benzofurans and Body-Weight

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; 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Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; 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Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; Cytokines; Databases, Genetic; Death; Dendritic Cells; Density Functional Theory; Depsides; Diabetes Mellitus, Type 2; Diamond; Diarylheptanoids; Dibenzofurans; Dibenzofurans, Polychlorinated; Diclofenac; Diet; Dietary Carbohydrates; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Dioxins; Diphenylamine; Disease Outbreaks; Disease Susceptibility; Disulfides; Dithiothreitol; Dizocilpine Maleate; DNA Methylation; DNA-Binding Proteins; DNA, Bacterial; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Doublecortin Protein; Drosophila melanogaster; Droughts; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Liberation; Drug Resistance; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Dust; Dynactin Complex; Dysferlin; Echo-Planar Imaging; Echocardiography; Edaravone; Egypt; Elasticity; Electrodes; Electrolytes; Emodin; Emtricitabine; Endometriosis; Endothelium, Vascular; Endotoxins; Energy Metabolism; Energy Transfer; Enterobacteriaceae; Enterococcus faecalis; Enterotoxigenic Escherichia coli; Environmental Monitoring; Enzyme Inhibitors; Epidemiologic Factors; Epigenesis, Genetic; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Vaccines; Esophageal Neoplasms; Esophagectomy; Esophagogastric Junction; Esterases; Esterification; Ethanol; Ethiopia; Ethnicity; Eucalyptus; Evidence-Based Practice; Exercise; Exercise Tolerance; Extracorporeal Membrane Oxygenation; Family; Fatty Acids; Feedback; Female; Ferric Compounds; Fibrin Fibrinogen Degradation Products; Filtration; Fish Diseases; Flavonoids; Flavonols; Fluorodeoxyglucose F18; Follow-Up Studies; Food Microbiology; Food Preservation; Forests; Fossils; Free Radical Scavengers; Freund's Adjuvant; Fruit; Fungi; Gallium; Gender Identity; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Genes, Bacterial; Genes, Plant; Genetic Predisposition to Disease; Genitalia; Genotype; Glomerulonephritis, IGA; Glottis; Glucocorticoids; Glucose; Glucuronides; Glutathione Transferase; Glycogen Synthase Kinase 3 beta; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Grassland; Guinea Pigs; Half-Life; Head Kidney; Heart Atria; Heart Rate; Heart Septum; HEK293 Cells; Hematopoietic Stem Cells; Hemodynamics; Hep G2 Cells; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Hepatocytes; Hesperidin; High-Frequency Ventilation; High-Temperature Requirement A Serine Peptidase 1; Hippocampus; Hirudins; History, 20th Century; History, 21st Century; HIV Infections; Homeostasis; Hominidae; Housing, Animal; Humans; Hydrocarbons, Brominated; Hydrogen Bonding; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydroxybutyrates; Hydroxyl Radical; Hypertension; Hypothyroidism; Image Interpretation, Computer-Assisted; Immunoconjugates; Immunogenic Cell Death; Indoles; Infant, Newborn; Infant, Premature; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Infrared Rays; Inhibitory Concentration 50; Injections, Intravenous; Interferon-gamma; Interleukin-23; Interleukin-4; Interleukin-6; Intermediate Filaments; Intermittent Claudication; Intestine, Small; Iridoid Glucosides; Iridoids; Iron; Isomerism; Isotope Labeling; Isoxazoles; Itraconazole; Kelch-Like ECH-Associated Protein 1; Ketoprofen; Kidney Failure, Chronic; Kinetics; Klebsiella pneumoniae; Lactams, Macrocyclic; Lactobacillus; Lactulose; Lakes; Lamivudine; Laparoscopy; Laparotomy; Laryngoscopy; Leucine; Limit of Detection; Linear Models; Lipid A; Lipopolysaccharides; Listeria monocytogenes; Liver; Liver Cirrhosis; Logistic Models; Longitudinal Studies; Losartan; Low Back Pain; Lung; Lupinus; Lupus Erythematosus, Systemic; Machine Learning; Macular Degeneration; Madin Darby Canine Kidney Cells; Magnetic Phenomena; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Magnetics; Malaria, Falciparum; Male; Mannans; MAP Kinase Signaling System; Mass Spectrometry; Melatonin; Membrane Glycoproteins; Membrane Proteins; Meniscectomy; Menisci, Tibial; Mephenytoin; Mesenchymal Stem Cells; Metal Nanoparticles; Metal-Organic Frameworks; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Obese; Mice, Transgenic; Microbial Sensitivity Tests; Microcirculation; MicroRNAs; Microscopy, Video; Microtubules; Microvascular Density; Microwaves; Middle Aged; Minimally Invasive Surgical Procedures; Models, Animal; Models, Biological; Models, Molecular; Models, Theoretical; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Morus; Mouth Floor; Multicenter Studies as Topic; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Muscle, Skeletal; Myocardial Ischemia; Myocardium; NAD; NADP; Nanocomposites; Nanoparticles; Naphthols; Nasal Lavage Fluid; Nasal Mucosa; Neisseria meningitidis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasms, Experimental; Neural Stem Cells; Neuroblastoma; Neurofilament Proteins; Neurogenesis; Neurons; New York; NF-E2-Related Factor 2; NF-kappa B; Nicotine; Nitriles; Nitrogen; Nitrogen Fixation; North America; Observer Variation; Occupational Exposure; Ochrobactrum; Oils, Volatile; Olea; Oligosaccharides; Omeprazole; Open Field Test; Optimism; Oregon; Oryzias; Osmolar Concentration; Osteoarthritis; Osteoblasts; Osteogenesis; Ovarian Neoplasms; Ovariectomy; Oxadiazoles; Oxidation-Reduction; Oxidative Stress; Oxygen; Ozone; p38 Mitogen-Activated Protein Kinases; Pakistan; Pandemics; Particle Size; Particulate Matter; Patient-Centered Care; Pelargonium; Peptides; Perception; Peripheral Arterial Disease; Peroxides; Pets; Pharmaceutical Preparations; Pharmacogenetics; Phenobarbital; Phenols; Phenotype; Phosphates; Phosphatidylethanolamines; Phosphines; Phospholipids; Phosphorus; Phosphorylation; Photoacoustic Techniques; Photochemotherapy; Photosensitizing Agents; Phylogeny; Phytoestrogens; Pilot Projects; Plant Components, Aerial; Plant Extracts; Plant Immunity; Plant Leaves; Plant Oils; Plants, Medicinal; Plasmodium berghei; Plasmodium falciparum; Platelet Activation; Platelet Function Tests; Pneumonia, Viral; Poaceae; Pogostemon; Poloxamer; Poly I; Poly(ADP-ribose) Polymerase Inhibitors; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polycyclic Compounds; Polyethylene Glycols; Polylysine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Population Dynamics; Portasystemic Shunt, Transjugular Intrahepatic; Positron Emission Tomography Computed Tomography; Postoperative Complications; Postprandial Period; Potassium Cyanide; Predictive Value of Tests; Prefrontal Cortex; Pregnancy; Prepulse Inhibition; Prevalence; Procalcitonin; Prodrugs; Prognosis; Progression-Free Survival; Proline; Proof of Concept Study; Prospective Studies; Protein Binding; Protein Conformation; Protein Domains; Protein Folding; Protein Multimerization; Protein Sorting Signals; Protein Structure, Secondary; Proton Pump Inhibitors; Protozoan Proteins; Psychometrics; Pulse Wave Analysis; Pyridines; Pyrrolidines; Quality of Life; Quantum Dots; Quinoxalines; Quorum Sensing; Radiopharmaceuticals; Rain; Random Allocation; Randomized Controlled Trials as Topic; Rats; Rats, Sprague-Dawley; Rats, Wistar; RAW 264.7 Cells; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Receptor, PAR-1; Receptors, CXCR4; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Interleukin-1; Receptors, Interleukin-17; Receptors, Notch; Recombinant Fusion Proteins; Recombinant Proteins; Reducing Agents; Reflex, Startle; Regional Blood Flow; Regression Analysis; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Tract Diseases; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Risk Assessment; Risk Factors; Rituximab; RNA, Messenger; RNA, Ribosomal, 16S; ROC Curve; Rosmarinic Acid; Running; Ruthenium; Rutin; Sarcolemma; Sarcoma; Sarcopenia; Sarcoplasmic Reticulum; SARS-CoV-2; Scavenger Receptors, Class A; Schools; Seasons; Seeds; Sequence Analysis, DNA; Severity of Illness Index; Sex Factors; Shock, Cardiogenic; Short Chain Dehydrogenase-Reductases; Signal Transduction; Silver; Singlet Oxygen; Sinusitis; Skin; Skin Absorption; Small Molecule Libraries; Smoke; Socioeconomic Factors; Soil; Soil Microbiology; Solid Phase Extraction; Solubility; Solvents; Spain; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Speech; Speech Perception; Spindle Poles; Spleen; Sporothrix; Staphylococcal Infections; Staphylococcus aureus; Stereoisomerism; Stomach Neoplasms; Stress, Physiological; Stroke Volume; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Rate; T-Lymphocytes, Cytotoxic; Tandem Mass Spectrometry; Temperature; Tenofovir; Terpenes; Tetracycline; Tetrapleura; Textiles; Thermodynamics; Thiobarbituric Acid Reactive Substances; Thrombin; Thyroid Hormones; Thyroid Neoplasms; Tibial Meniscus Injuries; Time Factors; Tissue Distribution; Titanium; Toluidines; Tomography, X-Ray Computed; Tooth; Tramadol; Transcription Factor AP-1; Transcription, Genetic; Transfection; Transgender Persons; Translations; Treatment Outcome; Triglycerides; Ubiquinone; Ubiquitin-Specific Proteases; United Kingdom; United States; Up-Regulation; Vascular Stiffness; Veins; Ventricular Remodeling; Viral Load; Virulence Factors; Virus Replication; Vitis; Voice; Voice Quality; Wastewater; Water; Water Pollutants, Chemical; Water-Electrolyte Balance; Weather; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Young Adult; Zoogloea

Perioperative malignant ventricular tachyarrhythmias pose an imminent clinical danger by potentially precipitating myocardial ischemia and severely compromising hemodynamics. Thus, immediate and effective therapy is required, which is not always provided by currently recommended IV drug regimens, indicating a need for more effective drugs. We examined antiarrhythmic effects of the new benzofurane compound E 047/1 on spontaneous ventricular tachyarrhythmia in a conscious dog model. One day after experimental myocardial infarction, 40 dogs exhibiting tachyarrhythmia randomly received (bolus plus 1-h infusion) E 047/1 6 mg/kg plus 6 mg x kg(-1) x h(-1), lidocaine 1 mg/kg plus 4.8 mg x kg(-1) x h(-1), flecainide 1 mg/kg plus 0.05 mg x kg(-1) x h(-1), amiodarone 10 mg/kg plus 1.8 mg x kg(-1) x h(-1), or bretylium 10 mg/kg plus 20 mg x kg(-1) x h(-1). Electrocardiogram was evaluated for number of premature ventricular contractions (PVC), normally conducted beats originating from the sinoatrial node, and episodes of ventricular tachycardia. Immediately after the bolus, E 047/1 reduced PVCs by 46% and increased sinoatrial beats from 4 to 61 bpm. The ratio of PVCs to total beats decreased from 98% to 58%. Amiodarone and flecainide exhibited antiarrhythmic effects with delayed onset. Lidocaine did not suppress PVCs significantly, and bretylium was proarrhythmic. The antiarrhythmic E 047/1 has desirable features, suppressing ischemia-induced ventricular tachyarrhythmia quickly and efficiently, and may be a useful addition to current therapeutic regimens.. Life-threatening arrhythmias of the heart after myocardial infarction or ischemia may be treated quickly and efficiently by the new drug E 047/1.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzofurans; Blood Pressure; Body Weight; Coronary Vessels; Dogs; Excipients; Heart Rate; Infusions, Intravenous; Ligation; Myocardial Ischemia; Pilot Projects; Polysorbates

The uric-acid lowering effect was investigated in a group of 2220 patients. 1984 of these were employed for statistical evaluation purposes. On average, the uric acid level was reduced from 8,24 +/- 1,16 mg/100 ml to 5,32 +/- 1,265 mg/100 ml. In 82 % of all the cases, the uric acid level at the end of the treatment period was below 6,4 mg%, both in patients treated throughout with 50 mg benzbromarone (NarcaricinRmite) and in those changed over to 100 mg benzbromarone (NarcaricinR) after 1 to 3 weeks. The lowering of the uric acid levels was in no way related to hypertension, adiposity, hyperlipoproteinaemia, diabetes mellitus or age.

Topics: Benzbromarone; Benzofurans; Body Height; Body Weight; Clinical Trials as Topic; Female; Follow-Up Studies; Gout; Humans; Male; Uric Acid

Studies in 55 patients with benign essential hypertension showed that the beta-blockers bufuralol (22 patients) and propranolol (33 patients) at a dose ratio of 1:4, possess comparable antihypertensive efficacy despite different properties regarding intrinsic sympathomimetic activity. Beta-blocker-monotherapy normalized blood pressure ( less than 140/90 mm Hg) in one fourth of the patients. Body weight and plasma and blood volumes remained unchanged during beta-blockade of four to six weeks duration, the mean plasma potassium was slightly increased. The inhibition of plasma renin activity (PRA) was more pronounced with propranolol (-69%) than with bufuralol (-47%). Wirth both beta-blockers decreases in blood pressure correlated inversely with pre-treatment PRA (p less than 0.05). Propranolol-induced changes in blood pressure correlated also with associated changes in PRA (p less than 0.005); in contrast, no such relationship was observed with bufuralol. The blood pressure effects of bufuralol, however, correlated significantly with changes in urinary noradrenaline excretion (r=0.41; p less than 0.05). Patient sub-groups with low, normal or high pre-treatment PRA in the average showed a comparable pattern of pre-treatment noradrenaline excretion and patients with normal renin levels exreted more adrenaline than those with low renin levels (p less than 0.001). These data are consistent with the concept that in untreated essential hypertension PRA may be an index of adrenergic activiity, the latter representing an important determinant of blood pressure response to beta-blockade. The blood pressure lowering effects of bufuralol in benign essential hypertension seem to be independent of renin and may be related, at least partly, to diminished free peripheral noradrenaline levels.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Benzofurans; Blood Pressure; Blood Volume; Body Weight; Catecholamines; Ethanolamines; Female; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Potassium; Propranolol; Renin

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzofurans; Body Weight; Disease Models, Animal; Dopamine; Eating; Inflammation; Interleukin-6; Intestinal Mucosa; Janus Kinase 2; Male; Mice; Mice, Inbred C57BL; Motor Skills; MPTP Poisoning; Neostriatum; Parkinson Disease; Parkinson Disease, Secondary; STAT3 Transcription Factor

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Body Weight; Cell Line; Colon; Dinitrofluorobenzene; Drug Development; Electrophoresis, Gel, Two-Dimensional; Enzyme Activators; Gene Ontology; Inflammatory Bowel Diseases; Interleukin-10; Male; Malondialdehyde; Mice; Organ Size; Phosphorylation; Rats, Sprague-Dawley; Spleen; Tumor Necrosis Factor-alpha

The activation of NLRP3 inflammasome is closely related to ischemic brain injury and inhibition of NLRP3 inflammasome activation may be a new therapeutic strategy for ischemic stroke. Our previous studies showed that ligustilide (LIG) had a dose-dependent neuroprotective effect on various models of cerebral ischemia and dementia in vivo and in vitro. CD21, a kind of phthalide derivative, was modified from LIG. In this study, we established a global cerebral ischemia-reperfusion model in mice by bilateral common carotid artery ligation (2VO), and explored the neuroprotective effect of CD21 and its anti-inflammatory mechanism on cerebral ischemia mice. CD21 significantly improved weight loss, neurobehavioral deficits and neurons loss in hippocampal CA1 and caudate putamen (CPu) subregions, which were induced by 2VO in mice. CD21 significantly inhibited the overactivation of astrocyte and microglia, and decreased the mRNA level of IL-6, TNF-α and IL-1β. Moreover, CD21 significantly inhibited the activation of TLR4/NF-κB signaling pathway mediated by HMGB1 and NLRP3/ASC/Caspase-1 signaling pathway mediated by Cathepsin B, thus inhibiting the activation of NLRP3 inflammasome. Our results demonstrated that CD21 may exert a neuroprotection by inhibiting NLRP3 inflammasome activation after cerebral ischemia. These findings provide a new strategy for the treatment of ischemic stroke.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Benzofurans; Body Weight; Brain Injuries; Brain Ischemia; CARD Signaling Adaptor Proteins; Caspase 1; Cathepsins; Cytokines; Disease Models, Animal; HMGB1 Protein; Inflammasomes; Male; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; NF-kappa B p50 Subunit; NLR Family, Pyrin Domain-Containing 3 Protein; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4

Enteropeptidase is a serine protease localized on the duodenal brush border that catalyzes the conversion of inactive trypsinogen into active trypsin, thereby regulating protein breakdown in the gut. We evaluated the effects of SCO-792, a novel enteropeptidase inhibitor, in mice.. In vivo inhibition of enteropeptidase was evaluated via an oral protein challenge. Pharmacological effects were evaluated in normal mice, in diet-induced obese (DIO) mice and in obese and diabetic ob/ob mice.. A single oral administration of SCO-792 inhibited plasma branched-chain amino acids (BCAAs) in an oral protein challenge test in mice, indicating in vivo inhibition of enteropeptidase. Repeated treatment with SCO-792 induced reduction in food intake and decrease in body weight in DIO and ob/ob mice. Plasma FGF21 levels were increased in SCO-792-treated DIO mice, an observation that was probably independent of reduction in food intake. Hyperglycaemia was markedly improved in SCO-792-treated ob/ob mice. A hyperinsulinaemic-euglycaemic clamp study revealed improved muscle insulin sensitivity in SCO-792-treated ob/ob mice. SCO-792 also improved plasma and liver lipid profiles and decreased plasma alanine transaminase, suggesting a potential treatment for liver diseases. Dietary supplementation with essential amino acids attenuated the effect of SCO-792 on reduction in food intake and decrease in body weight in normal mice, suggesting a pivotal role for enteropeptidase in these biological phenomena.. SCO-792 inhibited enteropeptidase in vivo, reduced food intake, decreased body weight, increased insulin sensitivity, improved glucose and lipid control, and ameliorated liver parameters in mouse models with obesity and/or diabetes. SCO-792 may exhibit similar effects in patients.

