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31.
POTOKAR JOHN; COUPLAND NICK; GLUE PAUL; GROVES SIMON; MALIZIA ANDREA; BAILEY JAYNE; WILSON SUE; NUTT DAVID 《Alcohol and alcoholism (Oxford, Oxfordshire)》1997,32(5):605-611
The purpose of the present study was to study -aminobutyricacid (GABA)-A receptor function in alcohol-dependent subjectsduring withdrawal, using the benzodiazepine antagonist flumazenil.In particular, we wanted to examine the hypotheses that an endogenousinverse agonist ligand at the GABA-A benzodiazepine receptor(GBzR) is active during withdrawal (in which case flumazenilshould be anxiolytic), or whether chronic alcohol intake resultsin a shift in sensitivity of the receptor in the inverse agonistdirection (in which case flumazenil should be anxiogenic). Resultsfrom 15 alcohol-dependent subjects in a double-blind placebo-controlledcross-over study showed that flumazenil was neither anxiolyticnor anxiogenic, although withdrawal scores were reduced duringthe course of the study. The fact that flumazenil was not anxiogenic,as it is in panic disorder, suggests that the GBzR is functioningdifferently in these two clinically similar conditions. 相似文献
32.
The Relationship Between Choice of Outcome Measure and Hospital Rank in General Surgical Procedures: Implications for Quality Assessment 总被引:3,自引:0,他引:3
33.
NEWTON PAUL E.; BOLTE HENRY F.; DALY IRA W.; PILLSBURY BRIAN D.; TERRJLL JAMES B.; DREW ROBERT T.; BEN-DYKE ROGER; SHELDON ARTHUR W.; RUBIN LIONEL F. 《Toxicological sciences》1994,22(4):561-576
Fischer 344 rats were exposed by inhalation to Sb2O3 (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m3 for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m3 for 12 months followed by a 12-month observationperiod. The Sb2O3 in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb2O3 ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m3 males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb2O3 effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m3 groups inthe subchronic study. The 23.46 mg/m3 group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb2O3 from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m3group in the chronic study. The previously reported studies,which found Sb2O3 to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb2O3 was not a carcinogen. 相似文献
34.
BEERENDONK GEERTJE J. M. VAN; PEARSON PAUL G.; MEIJER DIRK K. F.; MULDER GERARD J.; NELSON SIDNEY D.; MEERMAN JOHN H. N. 《Toxicological sciences》1995,28(1):111-117
The metabolism of tris(2,3-dibromopropyl) phosphate (Tris-BP)was compared with that of completely deuterated Tris-BP (D15-Tris-BP)in an isolated, recirculating rat liver perfusion system inorder to determine the relative quantitative importance of twodifferent biotransformation pathways of Tris-BP: (i) cytochromeP450-mediated metabolism and (ii) GSH S-transferase-mediatedmetabolism. To accomplish this we quantitated the biliary excretionof S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolitefor cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl)glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediatedmetabolism. Completedeuterium substitution of Tris-BP significantlydecreased the formation of GSOH, whereas there was no effecton the formation of GSOHOH. Because our previous studies showeda large decrease in genotoxicity of D15-Tris-BP compared toTris-BP, the present results support our hypothesis that cytochromeP450-mediated metabolism is responsible for the genotoxic effectsof Tris BP in the rat liver. 相似文献
35.
SZAREK JOHN L.; STEWART NANCY L.; ZHANG JASON Z.; WEBB JEFFREY A.; VALENTOVIC MONICA A.; CATALANO PAUL 《Toxicological sciences》1995,28(2):199-208
Short-term exposure to high concentrations of ozone has beenshown to increase airway responsiveness in normal humans andin all laboratory animal species studied to date. While ourknowledge concerning the pulmonary effects of single exposuresto ozone has increased rapidly over recent years, the effectsof repeated exposures are less understood. The goal of the presentstudy was to determine whether airway responsiveness is increasedafter near-lifetime exposure to ozone. Airway segments representingapproximately eighth generation airways were isolated from Fischer344 rats of both genders that had been exposed for 6 hr perday, 5 days per week for 20 months to 0, 0.12, 0.5, or 1.0 partsper million (ppm) ozone. Circtimferential tension developmentwas measured in isolated airways in response to bethanechol,acetylcholine, and electrical field stimulation. Responsivenessof the airways to the contractile stimuli was described by theeffective dose or frequency that elicited half-maximum contraction(ED50) and the maximum response. Since ozone exposure is associatedwith remodeling of peripheral airways, smooth muscle area wasdetermined and tension responses were normalized to the areameasurements. Before normalization of tension data to smoothmuscle area, neither the ED50 nor maximum response of smallbronchi to the contractile stimuli was altered after chronicozone exposure. Smooth muscle area was greater in airways isolatedfrom animals that had been exposed to 0.5 ppm ozone. After accountingfor smooth muscle area, maximum responses of the small bronchiisolated from male rats were significantly reduced after 0.12and 0.5 ppm ozone. Although not significant statistically, asimilar trend was observed in airways isolated from female rats.These results suggest that the increase in airway responsivenessassociated with acute ozone exposure does not persist duringnear-lifetime exposure. Although the mechanism responsible forthe adaptation to the effects of 03 on airway responsivenessis unknown, the results indicate that smooth muscle cell functionwas compromised by the chronic exposure. The mechanism(s) responsiblefor mediating this effect and the relevance of these resultsto humans remains to be determined. 相似文献
36.
