piperidines and Asthma

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

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

The ARIA (Allergic Rhinitis and its Impact on Asthma) guidelines development group examined the properties of oral H(1)-antihistamines and made proposals about an 'optimal' drug. Several criteria should be met by oral H(1)-antihistamines in terms of their pharmacological, and clinical efficacy and safety profiles.. Bilastine, a new H(1)-antihistamine, has been approved in 28 European countries for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children older than 12 years. To determine its potential place in therapy in the treatment of allergic rhinitis, this manuscript examines whether bilastine meets the criteria defined in the European Academy of Allergy and Clinical Immunology (EAACI)/ARIA proposals for oral H(1)-antihistamines.. The optimal properties of oral H(1)-antihistamines and current ARIA recommendations for their use in allergic rhinitis are presented, as well as relevant pharmacological and clinical data for bilastine obtained from the published literature that specifically address the defined criteria.. Bilastine is a potent inhibitor of the histamine H(1) receptor. Data from preclinical studies have confirmed its selectivity for the histamine H(1) receptor over other receptors, and demonstrated antihistaminic properties in vitro and in vivo. Bilastine does not interfere with the cytochrome P450 system and is devoid of cardiac side effects. Studies in healthy volunteers and patients have shown that bilastine does not affect driving ability, cardiac conduction or alertness. In large pivotal randomized, placebo-controlled trials (RCTs), bilastine had a favourable safety profile. Bilastine 20 mg once daily improved all nasal and ocular symptoms of allergic rhinitis with greater efficacy than placebo and comparable to that of cetirizine and desloratadine. Moreover, bilastine was shown to improve quality of life, an important outcome of RCTs in allergic diseases. There were no significant changes in laboratory tests, electrocardiograms or vital signs. A potential limitation of this assessment of bilastine is that it is a literature-based review and the findings are dependent upon the quality of the published evidence.. Bilastine meets current EAACI/ARIA criteria for medications used in the treatment of allergic rhinitis.

Topics: Adolescent; Adult; Anti-Allergic Agents; Asthma; Benzimidazoles; Child; Humans; Piperidines; Practice Guidelines as Topic; Rhinitis, Allergic, Perennial

Topics: Alzheimer Disease; Animals; Asthma; Dermatitis, Atopic; Drug Design; Enzyme Inhibitors; Humans; Intramolecular Oxidoreductases; Leukodystrophy, Globoid Cell; Lipocalins; Muscular Dystrophies; Niacinamide; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyrimidines; Rhinitis, Allergic, Perennial; Spinal Cord Injuries; Thiazoles

Despite optimal treatment, asthma symptoms in about 5-10% of patients remain poorly controlled. Apart from having an impact on their asthma-related quality of life and adverse effects of the medications used (especially corticosteroids), their severe symptoms also impact healthcare resources due to frequent admission and requirement for intensive medications use. The last decade has seen an improved understanding in the pathophysiology of the complex cellular and molecular networks involved in the inflammatory and immunological phenotype of severe asthma. This knowledge may help providing strategies by which these phenotypes operate and pave the way for drug development and individualized treatment.. Here we review the current evidence of biological agents in patients with severe asthma recently assessed for safety and efficacy. Some of these agents have shown to be useful in specifically targeted subpopulations of patients with severe asthma, whereas others have proven to be unsafe and/or unsuccessful. In addition, we discuss recent data on clinical and pharmacokinetic-pharmacodynamic aspects of omalizumab, the only licensed anti-IgE therapy for severe atopic asthma.. More basic science work is required to improve the current understanding of severe asthma pathophysiology and proof-of-concept clinical studies are required to explore relevant biomolecular targets in this small subset of patients. At present, only one drug is licensed for allergic asthmatic patients with severe disease, omalizumab. Novel therapies in the form of oligonucleotide therapies and other biological agents are also being investigated in the difficult-to-treat asthmatic patient group.

Topics: Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Asthma; Benzamides; Biological Products; Daclizumab; Humans; Immunoglobulin G; Omalizumab; Piperidines; Pyridines; Receptors, Interleukin-4; Thiazoles; Treatment Outcome; Tumor Necrosis Factor-alpha

Asthma is a chronic inflammatory respiratory disease accompanied with airway inflammation, airway remodeling and bronchial hyperresponsiveness. Chemokines are important for the recruitment of immune cells to the lung, which play an important role in the formation and development of asthma. Targeting the chemokine receptors to anti-inflammation and anti-asthma is a new strategy and some candidate drugs are discovered recently. This review is focused on the development of chemokine receptor antagonists for anti-asthma, which will promote the compound designations.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Benzylamines; Cyclams; Heterocyclic Compounds; Humans; Phenylurea Compounds; Piperidines; Pyridazines; Receptors, CCR1; Receptors, CCR3; Receptors, CCR4; Receptors, Chemokine; Receptors, CXCR4

Tachykinins (TKs) are small peptides widely distributed in the central and peripheral nervous systems where they act as neurotransmitters. Potent and selective TKs antagonists have been developed in the last 20 years and many efforts have been made to prove their efficacy in the treatment of various diseases. Herein the most prominent results in the clinical development are reported and discussed. For aprepitant, the only compound of this class to have been launched to date, results of clinical studies and postmarketing cost-effectiveness data for the treatment of chemotherapy-induced emesis are discussed. The field is still well active, as currently proof-of-concept studies for indications initially missed (i.e., depression) are ongoing and new targets are under investigation.

Topics: Antiemetics; Aprepitant; Asthma; Clinical Trials as Topic; Gastrointestinal Diseases; Humans; Mental Disorders; Morpholines; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Sleep Initiation and Maintenance Disorders

Ebastine is a once-daily, non-sedating, selective, long-acting, second-generation antihistamine. The use of ebastine is indicated in patients suffering from intermittent and persistent allergic rhinitis and chronic idiopathic urticaria. Ebastine 10 mg/day, appears as effective as other second-generation antihistamines, such as cetirizine and loratadine. Ebastine 20 mg/day is indicated in patients with moderate and severe allergic symptoms. No cardiovascular effects of ebastine are described, although there is a pharmacokinetic interaction when ketoconazole or macrolides are co-administered. Ebastine has no relevant effects on the psychomotor performance. Even with ebastine 20 mg/day skilled performance does not appear to be impaired. Furthermore, ebastine 5-10 and 2.5 mg, appears to be efficient and can be used safely in children 6-11 and 2-5 years of age, respectively. Ebastine appears to be a safe, effective and well-tolerated second-generation antihistamine in the treatment of allergic rhinitis and chronic idiopathic urticaria.

Topics: Anti-Allergic Agents; Asthma; Butyrophenones; Clinical Trials as Topic; Histamine H1 Antagonists, Non-Sedating; Humans; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Urticaria

Carebastine, a histamine H1 antagonist, is under development by Almirall Prodesfarma for the potential treatment of allergic rhinitis, asthma and conjunctivitis. A nasal formulation was submitted for registration in Spain in June 1999 [343595]. It is also in phase III trials for conjunctivitis and phase I trials for asthma [343144,343243]. In a multicentered, multinational, double-blind, placebo-controlled study in patients with symptomatic SAR, patients were assigned a nasal spray formulation of carebastine (2.5 mg/ml) or placebo. Severity scores decreased significantly with carebastine compared to placebo. This findings suggest that carebastine nasal spray has the potential to be of value in the treatment of SAR [282185]. In a multicenter, multinational, double-blind, randomized, placebo-controlled study, patients with seasonal allergic conjunctivitis (SAC) were assigned an eye drop formulation of carebastine (25 mg/ml) or placebo. Carebastine was significantly better than placebo at relieving the effects of SAC, as early as 15 min after administration and the effect lasted for 14 days. Carebastine was well-tolerated and there were no difference in adverse events between the two groups [282897].

Topics: Animals; Anti-Asthmatic Agents; Asthma; Butyrophenones; Clinical Trials as Topic; Contraindications; Drugs, Investigational; Humans; Piperidines; Structure-Activity Relationship

Topics: Airway Obstruction; Animals; Asthma; Benzodiazepinones; Bronchi; Gallamine Triethiodide; Humans; Muscarinic Antagonists; Muscle, Smooth; Piperidines; Trachea

Identify and critically review the peer-reviewed, English-language studies of the effects of medical antireflux therapy in asthmatics with gastroesophageal reflux (GER).. Using the 1966 to 1996 MEDLINE database, asthma was combined with GER to identify all studies of the effects of medical antireflux therapy on asthma control. The articles' bibliographies were also reviewed. Studies were graded according to Sackett's criteria and grouped by levels of evidence.. A total of 242 citations were found; 171 were published in English. Twelve studies of the effects of medical antireflux therapy on asthma control, with a total of 326 treated patients, were identified. Eight studies were placebo-controlled, three were open studies, and one used an untreated control. Eight studies treated 20 or fewer patients. Reflux symptoms either did not improve or the effects of antireflux therapy on them were not reported in four studies. The combined data from the controlled medical antireflux studies showed that: (1) asthma symptoms improved in 69% of the subjects; (2) asthma medication use was reduced in 62% of the subjects; (3) evening peak expiratory flow (PEF), but not PEF at other times, improved in 26% of the subjects; and (4) spirometry did not improve in any of the placebo-controlled antireflux studies.. Analysis of the combined data suggests that medical antireflux therapy improves asthma symptoms, may reduce asthma medication use, but has minimal or no effect on lung function.

Topics: Antacids; Anti-Asthmatic Agents; Anti-Ulcer Agents; Asthma; Cimetidine; Circadian Rhythm; Cisapride; Gastroesophageal Reflux; Humans; Lung; Omeprazole; Peak Expiratory Flow Rate; Piperidines; Placebos; Randomized Controlled Trials as Topic; Ranitidine; Spirometry

Two nonpeptide tackykinin NK2 receptor antagonists have now been described, SR 48968 and GR 159897. These drugs are highly specific and very potent antagonists with affinity (binding and in vitro study) for NK2 receptors in the subnanomolar range (pKi = 9-10), without intrinsic activity. They act preferentially on the human NK2A receptor subtype. These drugs exert potent and long-acting antagonism by both i.v. and oral administration. Their use has first confirmed the preponderant role of NK2 receptors in airway smooth muscle contraction, especially in human bronchi. A role for NK2 receptor stimulation has also been clearly demonstrated in bronchoconstriction induced by various agents known to induce the release of tachykinins (capsaicin, resiniferatoxin, citric acid, sodium metabisulfite diethyl ether, serotonin, and bradykinin), in allergen-induced airway constriction in the guinea pig sensitized to ovalbumin, and in hyperpnea-induced bronchoconstriction. Inhibition of neurokinin A mediated or capsaicin-mediated dyspnea by SR 48968 has also been demonstrated in the guinea pig. SR 48968 also is very efficient in inhibiting cough induced by citric acid or capsaicin. Finally, SR 48968 is able to abolish in guinea pigs in vivo the bronchial hyperreactivity induced after 24 or 48 h by a citric acid challenge or an ovalbumin challenge, respectively. Thus, nonpeptide, long-acting NK2 receptor antagonists can be regarded as suitable tools for investigations in humans. They may shortly allow a precise determination of the role of tachykinins in asthmatic patients.

Topics: Animals; Asthma; Benzamides; Bronchoconstriction; Cough; Humans; Lung; Piperidines; Receptors, Neurokinin-2

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

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

The development of beta2-specific sympathomimetic bronchodilators (rimiterol, salbutamol, terbutaline) has made the basic treatment of asthmatic patients more safe and effective. Despite that, the asthmatics should be under careful control and all patients should be taught the correct way to use their bronchodilator aerosols. If a sympathomimetic drug has lost its effectiveness, the patient should be able to have easy contact to the treating physician or outpatient department.

Topics: Adrenergic beta-Agonists; Aerosols; Animals; Asthma; Bronchial Spasm; Bronchodilator Agents; Catechols; Humans; Piperidines

Topics: Absorption; Administration, Oral; Aerosols; Albuterol; Animals; Asthma; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Half-Life; Hemodynamics; Humans; In Vitro Techniques; Injections, Intravenous; Isoproterenol; Kinetics; Muscle Contraction; Myocardial Contraction; Organ Specificity; Piperidines; Terbutaline; Tremor

The substance 9,10-dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol (WA 335) was examined for its antagonistic effects against histamine and serotonin, for its atropine-like properties as well as for a series of other qualities in comparison with cyproheptadine and pimethixene. The anti-histamine and anti-serotonin activities of compound WA 335 on the smooth muscle and the capillary do not only exceed that of cyproheptadine but also that of pimethixene. WA 335 shows an extremely strong binding to histamine and serotonin receptors. In the dose range in which it causes already an antamine effect, its oral absorption is very good. The anti-anaphylactic effect is much stronger than that of cyproheptadine. Like pimethixene and cyproheptadine, WA 335 has no distinct antagonistic qualities against bradykinin. The anticholinergic effects of WA 335 are dependent on the test object. In examinations on the bronchus of the guinea pig and the pupil of the mouse, the atropine-like efficiency corresponds to that of cyproheptadine; it is stronger on the stimulated vagus of the cat and less efficient than cyproheptadine on the stomach of the rat. WA 335 has distinct central atropine-like properties. It possesses a strong surface anesthetic activity. The effects of WA 335 on circulation are dependent on species. In contrast to pimethixene, compound WA 335 like cyproheptadine potentiates the effects of norepinephrine in cats. The reduction of the carotid sinus reflex in the cat is more distinct after WA 335 than after pimethixene and corresponds to that produced by cyproheptadine. Higher doses of WA 335 than are necessary to demonstrate antaminic effects are needed to provoke central nervous effects. WA 335 shows no analgesic potency in mice. The influence on body temperature in the rat is similar to that of cyproheptadine. WA 335 is equally efficient as pimethixene with regard to the inhibition of spontaneous motility and prolongation of barbiturate sleep in mice, and shows the same anti-emetic activity as does chlorpromazine in dogs. In contrast to chlorpromazine the behaviour of dogs and cats is distinctly altered already by doses of WA 335 which cause a slight sedation.

Topics: Analgesics; Anaphylaxis; Animals; Anthracenes; Asthma; Behavior, Animal; Blood Pressure; Bronchial Spasm; Cats; Dogs; Drug Evaluation, Preclinical; Edema; Female; Gastric Juice; Gastrointestinal Motility; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Lethal Dose 50; Male; Mice; Muscle Contraction; Muscle, Smooth; Piperidines; Pupil; Rabbits; Rats; Receptors, Drug; Serotonin Antagonists; Uterine Contraction

Topics: Administration, Oral; Aerosols; Albuterol; Animals; Anisoles; Asthma; Bronchi; Bronchial Spasm; Bronchodilator Agents; Catechols; Drug Evaluation, Preclinical; Ethanolamines; Hexoprenaline; Humans; Injections; Isoproterenol; Isoquinolines; Methanol; Piperidines; Resorcinols; Respiratory Therapy

Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses.. This study investigated whether intranasal GSK2245035 reduced allergen-induced bronchial reactivity in mild allergic asthma.. This double-blind, placebo-controlled, parallel-group Phase IIa trial randomized (1:1) participants with mild allergic asthma to intranasal GSK2245035 20 ng or placebo once weekly for 8 weeks; follow-up was conducted 1, 4, and 12 weeks after treatment. Allergen-induced late asthmatic response 1 week after treatment was measured as minimum and weighted mean forced expiratory volume in 1 second (FEV1) 4-10 hours following bronchial allergen challenge (primary endpoint). Pharmacodynamic and allergic biomarkers, and adverse events, were assessed. A Bayesian analysis framework was used; a posterior probability >0.7 denoted primary endpoint success.. Thirty-six participants were randomized (GSK2245035, n = 22; placebo, n = 14). The percentage attenuation in late asthmatic response was -4.6% (posterior probability: 0.385) and -10.5% (posterior probability: 0.303) for minimum and weighted mean FEV1, respectively. Type 2 responses were confirmed by changes in lung function, eosinophils (blood and sputum), interleukin-5 (sputum) and fractional exhaled nitric oxide biomarkers pre- and post-bronchial allergen challenge. However, no treatment effect was observed. Adverse events were reported by 10/14 (71%) and 21/22 (95%) participants in the placebo and GSK2245035 groups, respectively; headache was the most common.. Although target engagement was observed, weekly intranasal GSK2245035 20 ng for 8 weeks did not substantially attenuate the late asthmatic response in participants with mild allergic asthma. Overall, treatment was well tolerated.

