interstitial pneumonitis. Two patients presenting a BRAF-mutated metastatic melanoma were treated with cobimetinib and vemurafenib. After 3 months, they developed severe feverish dyspnea. Thoracic imaging showed a pattern of organizing pneumonia in one case and a pattern of hypersensitivity pneumonitis in the other case. Infectious and cardiogenic causes were eliminated. An improvement was noted after discontinuation of cobimetinib, vemurafenib, and introducing steroids. Treatment was switched to dabrafenib (a BRAF inhibitor) with no recurrence of drug pneumonitis. To the best of our knowledge, it appears that cases of targeted-therapy-induced pneumonitis are predominantly an MEK-inhibitor effect. We, therefore, propose a management strategy of discontinuing targeted therapy, introducing steroid treatment and switching to dabrafenib.

Topics: Aged; Azetidines; Female; Humans; Male; Middle Aged; Piperidines; Pneumonia; Vemurafenib

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Topics: Anemia; Creatinine; Drug Administration Schedule; Drug Interactions; Exanthema; Fatigue; Female; Genes, BRCA1; Genes, BRCA2; Heart Rate; Humans; Hypertension; Indazoles; Leukopenia; Mutation; Myelodysplastic Syndromes; Nasopharyngitis; Nausea; Ovarian Neoplasms; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Thrombocytopenia; Transaminases; Vomiting

In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly "biological drugs." One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib. The first case was a 70-year-old woman with relapsed CLL who developed bilateral pneumonia with hypoxia 1 week after starting ibrutinib. She did not respond to broad-spectrum antibiotics and was treated empirically with trimethoprim-sulphamethoxazole and improved. In the second case, we describe a 76-year-old woman with relapsed CLL who developed recurrent pneumonia after 3 years of treatment with ibrutinib. Presuming that ibrutinib was the cause of pneumonitis with secondary infection, it was stopped with subsequent improvement. The third patient a 67 year-old man died because of severe bilateral necrotizing pneumonia due to invasive aspergillosis and mucormycosis with pulmonary hemorrhage. The fourth patient with relapsed mantle cell lymphoma died because of severe bilateral pneumonia, caused by pseudomonas and candida, despite receiving appropriate antibiotics. From this experience, we hypothesize that the etiology of severe pneumonia associated with ibrutinib treatment is probably multifactorial, involving factors like preexisting immune-suppression, drug induced pneumonitis and infections. We suggest that patients with CLL or other lymphoproliferative disorders with suspected pneumonia during monotherapy with ibrutinib should be very carefully evaluated and need to undergo complete diagnostic workup to establish an exact diagnosis. Understanding which patients with CLL or lymphoma treated with kinase inhibitors are at a higher risk for developing pulmonary complications could be one of the important future challenges, when selecting the best available therapy for these patients.

Topics: Adenine; Aged; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Piperidines; Pneumonia; Pyrazoles; Pyrimidines

Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger RNA levels. In vitro cell permeability and electric cell-substrate impedance sensing assays demonstrated that MC4 inhibited TNFα- and thrombin-mediated pulmonary endothelial cell permeability better than FK866. MC4 also exerted more potent effects than FK866, at concentrations as low as 0.3 nM, to attenuate TNFα-mediated intracellular cytokine expression, nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH levels, and nuclear factor kappa B p65 phosphorylation and nuclear translocation in A549 cells. Our results strongly suggest that the newly developed MC4 is a more potent suppressor of CLP-induced pulmonary inflammation and sepsis than FK866, with potential clinical application as a new treatment agent for sepsis and inflammation.

Topics: Acrylamides; Acrylates; Animals; Boron Compounds; Cecum; Dose-Response Relationship, Drug; Humans; Ligation; Male; Mice; Mice, Inbred C57BL; Piperidines; Pneumonia; Sepsis; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Triggering receptors expressed on myeloid cell-1 (TREM-1) is a superimmunoglobulin receptor expressed on myeloid cells. TREM-1 amplifies the inflammatory response. Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 enzyme, have anti-inflammatory properties. However, the effects of EETs on TREM-1 expression under inflammatory stimulation remain unclear. Therefore, inhibition of soluble epoxide hydrolase (sEH) with a highly selective inhibitor [1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, TPPU] was used to stabilize EETs. LPS was intratracheally injected into mice to induce pulmonary inflammation, after TPPU treatment for 3 h. Histological examination showed TPPU treatment-alleviated LPS-induced pulmonary inflammation. TPPU decreased TREM-1 expression, but not DAP12 or MyD88 expression. Murine peritoneal macrophages were challenged with LPS in vitro. We found that TPPU reduced LPS-induced TREM-1 expression in a dose-dependent manner, but not DAP12 or MyD88 expression. TPPU also decreased downstream signal from TREM-1, reducing pro-inflammatory cytokine TNF-α and IL-1β mRNA expression. Furthermore, TPPU treatment inhibited IkB degradation in vivo and in vitro. Our results indicate that the inhibition of sEH suppresses LPS-induced TREM-1 expression and inflammation via inhibiting NF-kB activation in murine macrophage.