Topics: Animals; Aspartic Acid; Benzofurans; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Enteropeptidase; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Serine Proteinase Inhibitors; Small Molecule Libraries

Activating transcription factor 3 (Atf3) has been previously demonstrated to impact obesity and metabolism. However, a metabolic role of Atf3 in mice remains debatable. We investigated the role of Atf3 in mice and further investigated Atf3 expression as a therapeutic target for obesity and metabolic diseases. Atf3 knockout (KO) mice fed with a high fat diet (HFD) aggravated weight gain and impaired glucose metabolism compared to littermate control wild type (WT) mice. Atf3 KO aged mice fed with a chow diet (CD) for longer than 10 months also displayed increased body weight and fat mass compared to WT aged mice. We also assessed requirements of Atf3 in a phytochemical mediated anti-obese effect. Effect of sulfuretin, a previously known phytochemical Atf3 inducer, in counteracting weight gain and improving glucose tolerance was almost completely abolished in the absence of Atf3, indicating that Atf3 induction can be a molecular target for preventing obesity and metabolic diseases. We further identified other Atf3 small molecule inducers that exhibit inhibitory effects on lipid accumulation in adipocytes. These data highlight the role of Atf3 in obesity and further suggest the use of chemical Atf3 inducers for prevention of obesity and metabolic diseases.

Topics: Activating Transcription Factor 3; Aging; Animals; Anti-Obesity Agents; Benzofurans; Body Weight; Diet, High-Fat; Flavonoids; Glucose Intolerance; Metabolic Diseases; Mice, Knockout; Molecular Targeted Therapy; Obesity

Studies about toxicological potential of usnic acid are limited. This way, the vast majority of data available in the literature are related only to biological activities. This is the first study that aimed to evaluate the oral toxicity of usnic acid during the period of organogenesis. Females rats were distributed in the control groups, treated I and II, at doses of 15 and 25 mg/kg, administered by gavage during the 6° to 15° days of pregnancy. After 20 days the fetuses were removed and analyzed. A reduction in weight gain during pregnancy, increased resorption, reduction in the number of viable fetuses, and their body weight were observed. Morphological changes in the litter were visualized as exposure of the eye and atrophy of the limbs at the dose of 25 mg/kg. Histological analysis of the liver of the fetus showed reduction in the number of megakaryocytes between experimental groups and increase in the number of hepatocytes in a dose of 25 mg/kg. The experimental model used in this study reveals teratogenic effect of usnic acid in the period of organogenesis. Since this achievement, the importance of evaluating the toxic effects of natural substances is imperative, in order to elucidate the care in their indication as drug.

Topics: Animals; Ascomycota; Benzofurans; Body Weight; Female; Fetal Development; Fetus; Male; Organ Size; Organogenesis; Pregnancy; Rats; Teratogenesis

Butylphthalide, a component extracted from seeds of Chinese celery, is an effective neuroprotective agent used for the treatment of ischemic stroke and dementia. Diabetes may cause central nervous system damage, and diabetes is closely associated with dementia. The aim of the present study was to investigate the effects of butylphthalide on cognitive impairment in a streptozotocin‑induced diabetic rat model, and the underlying mechanisms of action. A total of 30 healthy male Sprague Dawley rats were randomly divided into the following 2 groups: Normal control (NC; n=10) and diabetes model (DM) groups (n=20). Diabetes was induced in rats in the DM group by intraperitoneal injection of streptozotocin, and these rats were further subdivided into the following 2 groups: Diabetic control (n=10) and butylphthalide‑treated groups (n=10). Following 8 consecutive weeks of treatment, a Morris water maze test was performed and the levels of blood fasting plasma glucose (FPG), superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β, and IL‑6 inflammatory cytokines in the hippocampus were measured. FPG levels were significantly decreased in the butylphthalide‑treated group when compared with the DM group. In addition, cognitive deficits in diabetic rats were improved following butylphthalide treatment. Furthermore, butylphthalide significantly increased the level of SOD, reduced MDA levels, and reduced TNF‑α, IL‑1β, and IL‑6 levels in the hippocampus when compared with the DM group. The results of the present study suggest that butylphthalide may be an effective neuroprotective agent to improve cognitive dysfunction during diabetes.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Brain-Derived Neurotrophic Factor; Cognition; Cognitive Dysfunction; Cytokines; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Fasting; Gene Expression Regulation; Hippocampus; Inflammation Mediators; Maze Learning; Neuroprotective Agents; Rats

DL-3-n-butylphthalide (NBP) is a therapeutic drug used for ischemic stroke treatment. Here, we investigated the impact of NBP on the development of rat diabetic cataract induced by intraperitoneal injection of streptozotocin (STZ). NBP was then administrated by oral gavage for nine weeks. Cataract development was monitored through ophthalmoscope inspections. The levels of blood glucose and serum reactive oxygen species (ROS), malondialdehyde (MDA) and 8-Hydroxydeovexyguanosine (8-OHdG) were measured. Total and soluble protein and oxidative stress parameters, such as 2, 4- dinitrophenylhydrazone (DNP), 4-hydroxynonenal (4-HNE) and MDA in the lenses were determined by Western blot and thiobarbituric acid analyses. The expressions of NF-E2-related factor 2 (Nrf2) and its downstream antioxidant enzymes, thioredoxin (TRX), Catalase and nuclear accumulation of Nrf2 were determined by Western blot and immunohistochemistry analyses. We showed that NBP treatment significantly improved the cataract scores, the levels of DNP, 4-HNE, and MDA in the lens compared to the non-treated groups. NBP also enhanced the expressions of Nrf2, TRX and catalase in the lens of diabetic rats. In addition, NBP treatment also decreased levels of blood glucose, serum MDA and 8-OHdG. These results suggested that NBP treatment significantly delayed the onset and progression of diabetic cataract by inhibiting the oxidative stresses.

Topics: Animals; Benzofurans; Biomarkers; Blood Glucose; Body Weight; Catalase; Cataract; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Disease Progression; Immunohistochemistry; Lens, Crystalline; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Thioredoxins

This study examined the effects of imidazoline I2 receptor agonists on the development of tolerance to and physical dependence on repeated morphine treatment in rats.. Two groups of rats (n = 9 per group) were trained to lever press for sucrose (10%) presentation under a fixed-ratio 10 schedule. The rate-suppressing effects of the opioid receptor ligands morphine and naltrexone and the I2 receptor agonist 2-BFI were examined weekly in rats treated with either daily morphine (20 mg·kg(-1) , s.c.), alone or in combination with 2-BFI (10 mg·kg(-1) ) for 3 weeks. Changes in body weight were measured following naltrexone tests in both groups of rats. In separate experiments, the antinociceptive effects of morphine were assessed using a warm-water tail-withdrawal procedure in rats before and after daily treatments (7 days) with morphine (32 mg·kg(-1) , i.p.) alone or in combination with various doses of the I2 receptor agonists 2-BFI, BU224 and CR4056.. Daily treatment for 3 weeks, with morphine in combination with 2-BFI produced significantly less tolerance to the rate-suppressing effects of morphine and produced a decreased sensitivity to the rate-suppressing effects of naltrexone as well as decreased naltrexone-induced weight loss, compared with morphine-alone group. Repeated treatment for 7 days with morphine produced antinociceptive tolerance, which was attenuated by co-administration with 2-BFI, BU224 or CR4056.. Imidazoline I2 receptor agonists attenuated the development of tolerance to and physical dependence on morphine, further supporting the therapeutic potential of combining I2 receptor agonists and opioids for pain treatment.

Topics: Analgesics; Animals; Behavior, Animal; Benzofurans; Body Weight; Drug Tolerance; Imidazoles; Imidazoline Receptors; Male; Morphine; Pain; Rats; Rats, Sprague-Dawley

GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior.. Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test.. GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet.. Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.

Topics: Animals; Anxiety; Benzofurans; Body Weight; Conditioning, Operant; Diet, High-Fat; Eating; Energy Metabolism; Infusions, Intraventricular; Male; Maze Learning; Mice; Motor Activity; Receptors, G-Protein-Coupled; Reward; Sulfones

Salvianolic acid B (Sal B), a major polyphenolic compound of Salvia miltiorrhiza Bunge, has been shown to possess potential antidiabetic activities. However, the action mechanism of SalB in type 2 diabetes has not been investigated extensively. The present study was designed to investigate the effects of Sal B on diabetes-related metabolic changes in a spontaneous model of type 2 diabetes, as well as its potential molecular mechanism.. Male C57BL/KsJ-db/db mice were orally treated with Sal B (50 and 100 mg/kg) or metformin (positive drug, 300 mg/kg) for 6 weeks.. Both doses of Sal B significantly decreased fasting blood glucose, serum insulin, triglyceride and free fatty acid levels, reduced hepatic gluconeogenic gene expression and improved insulin intolerance in db/db mice. High dose Sal B also significantly improved glucose intolerance, increased hepatic glycolytic gene expression and muscle glycogen content, and ameliorated histopathological alterations of pancreas, similar to metformin. Sal B treatment resulted in increased phosphorylated AMP-activated protein kinase (p-AMPK) protein expression in skeletal muscle and liver, increased glucose transporter 4 (GLUT4) and glycogen synthase protein expressions in skeletal muscle, and increased peroxisome proliferator-activated receptor alpha (PPARα) and phosphorylated acetyl CoA carboxylase (p-ACC) protein expressions in liver.. Our data suggest that Sal B displays beneficial effects in the prevention and treatment of type 2 diabetes at least in part via modulation of the AMPK pathway.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Body Weight; Dyslipidemias; Gene Expression Regulation; Gluconeogenesis; Glucose; Glucose Intolerance; Glucose Transporter Type 4; Glycogen; Glycogen Synthase; Glycolysis; Hyperglycemia; Hyperinsulinism; Lipids; Liver; Male; Mice, Inbred C57BL; Muscle, Skeletal; Pancreas; Phosphorylation; PPAR alpha; RNA, Messenger; Signal Transduction

Diabetes mellitus is associated with rapid cognitive decline. Currently, there is no effective treatment for cognitive dysfunction induced by diabetes. L-3-n-Butylphthalide (L-NBP) is a nerve protective drug extracted from seeds of celery, which has been proved to improve learning and memory in vascular dementia animal models by improving microcirculation, protecting mitochondria and increasing long-term potentiation (LTP). NR2B, one of the subunits of N-methyl-D-aspartate receptor, has been proved to be an important factor for the formation of LTP. The study aimed to investigate the role of NR2B in cognitive dysfunction in the rats with type 1 diabetes and define the protective effects of L-NBP on cognition. A rat model of type 1 diabetes was established by a single intraperitoneal injection of streptozotocin at 60 mg/kg. Animals were randomly allocated to four groups: normal control (NC); diabetic control (DC); diabetic + low L-NBP (DL, administered L-NBP 60 mg/kg per day for 12 weeks); and diabetic + high L-NBP (DH, administered L-NBP 120 mg/kg per day, for 12 weeks). After 12 weeks, cognitive and memory changes were investigated in the Morris water maze. The expression of NR2B was assessed by real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Our results indicated that the escape latency was significantly increased and the number of crossing platform was significantly decreased in DC group compared to NC group. Also, the expression of NR2B was significantly declined in DC group. However, compared to DC group, the expression of NR2B of the L-NBP-treated groups was significantly increased and the escape latency was shortened with the DH group being the most obvious. Therefore, L-NBP can improve the cognitive function by up-regulating the expression of NR2B in STZ-diabetic rats, which may provide the direction for future diabetic encephalopathy therapy.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cognition; Diabetes Mellitus, Experimental; Gene Expression Regulation; Hippocampus; Male; Maze Learning; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger

Risk assessment for mixtures of dioxin-like compounds uses the toxic equivalency factor (TEF) approach. Although current WHO-TEFs are mostly based on oral administration, they are commonly used to determine toxicity equivalencies (TEQs) in human blood or tissues. However, the use of "intake" TEFs to calculate systemic TEQs in for example human blood, has never been validated. In this study, intake and systemic relative effect potencies (REPs) for 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3',4,4',5-pentachlorobiphenyl (PCB-118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB-156) were compared in rats. The effect potencies were calculated based on administered dose and liver, adipose or plasma concentrations in female Sprague-Dawley rats 3 days after a single oral dose, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatic ethoxyresorufin-O-deethylase activity and gene expression of Cyp1a1, 1a2, 1b1 and aryl hydrocarbon receptor repressor in liver and peripheral blood lymphocytes were used as endpoints. Results show that plasma-based systemic REPs were generally within a half log range around the intake REPs for all congeners tested, except for 4-PeCDF. Together with our previously reported systemic REPs from a mouse study, these data do not warrant the use of systemic REPs as systemic TEFs for human risk assessment. However, further investigation for plasma-based systemic REPs for 4-PeCDF is desirable.

Topics: Administration, Oral; Animals; Benzofurans; Body Weight; Cytochrome P-450 CYP1A1; Dioxins; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Lymphocytes; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Tissue Distribution

In the present study, the attenuation of type ІІ diabetes by dieckol, a phlorotannin derivative isolated from brown seaweed, Ecklonia cava was investigated in C57BL/KsJ-db/db, a type ІІ diabetes mouse model. Dieckol was administered intraperitoneal injection at doses of 10 and 20 mg/kg body weight diabetes mice for 14 days. The blood glucose level, serum insulin level and body weight were significantly reduced in the dieckol administered group, compared to that of the saline administered group. Furthermore, reduced thiobarbituric acid reactive substraces (TBARS), as well as increased activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px) in liver tissues were observed in the dieckol administered group. In addition, increased levels of the phosphorylation of AMPK and Akt were observed in the muscle tissues of the dieckol administered group in a Western blotting analysis. According to the findings of this study, it could be suggested that, dieckol can be developed as a therapeutic agent for type ІІ diabetes.