Topics: Adenine; Administration, Intranasal; Adult; Allergens; Anti-Asthmatic Agents; Asthma; Bronchial Provocation Tests; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Interferon-alpha; Male; Middle Aged; Piperidines; Proof of Concept Study; Rhinitis, Allergic; Toll-Like Receptor 7; Young Adult

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; 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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; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

Masitinib is a tyrosine kinase inhibitor targeting stem cell factor receptor (c-kit) and platelet-derived growth factor (PDGF) receptor, which are expressed on several cell types including mast cells and bronchial structural cells, respectively. We hypothesized that c-kit and PDGF receptor inhibition may decrease bronchial inflammation and interfere with airway remodeling, which are crucial features of severe asthma.. The primary endpoint was the percent change from baseline in oral corticosteroids after 16 weeks of treatment. Change in asthma control (asthma control questionnaire), exacerbation rate, pulmonary function tests, rescue medication requirement and safety were secondary endpoints.. A 16-week randomized, dose-ranging (3, 4.5, and 6 mg/kg/day), placebo-controlled study was undertaken in 44 patients with severe corticosteroid-dependent asthma who remained poorly controlled despite optimal asthma management.. At 16 weeks of treatment, a comparable reduction in oral corticosteroids was achieved with masitinib and placebo (median reduction of -78% and -57% in the masitinib and placebo arms, respectively). Despite this similar reduction, the Asthma Control Questionnaire score was significantly better in the masitinib arm as compared to placebo with a reduction by 0.99 unit at week 16 (P < 0.001) vs 0.43 unit in the placebo arm. Masitinib therapy was associated with more transient skin rash and edema.. Masitinib, a c-kit and PDGF-receptor tyrosine kinase inhibitor, may represent an innovative avenue of treatment in corticosteroid-dependent asthma. These preliminary results warrant further long-term clinical studies in severe asthma

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Asthmatic Agents; Asthma; Benzamides; Edema; Exanthema; Female; France; Humans; Hydroxycorticosteroids; Male; Medication Adherence; Middle Aged; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Receptors, Platelet-Derived Growth Factor; Thiazoles; Treatment Outcome

Aspiration of acid to the airway causes airway inflammation, and acid stress to the airway caused by gastroesophageal reflux disease (GERD) has been known as a potential mechanism of deteriorated asthma symptoms. However, the efficacy of the acid suppressive drugs, H(2)-receptor blockers (H(2) blocker) and proton pump inhibitors, on asthma symptoms and pulmonary functions remains controversial. We therefore designed the randomized prospective study to determine the efficacy of an H(2) blocker (roxatidine, 150 mg/day) and a proton pump inhibitor (lansoprazole, 30 mg/day) on asthma symptoms of 30 asthmatic patients with GERD. These patients were divided in the two groups (15 patients for each group) and treated with either roxatidine or lansoprazole. The diagnosis of GERD was established by the method of Los Angeles classification including mucosal minimum change of Grade M and questionnaire for the diagnosis of reflux disease (QUEST) score. The efficacy of acid suppressive drugs was evaluated by peak expiratory flow (PEF), asthma control questionnaire (ACQ) that evaluates the improvement of asthma symptoms, and forced expiratory volume in 1 second (FEV(1.0)). Lansoprazole, but not roxatidine, significantly improved PEF and ACQ scores (p < 0.05) with the improved QUEST scores. However, these acid suppressive drugs did not change the pulmonary function of FEV(1.0) in asthmatic patients. In conclusion, treatment with a proton pump inhibitor, lansoprazole, appears to be useful in improvement of asthma symptoms in asthmatic patients with GERD.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Adult; Aged; Asthma; Drug Evaluation; Female; Forced Expiratory Volume; Gastroesophageal Reflux; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Peak Expiratory Flow Rate; Piperidines; Prospective Studies; Proton Pump Inhibitors; Surveys and Questionnaires

When stimulated, excitatory nonadrenergic noncholinergic (e-NANC) nerves locally release tachykinins like Neurokinin (NK) A and Substance P, causing neurogenic inflammation and airway obstruction via activation of specific NK-1 and NK-2 receptors. The recently developed nonpeptide NK-2 receptor antagonist SR 48968C has a high affinity for the NK-2 receptor, and is a strong and selective antagonist of NK-2 receptor mediated airway obstruction. In a placebo-controlled cross-over study, we investigated the effect of SR 48968C, administrated orally once-daily in a dosage of 100 mg during 9 days, on airway responsiveness to adenosine 5'-monophosphate (AMP) in 12 allergic asthmatic patients. Furthermore, we assessed its effect on airway obstruction, by measuring FEV1 on the first and last day of each treatment period and by peak flow registration at home throughout the study period. SR 48968C had no significant effect on PC20AMP or on FEV1 measured on day 1 and 9, and morning and evening peakflow measured at home on day 2-8. Thus, although SR 48968C was administrated in a dosage that might cause a demonstrable blocking effect on airway NK-2 receptors in asthma, it did not have a significant bronchodilatory or bronchoprotective effect against adenosine hyperresponsiveness in this study. Further studies are needed to assess the value of SR 48968C and other NK receptor antagonists in the treatment of asthma

Topics: Adenosine Monophosphate; Adult; Airway Obstruction; Asthma; Benzamides; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cross-Over Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Receptors, Neurokinin-2

Inhalation of neurokinin (NK) A causes bronchoconstriction in patients with asthma. The NKA-induced bronchoconstriction in isolated human airways is mediated via the NK2 receptor and inhibited by SR 48968, a potent and specific nonpeptide tachykinin NK2 receptor antagonist. In the present study, the effect of orally administered SR 48968 on NKA-induced bronchoconstriction was examined in 12 mild asthmatics. On the screening day and during the study periods, increasing concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol x mL(-1)) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing. At 1.5 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0.05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0.05). At 24 h, the mean log10 PC20 FEV1 was -6.21 (0.17) after SR 48968 and -6.65 (0.11) after placebo (p=0.05); the mean log10 PC35 sGaw was -6.85 (0.23) after SR 48968 and -7.17 (0.15) after placebo (nonsignificant). As PC20 FEV1 and/or PC35 sGaw were not reached in up to 4 patients per SR 48968 group, the differences between SR 48968 and placebo were underestimated. In conclusion, oral treatment with 100 mg SR 48968 caused a significant inhibition of neurokinin A-induced bronchoconstriction in asthmatics. This finding constitutes the first evidence of inhibition of sensory neuropeptide-induced bronchoconstriction by a selective tachykinin receptor antagonist in humans.

Topics: Adult; Asthma; Benzamides; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Forced Expiratory Volume; Humans; Male; Neurokinin A; Piperidines; Receptors, Neurokinin-2; Treatment Outcome

To investigate the role of NK1 receptors in the pathogenesis of bronchoconstriction and cough in asthma, we performed a randomized, double-blind, crossover study on the effects of a selective non-peptide tachykinin NK1 receptor antagonist (CP-99,994) on baseline measures of lung function and on hypertonic saline-induced bronchoconstriction and cough in 14 male subjects with mild asthma. CP-99,994 (250 micrograms/2 hours) and placebo were administered intravenously in 2-h infusions during consecutive visits 5 to 7 d apart. Specific airway resistance (SRaw) was measured and spirometry was performed at baseline and at 35 and 60 min. Next, hypertonic saline challenge was performed by delivering 10 breaths of saline of increasing concentration (0.9 to 7% in 1% increments at 5-min intervals) via an ultrasonic nebulizer until SRaw increased from baseline by 200% or 20 units, whichever was greater. Throughout the challenge cough was counted from a taped record made from two microphones placed close to the subject's larynx. We found that CP-99,994 did not significantly affect SRaw or spirometric measures of lung function during the first hour of infusion. Although CP-99,994 infusion markedly attenuated the bronchoconstrictor response to the saline challenge in two subjects, it did not significantly decrease the area under curves obtained for SRaw and cough during saline challenge for the group as a whole (p = 0.9 for SRaw;p = 0.8 for cough). We conclude that administration of 250 micrograms/kg of CP-99,994 over 2 h does not significantly inhibit hypertonic saline-induced bronchoconstriction or cough in subjects with mild asthma and does not have acute bronchodilator activity in these subjects.

Topics: Adult; Airway Resistance; Asthma; Bronchoconstriction; Cough; Cross-Over Studies; Double-Blind Method; Humans; Male; Middle Aged; Piperidines; Respiratory Function Tests; Saline Solution, Hypertonic; Stereoisomerism

In a double blind, randomised, placebo controlled trial in a group of extrinsic asthmatics, we have evaluated the potency and selectivity of ebastine, a new piperidine-type H1-receptor antagonist, against histamine and methacholine-induced bronchoconstriction. The median histamine PC20FEV1 value following placebo was 3.15 mg/ml (0.24-58.84). When compared with placebo, ebastine produced significant protection at 10 mg (median PC20 = 31.36 mg/ml, p = 0.008) and 30 mg (median PC20 = 42.14 mg/ml, p = 0.001) but there appeared to be no significant dose effect. Ebastine also produced a small shift in the methacholine concentration-response curves to the right. We conclude that ebastine is an effective antagonist of histamine-induced bronchoconstriction in the asthmatic airway with evidence of minor blockade of methacholine-induced bronchoconstriction.

Topics: Adult; Asthma; Bronchi; Butyrophenones; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Male; Methacholine Compounds; Middle Aged; Piperidines

The potential for rimiterol to protect athletes from exercise-induced asthma (EIA) has not been fully established. Ten athletes with asthma (15 to 30 years of age) undertook 8 minutes of submaximal exercise (80% of anaerobic threshold) on the treadmill ergometer, once after inhaling rimiterol and once after inhaling a placebo. Treatment with all bronchodilator drugs was stopped for the 12 hours preceding each exercise test. Two puffs (400 micrograms) of rimiterol or placebo were administered in a double-blind crossover manner 2 minutes before each exercise test. Lung function measurements were made before exercise and immediately, 5, 10, 15, 20, 25, and 30 minutes after completion of exercise. The results of a two-way analysis of variance revealed significant (p less than 0.01) difference in the FEV1 scores obtained after rimiterol inhalation and placebo inhalation, 5, 10, 15, 20, 25, and 30 minutes after cessation of exercise. After inhalation of rimiterol, there were no significant changes in FEV1. After inhaling the placebo, significant reductions (p less than 0.01) in FEV1 occurred after cessation of exercise (5, 10, 15, and 20 minutes). All subjects exhibited EIA after placebo, and none after rimiterol. The mean maximum drop after exercise in FEV1 after inhalation of rimiterol (2.807 +/- 5.55) and placebo (24.54 +/- 8.4) was significantly different (t = 6.849). It was concluded that inhalation of rimiterol 2 minutes before exercise afforded significant protection from EIA in all subjects tested.

Topics: Administration, Inhalation; Adolescent; Adult; Asthma; Asthma, Exercise-Induced; Catechols; Double-Blind Method; Exercise Test; Female; Forced Expiratory Volume; Humans; Male; Piperidines; Sports

UCB JO28 [( 2-[2-[4-(diphenylmethylene)-1-piperidinyl] ethoxy] ethoxy] acetic acid, hydrochloride) is derived from diphenylmethylene piperidine. Animal experiments have shown that it has spasmolytic properties for smooth muscle, particularly in the bronchi, as well as anti-Hl, anticholinergic and anti-serotonin activities. The degree of protection by JO28 against histamine and methacholine-induced bronchospasm has been investigated in 20 asthmatic patients with serious airways hyper-reactivity. Protection against histamine-induced bronchospasm was almost complete in 11 out of 12 patients, whereas protection against methacholine-induced bronchospasm, although clearly present in seven of eight patients, was less marked.

Topics: Adolescent; Adult; Asthma; Bronchial Spasm; Clinical Trials as Topic; Female; Histamine; Humans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Piperidines; Prospective Studies

Parenterally administered diphemanil methylsulfate, a quarternary ammonium compound with both parasympatholytic and direct bronchial smooth muscle relaxing properties, has been found effective in the treatment of bronchial asthma. The present study was undertaken to test the effectiveness of inhaled diphemanil in preventing histamine induced bronchoconstriction in asymptomatic adult asthmatics. Twenty subjects, aged 19-40 years (average 25) were studied, each on three different days, observing an interval of at least 70 hours between testing. On day one, airway sensitivity to inhaled histamine was determined. On days two and three, histamine challenge was repeated 20 minutes after inhalation of either diphemanil (2 mg) or its vehicle in a double-blind crossover design. Airway sensitivity was assessed by determining cumulative log dose units of inhaled histamine required to provoke a 20% decline in FEV1 (log PD20 - FEV1). Diphemanil did not prevent histamine induced bronchoconstriction nor did it significantly affect log PD20 - FEV1 (p = 0.59). We conclude that a 2 mg dose of diphemanil, administered by oral inhalation 20 minutes before histamine challenge, is ineffective in protecting against induced bronchospasm in asymptomatic adult asthmatics.

Topics: Administration, Intranasal; Adult; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Bronchodilator Agents; Female; Forced Expiratory Volume; Histamine; Humans; Male; Parasympatholytics; Piperidines

Twenty chronic asthmatics who completed a double-blind cross-over study comparing sustained release aminophylline tablets with placebo had a significant improvement in airways obstruction. Inhaled rimiterol and the aminophylline tablets were shown to act in an additive manner. There was a significant reduction in asthmatic symptoms on active tablets. A further nine patients had to be withdrawn from the study because of adverse side effects.

Topics: Adolescent; Adult; Aerosols; Aged; Aminophylline; Asthma; Catechols; Delayed-Action Preparations; Double-Blind Method; Drug Interactions; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Placebos

Topics: Adolescent; Adult; Aged; Asthma; Bronchitis; Capsules; Clinical Trials as Topic; Double-Blind Method; Histamine H1 Antagonists; Humans; Ketotifen; Middle Aged; Piperidines; Placebos; Tablets; Thiophenes; Time Factors

The effect of ketotifen on allergic symptoms and parameters of respiratory function were studied in 23 allergic children during a period of 6 months therapy. A reduction in nocturnal dyspnea and dyspnea during exercise was observed in 17 patients. Improvement of the FVC, PEF and FEV1 was detected in 14, 15 and 19 patients, respectively. Following a 4-day treatment with ketotifen, a further 15 patients with allergen-induced bronchospasm were challenged by inhalative provocation test, comparing the protective effects of ketotifen and of DSCG in a randomized double-blind crossover study. 7 of 15 patients showed an improved allergen tolerance to the immediate hypersensitivity with ketotifen and 5 patients with DSCG. A protective effect with respect to the delayed hypersensitivity reaction was observe in 2 of 8 patients with ketotifen and in 1 with DSCG.

Topics: Adolescent; Asthma; Bronchial Provocation Tests; Child; Child, Preschool; Cromolyn Sodium; Follow-Up Studies; Histamine H1 Antagonists; Humans; Ketotifen; Piperidines; Prognosis; Respiratory Function Tests; Thiophenes

1 The effect of i.v. rimiterol was compared with aerosol rimiterol in twelve asthmatic patients. 2 A cumulative dose of rimiterol (1050 microgram) given in six separate injections over 90 min resulted in a mean increase in peak expiratory flow rate (PEFR) of 50.6% and FEV1 of 53.7%. 3 Comparison of the degree of bronchodilation to the same dose of rimiterol administered intravenously or by aerosol, suggested that on average the potency ratio was 10:1, i.e. ten times the aerosol dose was required to produce the equivalent bronchodilator effect. 4 Palpitations, tremor and postural hypotension were common during the first minute after the drug was injected intravenously, but did not occur after aerosol administration. 5 It is suggested that rimiterol by intravenous injection is a useful addition to the treatment of acute asthma.

Topics: Adult; Aged; Asthma; Blood Pressure; Catechols; Female; Forced Expiratory Volume; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines; Vital Capacity

Topics: Adult; Animals; Asthma; Child; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Humans; Ketotifen; Piperidines; Thiophenes

Sixty-four patients with mild of moderate extrinsic asthma were treated with placebo for 1 month and thereafter with ketotifen (1 mg twice daily, orally), disodium cromoglycate (inhalation of 20 mg, four times daily), or placebo for 2 subsequent months. The trial was performed at four different centres and the treatments were compared using double-blind technique. We found no difference between the effect of ketotifen, disodium cromoglycate and placebo on the patients' daily measurements of evening peak expiratory flow, daily score values or respiratory symptoms of the number of salbutamol puffs required to control symptoms. There was no difference between the treatment groups with regard to the patients' estimates of changes in airway sensitivity to different non-specific stimuli: fumes, tobacco smoke, cold air, and exercise. The only significant effect of DSCG was a minor (4%) increase in the mean morning value for peak expiratory flow. The findings suggest that the addition of ketotifen or disodium cromoglycate to the regimen is unlikely to give further benefit in asthmatic patients, whose symptoms are reasonably well controlled by small doses of bronchodilating drugs.

Topics: Adult; Albuterol; Asthma; Circadian Rhythm; Cromolyn Sodium; Female; Humans; Ketotifen; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Placebos; Thiophenes; Time Factors

Topics: Adolescent; Asthma; Asthma, Exercise-Induced; Bronchodilator Agents; Child; Child, Preschool; Cromolyn Sodium; Humans; Ketotifen; Piperidines; Thiophenes

Topics: Asthma; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Infant; Ketotifen; Male; Piperidines; Thiophenes

Topics: Administration, Oral; Asthma; Clinical Trials as Topic; Humans; Ketotifen; Piperidines; Thiophenes

The efficacy and adverse effects of ketotifen 1 mg twice daily and 2 mg twice daily were compared with placebo in 50 patients with atopic asthma in a multicentre, double-blind study. Ketotifen in the higher dosage caused a slight reduction in salbutamol usage and a modest improvement in breathing in patients not already receiving inhaled corticosteroids. The drug was ineffective in patients receiving inhaled corticosteroids. Drowsiness was a troublesome effect causing withdrawal from treatment or reduction of dosage in seven patients while receiving ketotifen compared with only three while receiving placebo.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Albuterol; Asthma; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Histamine H1 Antagonists; Humans; Ketotifen; Male; Middle Aged; Piperidines; Sleep Stages; Thiophenes

The results of clinical trials in patients with allergic bronchial asthma performed to demonstrate the therapeutic effect of the newly developed substance Ketotifen are reviewed: 1. In 154 patients the efficacy of ketotifen was superior to the antihistaminic clemastine. 2. The therapeutic value of ketotifen was similar to that of cromoglycate. 3. Ketotifen is a beneficial substance for long-term treatment of bronchial asthma. The main advantage of ketotifen is its prophylactic effect when given orally.

Topics: Administration, Oral; Adult; Asthma; Child; Cromolyn Sodium; Drug Administration Schedule; Drug Evaluation; Drug Tolerance; Histamine H1 Antagonists; Humans; Ketotifen; Piperidines; Thiophenes

A randomized multicentre trial was done to investigate the protective effects of ketotifen and disodium cromoglycate (DSCG) in the therapy of bronchial asthma. 236 patients with seasonal asthmatic symptoms were treated and controlled in the summer of 1978. Both drugs showed a significant improvement of the lung function and a marked reduction of asthmatic symptoms, cough and expectoration.

Topics: Adrenergic beta-Agonists; Asthma; Beclomethasone; Bronchitis; Clinical Trials as Topic; Cromolyn Sodium; Histamine H1 Antagonists; Humans; Ketotifen; Piperidines; Random Allocation; Seasons; Spirometry; Theophylline; Thiophenes

Topics: Asthma; Clinical Trials as Topic; Cromolyn Sodium; Female; Histamine H1 Antagonists; Humans; Ketotifen; Male; Piperidines; Thiophenes

1 Ketotifen (HC 20-511 Sandoz) 1 mg twice daily for 12 weeks was found to be equivalent to sodium cromoglycate (SCG) 20 mg four times daily for 12 weeks in 35 skin test positive asthmatic patients in a randomised double-blind cross-over study. 2 No statistically significant difference between the two drugs in mean values for daily peak flow rates, diary card scores and spirometry at monthly visits was demonstrated. 3 Treatment failures as judged by severe asthma requiring withdrawal from the trial or addition of short courses of prednisone occurred in three patients on each drug. 4 Sedation was noted by 10 patients onHC 20-511 and 5 on SCG. 5 Weight loss was noted in those patients on SCG, but not those on HC 20-511.