Topics: Animals; Cells, Cultured; Cytokines; Epoxide Hydrolases; Gene Expression; I-kappa B Proteins; Macrophages; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Myeloid Cells; NF-kappa B; Phenylurea Compounds; Piperidines; Pneumonia; Receptors, Immunologic; Solubility; Triggering Receptor Expressed on Myeloid Cells-1

Persons with Alzheimer's disease are at an increased risk of pneumonia, but the comparative risks during specific antidementia treatments are not known. We compared the risk of pneumonia in the use of donepezil, rivastigmine (oral, transdermal), galantamine and memantine.. We used data from a nationwide cohort of community-dwelling individuals diagnosed with Alzheimer's disease during 2005-2011 in Finland, who initiated monotherapy with acetylcholinesterase inhibitor or memantine (n = 65,481). The risk of hospitalization or death due to pneumonia was investigated with Cox proportional hazard models.. The risk of pneumonia was higher in persons using rivastigmine patch (n = 9709) (adjusted hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04-1.27) and memantine (n = 11,024) (HR 1.59, 95% CI 1.48-1.71) compared with donepezil users (n = 26,416) whereas oral rivastigmine (n = 7384) (HR 1.08, 95% CI 0.98-1.19) and galantamine (n = 10,948) (HR 0.91, 95% CI 0.83-1.00) were not associated with an increased risk. These results did not change when adjusting for comorbid conditions, use of psychotropic drugs or with inverse probability of treatment weighting.. The increased risk of pneumonia in this fragile group of aged persons should be taken into account. Memantine is associated with the highest risk in the comparison of antidementia drugs. KEY Message Pneumonia risk is increased in persons with Alzheimer's disease who use memantine or rivastigmine patches.

Topics: Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Female; Finland; Galantamine; Hospitalization; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Pneumonia; Risk; Rivastigmine

The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model.. Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o.. Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue.. In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.

Topics: Animals; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Inflammation; Janus Kinases; Lipopolysaccharides; Lung; Male; Neutrophils; Phosphorylation; Piperidines; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor

Topics: Cholinesterase Inhibitors; Dementia; Female; Galantamine; Humans; Indans; Male; Phenylcarbamates; Piperidines; Pneumonia

Topics: Cholinesterase Inhibitors; Dementia; Female; Galantamine; Humans; Indans; Male; Phenylcarbamates; Piperidines; Pneumonia

Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Chromosome Deletion; Disease-Free Survival; Drug Resistance, Neoplasm; Fatigue; Female; Follow-Up Studies; Humans; Hypertension; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Pyrazoles; Pyrimidines; Recurrence; Remission Induction; Time Factors; Treatment Outcome; Young Adult

To compare the risk of pneumonia in older adults receiving donepezil, galantamine, or rivastigmine for dementia.. Retrospective cohort study.. Nationally representative 5% sample of Medicare databases.. Medicare beneficiaries aged 65 and older who newly initiated cholinesterase inhibitor therapy between 2006 and 2009.. Pneumonia, defined as the presence of a diagnosis code for pneumonia as the primary diagnosis on an inpatient claim or on an emergency department claim followed by dispensing of appropriate antibiotics. Cox proportional hazards models were used to estimate the risk of pneumonia. Subgroup analyses and sensitivity analyses were conducted using alternative pneumonia definitions and adjustments using high-dimensional propensity scores to test the robustness of the results.. The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person-years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR)=0.75, 95% confidence interval (CI)=0.60-0.93). Risk in galantamine users (HR=0.87, 95% CI=0.62-1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results.. The risk of pneumonia was lower in individuals receiving rivastigmine than in those receiving donepezil. Additional studies are needed to confirm the findings of pneumonia risk between the oral and transdermal forms of rivastigmine and in users of galantamine.