Topics: AMP-Activated Protein Kinases; Animals; Benzofurans; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Disease Models, Animal; Glutathione Peroxidase; Hypoglycemic Agents; Insulin; Lipid Peroxidation; Mice; Mice, Inbred C57BL; Phaeophyceae; Phosphorylation; Proto-Oncogene Proteins c-akt; Seaweed; Signal Transduction; Superoxide Dismutase

Alcoholic liver disease, which is one of the most serious liver disorders, has been known to cause by ethanol intake. In the present study, in vivo hepatoprotective effects of dieckol-rich phlorotannins (DRP) from Ecklonia cava, a brown seaweed, on ethanol induced hepatic damage in BALB/c mice liver were investigated. After administration of 5 and 25mg/kg mouse of DRP and 4 g/kg mice ethanol, the body weights and survival rates were increased as compared to the control, which is ethanol-treated group without DRP. The glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels in the serum were lower than those of the control. DRP exhibited a reduction of the total cholesterol. The lower levels of SOD enzyme and a reduction of the formation of malondialdehyde were occurred in mice fed with 5 and 25mg/kg mouse of DRP. Finally the effect on improvement of fatty liver induced by ethanol was observed by taking out the liver immediately after dissecting the mouse. However, no significant difference was observed on hepatic histopathological changes. In conclusion, this study indicated that DRP could protect liver injury induced by ethanol in vivo. It suggested that DRP possesses the beneficial effect to human against ethanol-induced liver injury.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Benzofurans; Body Weight; Cholesterol; Glutathione Peroxidase; Hepatitis, Alcoholic; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Republic of Korea; Seaweed; Survival; Tannins; Thiobarbituric Acid Reactive Substances

To compare the efficacy of mapracorat (formerly ZK-245186, and subsequently BOL-303242-X), a novel selective glucocorticoid receptor agonist (SEGRA), with that of dexamethasone (DEX) in rabbit models of ocular disease. The effects of topical BOL-303242-X and DEX on intraocular pressure (IOP) and body weight changes were also evaluated.. Dry eye was induced by atropine sulfate administration and was treated with saline, BOL-303242-X (0.1%-1.0%), DEX (0.1%), Restasis 0.05% (Allergan, Inc., Irvine, CA), or Refresh Endura (Allergan, Inc.) three times per day for 7 to 8 days. For paracentesis studies, vehicle, BOL-303242-X (0.1%, 0.5%, and 1.0%), or DEX (0.1%) were repeatedly administered topically 3 hours before paracentesis and continued for 90 minutes afterward. For IOP and body weight measurements, right eyes of rabbits were topically treated with vehicle, BOL-303242-X (1.0% or 0.1%), or DEX (0.1%) four times per day for 6 weeks.. In the dry eye model, BOL-303242-X and DEX were fully efficacious, maintaining tear volume and tear breakup time (TBUT) at baseline levels. Although Restasis improved tear volume compared with vehicle, no changes were observed in TBUT. In the paracentesis study, BOL-303242-X and DEX improved ocular inflammation. BOL-303242-X reduced protein and PGE(2) levels. Finally, BOL-303242-X showed no effects on integrated IOP or body weight, whereas DEX significantly increased integrated IOP and prevented the increase of body weight observed in the vehicle-treated animals.. BOL-303242-X shows full anti-inflammatory efficacy (similar to DEX) in experimental models of dry eye and postoperative inflammation while demonstrating reduced effects in IOP and body weight. These data indicate that mapracorat, a SEGRA, shows efficacy similar to that of traditional steroids while exhibiting an improved side effect profile in IOP and muscle wasting.

Topics: Administration, Topical; Animals; Aqueous Humor; Benzofurans; Body Weight; Dexamethasone; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Dry Eye Syndromes; Female; Glucocorticoids; Intraocular Pressure; Pentanols; Quinolines; Rabbits; Receptors, Glucocorticoid; Tears; Treatment Outcome

The actions of angiotensin II on type 1 (AT₁) and type 2 (AT₂) receptor subtypes are important for normal kidney development before birth. This study investigated the effect of AT₁ receptor antagonism on renal growth and growth regulators in fetal sheep during late gestation. From 125 days of gestation (term 145±2 days), chronically catheterised sheep fetuses were infused intravenously for 5 days with either an AT₁-specific receptor antagonist (GR138950, 2-4 mg/kg per day, n=5) or saline (0.9% NaCl, n=5). Blockade of the AT₁ receptor decreased arterial blood oxygenation and pH and increased blood pCO₂, haemoglobin and lactate, and plasma cortisol and IGF-II. Blood glucose and plasma thyroid hormones and IGF-I were unchanged between the treatment groups. On the 5th day of infusion, the kidneys of the GR-treated fetuses were lighter than those of the control fetuses, both in absolute and relative terms, and were smaller in transverse cross-sectional width and cortical thickness. In the GR-infused fetuses, renal AT₂ receptor protein concentration and glomerular density were significantly greater than in the saline-infused fetuses. Blockade of the AT₁ receptor had no effect on relative cortical thickness, fractional or mean glomerular volumes, or renal protein levels of the AT₁ receptor, IGF type 1 receptor, insulin receptor or protein kinase C ζ. Therefore, in the ovine fetus, AT₁ receptor antagonism causes increased renal protein expression of the AT₂ receptor subtype, which, combined with inhibition of AT₁ receptor activity, may be partly responsible for growth retardation of the developing kidney.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Arteries; Benzofurans; Body Weight; Fetal Development; Fetal Growth Retardation; Fetus; Gestational Age; Hormones; Infusions, Intravenous; Kidney; Organ Size; Osmolar Concentration; Oxygen; Proteins; Receptor, Angiotensin, Type 2; Sheep

PTP1B is a negative regulator of insulin signaling pathway. This study investigated the effects of compound CCF06240, a PTP1B inhibitor, on insulin sensitivity and lipid metabolic abnormalities in vivo and in vitro, respectively. The insulin resistant IRM mouse model was induced by HFD. The responses to insulin were determined by OGTT, ITT, and hyperinsulinemic-euglycemic clamp test. The body weight and the levels of serum TC and TG were measured to estimate the lipid metabolism in vivo. Recombinant human GST-PTP1B protein was used to measure the inhibition of CCF06240 on PTP1B activity. The hepatocyte lipid accumulation was induced by high concentrations of FFA and insulin in HepG(2) cells, and evaluated by the Oil Red O method. In IRM mice, the insulin resistance was improved; the body weight and the levels of TC and TG were also reduced by oral CCF06240 administration. In lipid accumulated model cells, CCF06240 was found to reverse the increased PTP1B activity, enhance the insulin-induced tyrosine phosphorylation in insulin signaling pathway, attenuate the FFA-insulin-induced cellular lipid accumulation, and down-regulate the expressions of genes related fatty acid synthesis. These results demonstrated that the PTP1B inhibitor, compound CCF06240, could increase insulin sensitivity through the regulation of insulin signaling pathway, and decrease FFA-insulin-induced hepatocytes lipid accumulation by reducing fatty acid syntheses.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Fatty Acids; Glucose Clamp Technique; Glucose Tolerance Test; Hepatocytes; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; Mice; Phenylpropionates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction

Increased smooth muscle tone in the human prostate contributes to the symptoms associated with benign prostatic hyperplasia. In the mouse prostate gland, cholinergic innervation is responsible for a component of the nerve-mediated contractile response. This study investigates the muscarinic receptor subtype responsible for the cholinergic contractile response in the mouse prostate gland. To characterize the muscarinic receptor subtype, mouse prostates taken from wild-type or M(3) muscarinic receptor knockout mice were mounted in organ baths. The isometric force that tissues developed in response to electrical-field stimulation or exogenously applied cholinergic agonists in the presence or absence of a range of muscarinic receptor antagonists was evaluated. Carbachol elicited reproducible and concentration-dependent contractions of the isolated mouse prostate, which were antagonized by the presence of muscarinic receptor antagonists. Calculation of antagonist affinities (pA(2) values) indicated a rank order of antagonist potencies in the mouse prostate of: darifenacin (9.08) = atropine (9.07) = 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (9.02) > cyclohexyl-hydroxy-phenyl-(3-piperidin-1-ylpropyl)silane (7.85) > cyclohexyl-(4-fluorophenyl)-hydroxy-(3-piperidin-1-ylpropyl)silane (7.39) > himbacine (7.19) > pirenzipine (6.88) > methoctramine (6.20). Furthermore, genetic deletion of the M(3) muscarinic receptor inhibited prostatic contractions to electrical-field stimulation or exogenous administration of acetylcholine. In this study we identified that the cholinergic component of contraction in the mouse prostate is mediated by the M(3) muscarinic receptor subtype. Pharmacological antagonism of the M(3) muscarinic receptor may be a beneficial additional target for the treatment of benign prostatic hyperplasia in the human prostate gland.

Topics: Acetylcholine; Adrenergic alpha-1 Receptor Antagonists; Animals; Benzofurans; Body Weight; Carbachol; Cholinergic Agonists; Drug Interactions; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscarinic Antagonists; Muscle Contraction; Nicotinic Antagonists; Prazosin; Prostate; Pyrrolidines; Receptor, Muscarinic M3

Using perfused hearts from streptozotocin-induced long-term diabetic rats, we studied the coronary vasoconstrictor effect of the endothelin-1 (ET-1) precursor big ET-1 and also whether this response was modulated by N(epsilon)-(carboxymethyl)lysine (CML; a representative advanced glycation end product that is implicated in the pathogenesis of diabetic vasculopathy). The big ET-1-induced vasoconstriction (a) developed more rapidly (i.e., was greater in the first 30 min) in the diabetic group than in the age-matched controls, and (b) in each group was largely suppressed by phosphoramidon [nonselective endothelin-converting enzyme (ECE)/neutral endopeptidase (NEP) inhibitor] or CGS35066 (selective ECE inhibitor), but not by thiorphan (selective NEP inhibitor). The ET-1 release occurring after treatment with big ET-1, which was greater in diabetic coronary arteries than in the controls, was reduced by CGS35066. The dose-response curve for ET-1 was shifted to the left in the diabetics, so that at some lower doses of ET-1 the vasoconstriction was greater than in the controls. CML enhanced big ET-1- or ET-1-induced vasoconstriction in the controls, but not in the diabetics. Finally, the plasma level of CML was higher in diabetic than in control rats. These findings suggest (a) that the increased responsiveness to big ET-1 shown by diabetic coronary arteries may be attributable both to a more rapid conversion of big ET-1 to ET-1 (by ECE), allowing it to exert its contractile activity, and to an increased vascular sensitivity to ET-1, and (b) that CML may be at least partly responsible for the diabetes-associated enhancement of big ET-1-mediated coronary vasoconstriction.

Topics: Animals; Aspartic Acid Endopeptidases; Benzofurans; Blood Glucose; Body Weight; Coronary Vessels; Diabetes Mellitus, Experimental; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Heart; Lipids; Lysine; Male; Metalloendopeptidases; Myocardium; Oligopeptides; Organ Size; Organophosphonates; Peptides, Cyclic; Perfusion; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Thiorphan; Vasoconstriction

This study compared the effects of three anti-mutagenic lichen extracts on colorectal oncogenesis in azoxymethane (AOM)-treated mice and determined whether the extracts also regulated the homeostatic response to genotoxic damage. C57BL/6J mice (n = 12 per group) were treated with the lichen extracts Antimutagen-He (AMH): AMH-C, AMH-D, or AMH-E dimethyl sulfoxide (DMSO, control) for 2 weeks. At the end of the treatment, mice were given a single AOM injection to induce DNA damage and killed 6 h later for measuring apoptosis and proliferation. Apoptotic and proliferation indexes in mice treated with AMH-C, AMH-D, and AMH-E were 0.61%, 1.41%, and 0.77%; and 30.62%, 21.93%, and 27.27%, respectively, which were significantly lower than those of control mice (5.88% and 38.69%) (p < 0.05). To examine the effects of lichen extracts on colorectal cancer, separate groups of mice (n = 25 per group) treated with AMH-C, AMH-D, AMH-E, or DMSO were given 4-weekly AOM injections to induce oncogenesis. Mice were killed 24 weeks after the last AOM injection for assessing colon tumor formation. Colonic tumor incidences were 47.3%, 13%, and 20%; the tumor volumes were 18.47, 2.75, and 10.78 mm(3), respectively, in mice treated with AMH-C (p < 0.05), AMH-D (p < 0.05), and AMH-E (p > 0.05), compared to 24% and 13.28 mm(3) in mice of control correspondingly. No lichen extract showed evident toxic effects on mice. No usnic acid was found in these lichen extracts. The regulation of acute apoptosis and cell proliferation in colonic epithelial cells and the anti-mutagenesis do not seem directly related to the cancer protective effect.

Topics: Adenocarcinoma; Animals; Antimutagenic Agents; Apoptosis; Azo Compounds; Benzofurans; Body Weight; Carcinogens; Cell Proliferation; Colon; Colonic Neoplasms; DNA Damage; Intestinal Mucosa; Lichens; Longevity; Male; Mice; Mice, Inbred C57BL; Plant Extracts

Because placental polychlorinated dibenzo-p-dioxins,dibenzofurans (PCDD/Fs) levels are associated with decreased free thyroxine (FT(4)) and thyroid stimulating hormone (TSH) in neonates, we assessed development by gender and maternal PCDD/Fs exposure at years 2 and 5 in 92 mother and newborn pairs. RIA quantified thyroid, sex, and growth hormones. Of 200 subjects followed up from November 2000, 136 and 149 were observed at year 2 and year 5,respectively. PCDD/Fs exposure levels were low (n = 35) or high (n = 35) in 70 subjects at year 2, low (n = 21) or high (n = 20) in 41 at year 5. Height, weight, BMI, and head circumference were significantly higher in males, chest girth significantly higher in females at year 2. Significantly, more girls had higher bone age (BA) and chronological age (CA) at both times. Height, weight, FT(4) x TSH, and transthyretin(TTR) at year 2; and height, triiodothyronine, and IGF-1 at year 5 differed significantly by PCDD/Fs level. In females, height, weight, CA,BA, and thyroid hormones differed significantly at year 2. In males, FT(4) x TSH at year 2 and IGF-1 at year 5 were significantly higher in the high PCDD/Fs group. In utero exposure to PCDD/Fs differentially affects growth and hormone levels in male and female preschool children.

Topics: Age Factors; Aging; Benzofurans; Body Height; Body Mass Index; Body Weight; Bone Development; Cephalometry; Child Development; Child, Preschool; Environmental Pollutants; Female; Follow-Up Studies; Head; Humans; Linear Models; Male; Polychlorinated Dibenzodioxins; Prealbumin; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors; Thorax; Thyroid Gland; Thyrotropin; Thyroxine; Time Factors

The subacute toxicity of a commercial polybrominated diphenyl ether (PBDE) preparation, Bromkal 70-5DE, was investigated. In addition to a vehicle control, the mixture was given orally to male and female Sprague-Dawley rats for 28 d at three dose levels; 2.5, 25 and 250 mg kg(-1) b.w.d(-1). The observed effects include increased hepatic EROD activity (from 2.5 mg kg(-1)d(-1)); increased liver weight (males), increased PROD activity and depletion of hepatic retinoids (from 25 mg kg(-1)d(-1)); and increased liver weight (females), marked histological changes in the liver and lungs, as well as increased serum parameters such as total protein, cholesterol and albumin (from 250 mg kg(-1)d(-1)). Chemical analysis of the PBDE mixture with gas chromatography/mass spectrometry (GS/MS) showed impurities of polybrominated dibenzofurans and to a lesser extent dibenzodioxins, in total levels of about 7.0 microg g(-1) of Bromkal technical mixture. The animals were thereby exposed to an estimated dose of dioxin-like equivalents corresponding to 1.3-131 ng TEQ kg(-1) b.w.d(-1). It cannot be ruled out that this level of impurities can explain the hepatic EROD induction and hepatic retinoid depletion, which are considered typical markers of toxicity mediated via the aryl hydrocarbon receptor (AhR).

Topics: Administration, Oral; Animals; Benzofurans; Body Weight; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2B1; Dibenzofurans, Polychlorinated; Environmental Pollutants; Female; Flame Retardants; Halogenated Diphenyl Ethers; Kidney; Liver; Lung; Male; Organ Size; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Spleen

To investigate the effects of salvianolic acid B (Sal-B) on pancreatic damage in experimental chronic pancreatitis.. Chronic pancreatitis was induced by infusion of trinitrobenzene sulfonic acid into the pancreatic duct in male Sprague-Dawley rats. From the beginning of 5 weeks, the rats in group 2 were treated with Sal-B by gavage for 8 weeks. Salvianolic acid B was given at a daily dose of 10 mg/kg body weight. At the end of 12 weeks, the levels of serum biochemical indexes were measured on an automatic biochemical analyzer; serum hyaluronic acid and laminin levels were determined by radioimmunoassay; pancreatic tissue malondialdehyde (MDA) was analyzed, and the degree of pancreatic damage was determined.. The level of serum biochemical indexes were similar in all groups (P > 0.05 for all). Salvianolic acid B treatment did not obviously reduce hyaluronic acid and laminin concentration in blood (P > 0.05). Salvianolic acid B treatment decreased MDA concentration in pancreatic tissue (P < 0.01). Salvianolic acid B clearly improved pancreatic histological findings and prevented the activation of pancreatic stellate cells.. Sal-B treatment decreased MDA concentration in pancreatic tissue, attenuated morphological pancreatic damage, and prevented the activation of pancreatic stellate cells in experimental chronic pancreatitis.

Topics: Animals; Benzofurans; Biomarkers; Body Weight; Disease Models, Animal; Hyaluronic Acid; Laminin; Male; Malondialdehyde; Organ Size; Pancreas; Pancreatitis, Chronic; Protective Agents; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid

In our exploratory campaign for an antihyperglycemic agent with a novel mechanism of action, (-)-Cercosporamide 1, which is known as an antifungal agent, showed a potent plasma glucose lowering effect in hyperglycemic KK/Ta mice. The trouble was that it was accompanied by a decrease in food intake and a loss of body weight. We synthesized some (-)-Cercosporamide derivatives and succeeded to separate these actions. N,O-ketal type derivatives, especially compound 10, had the most potent plasma glucose lowering effect without affecting the food consumption or body weight.