Topics: Adolescent; Adult; Aged; Asthma; Cromolyn Sodium; Double-Blind Method; Drug Evaluation; Histamine H1 Antagonists; Humans; Ketotifen; Middle Aged; Piperidines; Skin Tests; Thiophenes

In a controlled single-blind study of 12 weeks' duration the prophylactic anti-asthmatic effects of ketotifen and clemastine in children with bronchial asthma were compared. The drugs were administered in syrup form in doses from 1 to 2 mg per day according to the body-weight. Fifty-seven children, twenty-nine in the ketotifen group and twenty-eight in the clemastine group took part. The clinical parameters, namely asthmatic complaints, dyspnoea and total duration of asthmatic attacks initially improved with both drugs but only with ketotifen was there a further marked benefit leading to a significant superiority of this drug over clemastine in the 8th and 12th week of treatment. In the overall assessment ketotifen was considered to be very effective and effective in 29%. Both drugs were well tolerated.

Topics: Asthma; Child; Child, Preschool; Clemastine; Dyspnea; Female; Histamine H1 Antagonists; Humans; Infant; Ketotifen; Male; Piperidines; Pyrrolidines; Thiophenes

Topics: Adult; Asthma; Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Histamine H1 Antagonists; Humans; Ketotifen; Male; Middle Aged; Piperidines; Placebos; Thiophenes

Thirty-six children with verified deciduous tree pollen-induced asthma were studied with respect to the prophylactic effect and tolerance of ketotifen, in comparison to disodium cromoglycate. Double-blind technique was used and the study was performed during the deciduous tree pollen season. Daily pollen counts were performed, and allergic symptoms, additional medication and pulmonary expiratory flow were recorded. Both drugs showed a good prophylactic effect on the asthma symptoms. No significant differences were found between the two substances tested and no adverse reactions or side effects were noted.

Topics: Asthma; Child; Cromolyn Sodium; Double-Blind Method; Humans; Ketotifen; Piperidines; Pollen; Thiophenes

The protective effect of ketotifen was examined by an open assessment trial in 261 asthmatics of variable types, a double blind trial comparing ketotifen and inert placebo in 189 asthmatics of extrinsic type including pure atopic asthma and asthma with atopic and infectious components (mixed type or combined type), and a double blind trial comparing ketotifen and disodium cromoglycate (DSCG) by double placebo technique in 132 asthmatics of a pure atopic type. The open clinical assessment trial suggested that ketotifen was most effective in atopic asthmatics having moderate and severe as well as mild asthmatic episodes. Efficacy increased with prolonged administration; 1 mg twice daily was better than a 1 mg daily dose. In the placebo-controlled double blind trial, the efficacy of ketotifen was demonstrated by the reduction of concomitant anti-asthmatic therapy. The results of the double blind trial comparing ketotifen and DSCG are not fully reported. However, preliminary data showed that the efficacy of both drugs was equivalent or that ketotifen was slightly superior to DSCG. Safety of ketotifen was confirmed by the three trials, transient day-time sedation being the major side effect of this agent. In conclusion, ketotifen is a promising drug for the prophylaxis of asthma.

Topics: Adult; Anaphylaxis; Asthma; Basophils; Cromolyn Sodium; Double-Blind Method; Humans; Hypersensitivity, Immediate; Japan; Ketotifen; Mast Cells; Piperidines; Placebos; Thiophenes

Topics: Adult; Aged; Asthma; Clinical Trials as Topic; Cromolyn Sodium; Humans; Ketotifen; Middle Aged; Piperidines; Prednisolone; Thiophenes

Topics: Adolescent; Asthma; Cromolyn Sodium; Double-Blind Method; Humans; Ketotifen; Piperidines; Thiophenes

Topics: Adult; Asthma; Clinical Trials as Topic; Cromolyn Sodium; Humans; Ketotifen; Peak Expiratory Flow Rate; Piperidines; Placebos; Thiophenes

Topics: Adolescent; Adult; Asthma; Clinical Trials as Topic; Cromolyn Sodium; Humans; Ketotifen; Middle Aged; Piperidines; Thiophenes

Thirty-six children with a mean age of 8.9 years were studied with respect to the prophylactic effect and tolerance of ketotifen in comparison with disodium cromoglycate. All had a verified deciduous tree pollen-induced asthma. The children were stratified into two matched groups and the double-blind technique was used. The study was performed during the whole deciduous tree pollen season. Daily pollen counts were performed during the whole observation period as well as daily registrations of allergic symptoms, additional medication and pulmonary expiratory flow. No significant differences were found between the two substances tested. No adverse reactions or side effects were noted.

Topics: Adolescent; Asthma; Child; Child, Preschool; Clinical Trials as Topic; Cromolyn Sodium; Desensitization, Immunologic; Double-Blind Method; Drug Tolerance; Eosinophils; Female; Forced Expiratory Flow Rates; Humans; Immunoglobulin E; Ketotifen; Leukocyte Count; Male; Piperidines; Placebos; Pollen; Tablets; Thiophenes; Trees

The protective effect of ketotifen and disodium cromoglycate (DSCG) was evaluated by a randomised double blind cross-over study in 15 children with allergic bronchial asthma. 13 children were allergic to house dust mite (Dermatophagoides pteronyssinus), two to grass pollen. After a positive bronchial challenge test ketotifen or DSCG was given for 4 days followed by bronchial challenge with increasing allergen concentrations. Seven patients showed better allergen tolerance after ketotifen, 5 after DSCG. Protective action against late reactions was found only in 2 children after ketotifen and one child after DSCG.

Topics: Adolescent; Asthma; Child; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Dust; Female; Humans; Ketotifen; Male; Mites; Piperidines; Pollen; Thiophenes

We studied 17 patients in a double-blind controlled trial to see if ketotifen, a new oral mast-cell stabilizing agent, would protect against bronchoconstriction induced by exercise on a treadmill. In addition eight of the patients also completed exercise tests without previous medication and again after inhalation of disodium cromoglycate (DSCG). The greatest amount of bronchoconstriction was caused by exercise without preliminary treatment. There was less bronchoconstriction after ketotifen, but this was no better than a placebo. DSCG provided significant protection. We were unable to confirm previous reports that ketotifen is as effective as DSCG in preventing exercise-induced asthma.

Topics: Adolescent; Adult; Asthma; Asthma, Exercise-Induced; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Female; Humans; Ketotifen; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Thiophenes

Topics: Administration, Oral; Asthma; Child; Clinical Trials as Topic; Humans; Piperidines; Thiophenes

Topics: Aminophylline; Asthma; Clinical Trials as Topic; Humans; Ketotifen; Lung Volume Measurements; Piperidines; Thiophenes

Topics: Asthma; Child; Humans; Ketotifen; Piperidines; Thiophenes

Topics: Adult; Aged; Albuterol; Aminophylline; Asthma; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Placebos

The therapeutic value of ketotifen (Zaditen), a new anti-allergic drug, was studied in patients with extrinsic bronchial asthma. a) In 8 persons the protective effect on bronchial provocation tests with allergen was examined 3 and 14 days after treatment and compared with cromoglycate (Intal); b) 19 patients were treated for 6 months with 2 x 1 milligram ketotifen (n = 7), 2 x 2 mg ketotifen (n = 7), 2 x 1 mg clemastine (Tavegil) (n = 5). The results were as follows: a) The amount of inhaled allergen causing a fall of 20% in FEV1.0/VC was 9-12 times larger with both therapeutic regimens. b) Ketotifen definitely improved the asthmatic symptoms as compared with clemastine. The improvement was independent of the dosage. Side-effects occurred more frequently with clemastine. The study confirms the in vitro demonstrated anti-analphylactic properties of ketotifen; that it can be taken by mouth is of particular clinical interest.

Topics: Asthma; Clemastine; Clinical Trials as Topic; Cromolyn Sodium; Drug Evaluation; Histamine H1 Antagonists; Humans; Piperidines; Thiophenes

Twenty-two children with perennial extrinsic allergic asthma participated in a double-blinded, controlled, cross-over study of Ketotifen syrup during a 2 x 6-week period. The placebo was identical with the active drug in taste, colour, and consistency. The dosage level was, on weight basis, a little higher than the standard dosage for adults. The double-blinded investigation was supplemented with a 1 2-week open study of the tolerance for Ketotifen. This study also involved 22 patients, 12 new ones, and 10 from the double-blind study. The study showed Ketotifen to have no effect on changes in lung function (peak flow), on reduction in frequency of asthmatic attacks, or on consumption of additional medicine. The tolerance for Ketotifen was good, but physicians are advised to watch for increases in weight and decreases in blood pressure during tests on children which involve higher dosage levels.

Topics: Asthma; Chemical Phenomena; Chemistry; Child; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Female; Histamine H1 Antagonists; Humans; Male; Peak Expiratory Flow Rate; Piperidines; Placebos; Thiophenes

We studied the preventive effect of ketotifen, an oral drug with antianaphylactic and antihistaminic properties on methacholine-induced bronchoconstriction in controlled cross-over experiments in twenty-six adult patients with extrinsic asthma. Both a single dose of 1 mg ketotifen and 4 weeks treatment of ketotifen, 1 mg twice daily, failed to reduce the methacholine-induced drop in peak expiratory flow. The spirometric findings remained unchanged during ketotifen treatment. There was no difference between treatments with ketotifen and placebo with regard to the patients assessment of the severity of asthma or airway sensitivity to tobacco smoke, fumes or dusts, or exercise. The results suggest that treatment during 4 weeks with ketotifen does not reduce unspecific broncial hyperreactivity in patients with extrinsic asthma.

Topics: Adolescent; Adult; Anaphylaxis; Asthma; Bronchial Spasm; Dose-Response Relationship, Drug; Double-Blind Method; Histamine H1 Antagonists; Humans; Methacholine Compounds; Middle Aged; Piperidines; Spirometry; Thiophenes

Topics: Animals; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Histamine H1 Antagonists; Humans; Mast Cells; Passive Cutaneous Anaphylaxis; Piperidines; Rats; Tachyphylaxis; Thiophenes

16 cooperative asthmatic patients with exercise-induced asthma (with more than 15% decrease in FEV1 after strenuous work on a treadmill with 10% upward; pulse rates over 180 per minute during the work-phase) were selected to take part in a double-blind crossover trial. The 8 women and 8 men, with ages ranging from 15 to 57 years (mean 25) underwent 4 exercise tests. The effects on exercise-induced asthma of 20 mg disodium cromoglycate (DSCG) inhaled with a spinhaler 30 minutes before exercise were compared to 2 mg of ketotifen taken orally 3 hours before exercise, and likewise DSCG was compared to a placebo powder inhaled with a spinhaler, and ketotifen with placebo tablets. The whole study lasted from January to March. Ten minutes after exercise the following changes in FEV1 (in percent of control value measured before exercise) were seen: after inhalation of a placebo powder the FEV1 decreased to 66% with an almost equal decrease after taking placebo tablets (67%) (0.45 greater than p greater than 0.40) whereas, in comparison, the decrease in FEV1 after DSCG (84%) is smaller than that after inhalation of a placebo powder (66%) (p less than 0.0025). In contrast to these results was the equal decrease in FEV1 after ketotifen (70%) (0.35 greater than p greater than 0.30) and placebo tablets (67%). Although a relatively high chosen dosage of ketotifen was given, it does not seem capable of inhibiting mediator release from the bronchial mast-cells as DSCG does. It is concluded that ketotifen given orally 3 hours before the exercise test is not effective against exercise-induced asthma.

Topics: Adolescent; Adult; Asthma; Cromolyn Sodium; Double-Blind Method; Female; Humans; Male; Middle Aged; Physical Exertion; Piperidines; Placebos; Thiophenes

Ketotifen failed to protect against cat fur allergen induced asthma in a double blind placebo-controlled trial in ten asthmatic children. Disodium cromoglycate gave effective protection against the immediate and the late asthmatic reactions but there were no significant differences between the effects of ketotifen and a placebo.

Topics: Adolescent; Allergens; Animals; Asthma; Cats; Child; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Female; Humans; Male; Peak Expiratory Flow Rate; Piperidines; Placebos; Thiophenes; Time Factors

Oral challenge tests with acetylsalicylic acid, tartrazine or benzoic acid were performed in 7 intolerant asthmatic patients after a 3-day treatment with either orally taken ketotifen (1 mg twice daily) or inhaled disodium cromoglycate (20 mg four times daily) at random. Protection was noted with ketotifen in 5, with DSCG in 3 patients. On the evaluation of the mean percentage of the maximum decline in the forced expiratory volume in 1 sec (FEV1) only ketotifen afforded significant protection statistically (p less than 0.05). All the intolerant asthmatics studies showed, as an immunological abnormity, a slight, but significant decrease of the C1-inhibitor levels. Moreover, in three out of these the alpha 1-antitrypsin serum values were under the lower normal range.

Topics: Adult; Aged; alpha 1-Antitrypsin; Aspirin; Asthma; Benzoates; Bronchial Spasm; Complement C1 Inactivator Proteins; Cromolyn Sodium; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Tartrazine; Thiophenes

12 patients with bronchial asthma received treatment with Ketotifen for three months. 8 patients then continued this medication for at least 9 months. During this period it was possible to reduce the amount of theophylline and bronchodilator amines as well as the maintenance dose of corticosteroids. Afterwards 6 patients showed clinical deterioration while on placebo; this was considered further evidence of the anti-asthmatic effect of Ketotifen. Ketotifen seems to be acceptable as a prophylactic agent in asthma.

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Asthma; Child; Female; Humans; Ketotifen; Male; Middle Aged; Piperidines; Placebos; Theophylline; Thiophenes

In a three week double-blind cross-over controlled trial in twenty asthmatic children, ketotifen (HC 20-511, 'Zaditen', Sandoz) showed no significant difference from placebo, although there was a consistent trend in favour of the active drug.

Topics: Asthma; Child; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Piperidines; Placebos; Respiratory Function Tests; Thiophenes

A therapeutical trial using ketotifen, a prophylactic agent for the long-term treatment of bronchial asthma, was undertaken. Twenty-nine patients with a mean age of 33 years and suffering from bronchial asthma for six months to 20 years (mean 8.6 years) were treated for three months. Ketotifen demonstrated good results in alleviating the impact of the disease on the asthmatic patient. The lowering of the frequency of asthmatic attacks, their duration and the degree of dyspnoea was accompanied by a normalization of lung function parameters. An analysis of further respiratory investigations showed that the best results are to be obtained in the uncomplicated asthmatic. The need for the prophylactic treatment of asthma with an agent such as ketotifen is stressed, as only in this way can irreversible changes be prevented.

Topics: Adult; Asthma; Carbon Dioxide; Clinical Trials as Topic; Dyspnea; Female; Humans; Lung; Male; Middle Aged; Oxygen; Piperidines; Respiratory Function Tests; Spirometry; Thiophenes; Time Factors

Thirty-six patients with confirmed allergic bronchial asthma were divided into 3 parallel groups and treated with ketotifen 1 mg b.i.d. (Group I), ketotifen 2 mg b.i.d. (Group II), and clemastine 1 mg b.i.d. (Group III) respectively for 6 months. Nine out of 12 patients in Group I and 10 out of 12 in Group II experienced a statistically significant improvement in dyspnoea and in pulmonary function (Tiffeneau test). Likewise there was a marked reduction in the number, severity and average duration (minutes per week) of asthmatic attacks. By the 12th week, 8 out of 12 patients in the clemastine group had dropped out because of inefficacy. Ketotifen was very well tolerated by all the patients. In both ketotifen groups pathological eosinophil counts returned to normal during treatment. It can be concluded that ketotifen is effective in the long-term prophylaxis of bronchial asthma.

Topics: Adolescent; Adult; Asthma; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Dyspnea; Female; Forced Expiratory Flow Rates; Histamine H1 Antagonists; Humans; Male; Middle Aged; Mucus; Piperidines; Thiophenes; Vital Capacity

The onset of action of three sympathomimetic drugs (rimiterol 0.2 mg, terbutaline 0.25 mg and isoprenaline 0.08 mg) administered by metered dose inhaler was compared in 12 asthmatics. In order to evaluate side effects of the drugs, a second dose of the aerosols, 8-10 times higher than the first one, was given after 30 min. The effects were measured in terms of VC, FEV1.0, PEF and heart rate. All the substances caused a significant increase in spirometric values within 1.5 min, the results with isoprenaline being slightly better than those with terbutaline. An increased heart rate was observed after the first dose of isoprenaline whereas no further increase was found after the higher dose. Two patients complained of palpitations, one after isoprenaline and one after rimiterol. No other side effects were recorded. It is concluded that there is a small, clinically insignificant, difference in the onset of action of isoprenaline compared with that of the selective beta2-stimulating aerosol, terbutaline.

Topics: Adult; Aged; Asthma; Bronchodilator Agents; Bronchospirometry; Catechols; Clinical Trials as Topic; Drug Evaluation; Female; Heart Rate; Humans; Isoproterenol; Male; Middle Aged; Piperidines; Terbutaline; Time Factors

1 Ten asthmatic children received on two separate occasions rimiterol (500 microgram) and orciprenaline (1.5 mg) as aerosols in a double-blind, crossover design trial. Respiratory parameters (FEV1, FVC and PEFR) and pulse rate were recorded for 60 min after each administration. 2 Rimiterol produced effective bronchodilation in children with negligible cardiac stimulation. It differed from orciprenaline in that the peak bronchodilator effect was not maintained during the 60 min observation period. 3 Rimiterol is a selective, short-acting, sympathomimetic bronchodilator in children.

Topics: Aerosols; Asthma; Catechols; Child; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Metaproterenol; Piperidines; Pulse; Respiratory Function Tests

The protective anti-asthmatic effect of a new anti-allergic drug with histaminolytic and anti-anaphylactic properties was tested in various controlled clinical studies of induced bronchospasm in asthmatic patients (provocation tests using a histamine aerosol, and exercise-induced asthma using a bicycle ergometer). The drug, ketotifen (a cycloheptathiophene derivative) was compared with a classical antihistaminic (clemastine) and a known cell stabiliser (disodium cromoglycate). In both models ketotifen provided significant protection.