Topics: Aged; Aged, 80 and over; Cholinesterase Inhibitors; Cohort Studies; Dementia; Donepezil; Female; Galantamine; Humans; Indans; Male; Phenylcarbamates; Piperidines; Pneumonia; Retrospective Studies; Risk Assessment; Rivastigmine

We investigated the role of intracerebroventricular (ICV) injection of rimonabant (500ng), a CB1 antagonist, on lipopolysaccharide ((LPS) 5mg/kg)-induced pulmonary inflammation in rats in an isolated perfused lung model. There were decreases in pulmonary capillary pressure (Ppc) and increases in the ((Wet-Dry)/Dry lung weight)/(Ppc) ratio in the ICV-vehicle/LPS group at 4h. There were decreases in TLR4 pathway markers, such as interleukin receptor-associated kinase-1, IκBα, Raf1 and phospho-SFK (Tyr416) at 30min and at 4h increases in IL-6, vascular cell adhesion molecule-1 and myeloperoxidase in lung homogenate. Intracerebroventricular rimonabant attenuated these LPS-induced responses, indicating that ICV rimonabant modulates LPS-initiated pulmonary inflammation.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Injections, Intraventricular; Lipopolysaccharides; Lung; Male; Peroxidase; Piperidines; Pneumonia; Pulmonary Edema; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction; Time Factors; Toll-Like Receptor 4

Pulmonary fibrosis (PF) is a progressing lung injury initiated by pulmonary inflammation (PI). Bleomycin (BLM) is the most common pathogenesis of PF through early PI and extensive extracellular matrix deposition. This study is aimed to determine whether NO-releasing KMUP-1 inhibits PI and PF, and if so, the benefits of KMUP-1S resulted from simvastatin (SIM)-bonding to KMUP-1.. C57BL/6 male mice were intra-tracheally administered BLM (4 U/kg) at day 0. KMUP-1 (1-5 mg/kg), KMUP-1S (2.5 mg/kg), SIM (5 mg/kg), Plus (KMUP-1 2.5 mg/kg + SIM 2.5 mg/kg), and clarithromycin (CAM, 10 mg/kg) were orally and daily administered for 7 and 28 days, respectively, to mice, sacrificed at day-7 and day-28 to isolate the lung tissues, for examining the inflammatory and fibrotic signaling and measuring the cell population and MMP-2/MMP-9 activity in broncholaveolar lavage fluid (BAL).. KMUP-1 and KUP-1S significantly decreased neutrophil counts in BAL fluid. Fibroblastic foci were histologically assessed by H&E and Masson's trichrome stain and treated with KMUP-1 and references. Lung tissues were determined the contents of collagen and the expressions of TGF-β, α-SMA, HMGB1, CTGF, eNOS, p-eNOS, RhoA, Smad3, p-Smad3, MMP-2 and MMP-9 by Western blotting analyses, respectively. These changes areregulated by NO/cGMP and inhibited by various treatments. KMUP-1 and KMUP-1S predominantly prevented HMGB1/MMP-2 expression at day-7 and reduced TGF-β/phosphorylated Smad3 and CTGF at day-28.. KMUP-1 and KMUP-S restore eNOS, inhibit iNOS/ROCKII/MMP-2/MMP-9, attenuate histologic collagen disposition and reduce BALF inflammatory cells, potentially useful for the treatment of BLM-lung PF.

Topics: Animals; Bleomycin; Blotting, Western; Bronchoalveolar Lavage Fluid; Clarithromycin; Disease Models, Animal; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Piperidines; Pneumonia; Pulmonary Fibrosis; Signal Transduction; Simvastatin; Time Factors; Xanthines

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (Ri) from 19 to 7 h and improved organ dysfunction with enhanced alveolar-capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (Ri; 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation.