Topics: Animals; Antifungal Agents; Benzofurans; Blood Glucose; Body Weight; Chemistry, Pharmaceutical; Drug Design; Eating; Feeding Behavior; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Mice; Mice, Transgenic; Models, Chemical

Toxic equivalency factors (TEFs) are assigned to dioxin-like chemicals based on relative potency (REP) values of individual adaptive and toxic responses compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Agilent 4x44K oligonucleotide microarrays were used to examine the hepatic gene expression potency of 2,3,7,8-tetrachlorodibenzofuran (TCDF), relative to TCDD with complementary histopathology, TCDD and TCDF tissue level analysis, and ethoxyresorufin-O-deethylase (EROD) assay data. Immature ovariectomized C57BL/6 mice were gavaged with 0.03, 0.1, 0.3, 1, 3, 10, 30, or 100 microg/kg TCDD, the World Health Organization TEF-adjusted doses (10 x TCDD dose) of TCDF (0.3, 1, 3, 10, 30, 100, or 300 microg/kg), or sesame oil vehicle and killed at 72 h. Two thousand two hundred eighty-eight and 1347 genes were differentially expressed (P1(t) > 0.90) at one or more doses by TCDD and TCDF, respectively. Automated dose-response modeling (ToxResponse Modeler) identified a total of 1027 and 837 genes with either a sigmoidal, exponential, linear, Gaussian, or quadratic dose-response relationship 72 h after treatment in TCDD and TCDF, respectively. Two hundred seventy genes exhibited a sigmoidal TCDD-induced dose-response (ED(50s) from 0.08 to 42.2 microg/kg) compared to only 179 sigmoidal responsive genes (ED(50s) from 0.74 to 299.9 microg/kg) elicited by TCDF. Of the 1027 TCDD dose-responsive genes, 654 were not examined further due to the lack of a dose response elicited by TCDF. Of the 373 genes that exhibited a TCDD and TCDF dose response, REPs were calculated for the 83 genes that exhibited comparable sigmoidal curve shapes and slopes. The median REP for these 83 genes was 0.10, with a maximum REP of 0.56 and a minimum of 0.01. REPs of 0.04 were also calculated for EROD and increase in relative liver weight (RLW) at 72 h. Collectively, the lower number of TCDF-induced genes compared to TCDD and the 0.04 REPs for EROD activity and increased RLW are not consistent with the TEF of 0.10 for the hepatotoxicity of TCDF in C57BL/6 mice at 72 h.

Topics: Animals; Automation; Benzofurans; Body Weight; Dose-Response Relationship, Drug; Female; Gene Expression Profiling; Liver; Mice; Mice, Inbred C57BL; Organ Size; Polychlorinated Dibenzodioxins; Polymerase Chain Reaction

Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), mono-ortho and non-ortho polychlorinated biphenyls (dioxin-like PCBs) were determined in samples of human fat tissue from nine Italian obese patients. The toxicity equivalent (TEQ) values ranged from 9 to 25 pg TEQ g(-1) lipid (WHO-TEF values, 2005 [Van den Berg, M., Birnbaum, L.S., Denison, M., De Vito, M., Farland, W., Feeley, M., Fiedler, H., Hakansson, H., Hanberg, A., Haws, L., Rose, M., Safe, S., Schrenk, D., Tohyama, C., Tritscher, A., Tuomisto, J., Tysklind, M., Walker, N., Peterson, R.E., 2006. The 2005 World Health Organization reevaluation of human and mammalian Toxic Equivalency Factors for dioxins and dioxin-like compounds. Toxicol. Sci. 93, 223-241]), the contribution of dioxin-like PCBs was more than 30% of the total TEQ values. The obese body burdens varied from 6 to 11 ng TEQ kg(-1) body weight (BW), exceeding the estimated steady-state body burden 5 ng TEQ kg(-1) BW, based on lipid adjusted serum concentrations from several populations in the mid-1990s, calculated in the risk assessment US EPA document.

Topics: Adipose Tissue; Benzofurans; Body Burden; Body Weight; Dibenzofurans, Polychlorinated; Environmental Exposure; Environmental Pollutants; Female; Humans; Male; Obesity; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Soil Pollutants

The present study was undertaken to assess whether A-3922, a dihydrobenzofuran derivative that possesses antioxidative effects, had any preventive effect on the onset and/or progression of diabetic cataract. Male Wistar rats were received a bolus intravenous injection of streptozotocin (65 mg/kg) and were given 5% glucose in drinking water for 10 weeks. The diabetic rats were divided into two groups and treated with 30 mg/kg/d A-3922 or vehicle during the experimental period. The opacities of eye lenses were observed by using both our original device and a slit lamp microscope. The lens opacities were initially detected as early as the 2nd week and the cataracts were developed in similar fashion in both A-3922-treated and untreated diabetic rats until 7th week, suggesting that A-3922 did not show any appreciable effect on the onset of diabetic cataract. In the later period (8th week or later), however, progression of cataract was retarded and significant reductions in both the total cataract score and the degree of opacity were apparently observed on 10th week of A-3922-treated diabetic rats. These results suggest that A-3922 can delay the progression but not the onset of diabetic cataract, and it has a possibility to be a candidate for drugs of cataract associated with diabetes.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cataract; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Progression; Lens, Crystalline; Male; Rats; Rats, Wistar

Concentrations of polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF) and polychlorinated biphenyls (PCB) in Baltic Sea fish like herring (Clupea harengus membras), sprat (Sprattus sprattus balticus), perch (Perca fluviatilis), pikeperch (Sander lucioperca) and flounder (Platichthys flesus trachurus) collected from four areas of the Estonian coastal waters are reported. All samples are studied for their relationship between the length (cm) and wet weight (g); length (cm) and age (years); lipid content and dry matter. The level of PCDD/F and PCB concentrations in younger 1-5 years old Baltic herring and sprat collected in 2002-2005 from the eastern and central parts of the Gulf of Finland, Gulf of Riga and Open Baltic Sea (Central Baltic) is related to the fish age and compared with those found in the 1990s. In addition, PCDD/F and PCB concentrations of different age groups herring, sprat, perch, pikeperch and flounder collected in 2003-2004 from the Lake Peipsi, Gulf of Finland, Gulf of Riga and Open Baltic Sea are related also to their age. Consequently, it was manifested that in older Baltic fish the concentrations of PCDD/F and PCB were higher than in the younger age groups. By the help of principle component analysis (PCA) the effect of gender on the concentrations of PCDD/F for the juvenile Baltic herring and sprat collected in 2004-2005 is investigated for the first time. It was summarized that the biological factor age plays a large role for the contamination of the fish with important toxic organohalogenated compounds such as PCDD/F.

Topics: Age Factors; Animals; Baltic States; Benzofurans; Body Size; Body Weight; Dibenzofurans, Polychlorinated; Finland; Fishes; Gender Identity; Oceans and Seas; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Water Pollutants, Chemical

The toxic equivalency factor (TEF) approach was employed to compare immunotoxic potency of mixtures containing polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), using the antibody response to sheep erythrocytes (SRBC). Mixture-1 (MIX-1) contained TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), and 1,2,3,4,6,7,8,9-octachlorodibenzofuran (OCDF). Mixture-2 (MIX-2) contained MIX-1 and the following PCBs, 3,3',4,4'-tetrachlorobiphenyl (IUPAC No. 77), 3,3',4,4',5-pentachlorobiphenyl (126), 3,3',4,4',5,5N-hexachlorobiphenyl (169), 2,3,3',4,4'-pentachlorobiphenyl (105), 2,3',4,4',5-pentachlorobiphenyl (118), and 2,3,3',4,4',5-hexachlorobiphenyl (156). The mixture compositions were based on relative chemical concentrations in food and human tissues. TCDD equivalents (TEQ) of the mixture were estimated using relative potency factors from hepatic enzyme induction in mice [DeVito, M.J., Diliberto, J.J., Ross, D.G., Menache, M.G., Birnbaum, L.S., 1997. Dose-response relationships for polyhalogenated dioxins and dibenzofurans following subchronic treatment in mice. I .CYP1A1 and CYP1A2 enzyme activity in liver, lung and skin. Toxicol. Appl. Pharmacol. 130, 197-208; DeVito, M.J., Menache, G., Diliberto, J.J., Ross, D.G., Birnbaum L.S., 2000. Dose-response relationships for induction of CYP1A1 and CYP1A2 enzyme activity in liver, lung, and skin in female mice following subchronic exposure to polychlorinated biphenyls. Toxicol. Appl. Pharmacol. 167, 157-172] Female mice received 0, 1.5, 15, 150 or 450 ng TCDD/kg/day or approximately 0, 1.5, 15, 150 or 450 ng TEQ/kg/day of MIX-1 or MIX-2 by gavage 5 days per week for 13 weeks. Mice were immunized 3 days after the last exposure and 4 days later, body, spleen, thymus, and liver weights were measured, and antibody response to SRBCs was observed. Exposure to TCDD, MIX-1, and MIX-2 suppressed the antibody response in a dose-dependent manner. Two-way ANOVA indicated no differences in the response between TCDD and the mixtures for body weight, spleen/body weight and decreased antibody responses. The results support the use of the TEF methodology and suggest that immune suppression by dioxin-like chemicals may be of concern at or near background human exposures.

Topics: Animals; Antibody Formation; Benzofurans; Body Weight; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Dibenzofurans, Polychlorinated; Dose-Response Relationship, Drug; Erythrocytes; Female; Immune Tolerance; Liver; Mice; Mice, Inbred Strains; Organ Size; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Sheep

Although doxorubicin is an effective antitumor agent, the serious cardiotoxicity mediated by the production of reactive oxygen species has remained a considerable clinical problem. In China, salvianolic acids has been widely used for cardioprotection. To test whether salvianolic acids holds the potential to be protective against cardiotoxicity of doxorubicin, we created an acute cardiac injury mice model. Therapeutic treatment with salvianolic acids (40 mg/kg for 3 connective days) significantly reduced doxorubicin-induced (15 mg/kg) toxicity, including elevation of body weight and heart weight/tibia length ratio, decrease of creatine kinase, improvement of electrocardiography and heart vacuolation. Furthermore, the antioxidative effects of salvianolic acids were verified by oxygen radicals absorbance capacities assay in vitro and malondialdehyde detection in vivo, suggesting one possible mechanism of salvianolic acids on cardioprotection through blocking oxidative stress.

Topics: Animals; Antibiotics, Antineoplastic; Benzofurans; Body Weight; Caffeic Acids; Cardiotonic Agents; Creatine Kinase; Doxorubicin; Electrocardiography; Heart Diseases; Lactates; Male; Malondialdehyde; Mice; Myocardium; Oxidative Stress; Reactive Oxygen Species; Tissue Fixation

The aim of this study was to analyze whether endogenous male sex hormones influence the release of thromboxane A2(TXA2) and its role in the electrical field stimulation (EFS)-induced response, as well as the mechanism involved. For this purpose, endothelium-denuded mesenteric arteries from control and orchidectomized male Sprague-Dawley rats were used to measure TXA2 release; EFS-induced response, nitric oxide (NO), norepinephrine (NA), and prostaglandin (PG) I2 release were also measured in the presence of the TXA2 synthesis inhibitor furegrelate. Orchidectomy increased basal and EFS-induced TXA2 release. Furegrelate decreased the EFS-induced contraction in arteries from control rats, but did not modify it in arteries from orchidectomized rats. The EFS-induced neuronal NO release and vasodilator response were increased by furegrelate in arteries from control rats, but were not modified in arteries from orchidectomized rats. Furegrelate did not modify the EFS-induced NA release or vasoconstrictor response in arteries from either control or orchidectomized rats. The EFS-induced PGI2 release was not modified by furegrelate in arteries from control rats, but was increased in arteries from orchidectomized rats. The results of the present study show that endogenous male sex hormone deprivation i) increases non-endothelial TXA2 release and ii) regulates the effect of endogenous TXA2 on the EFS-induced response through different mechanisms that, at the least, involve the NO and PGI2 systems. In arteries from control rats, inhibition of TXA2 formation decreases the EFS-induced response by increasing neuronal NO release. In arteries from orchidectomized rats, the EFS-induced response is unaltered after the inhibition of TXA2 formation, by increasing PGI2 release.

Topics: Animals; Benzofurans; Body Weight; Electric Stimulation; Epoprostenol; Male; Mesenteric Arteries; Nitric Oxide; Norepinephrine; Orchiectomy; Rats; Rats, Sprague-Dawley; Testosterone; Thromboxane A2; Thromboxane-A Synthase

For the general population the intake of food of animal origin is the main route of human exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F). Besides this the ingestion of contaminated soil might be an important exposure path for small children. For risk assessment the knowledge of the bioavailable fraction of soil bound contaminants is important. In a balance study with young Goettingen minipigs the oral bioavailability of PCDD/F from contaminated soil was estimated by determination of the retention of PCDD/F from soil in different organs and tissues. Relative bioavailability was estimated by comparing the retention from soil to the retention of PCDD/F in organs and tissues after oral administration of a PCDD/F mixture extracted from the same soil by solvent. The soil had a PCDD/F-contamination of 5.3 microg I-TEq/kg and originated from a former arable land that had been treated with sludge from the port of Hamburg some years ago. Two groups of each four animals were exposed daily for 28 days via their diet either to 0.5 g soil per kg body weight and day (2.63 ng I-TEq/(kg(bw).d)) or to a daily dose of 1.58 ng I-TEq/(kg(bw).d) given to the diet by solvent. Five unexposed animals were used as a control group. Liver, adipose tissue, muscle, brain and blood were analyzed for their PCDD/F content. Accumulation of PCDD/F from soil or solvent in comparison to control animals was only observed for congeners with 2378-chlorosubstitution and predominantly took place in the liver. Bioavailability of 2378-chlorosubstituted congeners was in the range of 0.64%-21.9% (mean: 10.1%) from soil and 2.8%-59.8% (mean: 31.5%) when administered by solvent. The soil matrix reduced the bioavailability by about 70%. Expressed as I-TEq only 13.8% of the PCDD/F contamination were bioavailable from soil. The relative bioavailability of 2378-chlorosubstituted congeners from soil in relation to administration by solvent was in the range of 2%-42.2% (mean: 28.4%). When not considering the bioavailability, the risk by oral uptake of PCDD/F contaminated soil might be overestimated.

Topics: Adipose Tissue; Administration, Oral; Age Factors; Animal Feed; Animals; Benzofurans; Biological Availability; Blood; Body Weight; Cities; Germany; Polychlorinated Dibenzodioxins; Risk Assessment; Soil Pollutants; Solvents; Swine; Swine, Miniature; Time Factors; Tissue Distribution

The Baltic Sea ecosystem and fish stocks contain high concentrations of environmental chemicals such as polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs), and polychlorinated biphenyls (PCBs). This study forecasts how changes in fishing or natural mortality would probably influence concentrations of PCDD/F and PCB in the Bothnian Sea (Northern Baltic) herring (Clupea harengus L.). An age-structured simulation model was developed to forecast herring stock dynamics, catches, and weight-at-age under different assumptions about exploitation and natural mortality. The simulated herring weight-at-age estimates were employed in a bioenergetics model capable of simultaneous estimation of bioaccumulation of 17 PCDD/F and 37 PCB congeners. Although the natural variability in recruitment greatly influences the stock dynamics, considerable changes in weight-at-age would ensue changes in exploitation rate or in natural mortality rate. If exploitation rates increase, growth rates would be higher and herring in the weight categories of commercial fisheries would be younger and contain less PCDD/F and PCB. Hence, the average toxicant concentrations in catches would also decline. However, it is likely that only fairly small changes would occur in toxicant concentrations-at-age. On the other hand, a drastic decrease in herring fishing would substantially increase PCDD/F and PCB concentrations in herring. The study indicated that, in spite of the clear influences of fishing on the toxicant concentrations, fishing alone cannot resolve the problems associated with a high concentration of toxicants in herring; further decreases in loading are still required.

Topics: Animals; Benzofurans; Body Weight; Computer Simulation; Dibenzofurans, Polychlorinated; Energy Metabolism; Finland; Fisheries; Fishes; Models, Theoretical; Oceans and Seas; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Population Dynamics; Water Pollutants, Chemical

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease resulting from lack of the sarcolemmal protein dystrophin. However, the mechanism leading to the final disease status is not fully understood. Several lines of evidence suggest a role for nuclear factor (NF)-kappaB in muscle degeneration as well as regeneration in DMD patients and mdx mice. We investigated the effects of blocking NF-kappaB by inhibition of oxidative stress/lipid peroxidation on the dystrophic process in mdx mice. Five-week-old mdx mice received three times a week for 5 weeks either IRFI-042 (20 mg/kg), a strong antioxidant and lipid peroxidation inhibitor, or its vehicle. IRFI-042 treatment increased forelimb strength (+22%, P < 0.05) and strength normalized to weight (+23%, P < 0.05) and decreased fatigue (-45%, P < 0.05). It also reduced serum creatine kinase levels (P < 0.01) and reduced muscle-conjugated diene content and augmented muscle-reduced glutathione (P < 0.01). IRFI-042 blunted NF-kappaB DNA-binding activity and tumor necrosis factor-alpha expression in the dystrophic muscles (P < 0.01), reducing muscle necrosis (P < 0.01) and enhancing regeneration (P < 0.05). Our data suggest that oxidative stress/lipid peroxidation represents one of the mechanisms activating NF-kappaB and the consequent pathogenetic cascade in mdx muscles. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.