Topics: Adult; Asthma; Bronchial Spasm; Clemastine; Cromolyn Sodium; Histamine; Histamine H1 Antagonists; Humans; Physical Exertion; Piperidines; Spirometry; Thiophenes

A double-blind cross-over study showed that orally taken ketotifen and inhaled DSCG have a comparable protective effect on allergen-induced bronchoconstriction. Both drugs significantly inhibit the immediate bronchial reaction after a 3 day treatment with either 1 mg ketotifen or 20 mg DSCG four times daily. Late reactions, which occurred in three out of the ten patients, were inhibited in two of the three patients by ketotifen as by DSCG.

Topics: Adult; Allergens; Asthma; Bronchi; Bronchial Spasm; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Thiophenes

To determine the efficacy of ketotifen as an oral anti-asthmatic agent, experimental and therapeutic long-term trials were carried out. Four models were used in the expirmental therapeutic trials nad the antihistaminic agent clemastine and disodium cromoglycate were used as comparative substances. It was demonstrated that ketotifen provides protection against bronchopasm induced by allergens, histamine and exercise, but not against that induced by acetylcholine. In the therapeutic long-term trials, the efficacy and tolerance of ketotifen were compared with that of clemastine and disodium cromoglycate for a period of 6 months. In another study ketotifen was administered for 1 year. Ketotifen proved very effective in decreasing the frequency and duration of asthmatic attacks, concomitant medication could be reduced and the patients improved subjectively. From these trials it can be concluded that ketotifen is a safe and effective oral anti-anaphylactic agent for use in the long-term treatment of bronchial asthma.

Topics: Acetylcholine; Aerosols; Asthma; Clemastine; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Forced Expiratory Volume; Histamine; Humans; Hypersensitivity; Physical Exertion; Piperidines; Thiophenes; Vital Capacity

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

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

Topics: Absorption; Administration, Oral; Aerosols; Albuterol; Animals; Asthma; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Half-Life; Hemodynamics; Humans; In Vitro Techniques; Injections, Intravenous; Isoproterenol; Kinetics; Muscle Contraction; Myocardial Contraction; Organ Specificity; Piperidines; Terbutaline; Tremor

1. Using the same technique of administering drugs by intermittent positive-pressure ventilation as used in previous studies a source of contamination of solutions nebulized was discovered. This was rectified by using a new ventilator and completely separate patient circuits for each solution nebulized. 2 Salbutamol 0.5% and 0.25% solutions achieved the same degree of bronchodilatation, but there was a significantly greater increase in heart rate produced by salbutamol 0.5%. 3 Rimiterol 0.5% and salbutamol 0.25% produced similar peak mean improvements in FEV and also induced the same degree of tachycardia, but the duration of these effects were significantly shorter in the case of rimiterol. 4 The sustained degree of bronchodilatation achieved by salbutamol 0.25% could not be mirrored by giving two doses of rimiterol 0.5%, the second dose 2 h after the first. 5 Rimiterol 0.5% induced a degree of tachycardia which was similar in peak effect to that observed after salbutamol 0.25%. However, in the controls the second dose of rimiterol, given 2 h after the first, was responsible for only a small increase in heart rate which was not significantly different than that after saline in the other three treatment groups.

Topics: Adult; Aged; Albuterol; Asthma; Catechols; Female; Forced Expiratory Volume; Heart Rate; Humans; Intermittent Positive-Pressure Breathing; Male; Middle Aged; Piperidines; Positive-Pressure Respiration; Time Factors

A clinical trial was performed with a new substance (HC 20-511) derived from the cycloheptothiophene group used in the management of asthma. Twenty-four asthma patients were treated at random, with HC 20-511 or placebo or the antihistaminic substance, clemastin (Tavegyl). A statistical evaluation of the results unequivocally demonstrates good protection with a single dose of 2.0 mg or two times 1.0 mg for 3 days against a challenging antigen, compared with the placebo or the antihistaminic agent. Tolerance was excellent.

Topics: Adolescent; Adult; Asthma; Clemastine; Clinical Trials as Topic; Cycloheptanes; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Placebos; Thiophenes; Vital Capacity

Topics: Animals; Asthma; Catechols; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Lung Diseases, Obstructive; Piperidines

Topics: Aerosols; Aged; Asthma; Bronchodilator Agents; Catechols; Circadian Rhythm; Clinical Trials as Topic; Female; Heart Rate; Humans; Hydrogen-Ion Concentration; Male; Methanol; Middle Aged; Oxygen; Partial Pressure; Piperidines

The bronchodilating efficacy and the degree of beta2-selectivity of rimiterol, salbutamol and isoprenaline were determined in seven asthmatic patients. Rimiterol, 0.5 (high dose) and 0.05 mug/kg/min (low dose), salbutamol, 0.3 and 0.03 mug/kg/min, isoprenaline, 0.05 and 0.005 mug/kg/min, and placebo were administered by a single intravenous injection over 6 minutes in a double-blind trial. Airway resistance, heart rate, blood pressure and skeletal muscle tremor were measured before and at various times for 2 hours after each injection. The high doses of rimiterol (37%), salbutamol (37%) and isoprenaline (32%) produced immediate and effective bronchodilatation. The duration of action of rimiterol and isoprenaline was similar and shorter than that of salbutamol. For these ventilatory responses there were heart rate increases of 32, 20 and 40 beats/min for rimiterol, salbutamol and isoprenaline, respectively. The three drugs produced similar increases in pulse pressure and tremor. Dose-responses were obtained for each drug with all parameters measured and significant differences at various times found. Isoprenaline was approximately 8 and 5 times as potent as rimiterol and salbutamol, respectively, in bronchodilator action, when equimolar doses were compared. Similarly, isoprenaline was approximately 16 and 12 times as potent in increasing the heart rate as rimiterol and salbutamol, respectively. For an equal bronchodilator action, isoprenaline increased the heart rate 2 and 2.5 times more than rimiterol and salbutamol, respectively. Rimiterol is an effective, short-acting bronchodilator, with similar beta2-selectivity to salbutamol, when administered intravenously to asthmatic patients. The relative potencies and degrees of beta2-selectivity of these drugs depend partly on their route of administration.

Topics: Adrenergic beta-Agonists; Adult; Albuterol; Asthma; Blood Pressure; Bronchi; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Forced Expiratory Volume; Heart Rate; Humans; Isoproterenol; Male; Middle Aged; Piperidines; Placebos; Tremor; Vital Capacity

A comparison between the acute effects of rimiterol (0.5 mg) and salbutamol (0.2 mg.) has been made using metered dose aerosols. In this dosage it was found that the peak effect of the two drugs was the same but that the effect of rimiterol was less prolonged than that of sulbutamol. No increase in blood pressure occurred and heart rate changes were minimal after both drugs. Rimiterol is an acceptable alternative to the short-acting isoprenaline but lacks the cardiovascular effects of isoprenaline and is an alternative to salbutamol where very prolonged action is unnecessary.

Topics: Adult; Aerosols; Airway Obstruction; Albuterol; Asthma; Blood Pressure; Bronchi; Bronchitis; Bronchodilator Agents; Cardiovascular System; Catechols; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Isoproterenol; Male; Methanol; Middle Aged; Piperidines; Respiratory Function Tests; Respiratory Therapy

The bronchodilating efficacies and beta2-adrenoceptor selectivities of rimiterol (0.2, 0.1, and 0.05 mug kg-minus1 min-minus1) and sal-utamol (0.1, 0.5, and 0.025 mug kg-minus1 min-minus1), intravenously infused for one hour, were determined in five patients with chronic asthma. Each drug infusion produced and maintained a dose-related improvement in forced expiratory volune in one second (FEV1). A further increase in FEV1 was produced by inhalation of the same drug by pressurized aerosol at the end of each infusion, which suggested that no resistance had occurred. Similar dose-related increases in heart rate, pulse pressure, and skeletal muscular tremor were produced by each drug. Peak heart rate increases varied greatly between individuals, ranging from 12 to 30 beats/min with the high doses but always less than 10 beats/min with the low doses of each drug. On rimiterol the heart rate reached equilibrium earlier during the infusions and declined more rapidly after they had stopped, thus providing an accurate means for monitoring dosage. Rimeterol with its short half life-a desirable property for an intravenous drug with respect to safety-may prove to be a valuable bronchodilator in severe asthma when intravenous infusions are indicated.

Topics: Albuterol; Asthma; Blood Pressure; Bronchodilator Agents; Catechols; Dose-Response Relationship, Drug; Forced Expiratory Volume; Heart Rate; Humans; Injections, Intravenous; Male; Methanol; Middle Aged; Muscles; Piperidines; Pulse; Respiratory Therapy; Vital Capacity

Topics: Acetylcholine; Airway Resistance; Asthma; Bronchi; Bronchodilator Agents; Catechols; Clinical Trials as Topic; Histamine; Humans; Male; Methanol; Piperidines

GSK2245035, a small molecule Toll-like Receptor 7 (TLR7) agonist developed for immunomodulatory treatment for allergic airways disease, aimed to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type I interferons (IFNs). GSK2245035 demonstrated selectivity for potent release of type I IFNs compared to TNF-α and IL-6, with dose dependent increases in the interferon inducible chemokine, IP-10, in the nasal compartment. Implantation and parturition require pro-inflammatory processes including IFNs, Interferon Stimulated Genes, TNFα and IP-10 while pregnancy requires immune regulation to maintain maternal fetal immune tolerance, and recombinant type I IFNs induced abortions in monkeys. Due to its mechanism of action, GSK2245035 was studied at pharmacologically and clinically relevant doses in a monkey pregnancy model. Monkeys received 0, 3 or 30 ng/kg/week GSK2245035 intranasally once weekly, from Day 20 postcoitum through Day 63 postpartum. Although systemic IFN-α and IP-10 levels were approximately 14.8 or 40 -fold (respectively) above predose levels at 3 or 30 ng/kg/week, respectively, there were no effects on pregnancy and infant outcome. Non-adverse effects included increased incidence of nasal discharge, increased maternal body temperature at 30 ng/kg/week and dose-dependent increases in maternal IP-10 and IFN-α and decreased infant anti-KLH IgM and IgG titers following KLH immunization at ≥3 ng/kg/week, relative to controls. Potentially, lower IFN-α and IP-10 levels as well as once-weekly intranasal dosing vs daily subcutaneous or intramuscular dosing with recombinant type I IFNs could explain the lack of pregnancy effects; however, there was an undesired impact on offspring immune function.

Topics: Abortion, Spontaneous; Adenine; Administration, Intranasal; Animals; Asthma; Chemokine CXCL10; Disease Models, Animal; Female; Humans; Interferon-alpha; Macaca fascicularis; Piperidines; Pregnancy; Pregnancy Complications; Toll-Like Receptor 7

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.

Topics: Adolescent; Adult; Aged; Animals; Asthma; Bone Marrow; Cell Differentiation; Chemokines, CC; Eosinophils; Female; Healthy Volunteers; Hematopoietic Stem Cells; Humans; Hypersensitivity; Inflammation; Lung; Macrophage Inflammatory Proteins; Male; Mice; Mice, Knockout; Middle Aged; Ovalbumin; Phenylurea Compounds; Piperidines; Receptors, CCR1; Signal Transduction; Young Adult

Topics: Acetates; Anti-Asthmatic Agents; Asthma; Benzimidazoles; Cyclopropanes; Humans; Piperidines; Quinolines; Seasons; Sulfides

Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (T

Topics: Animals; Asthma; Bronchoconstriction; Cell Differentiation; Diacylglycerol Kinase; Enzyme Inhibitors; Humans; Inflammation; MAP Kinase Signaling System; Mice, Knockout; Myocytes, Smooth Muscle; Piperidines; Quinazolinones; Respiratory Hypersensitivity; Signal Transduction; Th2 Cells

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We've previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.

Topics: Acetanilides; Adherens Junctions; Animals; Asthma; beta Catenin; Bronchoalveolar Lavage Fluid; Cadherins; Cytokines; Epithelial Cells; Inflammation; Lung; Mice; Mice, Inbred C57BL; Phosphorylation; Piperidines; Purines; Quinolines; Toluene 2,4-Diisocyanate; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Preformulation studies on tofacitinib citrate, a small molecule JAK3 specific inhibitor, have not been previously reported in literature. We therefore conducted several preformulation studies on tofacitinib citrate, and its free base, to better understand factors that affect its solubility, stability, and solid-state characteristics. Further, the results of the preformulation studies helped facilitate the development of a nebulized formulation of tofacitinib citrate for inhalational delivery to house dust mite allergen-challenged, BALB/c mice as a potential treatment for eosinophilic asthma. The preformulation results indicated tofacitinib having a basic pKa of 5.2, with its stability dependent on pH, ionic strength, and temperature. Degradation of tofacitinib follows apparent first-order kinetics. In order to maximize stability of the drug, ionic strength and temperature should be minimized, with an optimal range pH between 2.0 and 5.0. Additionally, our findings demonstrate that tofacitinib citrate can successfully be nebulized at a suitable droplet size for inhalation (1.2 ± 0.2 μm MMAD) through a nose-only chamber. Animals dosed with tofacitinib citrate demonstrated marked reductions in BAL eosinophils and total protein concentrations following HDM challenge. These data suggest that tofacitinib citrate represents the potential to be an effective therapy for eosinophilic asthma.

Topics: Administration, Inhalation; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Drug Compounding; Drug Stability; Female; Mice; Mice, Inbred BALB C; Piperidines; Pyrimidines; Pyroglyphidae; Pyrroles

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

Topics: Administration, Inhalation; Allergens; Animals; Asthma; Inflammation; Isoenzymes; Janus Kinase Inhibitors; Janus Kinases; Male; Nitriles; Phosphoproteins; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT Transcription Factors; Time Factors

Allergic asthma is an inflammatory condition accompanied by inflammation as well as oxidative stress. Supplementation of an anti-inflammatory agent having antioxidant properties may have therapeutic effects against this disease. Over the recent decades, the interest in combination therapy as new alternative medication has increased and it offers numerous benefits along with noticeable lack of toxicity as well as side effects. In this study, protective effects of curcumin alone and in combination with piperine were evaluated in mouse model of allergic asthma. Balb/c mice were sensitized on days 0, 7, and 14 and challenged from days 16-30 on alternate days with ovalbumin (OVA). Mice were pretreated with curcumin (Cur; 10 and 20 mg/kg) and piperine (Pip; 5 mg/kg) alone and in combination via the intraperitoneal route on days 16-30 and compared with intranasal curcumin (5 mg/kg) treatment. Blood, bronchoalveolar lavage fluid (BALF), and lungs were collected after mice were sacrificed on day 31st. Mice immunized with OVA have shown significant increase in airway inflammation and oxidative stress as determined by oxidative stress markers. A significant suppression was observed with all the treatments, but intranasal curcumin treatment group has shown maximum suppression. So, among all the treatment strategies utilized, intranasal curcumin administration was most appropriate in reducing inflammation and oxidative stress and possesses therapeutic potential against allergic asthma. Present study may prove the possibility of development of curcumin nasal drops towards treatment of allergic asthma.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Asthma; Benzodioxoles; Bronchoalveolar Lavage Fluid; Curcumin; Drug Administration Routes; Drug Therapy, Combination; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Oxidative Stress; Piperidines; Polyunsaturated Alkamides

Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.

Topics: Animals; Asthma; Basophils; Cell Degranulation; Chalcones; Dermatitis, Atopic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Mice; Models, Molecular; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors

Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma.. Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways.. In C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro.. AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells.. This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.

Topics: Allergens; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Differentiation; Cytokines; Desensitization, Immunologic; Disease Models, Animal; Humans; Janus Kinases; Mice; Mice, Inbred C57BL; Ovalbumin; Piperidines; Pyrimidines; Pyrroles

Bronchial thermoplasty (BT) is a rapidly emerging bronchoscopic treatment for patients with moderate-to-severe asthma. Different sedation strategies are currently used, ranging from mild midazolam sedation to general anesthesia requiring tracheal intubation.. The aim of this study was to assess the feasibility, safety, and both patients' and bronchoscopists' satisfaction with propofol and remifentanil sedation administered by specialized sedation anesthesiology nurses during BT in severe asthma patients.. A prospective observational cohort study in BT-treated severe asthma patients of the TASMA trial was designed. Patients were asked to rate their overall BT procedure satisfaction and tolerance with propofol/remifentanil sedation using a visual analogue scale (VAS) ranging from 0 to 10. Similarly, bronchoscopists were asked to rate patient cooperation and tolerance. Sedation-associated adverse events and the number of BT activations were recorded.. Thirty-two BT procedures in 13 severe asthma patients were performed under moderate target-controlled infusion (TCI) propofol/remifentanil sedation. Patients' median VAS scores were as follows: overall satisfaction 9.6 (interquartile range [IQR] 8.5-10.0), dyspnea 0.0 (IQR 0.0-0.6), pain 0.1 (IQR 0.0-1.0), cough 0.5 (IQR 0.0-2.1), and anxiety 0.1 (IQR 0.0-0.7). Bronchoscopists' median VAS scores were as follows: overall patient cooperation 9.1 (IQR 8.5-9.6), dyspnea 0.3 (IQR 0.0-0.9), pain 0.2 (IQR 0.0-1.3), cough 1.2 (IQR 0.7-2.0), and discomfort 0.6 (IQR 0.3-1.5). All patients were willing to undergo the procedure again and would recommend this form of sedation to their best friend. One case of conversion to general anesthesia occurred and no serious adverse events were reported.. Moderate sedation with propofol and remifentanil TCI provided by specialized sedation anesthesiology nurses is feasible and safe and results in high satisfaction rates of both patients and bronchoscopists.

Topics: Adult; Anesthetics, Intravenous; Asthma; Bronchoscopy; Conscious Sedation; Female; Humans; Male; Middle Aged; Piperidines; Propofol; Prospective Studies; Remifentanil

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

Topics: Adenine; Administration, Intranasal; Asthma; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship; Toll-Like Receptor 7

Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression.. Cells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry.. JAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells.. Targeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma.