Topics: Animals; Apoptosis; Caspases; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Lung; Macrophages; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neutrophil Infiltration; Neutrophils; Piperidines; Pneumonia; Pyrazoles

We previously identified the intracellular nicotinamide phosphoribosyltransferase (iNAMPT, aka pre-B-cell colony enhancing factor) as a candidate gene promoting acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) with circulating nicotinamide phosphoribosyltransferase potently inducing NF-κB signaling in lung endothelium. iNAMPT also synthesizes intracellular nicotinamide adenine dinucleotide (iNAD) in response to extracellular oxidative stress, contributing to the inhibition of apoptosis via ill-defined mechanisms. We now further define the role of iNAMPT activity in the pathogenesis of ARDS/VILI using the selective iNAMPT inhibitor FK-866. C57/B6 mice were exposed to VILI (40 ml/kg, 4 h) or LPS (1.5 mg/kg, 18 h) after osmotic pump delivery of FK-866 (100 mg/kg/d, intraperitoneally). Assessment of total bronchoalveolar lavage (BAL) protein, polymorphonuclear neutrophil (PMN) levels, cytokine levels (TNF-α, IL-6, IL-1α), lung iNAD levels, and injury scores revealed that FK-866-mediated iNAMPT inhibition successfully reduced lung tissue iNAD levels, BAL injury indices, inflammatory cell infiltration, and lung injury scores in LPS- and VILI-exposed mice. FK-866 further increased lung PMN apoptosis, as reflected by caspase-3 activation in BAL PMNs. These findings support iNAMPT inhibition via FK-866 as a novel therapeutic agent for ARDS via enhanced apoptosis in inflammatory PMNs.

Topics: Acrylamides; Animals; Anti-Inflammatory Agents; Apoptosis; Bronchoalveolar Lavage Fluid; Caspase 3; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Inflammation Mediators; Lung; Mice; Mice, Inbred C57BL; NAD; Neutrophils; Nicotinamide Phosphoribosyltransferase; Piperidines; Pneumonia; Respiratory Distress Syndrome; Ventilator-Induced Lung Injury

This study determines whether KMUP-1 inhalation suppresses ovalbumine (OVA)-sensitized and - challenged peri-bronchial vascular inflammation and remodeling in mice.. After short-term KMUP-1 (1-5 mM, 30 min)-nebulization and L-NAME (12 mM, 15 min)- pretreatment, endothelial nitric oxide synthase (eNOS) and matrix metalloproteinases-9 (MMP-9) expression in lung were measured by Western blotting analysis. In 28-days experiment, mice were sensitized with intraperitoneal OVA on day 1 and day 8, challenged with OVA nebulization and treated with KMUP-1 nebulization (5 mM, 30 mins) on day 21-27. Expression of eNOS, inducible nitric oxide synthase (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), MMP-9, VCAM-1 and ICAM-1 were measured by Western blotting analysis. eNOS- and MMP-9-immunostaining were used for peri-vascular or peri-bronchial localization. Hematoxylin and eosin staining was used to show the vascular and bronchial wall thickness and infiltration of inflammatory cells. Cell counting and measurement of NOmetabolite (NOx) in bronchoalveolar lavage fluid (BALF) were used to examine the NO production. KMUP-1 increased eNOS and decreased MMP-9 expression. L-NAME-pretreatment reversed these changes. KMUP-1 reduced OVA-sensitized vascular and bronchial wall thickening, eNOS-immunostaining at the alveolar septa, MMP-9-immunostaining in the bronchioles and infiltrated inflammatory cells in the peri-vascular and peri-bronchiolar regions. The OVA-sensitized decrease of sGC and PKG and increase of iNOS, ICAM-1/VCAM-1 and plasma cytokines IL-5/IL-13 were reversed; cell count, NOx and MMP-9-activity in BALF were decreased by KMUP-1.. Inhaled KMUP-1, preventing allergic pulmonary vascular inflammation and remodeling, would be useful for the treatment of asthma and respiratory obstruction disease.

Topics: Airway Remodeling; Animals; Bronchi; Cyclic GMP-Dependent Protein Kinases; Female; Guanylate Cyclase; Hypersensitivity; Intercellular Adhesion Molecule-1; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperidines; Pneumonia; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vascular Cell Adhesion Molecule-1; Xanthines