Topics: Animals; Antioxidants; Benzofurans; Body Weight; Creatine Kinase; DNA; Forelimb; Glutathione; Lipid Peroxidation; Male; Mice; Mice, Inbred mdx; Muscle Fatigue; Muscle, Skeletal; Muscular Dystrophy, Duchenne; NF-kappa B; Tumor Necrosis Factor-alpha

We previously showed that testosterone, administered in vivo, increases the tone of cerebral arteries. A possible underlying mechanism is increased vasoconstriction through the thromboxane A2 (TxA2) pathway. Therefore, we investigated the effect of chronic testosterone treatment (4 wk) on TxA2 synthase levels and the contribution of TxA2 to vascular tone in rat middle cerebral arteries (MCAs). Using immunofluorescence and confocal microscopy, we demonstrated that TxA2 synthase is present in MCA segments in both smooth muscle and endothelial layers. Using Western blot analysis, we found that TxA2 synthase protein levels are higher in cerebral vessel homogenates from testosterone-treated orchiectomized (ORX + T) rats compared with orchiectomized (ORX) control animals. Functional consequences of changes in cerebrovascular TxA2 synthase were determined using cannulated, pressurized MCA segments in vitro. Constrictor responses to the TxA2 mimetic U-46619 were not different between the ORX + T and ORX groups. However, dilator responses to either the selective TxA2 synthase inhibitor furegrelate or the TxA2-endoperoxide receptor (TP) antagonist SQ-29548 were greater in the ORX + T compared with ORX group. In endothelium-denuded arteries, the dilation to furegrelate was attenuated in both the ORX and ORX + T groups, and the difference between the groups was abolished. These data suggest that chronic testosterone treatment enhances TxA2-mediated tone in rat cerebral arteries by increasing endothelial TxA2 synthesis without altering the TP receptors mediating constriction. The effect of in vivo testosterone on cerebrovascular TxA2 synthase, observed here after chronic hormone administration, may contribute to the risk of vasospasm and thrombosis related to cerebrovascular disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Androgens; Animals; Benzofurans; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hydrazines; Male; Middle Cerebral Artery; Orchiectomy; Rats; Rats, Inbred F344; Receptors, Thromboxane; Testosterone; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

There are concerns that early life exposure to organochlorines, including aryl hydrocarbon receptor (AhR) agonists, may lead to long-term effects and increase the risk of developing breast cancer. Our objective was to test if postnatal exposure to a mixture of 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-like chemicals would modulate the development of methylnitrosourea (MNU)-induced mammary tumors. Females received by gavage a mixture containing 3 non-ortho-polychlorinated biphenyls (PCBs), 6 polychlorinated dibenzodioxins (PCDDs), and 7 polychlorinated dibenzofurans (PCDFs), at 1, 5, 10, 15, and 20d of age. The doses were equivalent to 0, 1, 10, 100, or 1000 times the amount ingested through breast milk by a human infant during its first 24 d of life. Subgroups of 1000 x reated rats and controls were sacrificed at 21 d of age for assessment of mammary-gland development, cell death, and proliferation. Mammary-tumor development was assessed in MNU (30 mg/kg body weight ip at 50 days of age)-induced rats pre-exposed to the mixture (MNU-0, MNU-1, MNU-10, MNU-100, MNU-1000). Rats were sacrificed when their mammary tumors reached 1 cm in diameter, or when the rats reached > or = 32 wk of age. Mammary-gland whole mounts were analyzed with all palpable and microscopic lesions (n = 1563) histologically classified and grouped as benign, intraductal proliferations, or malignant. There were no marked effects on age at onset of puberty (vaginal opening) and estrous cyclicity. Despite a significant decrease in proliferating cell nuclear antigen (PCNA)-positive mammary cells in 1000 x treated 21-d-old rats, there were no long-term dose-response effects on mammary-gland morphology and tumor development. In conclusion, postnatal exposure to the mixture of AhR agonists had no significant effects on the development of MNU-initiated mammary tumors.

Topics: Age Factors; Alkylating Agents; Animals; Animals, Newborn; Benzofurans; Body Weight; Dibenzofurans, Polychlorinated; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Environmental Exposure; Environmental Pollutants; Estrous Cycle; Immunohistochemistry; Mammary Neoplasms, Experimental; Methylnitrosourea; Milk; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Proliferating Cell Nuclear Antigen; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon; Risk Factors

Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) were analyzed by high-resolution gas chromatography/high-resolution mass spectrometry in human milk samples from an urban and an industrial area in Korea. All PCB congeners were analyzed to characterize the congener distribution as well as to evaluate the toxic equivalent quotient (TEQ) values and the total concentration. In homologue distributions of PCBs, two distinct patterns were found. The mean concentrations of PCDD/Fs and PCBs were 15.13 and 5.64 TEQ pg/g fat (based on WHO TEF, 1997), respectively. The contamination in Korean human milk is comparable to that found in other countries. From these results a daily intake of 60 TEQ pg/kg/day for an infant was estimated. The assumptions were that the infant breast feeds for 1 year, has an average body weight of 10 kg during this period, and ingests 800 g/day of human milk containing a mean concentration of 20.84 TEQ (PCDD/Fs) pg/g fat (based on primipara mothers).

Topics: Adult; Benzofurans; Body Weight; Breast Feeding; Dibenzofurans, Polychlorinated; Environmental Exposure; Environmental Pollutants; Female; Forecasting; Gas Chromatography-Mass Spectrometry; Humans; Infant, Newborn; Korea; Middle Aged; Milk, Human; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Risk Assessment; Soil Pollutants; Structure-Activity Relationship; Urban Population

The effects of nori (Porphyra yezoensis), a kind of red alga, on the gastrointestinal absorption and reabsorption of 17 types of dioxin were investigated in male Wistar rats. The rats were fed with 4 g of the control diet or 4 g of the nori diet containing a standard dioxin solution (233 ngTEQ/kg of body weight) for five consecutive days. In the group fed with the 10% nori diet, the fecal excretion of dioxin from days 1 to 5 was higher (p<0.01) than that of the control group by 5.5-fold for 2,3,7,8-TCDD, 6.6-fold for 1,2,3,7,8-pentaCDD, and 6.0-fold for 2,3,4,7,8-pentaCDF. In another experiment, the rats were fed with 4 g of the control diet containing a standard dioxin solution (2991 ngTEQ/kg of body weight) on the first day of the experiment and then given the control diet for 7 consecutive days, before being given either the control diet or the nori diet for 28 consecutive days more. In the group fed with the 10% Nori diet, the fecal excretion of dioxin during the period from days 8 to 35 was higher (p<0.01 or p<0.05) than that of the control group by 2.4-fold for 2,3,7,8-TCDD, 2.3-fold for 1,2,3,7,8-pentaCDD, and 2.4-fold for 2,3,4,7,8-pentaCDF. These results suggest that the administration of nori prevented dioxin from being efficiently absorbed and reabsorbed from the gastrointestinal tract, and might be useful for protecting humans exposed to dioxin from ill effects.

Topics: Animals; Benzofurans; Body Weight; Diet; Dioxins; Feces; Feeding Behavior; Hydrocarbons, Chlorinated; Intestinal Absorption; Male; Plant Oils; Rats; Rats, Wistar; Rhodophyta; Time Factors

Recent developments in antiarrhythmic therapy have indicated that the best approach to pharmacologically controlling supraventricular arrhythmias and life-threatening ventricular tachyarrhythmias is by prolonging cardiac repolarization rather than by blocking conduction. In this context, amiodarone has emerged as the most potent compound, but its universal use has been limited by its toxicity profile. There are data to suggest that an important component of amiodarones antiarrhythmic action might be mediated via inhibition of thyroid hormone action in the heart. Therefore, a new series of carboxymethoxybenzoyl and benzyl derivatives of benzofuran has been prepared and evaluated as thyroid hormone receptor antagonists. Within this series, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran KB130015 (7) was found to reveal the most promising in vitro data. It inhibits the binding of (125)I-T(3) to the human thyroid hormone receptors (hThR) alpha(1) and beta(1). T(3)-Antagonism was confirmed in reporter cell assays employing CHOK1 cells (Chinese hamster ovary cells) stably transfected with hThR alpha(1) or hThR beta(1) and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC(50) values were 2.2 microM for hThR alpha(1) and 4.1 microM for hThR beta(1). Compound 7 was selected for further characterization of chronic effects on ventricular papillary muscle by transmembrane electrophysiology after daily intraperitoneal injection of the ligand (40 mg/kg body weight) in guinea pigs. Compound 7 was found to prolong the action potential duration at 90% (APD(90)) repolarization time (219 +/- 22 ms, control: 186 +/- 9 ms, p < 0.01) without exhibiting any reverse rate dependency of action in a manner similar to that of amiodarone. In general, preliminary tolerance experiments with 7 demonstrated an improved safety profile compared to that of amiodarone. In summary, 7 appears to be less toxic than amiodarone while maintaining its electrophysiologic properties consistent with antiarrhythmic activity. Its potential antiarrhythmic actions warrant further investigations.

Topics: Action Potentials; Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Body Weight; Brain; Calcium Channels, L-Type; CHO Cells; Cholesterol; Cricetinae; Guinea Pigs; Heart; Humans; In Vitro Techniques; Liver Function Tests; Radioligand Assay; Rats; Receptors, Thyroid Hormone; Thyroid Function Tests; Transfection

We determined breast milk concentration of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) in 24 mothers living in Korea, and assessed the maternal body burden based on PCDDs/PCDFs and PCBs concentrations in breast milk and an infant intake rate through breast-feeding based on their concentration in breast milk. PCDDs/PCDFs and PCBs levels in breast milk from primipara mothers were found to be higher than those from multipara mothers. For total PCDDs/PCDFs TEQ level, 2,3,4,7,8-PeCDD was the predominant congener, and the proportion of 2,3,7,8-TCDD was less than 3% of total PCDDs/PCDFs TEQ level. For PCBs TEQ level, PCB-126 was the predominant congener. Maternal body burden levels of PCDDs/PCDFs and PCBs based on their concentrations in breast milk were 268-622 TEQ ng. The daily dioxin intakes of mothers were predicted to be 0.78-2.18 TEQ pg/kg/day for PCDDs/PCDFs and 0.34-0.66 TEQ pg/kg/ day for PCBs. For the first year, the body burden of an infant was predicted to be 212 TEQ ng and the daily intake of an infant was predicted to be 85 TEQ pg/kg/day, assuming the mean dioxin-related compounds concentration (27.54 TEQ pg/g fat).

Topics: Adult; Benzofurans; Body Weight; Dibenzofurans, Polychlorinated; Eating; Environmental Pollutants; Female; Humans; Korea; Middle Aged; Milk, Human; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Urban Population

To prevent health problems of humans exposed to dioxin, it is important to enhance the fecal excretion of dioxin stored in the body. The effects of seaweed such as wakame, hiziki, and kombu on the gastrointestinal absorption and reabsorption of 17 types of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) congeners was investigated in Wistar rats. Rats were fed 4 g of the basal diet or a seaweed diet containing PCDD and PCDF standard solution [233 ng of toxic equivalents (TEQ)/kg of body weight] once during the experiment period. In the group fed the 10% wakame diet, the levels of fecal excretion of PCDD and PCDF congeners were higher (p < 0.01) from days 1 to 5 by 2.8-fold for 2,3,7,8-TCDD, by 4.0-fold for 1,2,3,7,8-pentaCDD, by 3.4-fold for 1,2,3,4,7,8-hexaCDD, by 3.2-fold for 1,2,3,6,7,8-hexaCDD, by 2.5-fold for 1,2,3,7,8,9-hexaCDD, by 1.7-fold for 1,2,3,4,6,7,8-heptaCDD, by 1.1-fold for 1,2,3,4,6,7,8,9-octaCDD, by 3.0-fold for 2,3,7,8-tetraCDF, by 3.7-fold for 1,2,3,7,8-pentaCDF, by 3.7-fold for 2,3,4,7,8-pentaCDF, by 3.2-fold for 1,2,3,4,7,8-hexaCDF, by 3.0-fold for 1,2,3,6,7,8-hexaCDF, by 3.2-fold for 1,2,3,7,8,9-hexaCDF, by 2.9-fold for 2,3,4,6,7,8-hexaCDF, by 1.6-fold for 1,2,3,4,6,7,8-heptaCDF, by 2.2-fold for 1,2,3,4,7,8,9-heptaCDF, and by 1.2-fold for 1,2,3,4,6,7,8,9-octaCDF than those of the basal group, respectively. Rats were fed 4 g of the basal diet containing PCDD and PCDF standard solution (2991 ng of TEQ/kg of body weight) once on day 1 and then place on the basal diet for 7 days. After 1 week, the rats were fed either the basal diet or seaweed diet from days 8 to 35. In the group fed the 10% wakame diet, the levels of fecal excretion of PCDD and PCDF congeners were higher (p < 0.01 or p < 0.05) during the period from days 8 to 35 by 1.7-fold for 2,3,7,8-TCDD, by 1.8-fold for 1,2,3,7,8-pentaCDD, by 2.0-fold for 1,2,3,4,7,8-hexaCDD, by 1.9-fold for 1,2,3,6,7,8-hexaCDD, by 1.6-fold for 1,2,3,7,8,9-hexaCDD, by 1.5-fold for 1,2,3,4,6,7,8-heptaCDD, by 2.0-fold for 2,3,4,7,8-pentaCDF, by 2.1-fold for 1,2,3,4,7,8-hexaCDF, by 1.9-fold for 1,2,3,6,7,8-hexaCDF, by 1.7-fold for 2,3,4,6,7,8-hexaCDF, by 1.5-fold for 1,2,3,4,6,7,8-heptaCDF, and by 1.9-fold for 1,2,3,4,7,8,9-heptaCDF than those of the basal group, respectively. These findings suggest that the administration of seaweed such as wakame is efficient in preventing the absorption and reabsorption of dioxin from the gastrointestinal tract and might be useful in

Topics: Animals; Benzofurans; Body Weight; Dibenzofurans, Polychlorinated; Diet; Dioxins; Eating; Feces; Health Promotion; Intestinal Absorption; Male; Polychlorinated Dibenzodioxins; Rats; Rats, Wistar; Seaweed

We examined whether delayed gastric emptying could be produced by diabetes in dogs. Diabetes was produced by a single injection of streptozotocin (30 mg/kg i.v.), and diabetic hyperglycemia was observed from 2 to 15 months after injection. The plasma acetaminophen concentration, which is an indirect indicator of the gastric emptying rate, was delayed in 2 of 5 diabetic dogs from 15 months after the induction of diabetes. The effects of SK-951, a benzofuran derivative, on delayed gastric emptying were also examined in diabetic gastroparetic dogs in comparison with those of cisapride. SK-951 (1 mg/kg i.v.) significantly enhanced delayed gastric emptying in diabetic dogs, but cisapride (1 mg/kg i.v.) had no effect. In addition, SK-951 increased the plasma glucose levels in a manner correlated with its effect on gastric emptying. The present study suggested that SK-951 may be useful in the treatment of diabetic gastroparesis.

Topics: Acetaminophen; Animals; Benzofurans; Blood Glucose; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Diabetes Mellitus, Experimental; Dogs; Gastric Emptying; Gastrointestinal Agents; Gastroparesis; Male; Time Factors

New Bedford Harbor (NBH), MA, is a federal Superfund site that is heavily contaminated with polychlorinated biphenyls (PCBs) and other halogenated aromatic hydrocarbons (HAHs), including some potent aryl hydrocarbon receptor (AhR) agonists. A population of Atlantic killifish (Fundulus heteroclitus) continues to inhabit this site, despite accumulating extraordinarily high concentrations of PCBs (272 microg/g dry weight). To determine if NBH killifish have developed resistance to HAHs that act through the AhR, we examined the inducibility of cytochrome P4501A1 (CYP1A1), UDP glucuronosyl transferase (UGT), and glutathione S-transferase (GST) in fish from NBH and a reference site, Scorton Creek (SC, Cape Cod, MA; PCB concentrations 0.177 microg/g dry weight). 2,3,7,8-Tetrachlorodibenzofuran (TCDF) induced CYP1A1 mRNA, protein, and activity in SC fish in all tissues examined (liver, heart, gut, gill, kidney, spleen, and gonad). In contrast, NBH fish expressed low levels of CYP1A1 and showed no induction of CYP1A1 mRNA, protein, or activity by TCDF, or induction that was lower in magnitude or required higher doses of inducer. p-Nitrophenol UGT activity was not induced by TCDF in either population, while GST activity with 1-chloro-2,4-dinitrobenzene as substrate was induced only in NBH fish in one experiment. Inducibility of CYP1A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or beta-naphthoflavone (BNF) was measured in primary hepatocyte cultures prepared from SC and NBH fish. TCDD induced CYP1A1 activity (ethoxyresorufin O-deethylase) to the same degree in hepatocytes from both populations, demonstrating the functionality of the AhR signaling pathway in NBH fish. However, hepatocytes from NBH fish were 14-fold less sensitive to TCDD than were those from SC fish. The nonhalogenated AhR agonist BNF also induced CYP1A1 in cells from both populations, although with only a 3-fold difference in sensitivity (NBH < SC). These results indicate that chronic exposure to high levels of HAHs has led to a reduction in the sensitivity of NBH killifish to AhR agonists. The resistance is systemic and pretranslational, and exhibits compound-specific differences in magnitude. These findings suggest an alteration in the AhR signal transduction pathway in NBH fish.