Topics: Adult; Anti-Inflammatory Agents; Asthma; Bronchoalveolar Lavage Fluid; Case-Control Studies; CD3 Complex; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases; Dexamethasone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Inflammation Mediators; Interferon-gamma; Interleukin-13; Interleukin-17; Janus Kinase Inhibitors; Janus Kinases; Lung; Lymphocyte Activation; Male; Middle Aged; Molecular Targeted Therapy; Piperidines; Pyrimidines; Pyrroles; Signal Transduction; T-Lymphocytes

Asthma is a disease of acute and chronic inflammation in which cytokines play a critical role in orchestrating the allergic inflammatory response. IL-13 and transforming growth factor (TGF)-β promote fibrotic airway remodeling, a major contributor to disease severity. Improved understanding is needed, because current therapies are inadequate for suppressing development of airway fibrosis. IL-13 is known to stimulate respiratory epithelial cells to produce TGF-β, but the mechanism through which this occurs is unknown. Here, we tested the hypothesis that reactive oxygen species (ROS) are a critical signaling intermediary between IL-13 or allergen stimulation and TGF-β-dependent airway remodeling. We used cultured human bronchial epithelial cells and an in vivo mouse model of allergic asthma to map a pathway where allergens enhanced mitochondrial ROS, which is an essential upstream signal for TGF-β activation and enhanced collagen production and deposition in airway fibroblasts. We show that mitochondria in airway epithelium are an essential source of ROS that activate TGF-β expression and activity. TGF-β from airway epithelium stimulates collagen expression in fibroblasts, contributing to an early fibrotic response to allergen exposure in cultured human airway cells and in ovalbumin-challenged mice. Treatment with the mitochondrial-targeted antioxidant, (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), significantly attenuated mitochondrial ROS, TGF-β, and collagen deposition in OVA-challenged mice and in cultured human epithelial cells. Our findings suggest that mitochondria are a critical source of ROS for promoting TGF-β activity that contributes to airway remodeling in allergic asthma. Mitochondrial-targeted antioxidants may be a novel approach for future asthma therapies.

Topics: Animals; Antioxidants; Asthma; Cells, Cultured; Collagen; Disease Models, Animal; Humans; Interleukin-13; Mice; Mice, Transgenic; Mitochondria; Organophosphorus Compounds; Piperidines; Reactive Oxygen Species; Transforming Growth Factor beta

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophilia; Female; Histamine H3 Antagonists; Immunoglobulin E; Indoles; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Piperazines; Piperidines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

When neostigmine is used to reverse muscle relaxants in patients with asthma without signs of airway inflammation, asthma attack is occasionally encountered. It is likely that abnormally increased electrical impulses traveling from the brain through cholinergic nerves to airway smooth muscles may be one of the pathogeneses of asthma attack. We applied continuous electrical field stimulation (c-EFS) or continuous electrical stimulation (c-ES) of low frequency to the vagal nerve of the rat in vitro and in vivo to determine the role of cholinergic nerve activation in inducing airway constriction.. Fifty-seven male Wistar rats were used. In an in vitro study we examined whether tetrodotoxin (TTX), an Na(+)-channel blocker, 4-DAMP, a muscarinic M(3) receptor antagonist, or neostigmine could affect c-EFS-induced contraction of the tracheal ring. In an in vivo study, we examined whether c-ES of the vagal nerve could increase maximum airway pressure (P (max)) and whether neostigmine could potentiate c-ES-induced P (max).. TTX and 4-DAMP completely inhibited c-EFS-induced contraction whereas neostigmine potentiated c-EFS-induced contraction dose-dependently. P (max) was not increased by neostigmine. P (max) was not increased by 2-Hz c-ES, but was increased by the addition of neostigmine. P (max) was increased by 5-Hz c-ES, and further increased by the addition of neostigmine.. The contractile response of the tracheal ring to c-EFS is potentiated by neostigmine. P (max) is increased by c-ES of the vagal nerve, and is potentiated by neostigmine. These data suggest that increased activity of the cholinergic nerve could be involved in asthma attack.

Topics: Animals; Asthma; Bronchoconstriction; Electric Stimulation; Male; Neostigmine; Parasympathomimetics; Piperidines; Rats; Rats, Wistar; Tetrodotoxin; Trachea

The chemokine receptor CCR8 is associated with asthma. Herein, we describe that both mature and immature dendritic cells (DC) express CCR8, whereas only mature DC migrate towards CCL1. Moreover, transient LPS challenge significantly down-regulates CCR8 expression hence attenuating CCL1 chemotaxis. To inhibit CCR8 pathophysiology, we recently developed a novel series of small molecule CCR8 antagonists containing a diazaspiroundecane scaffold, which had micromolar potency. However, these first generation antagonists had high lipophilicity that endowed the compounds with poor physicochemical properties, and were thus not suitable for further development. By introducing polar bicyclic groups on the N-benzyl substituent and building in further polar interactions on the amide group we now show second generation diazospiroundecane antagonists with significantly improved overall properties. Potency is substantially improved from micromolar to nanomolar potency in CCR8 binding and inhibition of chemotaxis in human primary T cells, DC and in an eosinophil cell line. In addition to high potency, the most attractive antagonist, AZ084 showed excellent selectivity, high metabolic stability in vitro and an attractive in vivo PK profile with a long half-life in rat. Interestingly, in ligand saturation experiments and in wash-off experiments, CCL1 was shown to have two binding sites to CCR8 with K(d) at 1.2/68pM respectively, and on-off rates of 0.004 and 0.0035/0.02pMmin, respectively. The lead antagonist, AZ084, appears to act as an allosteric inhibitor with a K(i) at 0.9nM. Taken together, we herein report a novel oral allosteric CCR8 antagonist with predicted low once-daily dosing capable of potent inhibition of both human T cell and DC functions.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Biological Availability; Cell Line; Cell Movement; Chemokine CCL1; Chemotaxis; Dendritic Cells; Dogs; Eosinophils; Female; Half-Life; Humans; Male; Mice; Piperidines; Protein Binding; Pyridazines; Rats; Receptors, CCR8; Small Molecule Libraries; Spiro Compounds; T-Lymphocytes

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

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

Topics: Adult; Airway Management; Anesthesia, Inhalation; Anesthesia, Intravenous; Anesthesia, Obstetrical; Anesthesia, Spinal; Anesthetics, Local; Appendectomy; Appendicitis; Asthma; Cesarean Section; Charcot-Marie-Tooth Disease; Contraindications; Emergencies; Female; Humans; Middle Aged; Neuromuscular Depolarizing Agents; Neuromuscular Nondepolarizing Agents; Piperidines; Pregnancy; Pregnancy Complications; Propofol; Remifentanil

Topics: Asthma; Benzamides; Churg-Strauss Syndrome; Humans; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyridines; Thiazoles; Treatment Outcome

This study aimed to investigate the effect of piperine on airway hyperresponsiveness, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokine production, immunoglobulin E and histamine production in a murine model of asthma.. Asthma was induced in Balb/c mice by ovalbumin sensitization and inhalation. Piperine (4.5 and 2.25 mg/kg) was orally administered 5 times a week for 8 weeks. At 1 day after the last ovalbumin exposure, airway hyperresponsiveness was determined and samples of bronchoalveolar lavage fluid, lung cells and serum were collected for further analysis.. Piperine-treated groups had suppressed eosinophil infiltration, allergic airway inflammation and airway hyperresponsiveness, and these occurred by suppression of the production of interleukin-4, interleukin-5, immunoglobulin E and histamine. Moreover, polymerase chain reaction products for thymus and activation regulated chemokine from lung cell RNA preparations were decreased in the piperine-treated group compared with control groups, although transforming growth factor-beta products were increased in the piperine-treated group.. The results suggest that the therapeutic mechanism by which piperine effectively treats asthma is based on a reduction of Th2 cytokines (interleukin-4, interleukin-5), eosinophil infiltration, and by marked reduction of thymus and activation regulated chemokine, eotaxin-2 and interleukin-13 mRNA expression (especially transcription of nuclear factor-kappaB dependent genes) in lung tissue, as well as reduced interleukin-4, interleukin-5 and eotaxin levels in bronchoalveolar lavage fluid, and histamine and ovalbumin-specific immunoglobulin E production in serum.

Topics: Alkaloids; Animals; Asthma; Benzodioxoles; Bronchial Hyperreactivity; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Female; Histamine; Immunoglobulin E; Mice; Mice, Inbred BALB C; Ovalbumin; Piperidines; Polyunsaturated Alkamides; RNA, Messenger; T-Lymphocytes; Th2 Cells

The applications WO2008103126 and WO2009011653, respectively, claim: i) Combinations of a spirocyclic piperidine chemokine CCR1 antagonist with a corticosteroid, and their use for the treatment of asthma and chronic obstructive pulmonary disease. ii) Processes for the preparation of a spirocyclic piperidine derivative, a chemokine CCR1 antagonist. These applications point to the preferred compound being a development compound. The evidence for this compound being AZD-4818, a chemokine CCR1 antagonist that was in Phase II development for the treatment of chronic obstructive pulmonary disease, is reviewed in the light of these and earlier patents relating to it.

Topics: Animals; Asthma; Clinical Trials, Phase II as Topic; Drug Design; Drug Therapy, Combination; Glucocorticoids; Humans; Patents as Topic; Piperidines; Pulmonary Disease, Chronic Obstructive; Receptors, CCR1; Spiro Compounds

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Butyrophenones; Cetirizine; Child; Chlorpheniramine; Dermatitis, Atopic; Dibenzazepines; Dibenzoxepins; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Imidazoles; Japan; Male; Middle Aged; Olopatadine Hydrochloride; Pain Measurement; Piperidines; Population Surveillance; Psychomotor Performance; Pyridines; Quality of Life; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sleep Stages; Surveys and Questionnaires; Terfenadine; Urticaria

In this study, we investigated the effects of the selective ET(A) (BQ-123) and ET(B) (BQ-788) receptor antagonists for endothelin-1 (ET-1) against several flogistic agent-induced paw edema formation and ovalbumin-induced allergic lung inflammation in mice. The intraplantar injection of BQ-123, but not BQ-788, significantly inhibited carrageenan-, PAF-, ET-1- and bradykinin-induced paw edema formation. The obtained inhibitions (1h after the inflammatory stimulus) were 79+/-5%, 55+/-4%, 55+/-6% and 74+/-4%, respectively. In carrageenan-induced paw edema, the mean ID(50) value for BQ-123 was 0.77 (0.27-2.23)nmol/paw. The neutrophil influx induced by carrageenan or PAF was reduced by BQ-123, with inhibitions of 55+/-2% and 72+/-4%, respectively. BQ-123 also inhibited the indirect macrophage influx induced by carrageenan (55+/-6%). However, BQ-788 failed to block the cell influx caused by either of these flogistic agents. When assessed in the bronchoalveolar lavage fluid in a murine model of asthma, both BQ-123 and BQ-788 significantly inhibited ovalbumin-induced eosinophil recruitment (78+/-6% and 71+/-8%), respectively. Neither neutrophil nor mononuclear cell counts were significantly affected by these drugs. Our findings indicate that ET(A), but not ET(B), selective ET-1 antagonists are capable of preventing the acute inflammatory responses induced by carrageenan, PAF, BK and ET-1. However, both ET(A) and ET(B) receptor antagonists were found to be effective in inhibiting the allergic response in a murine model of asthma.

Topics: Animals; Anti-Allergic Agents; Antihypertensive Agents; Asthma; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Female; Inflammation; Male; Mice; Mice, Inbred BALB C; Oligopeptides; Peptides, Cyclic; Piperidines

In this study we evaluated the effects of the CB1/CB2 cannabinoid receptor agonist CP55, 940 (CP) on antigen-induced asthma-like reaction in sensitized guinea pigs and we tested the ability of the specific CB2 receptor antagonist SR144528 (SR) and CB1 receptor antagonist AM251 (AM) to interfere with the effects of CP. Ovalbumin-sensitized guinea pigs placed in a respiratory chamber were challenged with the antigen given by aerosol. CP (0.4 mg/kg b.wt.) was given i.p. 3 hrs before ovalbumin challenge. Sixty minutes before CP administration, some animals were treated i.p. with either AM, or SR, or both (0.1 mg/kg b.wt.). Respiratory parameters were recorded and quantified. Lung tissue specimens were then taken for histopathological and morphometric analyses and for eosinophilic major basic protein immunohistochemistry. Moreover, myeloperoxidase activity, 8-hydroxy-2-deoxyguanosine, cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) levels, and CB1 and CB2 receptor protein expression by Western blotting were evaluated in lung tissue extracts. In the bronchoalveolar lavage fluid, the levels of prostaglandin D2 and tumour necrosis factor-alpha TNF-alpha were measured. Ovalbumin challenge caused marked abnormalities in the respiratory, morphological and biochemical parameters assayed. Treatment with CP significantly reduced these abnormalities. Pre-treatment with SR, AM or both reverted the protective effects of CP, indicating that both CB1 and CB2 receptors are involved in lung protection. The noted treatments did not change the expression of cannabinoid receptor proteins, as shown by Western blotting. These findings suggest that targeting cannabinoid receptors could be a novel preventative therapeutic strategy in asthmatic patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antigens; Asthma; Camphanes; Cyclic AMP; Cyclohexanols; Deoxyguanosine; DNA Damage; Guinea Pigs; Humans; Leukocytes; Lung; Male; Mast Cells; Models, Biological; Ovalbumin; Piperidines; Prostaglandin D2; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

Topics: Adrenergic beta-Agonists; Albuterol; Amantadine; Analgesics, Non-Narcotic; Androstadienes; Aromatase Inhibitors; Asthma; Bronchodilator Agents; Donepezil; Drug Therapy, Combination; Female; Fluticasone; Food Hypersensitivity; Humans; Indans; Interferons; Latex Hypersensitivity; Letrozole; Mandelic Acids; Middle Aged; Multiple Sclerosis; Nebulizers and Vaporizers; Nitriles; Nootropic Agents; Parasympatholytics; Paresthesia; Piperidines; Respiratory Function Tests; Salmeterol Xinafoate; Thyroxine; Triazoles

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

A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Asthma; Cell Line; Chemotaxis; Crystallography, X-Ray; Humans; Male; Mice; Piperidines; Rats; Rats, Inbred Lew; Receptors, CCR2; Stereoisomerism; Structure-Activity Relationship

To investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.. Anesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.. (1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.. Brain histamine H3 receptors may be related to asthmatic respiratory responses.

Topics: Animals; Asthma; Brain; Guinea Pigs; Histamine Agonists; Histamine H3 Antagonists; Lateral Ventricles; Male; Methylhistamines; Muscle Contraction; Piperidines; Receptors, Histamine H3; Substance P; Trachea

An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.

Topics: Administration, Oral; Animals; Asthma; Integrin alpha4beta1; Mice; Morpholines; Piperidines

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

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

In this study, we investigated the involvement of neurokinin NK3 receptors in a severe asthma model prepared by administering ovalbumin via inhalation three times to systemically sensitized guinea pigs. [3H]senktide, a neurokinin NK3 receptor ligand, showed significant specific binding to the lungs from the model animals, but not to those from negative control animals. The airway responsiveness to intravenous neurokinin B, a neurokinin NK3 receptor agonist, was increased in the model, indicating an increase in functional NK3 receptors. Furthermore, SB 223956 ((-)-3-methoxy-2-phenyl-N-[(1S)-phenylpropyl]quinoline-4-carboxamide), a selective neurokinin NK3 receptor antagonist, significantly inhibited the ovalbumin-induced airway hyperresponsiveness to inhaled methacholine, but it did not show significant effects on the ovalbumin-induced airway narrowing and eosinophil accumulation. These results suggest that the expressed neurokinin NK3 receptors in the severe asthma model are involved in the development of airway hyperresponsiveness.

Topics: Animals; Asthma; Benzamides; Binding, Competitive; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Bronchoconstrictor Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; Guinea Pigs; Lung; Male; Methacholine Chloride; Neurokinin B; Ovalbumin; Peptide Fragments; Piperidines; Receptors, Neurokinin-3; Substance P; Tritium

Respiratory syncytial virus (RSV) infection is associated with exaggerated neurogenic inflammation in the airways. This study sought to determine whether irritation of the mucosal sensory fibers affects the recruitment of lymphocytes and monocytes to RSV-infected airways. Pathogen-free rats were inoculated with RSV or with virus-free medium and were injected 5 days later with capsaicin to stimulate airway sensory nerves. Bronchoalveolar lavage was performed 1, 5, or 10 days after nerve stimulation, and samples were analyzed by differential cell count and flow cytometry. Without nerve stimulation, RSV caused a minimal increase in the number of lymphocytes and monocytes above pathogen-free control levels. After nerve stimulation, numerous lymphocytes, predominantly CD4+ T cells, and monocytes were recruited in the airways of infected rats, whereas no difference was found in pathogen-free controls. RSV induced overexpression of the neurokinin 1 (NK1) receptor for substance P on discrete lymphocyte subpopulations within the bronchial-associated lymphoid tissue (BALT), and treatment with a specific NK1 receptor antagonist abolished the recruitment of both lymphocytes and monocytes to infected airways. Our data suggest that airborne irritants stimulating mucosal sensory fibers during RSV infection exert important immunomodulatory effects by attracting to the infected airways selected lymphocyte subpopulations from the local BALT as well as monocytes.