We tested the potential role of the mAChR in lipopolysaccharide (LPS)-induced inflammatory response in in vivo and in vitro models and a possible signaling pathway involved in the inflammatory process.. Anesthetized mice were challenged with intratracheal LPS to induce acute lung injury. The cytology and histopathology changes, expression of cytokines and pulmonary vascular permeability were used to evaluate the effects of the cholinergic agent. Alveolar macrophage cell line NR8383 was also used to confirm the role of mAChRs and the molecular mechanisms underlying the LPS-induced events.. LPS-induced acute lung injury (ALI) was significantly improved by atropine (a non-selective mAChR antagonist) and 4-DAMP (a M3 mAChR antagonist), as indicated by the diminution of neutrophil infiltration, pulmonary vascular permeability and IL-6 and TNF-α production. LPS-induced TNF-α production from the alveolar macrophage was significantly inhibited by atropine and 4-DAMP, but not pirenzepine (a M1 mAChR antagonist) and methoctramine (a M2 mAChR antagonist). Interestingly, LPS-induced TNF-α production was enhanced by the muscarinic receptor agonist pilocarpine, and treatment with pilocarpine alone was able to trigger TNF-α production from the alveolar macrophage, which was effectively attenuated by 4-DAMP. Western blot analysis showed that LPS-induced degradation of IκBα was strongly blocked by atropine/4-DAMP both in vivo and in vitro, indicating that M3 mAChR was involved in LPS-induced lung inflammation by mediating the NF-κB signaling pathway.. Our findings bring the evidence that the blockage of mAChR exerts anti-inflammatory properties, in which the M3 mAChR plays an important role in the LPS-induced lung inflammation.

Topics: Acute Lung Injury; Animals; Atropine; Cell Line; Lipopolysaccharides; Macrophages, Alveolar; Male; Mice; Muscarinic Antagonists; NF-kappa B; Piperidines; Pneumonia; Receptor, Muscarinic M3

Cholinesterase inhibitors (ChEIs) may interact with muscle relaxants given during general anesthesia (GA), increasing the risk of postoperative complications. We evaluated the effects of ChEIs on the postoperative outcomes of older adults who underwent hip fracture surgery.. Population-based cohort study using linked administrative databases.. All individuals with dementia age 66 years or older, who underwent hip fracture surgery between April 1, 2003, and December 31, 2007, in Ontario, Canada.. Use of any ChEI (donepezil, rivastigmine, or galantamine) before surgery.. The primary composite outcome included any of the following: 30-day postoperative mortality; intensive care unit admissions; or in-hospital resuscitation. Secondary outcomes included postoperative respiratory failure and pneumonia.. We stratified the study sample on the basis of residence (community or long-term care [LTC]) and type of anesthetic (general or regional) to create four residence/anesthesia groups. We used propensity scores to match users and nonusers of ChEIs within the residence/anesthesia strata. We then calculated the relative risks (RR) and 95% confidence intervals (CI) for outcomes associated with ChEIs in the matched groups.. A total of 624 pairs of individuals from the community and 725 pairs from LTC were created among individuals who received GA. High rates of postoperative mortality and complications were observed in both ChEI users and nonusers. The RR of the primary outcome associated with ChEI use for individuals receiving GA was 0.88 (95% CI: 0.68-1.16; χ2 = 0.93; df = 1; p = 0.34) and 0.82 (95% CI: 0.63-1.04; χ2 = 2.59; df = 1; p = 0.11) in the community and LTC groups, respectively. In addition, ChEIs were not associated with any significant increased risk of postoperative respiratory complications.. ChEI use was not associated with an increased risk of postoperative complications among older adults with dementia who underwent hip fracture surgery. However, the poor postoperative outcomes overall reinforced the need to prevent fractures and improve outcomes in this population.

Topics: Aged; Aged, 80 and over; Anesthesia, General; Cholinesterase Inhibitors; Cohort Studies; Critical Care; Dementia; Donepezil; Female; Galantamine; Hip Fractures; Humans; Indans; Male; Outcome and Process Assessment, Health Care; Phenylcarbamates; Piperidines; Pneumonia; Postoperative Complications; Respiratory Insufficiency; Resuscitation; Risk; Rivastigmine