Topics: Animals; Benzofurans; beta-Naphthoflavone; Body Weight; Cells, Cultured; Cytochrome P-450 CYP1A1; Drug Tolerance; Enzyme Induction; Female; Glucuronosyltransferase; Glutathione Transferase; Gonads; Hazardous Waste; Hepatocytes; Killifishes; Liver; Male; Microsomes; Organ Size; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; RNA, Messenger

The splenic antibody plaque forming cell (PFC) assay is a widely used assay in immunotoxicity testing. A recent revision of the Federal Insecticide, Fungicide and Rodenticide (FIFRA) Immunotoxicity test guidelines by the EPA recommended that either the PFC assay or the sheep red blood cell (SRBC) specific serum IgM enzyme-linked immunosorbent assay (ELISA) be used to assess the primary humoral response to SRBCs. The PFC assay quantifies the number of plasma cells in the spleen producing SRBC-specific antibody, while the ELISA measures SRBC-specific IgM antibody in the serum. Because these two assays measure different endpoints, there is a need for comparison of their sensitivity and reliability. The purpose of this project was to determine if these two assays are equally sensitive to suppression of the SRBC response in B6C3F1 female mice. Female B6C3F1 mice were given a single oral exposure to different doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or four TCDD-like congeners. One week later, two sets of mice were immunized with SRBC. The first set was evaluated for the PFC response and the second for the ELISA response, on day 4 or 5 post-immunization, respectively. The four TCDD-like congeners tested were: 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,2,3,4,7-pentachlorodibenzofuran (4PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB126) and 2,3',4,4',5-pentachlrorbiphenyl (PCB118). The results were used to generate dose-response curves for the determination of the ED(50) for TCDD and each TCDD-like congener. For all chemicals tested, measuring the level of SRBC-specific IgM antibody by ELISA was more sensitive than the PFC assay to detect immunosuppression, as indicated by lower ED(50) values. These results indicate that the SRBC-specific IgM ELISA is a more sensitive assay for detecting the T-cell mediated immunotoxicity of dioxin-like chemicals in this rodent model.

Topics: Animals; Benzofurans; Body Weight; Dibenzofurans, Polychlorinated; Enzyme-Linked Immunosorbent Assay; Female; Hemolytic Plaque Technique; Immunosuppressive Agents; Mice; Organ Size; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Sensitivity and Specificity

TCDD is the prototype and most potent member of the highly lipophilic polyhalogenated aromatic hydrocarbons (PHAHs), which are persistent and ubiquitous environmental contaminants. In both acute and subchronic animal studies, there is a specific accumulation of TCDD in liver greater than in adipose tissue. The inducible hepatic binding protein responsible for this hepatic sequestration of TCDD and its congeners has been shown by our laboratory to be CYP1A2 (J. J. Diliberto, D. Burgin, and L. S. Birnbaum, 1997, Biochem. Biophys. Res. Commun. 236, 431-433). The present study was conducted using knockout (KO) mice lacking expression of CYP1A2 (CYP1A2-/-) in order to investigate the role of CYP1A2 gene on the disposition of TCDD, 4-PeCDF (a dioxin-like PHAH), and PCB 153 (a nondioxin-like PCB) in KO (CYP1A2-/-) mice and age-matched parental mice strains (C57BL/6N: CYP1A2+/+, Ah(b/b) and 129/Sv: CYP1A2+/+, Ah(d/d)). Mice were dosed (25 microgram [(3)H]TCDD/kg, 300 microgram [(14)C]4-PeCDF/kg, or 35.8 mg [(14)C]PCB 153/kg bw in a corn oil vehicle) orally and terminated after 4 days. Residues of administered compounds in collected tissues and daily excreta were quantitated using (3)H or (14)C activity. Results demonstrated differential effects in disposition for the various treatments within the three genetically different groups of mice. In KO mice, TCDD, 4-PeCDF, and PCB 153 had very little hepatic localization of chemical, and the major depot was adipose tissue. In contrast, parental strains demonstrated hepatic sequestration of TCDD and 4-PeCDF, whereas disposition of PCB 153 in parental strains was similar to that in KO mice. Another difference between KO mice and parental strains was the enhanced urinary excretion of 4-PeCDF. This study demonstrates the importance of CYP1A2 in pharmacokinetic behavior and mechanistic issues for TCDD and related compounds.

Topics: Animals; Benzofurans; Body Weight; Cytochrome P-450 CYP1A2; Environmental Pollutants; Feces; Liver; Mice; Mice, Inbred Strains; Mice, Knockout; Organ Size; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Tissue Distribution

Recent studies have shown that acyl-CoA:cholesterol acyltransferase (ACAT) plays an important role in the initiation of diabetes-associated hypercholesterolemia. To confirm this hypothesis, effects of a potent ACAT inhibitor, FR145237, on diet-induced hypercholesterolemia were examined in streptozotocin (STZ)-induced diabetic rats. One-week feeding of 1% cholesterol and 0.5% cholic acid to normal rats and STZ-induced diabetic rats increased plasma cholesterol levels in both groups, and the response was more remarkable in the STZ rats than in the normal ones (1266 +/- 476 mg/dl and 146 +/- 7 mg/dl, respectively). FR145237 dose-dependently reduced the rise in plasma cholesterol levels in the STZ rats and the levels were almost normalized by treatment with 1 mg/kg/day of the compound. These results suggest that hyperresponse to dietary cholesterol was induced in the STZ rats and that ACAT is involved in the hyperresponse. The effects of FR145237 on other plasma lipids such as high density lipoprotein (HDL) cholesterol and triglyceride (TG) levels were also examined.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Diabetes Mellitus, Experimental; Eating; Enzyme Inhibitors; Hypercholesterolemia; Male; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Sterol O-Acyltransferase; Triglycerides

Glucose levels in rats with hyperglycemia induced by streptozotocin were determined after i.p. administration of marsupsin (1), pterosupin (2), and pterostilbene (3), three important phenolic constituents of the heartwood of Pterocarpus marsupium. Marsupsin and pterostilbene significantly lowered the blood glucose level of hyperglycemic rats, and the effect was comparable to that of 1,1-dimethylbiguanide (metformin).

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cresols; Diabetes Mellitus, Experimental; Female; Glucosides; Hypoglycemic Agents; Male; Metformin; Phenols; Plants, Medicinal; Rats; Stilbenes; Wood

Some new alkylating agents which bind to the minor groove of DNA and have sequence-specific patterns of alkylation have shown anti-neoplastic activity in pre-clinical systems. Two of them, carzelesin and tallimustine, are now in phase II. Considering the severe dose-limiting bone marrow toxicity of both these drugs in clinical use, it was of interest to investigate the mechanism of their myelotoxicity in a detailed pre-clinical study and compare it with a conventional alkylating agent, such as melphalan. The origin and progression of the myelotoxicity of carzelesin, tallimustine and melphalan were investigated comparatively in mice, combining data on bone marrow and peripheral blood cellularity with data on the proliferative activity of bone marrow cells, obtained by in vivo administration of bromodeoxyuridine. Significant differences were found between the hematopoietic response to the 3 drugs, though all caused severe leukopenia. Carzelesin induced a short-term increase in myeloid proliferative activity, which prevented the high leukocytopenia on day 3 observed with the other drugs. However, when this effect was exhausted, a second nadir was seen in peripheral blood, with a new wave of cell proliferation of all lineages in the bone marrow. Reconstruction of the lymphoid lineage was slow for all 3 drugs but particularly difficult with high-dose tallimustine. In general, the hematopoietic system response to tallimustine was dampened, with no overshoots, suggesting either lasting effects or extensive cytotoxicity from the early to late precursors of all lineages.

Topics: Animals; Antineoplastic Agents, Alkylating; Benzofurans; Body Weight; Bone Marrow Cells; Cell Cycle; Cell Division; Distamycins; Duocarmycins; Flow Cytometry; Indoles; Leukocyte Count; Male; Melphalan; Mice; Mice, Inbred Strains; Neutropenia; Nitrogen Mustard Compounds; Survival Rate; Thrombocytopenia

Effects of NBP on liability of stroke, life span and neurological deficits following stroke were studied in stroke prone spontaneously hypertensive rats (SHRsp). The SHRsp rat was kept on 1% NaCl solution as drinking water and was fed 15 g soft food containing 0.6-0.8 g NaCl per day. Total NaCl intake for one rat was 1.1-1.3 g per day. After the onset of stroke, tap water and normal food was given instead of that containing NaCl. The neurological deficits were evaluated by a specially designed scoring system. These symptoms were divided into 4 degrees (1-4). Grade 1. stress (mild). Grade 2. forelimb or head twitch or with stress (severe). Grade 3. hemiparalysis, body inclined or disabled. Grade 4. paralysis, tremor or convulsion. Blood pressure, heart rate and body weight were measured once every 2 weeks. The weights of heart, brain and kidneys were also measured. The results show that NBP pre-treatment at the dose of 100 mg.kg-1.d-1 po delayed the onset of stroke. So, like nimodipine, NBP showed a stroke preventive action in SHRsp rats. In addition, treatment with NBP 100 mg.kg-1.d-1 po after the onset of stroke, the life span was prolonged and the score of neurological deficit decreased significantly. Because high blood pressure can not be lowered by NBP treatment, therefore, the protective effect against stroke can not be explained by the effect of hypotension. No change was found in BP, HR and the organ weight. The results indicate that NBP is expected to be useful in the treatment of stroke.

Topics: Animals; Benzofurans; Blood Pressure; Body Weight; Cerebrovascular Disorders; Heart Rate; Male; Neuroprotective Agents; Nimodipine; Rats; Rats, Inbred SHR; Stereoisomerism

The concentrations of chlorinated dibenzodioxins and dibenzofurans (PCDD/F) in human blood and in milk from non-occupationally exposed persons living in the vicinity of a municipal waste incinerator were determined. As compared to background levels in the general population in Germany the results give no indication of an enhanced body burden of PCDD/F. This is in agreement with earlier investigations in the same area, showing normal background concentrations in soil, fruit and vegetables. In conclusion, no direct health hazard related to PCDD/F-emissions from a local municipal waste incinerator may be expected.

Topics: Adolescent; Adult; Aged; Benzofurans; Body Burden; Body Weight; Child; Cohort Studies; Dibenzofurans, Polychlorinated; Environmental Exposure; Female; Germany; Humans; Incineration; Male; Middle Aged; Milk, Human; Polychlorinated Dibenzodioxins; Soil Pollutants; Waste Management

Great blue heron hatchlings from colonies in the Strait of Georgia, British Columbia, Canada are being monitored for environmental contaminant exposure and effects by the Canadian Wildlife Service. The contaminants of concern are polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), primarily derived from kraft pulp mill effluent. The levels of PCDDs and PCDFs in eggs from the most contaminated colonies peaked in 1988 and 1989 and dropped dramatically through 1990 to 1992. Brains of heron hatchlings (taken as eggs from the wild and hatched in the laboratory) were analyzed for gross morphological abnormalities. Brains from highly contaminated colonies (Crofton, British Columbia and University of British Columbia Endowment Lands) in 1988 exhibited a high frequency of intercerebral asymmetry. The frequency of this abnormality decreased in subsequent years as the levels of TCDD and TCDD-TEQs (toxic equivalence factors) decreased. The asymmetry was significantly correlated with the level of TCDD and TCDD-TEQs in eggs taken from the same nest. Yolk-free body weight negatively correlated and the brain somatic index positively correlated with the TCDD level in such pair-matched eggs. These results indicate that gross brain morphology, and specifically intercerebral asymmetry, may be useful as a biomarker for the developmental neurotoxic effects of PCDDs and related chemicals.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Wild; Benzofurans; Birds; Body Weight; Brain; British Columbia; Dibenzofurans, Polychlorinated; Female; Hazardous Waste; Linear Models; Morphogenesis; Organ Size; Ovum; Polychlorinated Dibenzodioxins

Polychlorinated dibenzo-p-dioxins and dibenzofurans induce exthoxyresorufin-O-deethylase (EROD) activity, a marker for CYP1A1. Differences in potency of these compounds can be attributed to differences in their affinity for the Ah receptor as well as differences in pharmacokinetics. To test the role of pharmacokinetics in the in vivo potency of these chemicals, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) were administered to female B6C3F1 mice for 4 or 13 weeks of treatment and EROD activity in liver and skin was determined. The doses were designed to be equally potent based on the published Toxic Equivalency Factor (TEF) values for these compounds. Mice received either 150 ng TCDD/kg/day or 1500 ng TCDF/kg/day, 5 days/week for either 4 or 13 weeks. At 4 weeks, hepatic EROD was induced 11- and 7-fold by TCDD and TCDF, respectively. These data indicate that the published TEFs accurately estimated the relative potency of TCDF after 4 weeks of treatment. After 13 weeks, hepatic EROD was induced 41- and 6-fold by TCDD and TCDF, respectively. The TEFs did not accurately estimate the relative inductive potency of these compounds when compared after 13 weeks of treatment. The inability of the TEFs to predict the relative potency of these compounds after 13 weeks of treatment may be due in part to the differences in the pharmacokinetic properties of each congener. The half-life of TCDF and TCDD is approximately 2 and 15 days, respectively. Steady-state levels of TCDD were not attained by 4 weeks, which is reflected in the increase in hepatic EROD between 4 and 13 weeks. In contrast, steady-state levels of TCDF were reached within 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Body Weight; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Enzyme Induction; Female; Half-Life; Mice; Mice, Inbred Strains; Organ Size; Oxidoreductases; Polychlorinated Dibenzodioxins; Sensitivity and Specificity; Skin

RG 12915, a selective 5-HT3 antagonist developed for the treatment of emesis and nausea associated with cancer chemotherapy, was administered by gavage to four groups of pregnant rats from Gestation Day 6 to 17 at doses of 0, 1, 10, and 100 mg/kg/day, as part of a Segment II (developmental toxicity) study. The 100 mg/kg/day dose was maternally toxic as indicated by decreased body weight gain and food consumption during the treatment period. A portion of the rats were allowed to deliver and rear their litters and three pups from two litters in the 100 mg/kg/day group were observed to have lens opacities (visible to the naked eye) at weaning. At a later examination, when the offspring were approximately 4 months old, four additional animals from the same two litters had cataracts. A slight growth retardation was also observed postweaning in the offspring of the 100 mg/kg/day group. To confirm the lens findings and more precisely define the no-effect dose, another study was conducted in which pregnant rats were administered daily RG 12915 doses of 0, 10, 30, 60, or 100 mg/kg/day from Gestation Day 6 to 17. There was a dose-related decrement in maternal body weight gain during the treatment period in the 30, 60, and 100 mg/kg/day groups (12, 28, and 47%, respectively) compared to the control group. A treatment-related incidence of nuclear cataract was observed in the offspring of the 60 and 100 mg/kg/day groups (litter incidence 6 and 45%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Cataract; Female; Lens, Crystalline; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Serotonin Antagonists

We have previously characterized abnormal Ca2+ handling in platelets of spontaneously hypertensive rats (SHRs). In this study, we investigated whether cellular Ca2+ metabolism and/or Na+ concentration is altered in platelets of deoxycorticosterone acetate-salt hypertensive rats (DOCA rats). The resting cytosolic Ca2+ concentration ([Ca2+]i) in platelets was significantly lower in DOCA rats than controls (54.5 +/- 1.4 vs. 61.2 +/- 2.3 nmol/l). The amplitude of the [Ca2+]i transient induced by thrombin was significantly increased in the absence, but not the presence, of external Ca2+ in DOCA rats compared with control rats. The [Ca2+]i response to 5 mumol/l ionomycin in the Ca(2+)-free buffer was greater in DOCA rats than in controls (546 +/- 23 vs. 470 +/- 18 nmol/l), indicating larger intracellular Ca2+ stores. The rate of recovery of [Ca2+]i after the peak response to thrombin was decreased in DOCA rats (79% at 0.1 U/ml and 91% at 1.0 U/ml thrombin of control rats). Cytosolic Na+ concentration ([Na+]i) in platelets was similar in DOCA and control rats. Altered Ca2+ levels are not correlated with [Na+]i in this salt-sensitive hypertensive model. Therefore, an increased [Ca2+]i is not an obligatory phenomenon in hypertension.