Topics: Adjuvants, Immunologic; Animals; Asthma; Leukocyte Count; Lung; Lymphocyte Subsets; Male; Monocytes; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Piperidines; Pneumonia, Viral; Rats; Rats, Inbred F344; Receptors, Neurokinin-1; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Specific Pathogen-Free Organisms; Substance P

A piperidinyl chlorotriazine (PCT) derivative, used as a plastic UV-stabilizer, caused an outbreak of occupational asthma. We verified, in BALB/c mice, the sensitizing potential of PCT in comparison to a known respiratory sensitizer (toluene diisocyanate [TDI]) and a known dermal sensitizer (oxazolone), using three different methods in order to evaluate the validity of current models of sensitization. These included the local lymph node assay (LLNA) and the mouse IgE test. In addition, respiratory hyper-reactivity was assessed following a novel protocol involving dermal sensitization (20 microl of a 3% solution on each ear for three days) and intranasal challenge (0.1% or 1%, 10 microl per nostril on day 10), followed, after 24 h, by a methacholine challenge (using whole-body plethysmography), bronchoalveolar lavage, and histology. PCT was also used for structure-activity relationship (SAR) models for (respiratory) sensitization. High concentrations of PCT (10 and 20%) resulted in significant responses in the local lymph node assay (LLNA; stimulation indices (SI) of 2.7 +/- 0.9 and 3.2 +/- 0.6, respectively). The mouse IgE test was positive with 20% PCT only. Methacholine responsiveness was increased only in previously sensitized mice receiving a challenge with TDI or PCT. However, there was no evidence for pulmonary inflammation. The SAR studies indicated that PCT could be a respiratory sensitizer. Based on an approved test protocol such as the LLNA and the mouse IgE test, PCT proved to be a weak sensitizer when compared to TDI and oxazolone. However, in a protocol involving an intranasal challenge, PCT appeared to be a respiratory sensitizer of similar potency to TDI.

Topics: Adjuvants, Immunologic; Administration, Cutaneous; Allergens; Animals; Asthma; Bronchoalveolar Lavage; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Female; Immunoglobulin E; Local Lymph Node Assay; Lung; Lymph Nodes; Methacholine Chloride; Mice; Mice, Inbred BALB C; Occupational Exposure; Oxazolone; Piperidines; Predictive Value of Tests; Structure-Activity Relationship; Toluene 2,4-Diisocyanate; Triazines

Gastro-oesophageal reflux is a common clinical disorder associated with a variety of respiratory symptoms, including chronic cough and exacerbation of asthma. In this study, the potential role of acid-induced tachykinin release was examined in guinea pigs and rabbits, by examining the effects of the tachykinin NK1 and NK3 receptors antagonists (SR 140333 and SR 142801, respectively) (1-10 mg x kg(-1)) on plasma protein extravasation induced in airways by hydrochloric acid (HCl) infusion in the oesophagus. Guinea pigs were anaesthetised with urethane, while rabbits were subject to neuroleptoanalgesia with hypnorm. Airway vascular leakage was evaluated by measuring extravasation of Evans blue dye. All animals were pretreated with atropine (1 mg x kg(-1) i.p.), propranolol (1 mg x kg(-1) i.p.), phosphoramidon (2.5 mg x kg(-1) i.v.) and saline or tachykinin receptor antagonists (1-10 mg x kg(-1) i.p.). Infusion of 1 N HCl into the oesophagus led to a three- and five-fold increase in plasma extravasation in the main bronchi and trachea, respectively. This increase was largely prevented by the tachykinin NK1 and NK3 receptor antagonists SR 140333 and SR 142801 (1-10 mg x kg(-1)). These results suggest that protein extravasation in the airways, as induced by intraoesophageal HCl infusion, is mainly dependent on the release of tachykinins, and that both NK1 and NK3 tachykinin receptors are involved. The results suggest that HCl-induced sensory nerve stimulation may act in the periphery on intermediate neurons and/or ganglia where NK3 receptors have been shown to play an important role.

Topics: Animals; Asthma; Capillary Permeability; Disease Models, Animal; Esophagus; Female; Gastroesophageal Reflux; Guinea Pigs; Hydrochloric Acid; Instillation, Drug; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rabbits; Receptors, Neurokinin-1; Receptors, Neurokinin-3

Release of human lung mast cell tryptase may be important in the pathophysiology of asthma. We examined the effect of the reversible, nonelectrophilic tryptase inhibitor MOL 6131 on airway inflammation and hyper-reactivity in a murine model of asthma. MOL 6131 is a potent selective nonpeptide inhibitor of human lung mast cell tryptase based upon a beta-strand template (K(i) = 45 nM) that does not inhibit trypsin (K(i) = 1,061 nM), thrombin (K(i) = 23, 640 nM), or other serine proteases. BALB/c mice after i.p. OVA sensitization (day 0) were challenged intratracheally with OVA on days 8, 15, 18, and 21. MOL 6131, administered days 18-21, blocked the airway inflammatory response to OVA assessed 24 h after the last OVA challenge on day 22; intranasal delivery (10 mg/kg) had a greater anti-inflammatory effect than oral delivery (10 or 25 mg/kg) of MOL 6131. MOL 6131 reduced total cells and eosinophils in bronchoalveolar lavage fluid, airway tissue eosinophilia, goblet cell hyperplasia, mucus secretion, and peribronchial edema and also inhibited the release of IL-4 and IL-13 in bronchoalveolar lavage fluid. However, tryptase inhibition did not alter airway hyper-reactivity to methacholine in vivo. These results support tryptase as a therapeutic target in asthma and indicate that selective tryptase inhibitors can reduce allergic airway inflammation.

Topics: Animals; Asthma; Bridged Bicyclo Compounds, Heterocyclic; Bronchial Diseases; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Movement; Cytokines; Eosinophils; Humans; Inflammation; Lung; Mice; Mice, Inbred BALB C; Models, Molecular; Mucus; Ovalbumin; Piperidines; Pulmonary Edema; Pulmonary Eosinophilia; Serine Endopeptidases; Serine Proteinase Inhibitors; Tryptases; Vascular Cell Adhesion Molecule-1

To determine vascular cell adhesion molecule-1 (VCAM-1) expression and eosinophil infiltration in the lungs of the rats with allergic airway inflammation, and their possible modulation by dexamethasone and neurokinin-1 receptor antagonist SR140333.. Sensitized rats were challenged with inhalation of 1 % ovalbumin aerosol. Protein expression of VCAM-1 in the lungs and eosinophil infiltration around bronchi in different groups were determined 24 h after challenge. SR140333 (0.01 and 0.10 mg/kg) and dexamethasone (0.50 mg/kg) were injected ip, twice a day, for 3 d before challenge.. The expression of VCAM-1 was increased in the sensitized rat lungs as compared with the non-sensitized rats (P<0.05). The increment was inhibited by pretreatment with dexamethasone (P<0.05), but not with SR140333 (P>0.05). On the other hand, antigen challenge in sensitized rats evoked eosinophil infiltration (P<0.05) but no further increase in VCAM-1 expression (P>0.05). Furthermore, SR140333 inhibited eosinophil infiltration (P<0.05) but had no effect on VCAM-1 expression (P>0.05), whereas dexamethasone inhibited both responses (P<0.05).. The expression of VCAM-1 increases during antigen sensitization in rat lungs, and dexamethasone and SR140333 may inhibit allergic airway inflammation in different mechanisms.

Topics: Animals; Asthma; Dexamethasone; Eosinophils; Female; Gene Expression; Lung; Male; Neurokinin-1 Receptor Antagonists; Ovalbumin; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Vascular Cell Adhesion Molecule-1

Several observations suggest that tachykinins (substance P, neurokinin A and neurokinin B) are involved in the pathogenesis of pulmonary diseases and elicit several airway responses such as bronchoconstriction and neurogenic inflammation via interactions with specific receptors denoted NK(1), NK(2) and NK(3). We have investigated the effect of a selective antagonist for tachykinin NK(3) receptor, SR 142801 ((R)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl-N-methylacetamide), on the inflammatory cell recruitment in ovalbumin-sensitized and -challenged mice used as a model of allergic asthma. Twenty hours after the two-ovalbumin challenges, differential cell counts were calculated and indicated that SR 142801 caused a significant decrease in the number of neutrophils and eosinophils. Forty hours after the last ovalbumin exposure, SR 142801 induced a significant decrease in the recruitment of eosinophils. These results suggest that tachykinins and tachykinin NK(3) receptors can interfere with cell recruitment in inflammatory response.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Disease Models, Animal; Eosinophils; Lymphocytes; Macrophages; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Piperidines; Receptors, Neurokinin-3

The effects of an oral anti-allergic agent, TMK-688, which inhibits 5-lipoxygenase, at doses of 3.2 and 10 mg/kg were studied in guinea pigs with dual-phase asthmatic response. We previously observed that pretreatment with TMK-688 inhibited the late asthmatic response (LAR) induced by ovalbumin inhalation exposure. The present study focused on the effect of TMK-688 on infiltration by T-cells and eosinophils. TMK-688 inhibited both T-cell and eosinophilic infiltration. These findings suggest that TMK-688 is effective in inhibiting infiltration of T-cells and eosinophilic chemotaxis, and thereby suppresses LAR.

Topics: Animals; Anti-Asthmatic Agents; Arachidonate 5-Lipoxygenase; Asthma; Bronchi; Eosinophils; Guinea Pigs; Lipoxygenase Inhibitors; Male; Ovalbumin; Piperidines; T-Lymphocytes

It has been suggested that tachykinin NK1 receptor-mediated neurogenic inflammation, characterized by microvascular leakage, mucus secretion, and infiltration and activation of inflammatory cells in the airways, may be involved in allergic asthma. Therefore, in a guinea pig model of allergic asthma, we investigated the involvement of the NK1 receptor in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and airway inflammation, using the selective nonpeptide NK1 receptor antagonist SR140333. On two different occasions, separated by 1 wk interval, OA-sensitized guinea pigs inhaled either saline (3 min) or SR140333 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design. A control group, receiving saline inhalations before and at 5.5 h after the two OA provocations, was included as well. SR140333 had no significant effect on either the EAR or the LAR compared with saline control inhalations. However, the NK1 receptor antagonist significantly reduced the OA-induced AHR to histamine, both after the EAR at 5 h after OA challenge (1.77 +/- 0.13-fold increase in histamine reactivity versus 2.50 +/- 0.25-fold increase in the control animals, p < 0.01) and after the LAR at 23 h after OA challenge (1.15 +/- 0.12-fold increase versus 1.98 +/- 0. 34-fold increase, respectively, p < 0.05). Moreover, bronchoalveolar lavage studies performed at 25 h after the second OA provocation indicated that SR140333 significantly inhibited the allergen-induced infiltration of eosinophils, neutrophils, and lymphocytes in the airways (p < 0.05 for all observations), whereas a tendency to reduced accumulation of ciliated epithelial cells in the airway lumen was observed (p = 0.10). These results indicate that the NK1 receptor is involved in the development of allergen-induced AHR to histamine, and that NK1 receptor-mediated infiltration of inflammatory cells in the airways may contribute to this AHR.

Topics: Allergens; Animals; Asthma; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Consciousness; Cross-Over Studies; Disease Models, Animal; Female; Follow-Up Studies; Guinea Pigs; Histamine; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Random Allocation; Receptors, Neurokinin-1; Respiratory Function Tests

Gastroesophageal acid reflux into the airways can trigger asthma attacks. Indeed, citric acid inhalation causes bronchoconstriction in guinea pigs, but the mechanism of this effect has not been fully clarified. We investigated the role of tachykinins, bradykinin, and nitric oxide (NO) on the citric acid- induced bronchoconstriction in anesthetized and artificially ventilated guinea pigs. Citric acid inhalation (2-20 breaths) caused a dose-dependent increase in total pulmonary resistance (RL). RL value obtained after 10 breaths of citric acid inhalation was not significantly different from the value obtained after 20 breaths (p = 0.22). The effect produced by a half-submaximum dose of citric acid (5 breaths) was halved by the bradykinin B2 receptor antagonist HOE 140 (0.1 micromol x kg-1, intravenous) and abolished by the tachykinin NK2 receptor antagonist SR 48968 (0.3 micromol x kg-1, intravenous). Bronchoconstriction induced by a submaximum dose of citric acid (10 breaths) was partially reduced by the administration of HOE 140, SR 48968, or the NK1 receptor antagonist CP-99,994 (8 micromol x kg-1, intravenous) alone and completely abolished by the combination of SR 48968 and CP-99,994. Pretreatment with the NO synthase inhibitor, L-NMMA (1 mM, 10 breaths every 5 min for 30 min) increased in an L-arginine-dependent manner the effect of citric acid inhalation on RL. HOE 140 and CP-99,994 markedly reduced the L-NMMA-potentiated bronchoconstriction to inhaled citric acid. We conclude that citric acid-induced bronchoconstriction is caused by tachykinin release from sensory nerves, which, in part, is mediated by endogenously released bradykinin. Simultaneous release of NO by citric acid inhalation counteracts tachykinin-mediated bronchoconstriction. Our study suggests a possible implication of these mechanisms in asthma associated with gastroesophageal acid reflux and a potential therapeutic role of tachykinin and bradykinin antagonists.

Topics: Administration, Inhalation; Adrenergic beta-Antagonists; Airway Resistance; Animals; Asthma; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Citric Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Piperidines; Receptors, Neurokinin-2

Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK1 and NK2 receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK2 receptor antagonist SR 48968, but not the NK1 receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR. By contrast, SR 48968 did not affect the AHR after the EAR, but significantly attenuated the AHR after the LAR. Bronchoalveolar lavage studies performed after the LAR indicated that SR 140333 caused significant inhibition of allergen-induced infiltration of eosinophils, neutrophils and lymphocytes, while SR 48968 attenuated the infiltration of neutrophils and lymphocytes, but not of eosinophils. Both NK receptor antagonists tended to reduce the accumulation of ciliated epithelial cells in the airways. These results indicate that NK1 and NK2 receptors are importantly, but differentially, involved in the development of allergen-induced airways obstruction, AHR and infiltration of inflammatory cells in the airways. Therefore, both NK1 and NK2 receptor antagonists, or dual NK1 and NK2 antagonists, could be useful in the treatment of allergic asthma.

Topics: Allergens; Animals; Asthma; Benzamides; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchitis; Chemotaxis, Leukocyte; Eosinophils; Guinea Pigs; Lymphocytes; Neurokinin-1 Receptor Antagonists; Neutrophils; Ovalbumin; Piperidines; Quinuclidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2

1. In a guinea-pig model of allergic asthma, we investigated the involvement of the tachykinin NK2 receptors in allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions and inflammatory cell influx in the airways, using the selective non-peptide NK2 receptor antagonist SR48968. 2. On two different occasions, separated by a 1 week interval, ovalbumin (OA)-sensitized guinea-pigs inhaled either vehicle (3 min) or SR48968 (100 nM, 3 min) at 30 min before as well as at 5.5 h after OA provocation (between the EAR and LAR) in a random crossover design. 3. SR48968 had no significant effect on the EAR, but significantly attenuated the LAR by 44.2+/-16.4% (P<0.05) compared to saline control. 4. The NK2 receptor antagonist did not affect the OA-induced AHR to histamine after the EAR at 5 h after OA challenge (3.59+/-0.59 fold increase in histamine reactivity vs 3.79+/-0.61 fold increase in the controls, NS), but significantly reduced the AHR after the LAR at 23 h after OA challenge (1.59+/-0.24 fold increase vs 1.93+/-0.15 fold increase, respectively, P<0.05). 5. Bronchoalveolar lavage studies performed at 25 h after the second OA provocation showed that SR48968 significantly inhibited the allergen-induced infiltration of neutrophils (P<0.05) and lymphocytes (P<0.01) in the airways. 6. These results indicate that NK2 receptor activation is importantly involved in the development of the allergen-induced late (but not early) asthmatic reaction and late (but not early) AHR to histamine, and that NK2 receptor-mediated infiltration of neutrophils and lymphocytes in the airways may contribute to these effects.

Topics: Allergens; Animals; Asthma; Benzamides; Bronchial Hyperreactivity; Bronchoconstriction; Female; Guinea Pigs; Histamine; Inflammation; Lymphocytes; Male; Neutrophils; Piperidines; Receptors, Neurokinin-2

High levels of histamine can be found in the airways of asthma patients. This study describes the effects of histamine on anti-CD3-induced production of IL-4, IL-5, and IFN-gamma by T cell clones from subjects with allergic asthma and healthy subjects. T cell clones were obtained from bronchoalveolar lavage (BAL) fluid and blood. The number of clones tested, and the percentage of clones in which histamine inhibited or enhanced cytokine production by more than 25%, were as follows: IL-4, 47, 8.5%, and 4.3%; IL-5, 43, 14%, and 30%; and IFN-gamma, 52, 40%, and 15%. Inhibition of IL-5 and IFN-gamma production was reversed by IL-2. The enhancement of IFN-gamma production was associated with an enhancement of both IL-2 production and proliferation. In 21% of the clones a combined effect consisting of inhibition of IFN-gamma production and enhancement of IL-5 production was found. This response was reversed by H2-receptor antagonists and was significantly associated with a histamine-induced increase in intracellular levels of cAMP. The role of cAMP in mediating the histamine effects was supported by the observations that the beta2-agonist salbutamol had effects similar to histamine and that high concentrations of PGE2 mimicked the inhibitory effects of histamine. Clones from BAL fluid and blood showed similar responses, as did clones from patients with asthma and from control subjects. The enhancement of IFN-gamma production by histamine, however, was found only in clones from healthy subjects. The results warrant further investigations on the role of cAMP in the regulation of cytokine production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Albuterol; Asthma; Bronchoalveolar Lavage Fluid; Clone Cells; Cyclic AMP; Dinoprostone; Enzyme Activation; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Impromidine; Interferon-gamma; Interleukin-2; Interleukin-4; Interleukin-5; Lung; Methylhistamines; Piperidines; Pyridines; Ranitidine; T-Lymphocytes; Triprolidine

The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o. ) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (Rrs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3-10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.

Topics: Animals; Anti-Allergic Agents; Asthma; Bronchoconstriction; Disease Models, Animal; Eosinophilia; Eosinophils; Female; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity; Ketotifen; Male; Passive Cutaneous Anaphylaxis; Piperidines; Platelet Activating Factor; Pyridines; Rats; Rats, Wistar

An increasing number of studies have been performed to address a possible role for endothelin-1 (ET-1) as a significant mediator in asthma. However, the effects of subthreshold concentrations of ET-1, which cannot elicit bronchial smooth muscle contraction itself, in asthma has yet to be determined. This study determined these effects of ET-1 on capsaicin-induced bronchoconstriction in anaesthetized guinea-pigs. Aerosolized ET-1 administered at doses of 10(-9) M and higher induced a dose-dependent increase in pulmonary resistance, but ET-1 at 10(-10) M did not have any bronchoconstrictive effect. However, this subthreshold concentration of ET-1 potentiated capsaicin-induced bronchoconstriction. In addition, the potentiation of capsaicin-induced bronchoconstriction by this subthreshold concentration of ET-1 was completely abolished by BQ788 (ET(B) receptor antagonist), but not BQ123 (ET(A) receptor antagonists). Immunoreactive substance P (SP) levels in bronchoalveolar lavage fluid after capsaicin administration were significantly higher than those after solvent administration. However, ET-1 alone did not significantly stimulate immunoreactive SP release and ET-1 (10(-10) M) did not potentiate capsaicin-induced immunoreactive SP release. In contrast, ET-1 (10(-10) M) potentiated exogenous neurokinin A- and SP-induced bronchoconstriction. These findings suggest that a subthreshold concentration of endothelin-1 does not potentiate the tachykinin release induced by capsaicin but the airway smooth muscle contraction through endothelin-B receptors.