Repaglinide is an FDA-approved treatment for type 2 diabetes mellitus. The anti-inflammatory effect of repaglinide in the absence of diabetes has not been reported previously. It is the objective of this set of studies to investigate the potential anti-inflammatory effects of repaglinide.. The in vivo anti-inflammatory effects of repaglinide were studied in two different models of delay type hyperreactivity (DTH) response induced by sheep red blood cells (sRBC) and 2,5'-dinitrofluorobenzene (DNFB), and in two different rodent models of lipopolysaccharide (LPS) challenge.. In mice systemically sensitized with sRBC, which subsequently received a local injection of sRBC in the footpad, local swelling occurred within 24 h after challenge. Repaglinide was efficacious in attenuating this response. In an orthogonal DTH model using DNFB as the antigen, the animals received topical sensitization with DNFB on their shaved backs, followed by topical challenge on the left ears. Repaglinide efficaciously downregulated the resulting ear swelling response. In mice challenged systemically or intratracheally with LPS, repaglinide significantly decreased serum tumor necrosis factor α level and bronchial alveolar lavage fluid MCP-1 levels, respectively.. This set of data suggests novel anti-inflammatory effects of repaglinide in nondiabetic animals. However, the high dose required for an efficacious effect would make this application impractical in the clinic.

Topics: Animals; Anti-Inflammatory Agents; Carbamates; Chemokine CCL2; Dinitrofluorobenzene; Ear; Erythrocytes; Foot; Hypersensitivity, Delayed; Immunologic Factors; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Piperidines; Pneumonia; Sheep; Tumor Necrosis Factor-alpha

Topics: Aged; Antipsychotic Agents; Delirium; Humans; Male; Piperazines; Piperidines; Pneumonia; Psychiatric Status Rating Scales; Psychomotor Agitation; Risperidone

To assess efficacy of remifentanil in preterm newborns during mechanical ventilation.. Remifentanil was administered by continuous intravenous infusion to provide analgesia and sedation in 48 preterm infants who developed respiratory distress and required mechanical ventilation. We examined the doses needed to provide adequate analgesia, extubation time after the discontinuation of opioid infusion, the presence of side effects and safety of the use.. Remifentanil provided adequate analgesia, with a significant reduction of NIPS and COMFORT score since 1 h after starting the infusion of remifentanil. The drug was initially administered at a dose of 0.075 microg/kg/min, but in 73% of newborns the latter had to be increased; at a dose of 0.094 +/- 0.03 (mean +/- standard deviation) microg/kg/min, 97% of the newborns received adequate analgesia and sedation. The time elapsed between the discontinuation of remifentanil infusion and extubation was 36 +/- 12 min. Treatment was started between the 1st and the 17th day of life. The mean duration of therapy was 5.9 +/- 5.7 days. No side effects on the respiratory or cardiovascular system were observed.. Remifentanil is a manageable and effective opioid in the newborn undergoing mechanical ventilation, though randomized controlled trials and information about long-term outcomes are necessary.

Topics: Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Multivariate Analysis; Pain Measurement; Piperidines; Pneumonia; Remifentanil; Respiration, Artificial; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Respiratory Mechanics

Secretory phospholipases A2 (sPLA2s) induce acute pancreatitis when injected into the common bile duct of rats. Substance P via neurokinin 1 (NK-1) receptors and bradykinin via B2 receptors are described to play important roles in the pathophysiology of acute pancreatitis. This study was undertaken to evaluate the role of substance P and bradykinin in the sPLA2-induced pancreatitis.. Rats were submitted to the common bile duct injection of sPLA2 obtained from Naja mocambique mocambique venom at 300 microg/kg. At 4 hours thereafter, measurement of pancreatic plasma extravasation, pancreatic and lung myeloperoxidase (MPO), serum amylase, and serum tumor necrosis factor alpha levels were evaluated.. Injection of sPLA2 significantly increased all parameters evaluated. Pretreatment with either the NK-1 receptor antagonist SR140333 or the B2 receptor antagonist icatibant largely reduced the increased pancreatic plasma extravasation and circulating levels of tumor necrosis factor alpha. Both treatments partly reduced the MPO levels in the pancreas, whereas in the lungs, icatibant was more efficient to reduce the increased MPO levels. In addition, icatibant largely reduced the serum levels of amylase, whereas SR140333 had no significant effect.. We concluded that NK-1 and B2 receptors can regulate important steps in the local and remote inflammation during acute pancreatitis induced by sPLA2.