Topics: Animals; Benzofurans; Blood Platelets; Blood Pressure; Body Weight; Calcium; Cytosol; Desoxycorticosterone; Ethers, Cyclic; Fluorescent Dyes; Heart Rate; Hypertension; In Vitro Techniques; Male; Rats; Rats, Wistar; Reference Values; Sodium; Sodium, Dietary; Thrombin

Topics: Animals; Benzofurans; Body Weight; Brachyura; Fisheries; Gas Chromatography-Mass Spectrometry; Liver; Marine Biology; Muscles; Nephropidae; New Jersey; New York; Pancreas; Polychlorinated Dibenzodioxins; Water Pollutants, Chemical

The present project assessed the effect of environmental contamination with polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) on hepatic microsomal ethoxyresorufin O-deethylase (EROD) activities and morphological parameters in matched double-crested cormorant (Phalacrocorax auritus) hatchlings from egg clutches chosen for chemical analysis. Double-crested cormorant eggs were collected from five colonies across Canada, with differing levels of contamination. Levels of contamination expressed in sum of 2,3,7,8-tetrachlorodibenzo-p-dioxin-toxic equivalents (TCDD-toxic equivalents or TEQ, ng/kg egg; mean +/- SEM) were: Saskatchewan, 250 +/- 50; Chain Islands, 672 +/- 73; Christy Islet, 276 +/- 14; Crofton, 131, n = 1; and Lake Ontario, 1606 +/- 118. In the hatchlings, hepatic EROD activities (pmol/min/mg protein; mean +/- SEM) were: Saskatchewan, 283 +/- 42; Chain Islands, 516 +/- 98; Christy Islet, 564 +/- 91; Crofton, 391 +/- 52; and Lake Ontario, 2250 +/- 156. Hepatic microsomal EROD activity (pmol/min/mg protein) regressed positively on TEQ (r2 = .69; p < .00005; n = 25). Yolk weight (g) regressed negatively on TEQ (r2 = .44; p = .00005). Wing length (mm) regressed negatively on PCB-169 (r2 = .28; p = .007). Monospecific antibodies raised against rat cytochrome P-450 1A1 recognized a protein in the hepatic microsomes of the double-crested cormorant, and also in those of the great blue heron (Ardea herodias), using immunoblotting. The intensity of the stained band increased with increased EROD activity, supporting the assumption that ethoxyresorufin is a suitable substrate for avian cytochrome P-450 1A1. These results validate the use of avian hepatic microsomal EROD activity as an index of cytochrome P-450 1A1 induction by environmental levels of polychlorinated aromatic hydrocarbons and as a useful screening tool to determine the extent of exposure to such chemicals. Furthermore, the induction of cytochrome P-450 1A1 observed in the cormorant indicates that the Ah receptor-mediated process, by which TCDD and related chemicals exert many of their toxicities, has been activated.

Topics: Abnormalities, Drug-Induced; Animals; Benzofurans; Birds; Body Weight; Canada; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Dioxins; Eggs; Microsomes, Liver; Oxidoreductases; Polychlorinated Biphenyls

Topics: Abnormalities, Drug-Induced; Animals; Benzofurans; Body Weight; Bone Development; Embryonic and Fetal Development; Female; Male; Mice; Mice, Inbred ICR; Organ Size; Pregnancy

A great blue heron colony located near a pulp mill in British Columbia failed to fledge young in 1987, with a concurrent sharp increase in polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in their eggs. In 1988 we tested the hypothesis that the PCDD and PCDF contamination caused reproductive failure by increasing mortality of the heron embryos in ovo. Pairs of great blue heron eggs were collected from three British Columbia colonies with low, intermediate, and high levels of dioxin contamination: Nicomekl, Vancouver, and Crofton, respectively. One egg of each pair was incubated under laboratory conditions at the University of British Columbia (UBC) while the other egg was analyzed for PCDDs and PCDFs. All incubated eggs were fertile. All eggs from the Nicomekl colony hatched, while 13 of 14 eggs from Vancouver and 12 of 13 eggs from Crofton hatched. Subcutaneous edema was observed in 4 of 12 chicks from Crofton and 2 of 13 chicks from Vancouver. No edema was seen in the chicks from Nicomekl. There was a small, but significant, negative regression of plasma calcium concentration, yolk-free body weight, tibia length, wet, dry, and ash weight, beak length, and kidney and stomach weight of the hatched chicks on the tetrachlorodibenzo-p-dioxin (TCDD) level of the paired eggs. Fewer down follicles were present on the heads of TCDD-contaminated chicks. Hence while dioxins did not cause mortality of the heron embryos in ovo, the depression of growth and the presence of edema are suggestive that dioxins at the levels found in the environment have an adverse effect on the development of great blue heron embryos.

Topics: Animals; Benzofurans; Birds; Body Weight; Embryo, Nonmammalian; Environmental Pollutants; Microsomes, Liver; Organ Size; Polychlorinated Dibenzodioxins; Polymers; Tissue Distribution

The polychlorinated dibenzofurans (PCDFs) are one group of man-made toxicants for which reasonably extensive data exist relevant to dose-response relationships in humans. Examination of contaminated food oil consumption from the yusho (Japan) poisoning incident indicates the mean uptake or body burden of 2, 3, 4, 7, 8-pentachlorodibenzofuran (PnCDF) equivalents (PEQ) associated with nausea and anorexia to be 4.4 micrograms/kg body wt and that associated with chloracne to be 5.9 micrograms/kg. For the yucheng (Taiwan) poisoning incident, blood measurements for chloracne show a similar body burden of 4.0 micrograms/kg. The latter value is toxicologically equivalent to a 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalent (TEQ) body burden of 2.0 micrograms/kg body wt or about 150 micrograms for an adult person. This corresponds to an adipose tissue level of about 10 micrograms/kg fat, and is comparable to that known to cause chloracne in rhesus monkeys. These body burdens on a TEQ basis are more than 200 times higher than the average current levels of PCDDs/PCDFs found in North American populations and are the first to relate human body burdens of PCDFs with a known effect and to compare them to animal data. Since the effects reported may not be the most sensitive indicator of human toxicity, lower body burdens could be associated with more subtle toxicological events.

Topics: Adolescent; Adult; Age Factors; Aged; Animals; Benzofurans; Body Burden; Body Weight; Child; Child, Preschool; Dibenzofurans, Polychlorinated; Female; Food Contamination; Humans; Infant; Infant, Newborn; Male; Middle Aged; Oryza; Plant Oils; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Pregnancy; Skin Diseases; Species Specificity

The biological activity of 2,4,8-trichlorodibenzofuran (2,4,8-TCDF) was tested using 2 endpoints: (a) the promotion of enzyme-altered, preneoplastic foci initiated by diethylnitrosamine (DEN) in livers of weanling female Sprague-Dawley rats; and (b) the induction of aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH), a marker for cytochrome P-4501 activity, in livers of adult female Sprague-Dawley rats and in H4IIEC3 rat hepatoma cells. When animals were treated with 200 or 500 mg/kg 2,4,8-TCDF 5 X weekly over 10 weeks after a single application of 10 mg/kg DNA, the higher dose of 2,4,8-TCDF had a promoting effect on the appearance of preneoplastic foci. Thus number and total area of foci deficient in adenosine-5'-triphosphatase were significantly increased by a factor of 1.6. 2,4,8-TCDF induced AHH-activities in 9000 X g supernatants of liver 2-3-fold, when rats were treated with 100-1000 mg/kg/day for 5 days and monooxygenase activities determined after another 3 days. The amounts of 2,4,8-TCDF required for inducing AHH activity in H4IIEC3 cells were 7 orders of magnitude higher than those of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). the results indicate that the 2,4,8-TCDF has a biological activity which is extremely low compared to that of 2,3,7,8-TCDD.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Benzopyrene Hydroxylase; Body Weight; Carcinogens; Cell Line; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Enzyme Induction; Female; Liver; Organ Size; Oxygenases; Rats; Rats, Inbred Strains

Fischer 344 rats were exposed acutely to 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) during the organogenic period to evaluate its potential as an inducer of teratogenic and embryolethal effects. All dams were treated by gavage with a single dose of 0, 30, 100, or 300 micrograms 4-PeCDF/kg body wt on gestation Day (gd) 8, 10, or 12. An additional treatment group was included on gd 12 and administered 10 micrograms 4-PeCDF/kg body wt po. All animals were killed on gd 20 and maternal and fetal toxicities were assessed. Determination of embryotoxicity involved both soft tissue and skeletal examinations. 4-PeCDF induced a dose-related decrease in corrected maternal weight gain following treatment on gd 8 and 10, as well as resulted in a concomitant increase in the liver/body weight ratios, first evident at 30 micrograms/kg for all 3 days of exposure. The maternal thymus weight decreased relative to body weight compared with those of controls. Embryo-fetal toxicity was evident from the high mortality (greater than 80%) observed at 300 micrograms/kg for all 3 days of exposure. Mean fetal weight, a sensitive indicator of fetal toxicity, decreased compared to that of controls at 30, 100, and 300 micrograms/kg following treatment on either gd 8, 10, or 12.4-PeCDF induced cleft palate in survivors at a dose of 300 micrograms/kg for all 3 days of exposure. In conclusion, 4-PeCDF is maternally and fetally toxic regardless of the gestation day of exposure, but induced terata only at doses where overt maternal and fetal toxicity were observed, in contrast to previously reported studies in the mice where teratogenic effects were observed at nonfetotoxic dose levels. Thus, the mouse may be a more sensitive model for evaluating specific toxic responses induced prenatally following exposure to the structurally related polyhalogenated aromatic hydrocarbons which include the dioxins, furans, biphenyls, and naphthalenes.

Topics: Animals; Benzofurans; Body Weight; Female; Fetus; Gestational Age; Male; Organ Size; Pregnancy; Rats; Rats, Inbred F344; Teratogens

Two isomers of polychlorinated dibenzofurans, 2,3,4,7,8-pentachlorodibenzofuran or 1,2,3,4,7,8-hexachlorodibenzofuran, both of which are present in the yusho patients, were subcutaneously administered to rats in a single non-lethal dose to examine acute or subacute toxicity. Maximal inhibition of increase in body weight and decrease in daily locomotor activity were observed in the rats treated with 370 micrograms/kg of these compounds at 3 to 4 weeks after treatment, especially with 2,3,4,7,8-pentachlorodibenzofuran. Histopathologically, hypertrophy of the liver and atrophy of the thymus were noted at 4 weeks after treatment with this dose, while bile duct hyperplasia in the liver was observed at 40 weeks after treatment with 250 micrograms/kg of these compounds.

Topics: Animals; Benzofurans; Body Weight; Dose-Response Relationship, Drug; Liver; Male; Motor Activity; Rats; Rats, Inbred Strains; Time Factors

Polychlorinated dibenzofurans are ubiquitous environmental pollutants which have great potential for human exposure. To characterize the toxicity of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), male F344 rats were administered a single oral dose of 0, 100, 250, 500, 1000, or 2000 micrograms 4PeCDF/kg. A progressive and dose-dependent loss of body weight was evident by 3 days after treatment. Signs of toxicity included piloerection, hair loss, hypoactivity, morbidity, and death. Death occurred as soon as 14 days after treatment and continued throughout the 35-day observation period. The LD50/35 was estimated to be 916 micrograms/kg with a 95% confidence interval of 565-1484 micrograms/kg. Dose-dependent increases were observed in serum cholesterol, triglyceride, and bile acid concentrations and in sorbitol dehydrogenase and aspartate aminotransferase activities. The hematocrit, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentrations were depressed in a dose-dependent fashion. Hepatic ethoxyresorufin-O-deethylase (EROD) activity was increased in all treatment groups approximately 25 times above that of control animals. Lymphoid depletion in the thymus and spleen was observed in the three highest doses and thymic atrophy was present at all dose levels. Absolute liver weight and the liver:body weight ratio were significantly increased above controls. Hepatotoxicity was dose-dependent and was characterized by lipid accumulation resulting in hepatocytomegaly. Epithelial hyperplasia and focal ulcerations of the forestomach was observed in animals administered 500 micrograms 4PeCDF/kg. Spontaneous cardiomyopathy was exacerbated by treatment with 2000 micrograms/kg. Since 4PeCDF and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produce a similar spectrum of toxic effects, the biochemical mechanism(s) of toxicity for these chemicals may be similar.

Topics: Animals; Benzofurans; Bile Acids and Salts; Body Weight; Cholesterol; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Lethal Dose 50; Liver; Macaca mulatta; Male; Organ Size; Oxidoreductases; Rats; Rats, Inbred F344; Triglycerides

The toxicity and disposition of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), a ubiquitous and acutely toxic environmental contaminant, was examined in three adult male Rhesus monkeys administered a single iv dose of 34 micrograms (0.1 mumol)/kg. Within 20 min, 4PeCDF was eliminated from the blood and was distributed to the liver, skin, adipose, and muscle tissues. Excretion occurred primarily via the feces with a minimum whole body half-life approximately 38 days. Within 7-14 days after administration, the packed cell volume and serum triglyceride and bile acid concentrations were significantly increased while serum cholesterol, protein, and albumin concentrations were decreased relative to pretreatment levels. Thyroid hormone levels were also altered with an increase in TSH and a decrease in T3 and T4 concentrations. After 28 days, two monkeys began exhibiting alopecia, hyperkeratinization of the toe and finger nails, facial chloracne-like lesions, and loss of body weight. They subsequently died 40 and 48 days after treatment. Similar symptoms of toxicity were observed in the third animal 58 days after 4PeCDF administration, but this animal appeared to fully recover and was administered 4PeCDF orally and [3H]1,2,3,7,8-pentachloro-dibenzofuran (1PeCDF) dermally 238 days after the initial iv dose. In this animal, approximately 2% of an oral dose of [14C]-4PeCDF was absorbed from the stomach and small intestine in 6 hr and was distributed mainly to the muscle and skin and less than 99% of a dermal dose of 1PeCDF remained at the site of application. Pathological findings in the monkeys that died indicated hyperplastic and metaplastic changes in the gastric mucosa, the Meibomian glands of the eyelid, and the ceruminous glands of the ear. Regression of these lesions was present in the surviving animal. Therefore, 4PeCDF produces dioxin-like toxicity in the monkey similar to that reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in the same dose range.

Topics: Absorption; Animals; Benzofurans; Body Weight; Carbon Radioisotopes; Environmental Pollutants; Gastric Mucosa; Half-Life; Macaca mulatta; Male; Muscles; Polychlorinated Dibenzodioxins; Thyroid Hormones; Tissue Distribution

The dose-response effects of 2,3,7,8-tetrachorodibenzo-p-dioxin, 1,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,4,7,8-pentachlorodibenzo-p-dioxin, 2,3,4,7,8-, 1,2,3,7,9-, and 2,3,4,7,9-pentachlorodibenzofuran on body weight loss and hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction were determined in the immature male guinea pig. The ED50 values for each compound were measured for the three in vivo responses. The quantitative structure-activity relationships clearly illustrated that the most toxic congeners were substituted in the lateral 2, 3, 7 and 8 positions, and removal of a lateral chlorine group substantially reduced the potency of the resulting compound. The most toxic congener in this series was 2,3,7,8-tetrachlorodibenzo-p-dioxin in which the in vivo ED50 values for AHH and EROD induction and body weight loss were 2.8 X 10(-10), 9.3 X 10(-11) and 5.6 X 10(-9) mol/kg. The structure-activity relationships observed in this study were comparable to those previously reported in rats and rat hepatoma H-4-II E cells in culture. Moreover, there was an excellent linear correlation between in vivo -log ED50 values for body weight loss, AHH and EROD induction and the corresponding in vitro -log EC50 data for AHH induction in rat hepatoma cells [S. Safe, Chemosphere 16, 791 (1987)].

Topics: Animals; Benzofurans; Body Weight; Dioxins; Dose-Response Relationship, Drug; Guinea Pigs; Male; Microsomes, Liver; Polychlorinated Dibenzodioxins; Polymers; Structure-Activity Relationship

The presumption that sensory information does not arise from white adipose tissue was reevaluated using the neuroanatomical tracer, "true blue." Fluorescent cell bodies were observed in dorsal root ganglia of rats after tracer was implanted into inguinal or dorsal subcutaneous fat depots. Sensory information from adipose tissue may play an important role in the regulation of regional and total body fat mass.