Topics: Aerosols; Airway Resistance; Anesthesia; Animals; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Capsaicin; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Guinea Pigs; Male; Neurokinin A; Oligopeptides; Peptides, Cyclic; Piperidines; Substance P

Airway goblet cell hypersecretion may contribute to the pathophysiology of asthma. However, it is unknown whether histamine affects goblet cell secretion and, if so, which subtype of histamine receptor is involved and whether endogenous histamine-degrading enzymes modulate these actions.. We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and periodic acid Schiff stains by measuring the mucus score, which was inversely related to the degree of mucus glycoprotein discharge.. Inhalation of histamine caused a dose-dependent decrease in mucus score, an effect that was inhibited by pretreatment with the H2-receptor antagonist cimetidine but not with the H1-receptor antagonist mepyramine or the H3-receptor antagonist thioperamide. Inhaled Dimaprit, a selective H2-receptor agonist, likewise decreased mucus score; whereas stimulation of H1- and H3-receptors with 2-methylhistamine and (R)-alpha-methylhistamine, respectively, had no effect. Pretreatment with the histamine N-methyltransferase inhibitor SKF 91488, but not the diamine oxidase inhibitor aminoguanidine, potentiated the dose-dependent effect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The histamine methyltransferase activity in the tracheal mucosa was 29 times higher than diamine oxidase activity.. These findings suggest that histamine stimulates airway goblet cell secretion through H2-receptors and that this effect may be modulated principally by endogenous histamine methyltransferase through a degradation of histamine.

Topics: Amine Oxidase (Copper-Containing); Animals; Asthma; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoproteins; Guanidines; Guinea Pigs; Histamine; Histamine Agonists; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Histamine N-Methyltransferase; Male; Methylhistamines; Mucus; Piperidines; Pyrilamine; Recombinant Proteins; Trachea

TMK688 is being developed as an anti-allergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity.. We compared the inhibition of the late asthmatic responses by TMK688 with that by other anti-allergic agents in actively sensitized guinea pigs, and examined the relationship between 5-lipoxygenase inhibition and the late asthmatic responses.. At 1-3.2 mg/kg, TMK688 inhibited the increases in respiratory resistance, leukotriene (LT) B4 and C4 production in the lungs and eosinophil infiltration into the alveoli during the late asthmatic response, whereas the effects tended to lessen at the dose of 10 mg/kg. These effects are thought to be caused by the 5-lipoxygenase inhibitory activity of TMK688 because Azelastine, an anti-allergic drug having potent antihistamine activity, exhibited no effect. ONO-1078, a peptide LT antagonist, inhibited the late-phase bronchoconstriction at a dose of 100 mg/kg p.o., but not the increase in the infiltration of inflammatory cells into the alveoli, suggesting that the late-phase bronchoconstriction is induced, in part, by peptide LTs, i.e. LT C4, D4 and E4 and that the inflammatory cell infiltration may be caused by LTB4. TMK688 inhibited the immediate bronchoconstriction dose-dependently, and the effect was significant at a dose of 10 mg/kg orally. Since Azelastine, Ketotifen and Oxatomide suppressed the bronchoconstriction at far lower doses than did TMK688, the inhibitory effect was mainly caused by its antihistamine activity.. TMK688 appears to be a novel anti-allergic drug having inhibitory effects on both the bronchoconstriction and the infiltration of inflammatory cells during late asthmatic responses.

Topics: Animals; Anti-Allergic Agents; Asthma; Bronchoconstriction; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Eosinophils; Granulocytes; Guinea Pigs; Histamine Antagonists; Leukotrienes; Lipoxygenase Inhibitors; Lung; Male; Ovalbumin; Piperidines; Serine Proteinase Inhibitors

In conscious sensitized guinea pigs, CP-96345 (2.06 mumol.kg-1, i.p.), a specific antagonist for tachykinin NK-1 receptors, SR-48968 (1.66 mumol.kg-1, i.p.), an NK-2 receptor antagonist, and the combination of both agents decreased the wheezing percentage and the mortality from anaphylactic shock induced by 0.25% ovalbumin (OA, for 0.5 or 2 min) aerosol inhalation. In the anesthetized guinea pigs, SR-48968 attenuated OA (5 mg.kg-1, i.v.)-induced bronchoconstriction, while CP-96345 inhibited OA-induced Evans blue extravasation in bronchi and intrapulmonary airways. In the isolated tracheal and bronchial smooth muscle preparations of guinea pigs, SR-48968 concentration-dependently inhibited OA (10 micrograms.ml-1)-induced contraction both in trachea and in bronchi, while CP-96345 only attenuated the contraction of bronchi. Pretreatment with capsaicin, a depleting agent of sensory neuropeptides from sensory nerve C-fibers, attenuated the OA-induced contractions both in trachea and in bronchi. The results indicate that (1) tachykinins in the airways are involved in the pathogenesis of allergic asthma; (2) tachykinin receptor antagonists have inhibitory effects on the allergic asthmatic responses, which is at least partly through the inhibition of antigen-induced contraction of airway smooth muscles (NK-2 receptor effect) and airway microvascular leakage (NK-1 receptor effect).

Topics: Animals; Asthma; Benzamides; Biphenyl Compounds; Bronchi; Bronchoconstriction; Female; Guinea Pigs; Male; Muscle Contraction; Muscle, Smooth; Neurokinin-1 Receptor Antagonists; Ovalbumin; Piperidines; Receptors, Neurokinin-2; Receptors, Tachykinin; Trachea

We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.

Topics: Amino Acid Sequence; Animals; Asthma; Bronchoconstriction; Capillary Permeability; Guinea Pigs; Humans; Inositol Phosphates; Male; Methacholine Chloride; Mice; Molecular Sequence Data; Neurokinin A; Neurokinin-1 Receptor Antagonists; Piperidines; Pyrrolidines; Rats; Receptors, Neurokinin-2; Respiration; Species Specificity; Substance P

To explore the pathophysiological roles of endothelin isopeptides and receptor subtypes in asthmatic responses, a guinea pig model for asthma was used to test the effects of antiendothelin (ET) serum and selective ET receptor antagonists for antigen-induced specific airway conductance changes as measured by whole-body plethysmography. In this model, all of the animals so far tested demonstrated both the immediate and late asthmatic responses. Although preimmune serum had no apparent effects, anti-ET antiserum suppressed the maximal reduction of specific airway conductance in both the immediate and late asthmatic responses, which suggested that ET(s) are involved in the pathophysiology of both the immediate and late asthmatic responses. The ETB selective antagonists, BQ788 and RES701-1, blocked the immediate asthmatic response but not the late asthmatic response, whereas the ETA antagonists, BQ123 and (Shionogi) 97-139, suppressed only the late asthmatic response without influencing the immediate asthmatic response. In vitro constrictive responses of isolated tracheas and bronchi to ET1 were inhibited mainly by BQ123 and BQ788, respectively, which suggested that distribution of ETA and ETB receptors for bronchoconstriction are topographically distinct along airways. Furthermore, thromboxane A2 and platelet activating factor (PAF) antagonists were effective in suppressing the late asthmatic response but not the immediate asthmatic response. Taken together, our present observations suggest that ET(s) influences pulmonary functions by constricting airway smooth muscle via ETB receptors during the immediate asthmatic response and by modulating pulmonary inflammation via ETA receptors during the late asthmatic response, respectively.

Topics: Analysis of Variance; Animals; Asthma; Dose-Response Relationship, Drug; Endothelins; Female; Guinea Pigs; Oligopeptides; Peptides, Cyclic; Piperidines; Time Factors; Trachea

The ability of linetastine (TMK688, 1-[¿5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadieno yl¿ aminoethyl]-4-diphenylmethoxypiperidine, CAS 110501-66-1) to inhibit leukotriene production and to antagonize the effect of histamine was examined in comparison with the ability of azelastine, an antiallergic drug having an antihistamine activity. Linetastine and its active metabolite TMK777 (1-[¿5'-(3"-methoxy-4"-hydroxyphenyl)-2',4'-pentadienoyl¿ aminoethyl]-4-diphenylmethoxypiperidine, CAS 101619-11-8) inhibited the release of leukotrienes B4 and C4 from calcium ionophore-stimulated human leukocytes. The respective IC50 values of leukotriene B4 were 1.2 x 10(-7) mol/l and 8.6 x 10(-8) mol/l, and those of leukotriene C4 were 1.5 x 10(-7) mol/l and 7.1 x 10(-8) mol/l. Azelastine also inhibited the release of leukotriene B4 and C4, but its IC50 values were higher than 1 x 10(-5) mol/l. Linetastine at 1-10 mg/kg p.o. inhibited the increase in leukotriene B4 and C4 production in the lungs during late asthmatic responses in actively sensitized guinea-pigs. The effect of 3.2 mg/kg lasted for more than 16 b. Since repeated oral administration of linetastine, 1 mg/kg once a day for 7 successive days, showed the same inhibitory effect on the increase in respiratory resistance and the leukotriene production as single oral administration, the effect of linetastine was neither tachyphylactic nor cumulative. Azelastine at 10 mg/kg had no effect on the leukotriene production. Linetastine TMK777 and azelastine dose-dependently inhibited the histamine-induced contraction of isolated guinea-pig trachea in a noncompetitive manner, the respective pD2 values were 7.28, 7.98 and 8.07. Linetastine inhibited histamine-induced bronchoconstriction dose-dependently at 1-10 mg/kg (p.o.) in guinea-pigs, and the effect lasted for more than 24 h. Repeated oral administration of linetastine, 0.32 to 3.2 mg/kg once a day for 7 successive days inhibited the histamine-induced bronchoconstriction, the same as single oral dosing. Azelastine at 0.32 mg/kg p.o. also showed antihistamine activity. In conclusion, linetastine inhibits both the production of leukotrienes and the effect of histamine at almost the same dose and the effects were long lasting.

Topics: Animals; Arachidonate 5-Lipoxygenase; Asthma; Bronchoconstriction; Female; Guinea Pigs; Histamine Antagonists; Humans; In Vitro Techniques; Leukocytes; Leukotriene B4; Leukotriene C4; Lipoxygenase Inhibitors; Lung; Male; Mammary Neoplasms, Experimental; Mast-Cell Sarcoma; Mice; Piperidines; Stimulation, Chemical; Trachea; Tumor Cells, Cultured

1. Using a guinea-pig model of allergic asthma, in which the animals display early (0-5 h) and late phase (8-23 h after antigen challenge) bronchoconstrictor reactions, the function of prejunctional inhibitory M2 and postjunctional M3 receptors in isolated tracheal preparations have been investigated. In addition, cardiac M2 receptor function in vitro and bronchial responsiveness to histamine in vivo were evaluated. 2. Sensitivity to inhaled histamine was increased 3.1 fold and 1.6 fold after the early and late allergic reactions (i.e. at 5 h and 23 h after a single ovalbumin challenge), respectively. At 23 h after the last of four allergen challenges, executed on four consecutive days, bronchial hyperresponsiveness to histamine was diminished to 1.3 fold. 3. After the early response, there was no change in cardiac muscarinic M2 receptor function, since in left atria pD2 (-log EC50) and Emax values of pilocarpine and pKB values of AQ-RA 741, a selective M2 receptor antagonist, were not significantly different from controls (unchallenged sensitized animals), and this also applied to methacholine pD2 values for muscarinic M3 receptors in tracheal smooth muscle. 4. Prejunctional inhibitory muscarinic M2 autoreceptors in airway smooth muscle were markedly dysfunctional after the early allergic response, since potentiation of electrically evoked twitch contractions of tracheal preparations by low concentrations of the M2-selective muscarinic receptor antagonists, gallamine, methoctramine, AQ-RA 741 and AF-DX 116, which is the result of M2 receptor blockade, was clearly and significantly diminished compared to controls. However, after the late response, both in single and repeatedly challenged animals, twitch potentiation was not significantly different from and similar to controls, indicating restoration of M2 receptor function during the late allergic reaction.5. It is concluded that dysfunction of muscarinic M2 autoreceptors in the airways of sensitized and challenged guinea-pigs is already present after the early allergic reaction, and that it has recovered after the late response. Since histamine-induced bronchoconstriction involves vagal pathways, the present results suggest that bronchial hyperresponsiveness to histamine is partly due to M2 auto receptor dysfunction, leading to increased release of acetylcholine.

Topics: Administration, Inhalation; Allergens; Animals; Asthma; Benzodiazepinones; Bronchial Hyperreactivity; Diamines; Disease Models, Animal; Electric Stimulation; Female; Gallamine Triethiodide; Guinea Pigs; Heart; Histamine; Hypersensitivity; In Vitro Techniques; Male; Muscarinic Antagonists; Muscle, Smooth; Neuromuscular Junction; Parasympatholytics; Pilocarpine; Piperidines; Pirenzepine; Receptors, Muscarinic; Trachea

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

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

A 60-year-old male had visited our hospital periodically, because of perennial moderate atopic asthma, since 53 years of age. His symptoms had stabilized following treatment with oral theophylline 400 mg, tranilast 300 mg and inhalation of beclomethasone dipropionate 400 micrograms and procaterol hydrochloride. His peak expiratory flow rate early in the morning was 465 L/min, %VC was 115% and FEV1.0% was 62.4% in May of 1993. On May 24, 1993, though he had no gastrointestinal symptoms, gastrointestinal fiberscopy revealed a hiatal hernia, reflux esophagitis and active gastroduodenal ulcer. The upper gastrointestinal x-ray films showed gastroesophageal reflux. Therefore, we diagnosed bronchial asthma associated with reflux esophagitis and gastroduodenal ulcer. He was started on omeprazole, as a proton pump inhibitor (PPI), and cisapride. After the treatment with PPI and cisapride, his peak expiratory flow rate early in the morning and in the evening, %VC and FEV1.0 increased. Three months later gastrointestinal fiberscopy revealed improvement in the reflux esophagitis and the gastroduodenal ulcer. We speculate that the improvement in the peak expiratory flow rate is related to that of the gastroesophageal reflux.

Topics: Asthma; Cisapride; Esophagitis, Peptic; Humans; Male; Middle Aged; Omeprazole; Peak Expiratory Flow Rate; Peptic Ulcer; Piperidines

There is increased recognition that lung mast cell mediators not only produce the symptoms of acute asthma, but also result in the recruitment and activation of additional proinflammatory cells, such as eosinophils. Histamine, one of the major mast cell mediators, is known to have numerous effects on eosinophil function. These effects of histamine are mediated by distinct receptors on the surface of eosinophils, only some of which have been characterized. Prior studies have suggested that eosinophils have non-H1, non-H2 histamine receptors which mediate the chemotactic effects of histamine. We observed previously that the histamine-induced increase in cytosolic calcium in human eosinophils could not be blocked by classic H1 or H2 antagonists, but could be inhibited by the H3 antagonist thioperamide. The purpose of this study was to further characterize the pharmacologic properties of this calcium-linked histamine receptor. Using Fura-2 loaded eosinophils to measure the concentration of cytosolic calcium, we examined the effect of additional histamine receptor antagonists and agonists. We found that the pKb for the H3 antagonists thioperamide, impromidine, and burimamide (8.1, 7.6, and 7.2, respectively), were similar to those reported for H3 receptors in the central nervous system, suggesting that the eosinophil histamine receptor was similar to H3 receptors. However, when the known H3 agonists were tested for activity ([R]-alpha-methylhistamine, N alpha-methylhistamine), the potencies of these compounds were much less than the potency of histamine itself, indicating a significant difference between H3 receptors and this eosinophil histamine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Anticonvulsants; Asthma; Burimamide; Calcium; Eosinophils; Fura-2; Histamine Agonists; Histamine Antagonists; Humans; Impromidine; Inflammation; Intracellular Fluid; Mast Cells; Methylhistamines; Phosphatidylethanolamines; Piperidines; Platelet Aggregation Inhibitors; Receptors, Histamine

We evaluated the prevalence of gastroesophageal reflux in 36 children, 22 (61.2%) male and 14 (38.8%) female (median age, 75.5 months; range, 18-178), with noncontrolled asthma by means of prolonged (22-24 h) esophageal pH monitoring. None of the children had gastrointestinal symptoms suggesting gastroesophageal reflux. Atopy was seen in 21 of 36 (58.3%) patients. Pathological gastroesophageal reflux was present in 27 (75%) children. All patients were given cisapride (0.2 mg/kg q.i.d.) for 3 months. A clinical and pharmacological score was determined, and a second pH-metric study was made at the end of the follow-up period. The following pH-metric parameters were evaluated: the total percentage of time pH was < 4, the number of reflux episodes, the number of reflux episodes lasting > 5 min, the length of the longest single reflux episode, and the percentage of time the esophageal pH was < 4 during sleep. The study was completed in 11 of 27 children. The percentage of time that esophageal pH was < 4 improved in nine of 11 (81.8%) patients (p = 0.013). The percentage of time that esophageal pH was < 4 during sleep showed the most significant decrease (p = 0.002) after treatment. Improvement in both clinical and pharmacological scores was highly significant (p < 0.0001) in 19 of 27 patients, eight of whom did not want to repeat the pH study. We conclude therefore that gastroesophageal reflux is frequently associated with noncontrolled asthma and that medical therapy for reflux may improve the further course of respiratory disease.