Topics: Acute Disease; Amylases; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Lung; Male; Neurokinin-1 Receptor Antagonists; Pancreas; Pancreatitis; Peroxidase; Phospholipases A2, Secretory; Piperidines; Pneumonia; Quinuclidines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Receptors, Neurokinin-1; Substance P; Tumor Necrosis Factor-alpha

Eosinophilic chemokines and histamine play distinct but important roles in allergic diseases. Inhibition of both eosinophilic chemokines and histamine, therefore, is an ideal strategy for the treatment of allergic inflammation, such as asthma, allergic rhinitis, and atopic dermatitis. YM-344484 was found to potently inhibit both the CCL11-induced Ca2+ influx in human CCR3-expressing cells (Kb=1.8 nM) and histamine-induced Ca2+ influx in histamine H1 receptor-expressing PC3 cells (Kb=47 nM). YM-344484 also inhibited the CCL11-induced chemotaxis of human CCR3-expressing cells (IC50=6.2 nM) and CCL11-induced eosinophil-derived neurotoxin release from human eosinophils (IC50=19 nM). Orally administered YM-344484 inhibited the increase in histamine-induced vascular permeability in mice (82% inhibition at a dose of 10 mg/kg) and the accumulation of eosinophils in a mouse asthma model (74% at a dose of 300 mg/kg). These results indicate that YM-344484, a novel and functional dual antagonist for chemokine CCR3 receptor and histamine H1 receptor, is an attractive candidate for development as a novel anti-allergic inflammation drug.

Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Asthma; Calcium Signaling; Capillary Permeability; Cell Line, Tumor; Chemotaxis; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Histamine; Histamine Antagonists; Humans; Mice; Mice, Inbred BALB C; Ovalbumin; Piperidines; Pneumonia; Pulmonary Eosinophilia; Pyridazines; Rats; Receptors, CCR3; Receptors, Chemokine; Receptors, Histamine H1; Skin; Transfection

The participation of endothelins (ETs) in a model of neutrophil-dependent lung injury induced by intrabronchial instillation of rabbit antibodies to ovalbumin followed by i.v. injection of the antigens (Arthus reaction) was investigated. Hemorrhagic lesions were evaluated by measuring the extravasations of hemoglobin in lung parenchyma. From 5 min to 24 h after the Arthus reaction (AR), endothelin (ir-ET) levels in bronchoalveolar lavage fluid (BALF) and in plasma were measured by radioimmunoassay. BALF levels of ir-ET were not different between control and AR animals for the first 90 min after the antigen challenge but increased from 2 to 24 h after induction of AR. ET levels in the plasma did not change from the respective controls over the same 24 h period. Increased ir-ET in BALF was not affected by pretreatment with L-NAME (30 mg/kg, i.v.). A PAF antagonist (BN52021; 5 and 10 mg/kg, i.v.) increased ET content in BALF and decreased the intensity of the AR. Thiorphan (2 mg/kg, i.v.) inhibited the AR-induced hemorrhagic lesions in lungs. An ET(A) receptor antagonist, BQ-123 (1 mg/kg, i.v.) potentiated, whereas the ET(B) antagonist, BQ-788 (1 mg/kg, i.v.) inhibited the lung hemorrhage. It is concluded that ETs are released during and play a role in the lung AR.

Topics: Animals; Antigen-Antibody Complex; Arthus Reaction; Bronchoalveolar Lavage Fluid; Diterpenes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelins; Fibrinolytic Agents; Ginkgolides; Hemoglobins; Hemorrhage; Lactones; Lung Diseases; Male; Neutrophils; Oligopeptides; Ovalbumin; Peptides, Cyclic; Piperidines; Pneumonia; Rats; Rats, Wistar

In this study, we have examined the effect of endothelin (ET) receptor antagonists on lung granulocyte inflammation after antigen challenge in sensitized mice. The antagonists used were BQ-123, an ETA antagonist, BQ-788, an ETB antagonist, and SB209670, an ET(A&B) antagonist. Thirty minutes prior exposure to aerosolized ovalbumin, ET antagonists (50 pmol/mouse) were administered directly into the lungs of sensitized Balb/c mice via the intranasal route. BQ-123 and SB209670 significantly decreased eosinophil number in the bronchoalveolar lavage fluid by 47 and 68%, respectively. Both compounds also inhibited neutrophil infiltration into the lungs. In contrast, BQ-788 did not affect granulocyte infiltration. A similar inhibition of lung eosinophilia was also obtained with an anti-ET antibody applied via the intranasal route. BQ-123 and SB209670, but not BQ-788, significantly increased the production of interferon-gamma (Th1 cytokine) from purified lung Thy1.2+ cells without affecting interleukin-4 and interleukin-5 (Th2 cytokines) secretion. Furthermore, neutralizing antibody against interferon-gamma prevented the inhibitory effect of the ETA antagonist. Taken together, these results suggest an important pathophysiologic role for ET in the development of lung inflammation in asthma and highlight the potential of ET antagonists for the treatment of the disease.