Topics: Adipose Tissue; Animals; Benzofurans; Body Weight; Fluorescent Dyes; Male; Nervous System; Rats; Rats, Inbred Strains; Reference Values; Sensory Receptor Cells

Polychlorinated dibenzofurans (PCDFs) are widespread environmental contaminants which have been detected in human tissues and implicated in several poisoning incidents. Their toxic effects are similar to those observed with other related halogenated aromatic hydrocarbons such as TCDD. The teratogenic effects of three PCDFs, 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), were assessed in C57BL/6N mice. Pregnant mice were exposed on Gestation Days 10-13 to 10 ml corn oil/kg containing PCDFs. The dams were killed on Gestation Day 18 and maternal and fetal toxicity were assessed. All three compounds were highly teratogenic, with very steep and parallel dose-response curves for the two diagnostic indicators of dioxin-like teratogenicity, hydronephrosis, and cleft palate. 4-PeCDF was the most teratogenic with an ED50 of 36 micrograms/kg for cleft palate and 7 micrograms/kg for hydronephrosis. 4-PeCDF was approximately 4 times as potent as 1-PeCDF and 10 times as potent as HCDF. The teratogenic responses occurred at a dose below that where any obvious maternal or fetal toxicity was detected. Thus, these three compounds cause teratogenic responses similar to those seen with TCDD but are only 1/10 to 1/100 as potent.

Topics: Abnormalities, Drug-Induced; Animals; Benzofurans; Body Weight; Cleft Palate; Dibenzofurans, Polychlorinated; Dose-Response Relationship, Drug; Female; Hydronephrosis; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy

Polychlorinated dibenzofurans (PCDFs) are highly toxic environmental contaminants which have been involved in several incidents of human poisoning. Two congeners, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF), have been shown to persist in the tissues of victims of accidental ingestion from Japan and Taiwan. The teratogenicity of these compounds, both alone and in combination, was assessed in C57BL/6N mice. Pregnant mice were treated with 10 ml/kg corn oil containing no PCDFs, 4-PeCDF (0-30 micrograms/kg), HCDF (0-300 micrograms/kg), or a combination of the two on gestation Days 10-13, followed by necropsy on gestation Day 18. Maternal and fetal toxicity were assessed and selected soft tissues were examined for abnormalities. Both chemicals caused hydronephrosis and cleft palate in the absence of any overt toxicity. Hydronephrosis occurred at doses approximately fivefold lower than those causing cleft palate. The combination of 4-PeCDF and HCDF was additive for terata based on responses predicted by probit analysis. In addition, the combination of 2,3,4,5,3',4'-hexachlorobiphenyl (0-60 mg/kg), a structurally related compound also present in PCDF poisoning victims, and 4-PeCDF appears additive. Thus, these chemicals, which cause toxic effects similar to those of 2,3,7,8-tetrachlorodibenzo-p-dioxin, are additive in the induction of fetal anomalies in the mouse.

Topics: Animals; Benzofurans; Body Weight; Cleft Palate; Female; Fetal Death; Fetus; Hydronephrosis; Mice; Mice, Inbred C57BL; Polymers; Pregnancy; Structure-Activity Relationship; Teratogens

Rats were treated with amiodarone (20 mg/kg/day) up to 6 weeks and the neurotoxicity was assessed by determining changes in motor coordination, pain-threshold and rectal temperature every week during treatment. Body weight gain was decreased during amiodarone treatment and it was significant at and after 5 weeks. Food intake and water consumption were significantly reduced during treatment. After the first week of treatment with amiodarone, rats showed decreased ability to balance on horizontal rods. In the hot plate test (paw-lick), the amiodarone treated rats showed increased pain-thresholds throughout the treatment. Hypothermia was significant only at 6 weeks. These results show that amiodarone causes toxicity in rats and this model might be useful for further studies. Decreased motor-coordination, and increased pain-responding times may indicate development of peripheral neuropathy in addition to muscle weakness.

Topics: Amiodarone; Animals; Benzofurans; Body Temperature; Body Weight; Drinking Behavior; Feeding Behavior; Male; Motor Skills; Nervous System Diseases; Pain; Rats; Rats, Inbred Strains

The iodine-containing contrast medium iopanoic acid induces alterations of thyroid hormone metabolism comparable to those observed with the iodine-containing antiarrhythmic drug amiodarone. Both compounds inhibit the intracellular conversion of thyroxine (T4) to triiodothyronine (T3). Using iopanoic acid, the question was investigated, in guinea-pigs, whether inhibition of T4----T3 conversion is by itself associated with the same changes in the electrocardiogram, i.e. QT prolongation and bradycardia, as those observed during amiodarone treatment. At a dose of 4 g kg-1, iopanoic acid induced maximal inhibition of the T4----T3 conversion. Although these changes were even more pronounced than those in a control group of animals treated with 2.12 g amiodarone kg-1, neither prolongation of the QT nor a slowing of the heart rate was observed. QT prolongation and bradycardia were induced only by amiodarone treatment but not by iopanoic acid. Iopanoic acid at the high toxic dose of 12 g kg-1 induced the same degree of inhibition of T4----T3 conversion as the 4 g kg-1 dose. QT prolongation and slowing of the heart rate were apparent at this dose in parallel with a loss of weight. It is concluded that even a maximal inhibition of the T4----T3 conversion has no effect on the ECG of guinea-pigs. The inhibition of the T4----T3 conversion alone does not explain the QT prolongation and bradycardia observed with amiodarone treatment. The amiodarone effects on the ECG may represent a combination of interactions with thyroid hormones and antiadrenergic activity.

Topics: Amiodarone; Animals; Benzofurans; Body Weight; Electrocardiography; Guinea Pigs; Heart Rate; Male; Myocardium; Thyroid Hormones; Thyroxine; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

Enhancement of diethylnitrosamine(DENA)-induced hepatic tumor production in rats was observed by sequential exposure to 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) or 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF). This effect was more evident in the group of rats treated with 2,3,4,7,8-PenCDF (80 micrograms/rat), in which approximately 43% of this compound administered was accumulated in the liver at 8 weeks after the last treatment.

Topics: Animals; Benzofurans; Body Weight; Diethylnitrosamine; Liver Neoplasms, Experimental; Male; Polymers; Rats; Rats, Inbred Strains; Thymus Gland

Topics: Animals; Benzofurans; Body Weight; Female; Food Contamination; Isotretinoin; Liver; Macaca fascicularis; Polymers; Squalene; Tretinoin

Fifteen polychlorinated dibenzofuran (PCDF) congeners were administered in a dose-response fashion to immature male Wistar rats and ED50 values for body weight loss, thymic atrophy and the induction of the hepatic microsomal cytochrome P-448-dependent monooxygenases, aryl hydrocarbon hydroxylase (AHH) and 4-chlorobiphenyl hydroxylase were determined. There was an excellent correlation between the in vivo quantitative structure-activity relationships for these PCDFs and their in vitro activities as AHH inducers in rat hepatoma H-4-II E cells and as ligands for the 2,3,7,8-TCDD receptor protein. A comparison of isomers which differ at all 4 positions in the dibenzofuran ring system indicated that chlorine substitution at each position contributed differentially to the overall molecular activity [C-3 (or C-7) greater than C-2 (or C-8) greater than C-4 (or C-6) greater than C-1 (or C-9)]. There was also an excellent linear correlation between a plot of the -log ED50 for body weight loss vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.96) and -log ED50 for thymic atrophy vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.88). Since body weight loss and thymic atrophy in the rat are representative toxic responses to PCDFs and related toxic halogenated aryl hydrocarbons, the correlations noted above support the use of the in vitro AHH induction assay as a short term quantitative test system for this class of toxic halogenated aryl hydrocarbons.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Body Weight; Enzyme Induction; Injections, Intraperitoneal; Isomerism; Male; Microsomes, Liver; Mixed Function Oxygenases; Organ Size; Polychlorinated Biphenyls; Rats; Rats, Inbred Strains; Spleen; Structure-Activity Relationship; Thymus Gland

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) cause the same spectrum of fetal anomalies in C57BL/6N mice. Pregnant dams were treated with TCDD, TCDF and combinations of the 2 compounds on gestation day 10, and examined for maternal and fetal effects on day 18. The fetal kidneys were the most sensitive target for teratogenicity. The dose response for cleft palate induction fit the probit model for both compounds, suggesting that TCDD was approximately 30 times more potent than TCDF. The interaction between these 2 compounds was consistent with a model for additive toxicity.

Topics: Animals; Benzofurans; Body Weight; Cleft Palate; Dioxins; Dose-Response Relationship, Drug; Drug Interactions; Female; Hydronephrosis; Liver; Mice; Mice, Inbred C57BL; Organ Size; Polychlorinated Dibenzodioxins; Pregnancy; Teratogens

Rats of BD X strain and SHR/NIH Montreal Ingelheim strain (genetic hypertension) received a diet containing 3.9% cholesterol or 3.7% cholesterol plus 0.6% benzarone, respectively, and libitum for 5 or 9 months. The following chemical and ultrastructural results were obtained. 1. The cholesterol-benzarone diet causes a body weight reduction of 10%, a relative increase of serum HDL and a corresponding decrease of serum LDL and VLDL, as compared with the effects of the cholesterol diet. No differences of total serum cholesterol and serum triglycerides between the two groups were observed. 2. The aorta of cholesterol fed animals shows a slight but statistically not significant increase of total cholesterol content. 3. No differences in the composition of connective tissue components (collagen, elastin, uronic acid content) between the cholesterol fed animals and a control group on normal diet could be detected. 4. Electron micrographs of several vessel wall areas from cholesterol fed hypertensive animals revealed fibrosis, necrosis of media muscle cells and an increase of matrix vesicles. Severe damages were found in coronary arteries and in the caudal arteries. 5. Cholesterol feeding of hypertensive rats increases the cholesterol content of liver 10fold and the triglycerides content 3fold as compared with liver lipids of control rats. Benzarone application to cholesterol fed rats effects a statistically significant decrease of liver cholesterol and triglycerides.

Topics: Animals; Arteries; Benzbromarone; Benzofurans; Blood Pressure; Body Weight; Cholesterol, Dietary; Fibrinolytic Agents; Lipid Metabolism; Lipids; Male; Rats

The hepatic tumor-promoting activity of a commercial polychlorinated biphenyl mixture, Aroclor 1254 (AR 1254), with and without its intrinsic polychlorinated dibenzofuran (PCDF) impurities, was investigated. Male Sprague-Dawley non-inbred albino rats were treated with 66 microgram diethylnitrosamine (DENA)/ml drinking water for 5 weeks and subsequently given a control diet or a diet supplemented (100 ppm for 18 wk) with either AR 1254 or AR 1254 from which the PCDF moieties were removed (AR 1254-PCDF). Of those animals receiving DENA alone, 16% exhibited hepatocellular carcinomas. Of those rats treated with DENA followed by administration of AR 1254 or AR 1254-PCDF, 64 or 84%, respectively, developed hepatocellular carcinomas. Thus promotion with either AR 1254 or AR 1254-PCDF significantly (P less than 0.05) increased the incidence of DENA-initiated hepatocellular carcinomas. Administration of AR 1254 or AR 1254-PCDF alone did not induce hepatic tumors. Therefore, PCDF impurities were not necessary for the promoting activity of AR 1254.

Topics: Animals; Aroclors; Benzofurans; Body Weight; Carcinogens; Chlorodiphenyl (54% Chlorine); Cocarcinogenesis; Diet; Diethylnitrosamine; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Polychlorinated Biphenyls; Rats

Topics: Adipose Tissue; Administration, Oral; Aging; Animals; Benzofurans; Body Weight; Guinea Pigs; Injections, Intravenous; Liver; Male; Skin; Tissue Distribution

We have examined the effect of dietary protein deficiency on rat hepatic drug-metabolizing enzyme system for a period of two months. Cytochrome P-450 and b5 contents in liver microsomes, which were plotted on semilogarithmic paper as a function of the time of deficiency, showed biphasical reductions during protein deficiency: rapid decreases in the first 3 weeks were followed by more gradual decreases. However, the three enzymatic activities examined, i.e. aminopyrine demethylase, aniline hydroxylase and p-nitroanisole demethylase, were not reduced at a uniform rate. In the earlier phase, activities of the former two enzymes were reduced more rapidly than that of the last phase. This biphasical and non-uniform reduction of enzymatic activities suggests the existence of two or more cytochrome P-450 subspecies in non-depleted male rats. Intraperitoneal administration of well-known environmental pollutants, polychlorinated dibenzofurans and biphenyls (100 micrograms and 100 mg/kg, respectively) to the depleted rats resulted in a marked induction of drug-metabolizing enzymes. However, as the deficiency became more severe (2 months), the induction declined to a considerable degree, especially in the case of polychlorinated biphenyl administration.

Topics: Aminopyrine N-Demethylase; Aniline Hydroxylase; Animals; Benzofurans; Biphenyl Compounds; Body Weight; Cytochrome P-450 Enzyme System; Enzyme Induction; In Vitro Techniques; Male; Microsomes, Liver; Nitroanisole O-Demethylase; Organ Size; Protein Deficiency; Rats

Topics: Animals; Benzofurans; Body Weight; Chlorobenzenes; Dioxins; Drug Contamination; Female; Hexachlorobenzene; Liver; Lung; Mixed Function Oxygenases; Polychlorinated Biphenyls; Porphyrias; Rats

Topics: Animals; Benzofurans; Body Weight; Diet; Male; Organ Size; Polychlorinated Biphenyls; Rats; Time Factors

Topics: Animals; Benzofurans; Body Weight; Female; Lethal Dose 50; Male; Mice; Organ Size; Time Factors

Topics: Animals; Benzofurans; Body Weight; Chlorophenols; Diet; Dioxins; Drug Contamination; Female; Liver; Pentachlorophenol; Pharmaceutical Preparations; Porphyrias; Porphyrins; Rats

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzoates; Benzofurans; Body Weight; Electric Stimulation; Electrocardiography; Female; Growth; Heart; Heart Atria; Heart Rate; In Vitro Techniques; Iodobenzoates; Male; Organ Size; Ouabain; Propylamines; Rabbits; Refractory Period, Electrophysiological; Thiophenes; Time Factors; Ventricular Fibrillation

Topics: Animals; Benzofurans; Body Weight; Butyrates; Cholesterol; Clofibrate; Hypolipidemic Agents; Male; Mice; Mice, Inbred Strains; Rats; Structure-Activity Relationship; Triglycerides

Topics: Aniline Compounds; Animals; Benzofurans; Benzopyrans; Body Weight; Clofibrate; Cytochrome P-450 Enzyme System; Dioxins; Enzyme Induction; Hypolipidemic Agents; Liver; Male; Microsomes, Liver; Mixed Function Oxygenases; Morphinans; Organ Size; Oxidoreductases, N-Demethylating; Pharmaceutical Preparations; Phenobarbital; Proteins; Rats; Structure-Activity Relationship

Topics: Animals; Benzofurans; Bile; Body Weight; Iodine Radioisotopes; Iodipamide; Iodobenzenes; Male; Rats; Sulfobromophthalein; Time Factors

1. Amiodarone (2-butyl, 3-(4-diethylaminoethoxy, 3,5-diiodo, benzoyl) benzofuran hydrochloride), an anti-anginal drug which causes coronary dilatation and depresses myocardial oxygen consumption, was found to protect anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation.2. A 5% (73.4 mM) solution of amiodarone had no local anaesthetic action on guinea-pig skin.3. Amiodarone, 20 mg/kg (29.4 mumol/kg) given daily for 6 weeks intraperitoneally, had no effect on the resting potential or action potential height, and only a small effect on the maximum rate of depolarization, of isolated rabbit atrial or ventricular muscle fibres as shown by intracellular recording. It caused a considerable prolongation of the action potential in both tissues.4. Simultaneous administration of thyroxine (5 mug; 6.26 nmol), given daily for 3 weeks intraperitoneally, prevented the prolongation by amiodarone of the duration of the action potential.5. Treatment of rabbits with 20 mg/kg of amiodarone daily intraperitoneally for 6 weeks had no effect on the weight of the thyroid gland, but was associated with a reduction in body growth rate.6. Treatment of rabbits with 10 mg/kg (60.3 mumol/kg) of potassium iodide (equal in its iodine content to that of 20 mg/kg of amiodarone), given daily for 6 weeks intraperitoneally, had no effect on body growth rate or the duration of cardiac action potentials.7. It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzofurans; Body Weight; Female; Growth; Guinea Pigs; Heart; Heart Rate; Iodine; Male; Myocardium; Organ Size; Ouabain; Oxygen Consumption; Rabbits; Skin; Thyroid Gland; Thyroxine

Topics: Angina Pectoris; Animals; Anticoagulants; Antihypertensive Agents; Benzofurans; Body Weight; Coumarins; Dogs; Drug Synergism; Humans; Prothrombin Time; Vasodilator Agents