Topics: Adolescent; Asthma; Child; Child, Preschool; Cisapride; Esophagus; Female; Gastroesophageal Reflux; Humans; Hydrogen-Ion Concentration; Infant; Male; Piperidines; Prevalence; Serotonin Antagonists

We have used a short-acting beta 2-adrenoceptor agonist, rimiterol hydrobromide, to allow a larger dose of allergen to be administered to previous single "early allergen responders" to investigate if an increased dose of allergen could induce a late asthmatic response (LAR) and whether this would influence the subsequent level of allergen-acquired nonspecific bronchial hyperresponsiveness. Pretreatment with inhaled rimiterol hydrobromide 400 microgram enabled an increase in allergen dose inhaled by a geometric mean of 8.9-fold (range, 2 to 29.1) in eight atopic subjects with mild asthma who initially were classified as single early responders with a maximal fall in FEV 3 to 8 h after allergen challenge (Lmax) of less than 15% from baseline value. The magnitude of the early asthmatic response was similar to that obtained on the control day when allergen challenge was performed in the absence of rimiterol hydrobromide. Five subjects were converted to dual allergen responders with Lmax of greater than 15% from premedication baseline value. For the whole group, there was a significant increase in the magnitude of LAR whether calculated as Lmax (p less than 0.05) or as area under the FEV1 time response curve between 3 and 8 h postchallenge (p less than 0.01). The provocation concentrations of methacholine causing a 20% fall in FEV1 (PC20) at 8 h postchallenge were significantly reduced on both days when compared with the corresponding prechallenge values (p less than 0.05 on control day, p less than 0.01 on rimiterol day). However, despite the increase in the magnitude of LAR on the rimiterol day, the reduction in postchallenge PC20 did not differ significantly from that occurring on the control day.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Allergens; Asthma; Bronchi; Bronchial Provocation Tests; Catechols; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Piperidines; Spirometry; Time Factors

Topics: Aerosols; Asthma; Bronchodilator Agents; Dose-Response Relationship, Drug; Forced Expiratory Volume; Humans; Piperidines

Seven young extrinsic asthmatics participated in an open, pilot study to determine the protective effect of a selective 5-hydroxytryptamine (5-HT) blocking agent, ketanserin, on exercise induced asthma. Ketanserin in a dose of 10 mg given intravenously 20 min before exercise altered the basal bronchomotor tone in only 1 of 6 subjects and offered partial protection against exercise-induced bronchoconstriction in 1 of 5 asthmatics with no overall effect in the group. All patients experienced sleepiness after administration of ketanserin and one had bradycardia with hypotension. The ineffectiveness of ketanserin suggests indirectly that serotonin has a limited role in the pathogenesis of exercise-induced asthma.

Topics: Adolescent; Adult; Asthma; Asthma, Exercise-Induced; Bronchi; Child; Humans; Ketanserin; Piperidines; Receptors, Serotonin; Sleep Stages

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

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

Effects of 2-methyl-3-piperidino-beta-propionaphtone hydrochloride (KZ-111), 3-isobutyryl-2-isopropylpyrazolo-[1, 5-a]pyridine (KC-404) and FPL-55712 on experimental allergic reactions were investigated. Homologous passive cutaneous anaphylaxis (PCA) in rats was clearly inhibited by oral and intravenous administrations of KC-404 and KZ-111. FPL-55712 inhibited the PCA reaction only by intravenous injections, but not by oral administration. Maximum inhibition of the PCA reaction by KC-404 and KZ-111 was obtained by administration of these agents 2 hr prior to challenge. The immunological release of histamine from sensitized rat peritoneal mast cells was inhibited by KZ-111 at a concentration of 10(-4) g/ml. KC-404 and FPL-55712 did not inhibit the immunological release of histamine. All three compounds had no effect on the release of histamine from rat peritoneal mast cells and on the generation of SRS from rat polymorphonuclear leucocytes by calcium ionophore A23187. KC-404 and KZ-111 produced a downward displacement of the maximum without a parallel shift in LTD4 induced concentration-response curves of guinea pig ileal and tracheal smooth muscle at concentrations between 10(-6) and 10(-5) g/ml. FPL-55712 at a concentration of 10(-6) g/ml produced a parallel shift of LTD4 induced concentration-response curves to the right in both smooth muscle preparations. The 50% inhibitory concentration to the contraction by LTD4 of each of the three compounds is lower than those of other agonists, histamine, PGF2 alpha and BaCl2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Asthma; Chromones; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; In Vitro Techniques; Male; Muscle Contraction; Passive Cutaneous Anaphylaxis; Piperidines; Pyridines; Rats; Rats, Inbred Strains; SRS-A

Topics: Adult; Antidepressive Agents; Asthma; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Serotonin Antagonists

Topics: Asthma; Asthma, Exercise-Induced; Cromolyn Sodium; Humans; Ketotifen; Piperidines; Thiophenes

Topics: Asthma; Cromolyn Sodium; Humans; Ketotifen; Mast Cells; Piperidines; Thiophenes

Topics: Asthma; Bronchodilator Agents; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Histamine H1 Antagonists; Humans; Ketotifen; Piperidines; Thiophenes

Ketotifen administered prior to aspirin offered protection against bronchoconstriction in 13 of 14 patients with aspirin-sensitive asthma. In four other subjects, suffering from urticaria/angioedema following ingestion of aspirin-like drugs, pretreatment with ketotifen resulted in total prevention of the adverse reactions. These results support the suggestion of a common pathogenetic mechanism operating in two distinct clinical patterns of idiosyncrasy to aspirin and other cyclo-oxygenase inhibitors. They also indicate that ketotifen might find application in treatment of adverse reactions to aspirin.

Topics: Adult; Aspirin; Asthma; Bronchi; Bronchial Spasm; Drug Hypersensitivity; Female; Histamine H1 Antagonists; Humans; Ketotifen; Male; Middle Aged; Piperidines; Placebos; Thiophenes

Sixty-four patients with confirmed bronchial asthma were treated with HC 20-511 (Ketotifen). HC20-511 was evaluated to be very effective in 6.3%, effective in 50.0% and slightly effective in 10.9% of these patients. The appearance of reactive basophils was inhibited by HC 20-511 in 5 out of 6 cases of reaction to house dust, in all three cases with buckwheat allergy to their allergen and in 7 out of 11 cases to anti-IgE. These results confirm that HC 20-511 inhibits type I allergic reactions induced by specific allergen and IgE.

Topics: Adolescent; Adult; Allergens; Asthma; Basophils; Female; Humans; Immunoglobulin E; Ketotifen; Male; Middle Aged; Piperidines; Thiophenes

Some important pharmacodynamic and clinical data on ketotifen, a benzocycloheptathiophene used in the prophylaxis of allergic asthma, are provided as an introduction to papers discussing the therapeutic use of this substance in adults and children. Ketotifen, which is active when administered orally, has a therapeutic efficacy comparable to that of cromoglycate but characterized by a somewhat different mechanism of action. The therapeutic efficacy of ketotifen appears to be associated with a progressive diminution of bronchial hyper-reactivity to various specific or nonspecific spasmogenic factors (allergens, histamine, exercise). An antagonistic action to, and an inhibitory effect on, the activation and release of the principal mediators of anaphylactic hypersensibility (SRS-A, histamine) have been demonstrated in several experimental models both in animals and in man.

Topics: Administration, Oral; Animals; Asthma; Binding, Competitive; Cromolyn Sodium; Histamine Antagonists; Humans; Ketotifen; Piperidines; Rats; Receptors, Histamine H1; SRS-A; Thiophenes

Topics: Adolescent; Adult; Asthma; Cromolyn Sodium; Double-Blind Method; Female; Humans; Ketotifen; Male; Middle Aged; Piperidines; Thiophenes

Topics: Asthma; Cromolyn Sodium; Humans; Hypersensitivity; Ketotifen; Piperidines; Thiophenes

Topics: Asthma; Asthma, Exercise-Induced; Child; Cromolyn Sodium; Humans; Ketotifen; Piperidines; Thiophenes

In a multicentre, double-blind trial, the steroid sparing effect of a new anti-anaphylactic agent ketotifen was assessed against placebo in eighty-six steroid-dependent asthmatics. Mean reduction in total daily prednisolone dosage in patients on ketotifen was 4.0 +/- 3.6 mg compared to 1.7 +/- 2.8 mg on placebo, a result significantly in favour of the active drug (P < 0.01). This suggests that ketotifen has a place similar to that of disodium cromoglycate or steroid aerosols in the managment of steroid-dependent asthmatics. It has the advantage of requiring only twice-daily oral administration.

Topics: Adult; Aged; Anaphylaxis; Asthma; Cromolyn Sodium; Double-Blind Method; Female; Humans; Ketotifen; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Placebos; Prednisolone; Substance-Related Disorders; Thiophenes

A general scheme of long-term treatment of bronchial asthma and the author's own results of immunotherapy, prophylaxis and other experiences in controlling the disease are presented. The necessity of permanent hyposensitization and prophylaxis by Zaditen and Na-cromoglycate has been emphasized. The rising incidence of respiratory allergies makes it necessary to find new ways of collaboration of allergists and other specialists.

Topics: Adult; Asthma; Bacterial Vaccines; Cromolyn Sodium; Desensitization, Immunologic; Humans; Ketotifen; Piperidines; Respiratory Hypersensitivity; Thiophenes

23 children with perennial allergic bronchial asthma were treated with ketotifen syrup/capsules. The required therapeutic dose was 0,03 mg/kg body weight twice daily. Improvement was observed in 16 of the 23 patients in part associated with decreased allergic manifestations in the eyes, nose and skin. Steroids could be discontinued in 3 of 7 patients. In 6 children transient tiredness resulted however only in one was a dose reduction necessary.

Topics: Administration, Topical; Adolescent; Asthma; Bronchodilator Agents; Child; Child, Preschool; Cough; Dyspnea; Humans; Ketotifen; Piperidines; Steroids; Thiophenes

Topics: Adult; Asthma; Humans; Ketotifen; Piperidines; Sleep Stages; Thiophenes

Topics: Adult; Asthma; Humans; Ketotifen; Piperidines; Sleep Stages; Thiophenes

Topics: Administration, Oral; Asthma; Blood Pressure; Child; Child, Preschool; Double-Blind Method; Humans; Infant; Ketotifen; Piperidines; Pulse; Steroids; Thiophenes

Topics: Adult; Aspirin; Asthma; Bronchial Spasm; Drug Hypersensitivity; Humans; Ketotifen; Piperidines; Thiophenes

Topics: Adolescent; Adult; Asthma; Female; Humans; Ketotifen; Male; Middle Aged; Piperidines; Thiophenes

A 12-week open trial using varying dosages of ketotifen, an oral drug with a prophylactic anti-asthmatic effect, was carried out in 20 patients with stable chronic bronchial asthma (age 20--50 years, no steroid treatment) to determine whether the frequency of asthma attacks and bronchodilator consumption could be reduced, and whether pulmonary function would improve. The protective action of ketoifen against a histamine inhalation test was measured at the beginning of the trial and at regular intervals during the trial. The patients experienced a significant improvement in their asthma and a significant decrease in the number of asthma attacks during the trial. Concomitantly, the need for other anti-asthma agents was reduced. Pulmonary function tests improved before and following histamine inhalation after 4, 8 and 12 weeks of treatment. In some patients cromoglycate was successfully replaced by ketotifen. Efficacy was rated as very good or good in 17 patients and moderate in 3 patients. Tolerance was good in all patients, no serious side-effects were observed. Summing up, it may be stated that ketotifen is a compound which by virtue of its activity profile and route of administration offers a new approach to the prophylactic treatment of bronchial asthma.

Topics: Adult; Asthma; Bronchi; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Respiratory Function Tests; Thiophenes; Time Factors

The preventive effect of ketotifen, a new drug with anti-histaminic and antiallergic properties, on histamine-induced bronchoconstriction was studied by open assessment in twenty-four adult patients with extrinsic asthma. A single oral dose of 1 mg ketotifen reduced the post-histamine mean drop in peak expiratory flow from 33 to 16% of the basal values (P less than 0.001). After a 4 weeks' regimen of 1 mg ketotifen twice daily the post-drug histamine-induced fall in PEF was further significantly reduced (P less than 0.001). Tests performed after 8 and 12 weeks of treatment showed no additional decrease in bronchial reactivity to histamine. Tests performed 1 week after cessation of treatment showed return of bronchial reactivity to the pretreatment level. The results suggest that a single dose of ketotifen has a marked preventive effect on histamine-induced bronchoconstriction and that this effect is enhanced during continued treatment.

Topics: Adolescent; Adult; Asthma; Constriction, Pathologic; Female; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Thiophenes; Vital Capacity

Topics: Antigens; Asthma; Calcimycin; Cromolyn Sodium; Histamine Release; Humans; Immunoglobulin E; Leukocytes; Neutrophils; Piperidines; SRS-A; Thiophenes

Topics: Asthma; Cromolyn Sodium; Drug Administration Schedule; Drug Evaluation; Humans; Piperidines; Thiophenes

Topics: Adult; Aged; Asthma; Double-Blind Method; Female; Humans; Ketotifen; Male; Middle Aged; Piperidines; Random Allocation; Sputum; Thiophenes

Topics: Adolescent; Asthma; Child; Child, Preschool; Female; Humans; Male; Piperidines; Respiratory Hypersensitivity; Rhinitis, Allergic, Seasonal; Thiophenes

Topics: Aerosols; Asthma; Bronchi; Catechols; Forced Expiratory Volume; Humans; Piperidines

Rimiterol hydrobromide (Pulmadil) has been shown to have a dose-related bronchodilator effect; the optimum dose by inhalation appears to lie between 200 and 1,000 microgram. When given to a group of asthmatic patients at 'recommended' and 5--10 times 'recommended' dose by aerosol, cardiovascular effects were minimal and of a magnitude similar to that of salbutamol given in the same dosages to the same patients. The very rapid bronchodilator effect of rimiterol would appear to make the drug particularly suitable for the treatment of patients with intermittent asthmatic attacks, before exercise in patients with exercise-induced asthma and for bronchodilatation before using inhaled sodium cromoglycate or corticosteroid aerosols.

Topics: Aerosols; Albuterol; Asthma; Blood Pressure; Bronchial Spasm; Catechols; Heart Rate; Humans; Peak Expiratory Flow Rate; Piperidines

Topics: Animals; Asthma; Histamine H1 Antagonists; Histamine Release; Humans; In Vitro Techniques; Leukocytes; Piperidines; Rats; SRS-A; Thiophenes

Topics: Administration, Oral; Adult; Asthma; Bronchodilator Agents; Coumarins; Dose-Response Relationship, Drug; Drug Evaluation; Female; Forced Expiratory Flow Rates; Humans; Male; Middle Aged; Piperidines

Indoramin, an alpha-adrenoceptor blocking drug, has been found to prevent the occurrence of exercise-induced bronchoconstriction. Evidence is provided in two cases that this was not due to the antihistamine properties of indoramin.

Topics: Adolescent; Adrenergic alpha-Antagonists; Adult; Airway Resistance; Asthma; Benzamides; Blood Pressure; Female; Histamine H1 Antagonists; Humans; Indoles; Male; Physical Exertion; Piperidines; Spirometry

Topics: Adrenergic beta-Agonists; Asthma; Benzamides; Dose-Response Relationship, Drug; Humans; Indoles; Physical Exertion; Piperidines; Spirometry

Topics: Asthma; Benzamides; Exercise Test; Humans; Indoles; Piperidines

Topics: Administration, Oral; Adrenergic beta-Agonists; Aerosols; Asthma; Bronchodilator Agents; Bronchoscopy; Catechols; Humans; Methanol; Piperidines

Topics: Anaphylaxis; Animals; Asthma; Dose-Response Relationship, Drug; Glucocorticoids; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hydrocortisone; Male; Mice; Oxazoles; Piperidines; Rats; Serum Albumin, Bovine; Spiro Compounds

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

Topics: Aerosols; Asthma; Evaluation Studies as Topic; Female; Humans; Male; Piperidines; Respiration; Spirometry; Vital Capacity; Xanthenes

Topics: Acetylcholine; Animals; Asthma; Atropine; Barium; Blood Pressure; Blood Vessels; Carbachol; Cats; Chlorides; Dioxoles; Guinea Pigs; Heart Rate; Histamine; Ileum; Jejunum; Muscle Contraction; Muscles; Papaverine; Parasympatholytics; Piperidines; Rabbits; Respiration; Vagus Nerve

Topics: Adult; Aged; Analgesics; Asthma; Female; Humans; Male; Middle Aged; Piperidines

Topics: Airway Resistance; Animals; Asthma; Blood Pressure; Bronchi; Bronchodilator Agents; Dogs; Heart Rate; Humans; Lung Compliance; Piperidines; Respiratory System; Vital Capacity

Topics: Adult; Aged; Asthma; Biliary Tract Diseases; Dioxoles; Drug Tolerance; Duodenal Diseases; Dysmenorrhea; Esophagitis; Female; Gastritis; Heart Diseases; Humans; Kidney Calculi; Male; Middle Aged; Migraine Disorders; Muscles; Piperidines; Spasm

Topics: Alkaloids; Asthma; Bronchitis; India; Medicine, Ayurvedic; Piperidines

Topics: Animals; Asthma; Benzilates; Cardiovascular System; Cats; Dogs; Embryo, Mammalian; Gastric Juice; Gastrointestinal Motility; Guinea Pigs; Intestines; Mice; Muscle, Smooth; Muscles; Nervous System; Piperidines; Pupil; Rabbits; Rats; Respiration; Salivation; Trachea; Ulcer

Topics: Anti-Allergic Agents; Asthma; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines; Thioxanthenes

Topics: Anti-Allergic Agents; Asthma; Histamine H1 Antagonists; Parasympatholytics; Pharmacology; Piperidines; Selective Serotonin Reuptake Inhibitors; Serotonin; Thioxanthenes; Toxicology

Topics: Anti-Allergic Agents; Asthma; Bronchitis; Drug Therapy; Histamine H1 Antagonists; Piperidines; Respiratory Insufficiency; Thioxanthenes

Topics: Aminopyrine; Asthma; Biomedical Research; Piperidines; Prednisone; Sympathomimetics

Topics: Anti-Allergic Agents; Antifungal Agents; Asthma; Conjunctivitis; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis, Allergic, Seasonal

Topics: Asthma; Humans; Parasympatholytics; Piperidines; Spirometry

Topics: Airway Obstruction; Animals; Asthma; Behavior, Animal; Humans; Parasympatholytics; Piperidines; Social Behavior