Topics: Administration, Intranasal; Aerosols; Animals; Antibodies, Monoclonal; Antigens; Bronchoalveolar Lavage Fluid; Cell Movement; Endothelin Receptor Antagonists; Endothelins; Granulocytes; Interferon-gamma; Interleukin-4; Interleukin-5; Lung; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Ovalbumin; Peptides, Cyclic; Piperidines; Pneumonia

The effects of saline (control, group C) and metrenperone (treated, group M) on systemic and pulmonary hemodynamics were determined in conscious 7- to 15-day-old calves after they were intratracheally inoculated with Pasteurella haemolytica. Metrenperone, a specific serotonin (5-hydroxytryptamine) receptor antagonist, was injected intramuscularly (100 micrograms.kg-1) 2 h after the calves were inoculated. Central venous, pulmonary arterial and capillary wedge, and systemic arterial pressures were measured, using fluid-filled catheters. Cardiac output was measured by the thermodilution technique. Heart rate, stroke volume, and pulmonary and systemic vascular resistances were calculated. The parameters were measured hourly from the 1st to the 10th h after inoculation. In group C, cardiovascular response to P. haemolytica inoculation was marked and typically consisted of two systemic hypotensive phases and two pulmonary hypertensive phases. The first phase occurred by the 2nd h post inoculation and was induced by a transient bradycardia and a systemic vasodilation, leading to profound hypotension and reduced venous return. Cardiac performance then transiently recovered, but systemic hypotension persisted. The second hypotensive hypodynamic phase occurred by the 7th h after inoculation, and was associated with a decline in stroke volume, an increase in heart rate, and pulmonary hypertension and vasoconstriction. In group M, the early response to P. haemolytica exposure was similar to that in controls, indicating that, as in sheep, 5-hydroxytryptamine does not contribute to the early hypodynamic response to endotoxemia. In contrast, metrenperone completely abolished late increases in pulmonary arterial pressure and pulmonary vascular resistance, suggesting that 5-hydroxytryptamine contributes to the late pulmonary vasoconstriction. Metrenperone treatment also allowed better restoration of heart rate, and hence, cardiac output was maintained. In conclusion, 5-hydroxytryptamine might have a role in mediating pasteurellic endotoxin induced changes in pulmonary hemodynamics through its type-2 receptors.

Topics: Analysis of Variance; Animals; Carbon Dioxide; Cattle; Heart Rate; Hemodynamics; Lung; Male; Mannheimia haemolytica; Pasteurella Infections; Piperidines; Pneumonia; Serotonin Antagonists; Vascular Resistance

Deficiencies in the immune system that lead to increased morbidity and mortality from infectious complications have been well documented in patients suffering from trauma, malnutrition, sepsis, and thermal injuries. We investigated the potential benefit of immune stimulation for preventing infection in such conditions in an animal model by evaluating three drugs: Corynebacterium parvum, thymopentin (TP-5), and CP-46,665. One-hundred eighty female guinea pigs were rendered immunodeficient by first inflicting a 30% total body surface burn and then placing the animals on diets with calories inadequate to maintain body weight. One half of the animals were then given one of the three immunomodulators on the first, third, and fifth days after burn injury, to try to reverse immunodeficiency. The remaining animals received saline solution injections. Animal responses were evaluated by inserting a clot containing Escherichia coli and Bacillus fragilis into their peritoneal cavity 6 days after burn injury. The animals were followed for 21 days after burn injury. Autopsies on those that died revealed peritonitis and/or pneumonia; autopsies on these that survived showed no pneumonia and there was consistent resolution of peritonitis. TP-5 and CP-46,665, but not C. parvum, significantly improved survival rates and mean survival time in those animals receiving 100 kcal/kg/day. TP-5 and CP-46,665 may be of benefit to the severely stressed, malnourished surgical patient who is at risk of bacterial infection.

Topics: Adjuvants, Immunologic; Animals; Bacterial Vaccines; Burns; Female; Guinea Pigs; Nutrition Disorders; Peptide Fragments; Peritonitis; Piperidines; Pneumonia; Propionibacterium acnes; Thymopentin; Thymopoietins