COLLINS MICHAEL A.; RUSCH GEORGE M.; SATO FUMIAKI; HEXT PAUL M.; MILLISCHER RENE-JEAN 《Toxicological sciences》1995,25(2):271-280
Subchronic and chronic studies were carried out in the rat anda developmental toxicity study in the rabbit with exposuresto 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In therat repeated exposure to 50,000 ppm HFC 134a for 13,52, and104 weeks elicited no effect on clinical condition, growth,and survival, or on a variety of hematological, clinical chemistry,and urinary parameters. Treatment-related pathological changeswere seen only at study termination at 2 years and were confinedto increased incidence of Leydig cell hyperplasia and adenomain male rats exposed to 50,000 ppm. The tumors, which were alsoseen in control animals, were benign and not life-threatening.A battery of in vitro and in vivo tests gave no evidence ofgenotoxic activity. With exposure to pregnant rabbits, the onlytreatment-related effects were of minimal maternal toxicityat high exposure concentrations; there were no effects on fetaldevelopment. It is concluded that HFC 134a is of very low toxicityand should be an acceptable alternative to CFCs. 相似文献
37.
38.
KEYLER DANIEL E.; SALERNO DAVID M.; MURAKAMI MARYANN M.; RUTH GEORGE; PENTEL PAUL R. 《Toxicological sciences》1991,17(1):83-91
Rapid Administration of High-Dose Human Antibody Fab Fragmentsto Dogs: Pharmacokinetics and Toxicity. Keyler, D. E., Salerno,D. M., Murakami, M. M., Ruth, G., and Pentel, P. R. (1991).Fundam. Appl Toxicol 17, 83-91. The treatment of drug overdosewith drug-specific antibody fragments may require very highantibody doses. To address the feasibility of this therapy,we studied the pharmacokinetics and toxicity of high-dose humannonspecific Fab fragments in beagles. Three dogs received 5.3g/kg Fab iv over 1 hr. Because nephrotoxicity was observed,three subsequent dogs received 3.2 g/kg. The fraction of theFab dose excreted in urine (10 ± 6%%) was lower thanreported values for either high or low doses of Fab in otherspecies. The terminal serum elimination half-life (42 hr forthe higher and 48 hr for the lower dose) was also longer thanreported values for other species, due to lower renal and nonrenalFab clearance. Fab administration was tolerated without adversehemodynamic effects. One of three dogs at each dose developedtransient oliguria. All dogs developed a transient but markedincrease in the serum creatinine concentration. At 2 weeks creatinineclearance had returned to normal. Urinary protein and albuminexcretion at 2 weeks were within the normal range for dogs butwere increased over their baseline values. The histology ofall organs was normal at 3 weeks by light microscopy, and renalhistology by electron microscopy was also normal. The mechanismof Fab nephrotoxicity, not observed previously with high-doseFab in rats or lower doses of Fab in other species includingdogs, is not clear. These data suggest that further study ofthe potential toxicity of high-dose Fab, and its reversibility,is needed to assess the feasibility of treating drug overdosewith this antibody fragment The long terminal half-life of high-doseFab in the dog and its low renal clearance contrast with valuesobserved with lower doses of Fab in other species but wouldnot be expected to preclude the use of high-dose Fab for drugoverdose. 相似文献
39.
The Disposition of Coal Dusts in the Lungs and TracheobronchialLymph Nodes of Dogs. Morrow, P.E. and Yuile, C.L. (1982). Fundam.Appl. Toxicol. 2:300305. The pulmonary disposition, histopathologyand lymphatic uptake of anthracite (Tamaqua) and bituminous(Lower Kittaning) coal dusts were measured as part of a pulmonaryretention study which revealed a mean half-time of 1.92 yearsin dogs (Morrow et al. 1981). After brief (1-2.5 hr) exposuresto either natural or neutron-activated coals having an averageairborne mass concentration of {small tilde}90 mg m3and a 1.8 µm mass median aerodynamic diameter (g 2.5),dogs (n=12) were serially sacrificed up to 52 weeks after exposure.Coal dusts were found only in the lungs and pulmonary lymphnodes. The coals were considered indistinguishable as to theirpulmonary clearance and disposition and lymphatic uptake. Allcoals in the lung were associated mainly with the peribronchiolarand perivascular lymphatics or connective tissue spaces, andsome were found in alveolar macrophages. The lymphatic uptakeof coal dusts followed the powder function 0.55 t0.613 wheret is in weeks and uptake is expressed as percent of the initialalveolar burden. In terms of pulmonary dust clearance, only4 percent of the initial alveolar burden appeared to have beentranslocated to the tracheobronchial lymph nodes in the first50 weeks, but this constituted {small tilde}14 percent of thetotal alveolar clearance. Histopathologically, one distinctionwas found: animals exposed to the highest level of neutron-activatedanthracite showed patchy hyaline thickening of some small bloodvessels and alveolar septa. The response was low grade, probablyexposure-related, but otherwise unremarkable. 相似文献
40.
ELOI MARIJON M.D. Ph.D. SAMIA FAZAA M.D. KUMAR NARAYANAN M.D. BENOIT GUY‐MOYAT M.D. ABDESLAM BOUZEMAN M.D. RUI PROVIDENCIA M.D. M.S. FREDERIC TREGUER M.D. M.S. NICOLAS COMBES M.D. M.S. AGUSTIN BORTONE M.D. SERGE BOVEDA M.D. STEPHANE COMBES M.D. M.S. JEAN‐PAUL ALBENQUE M.D. 《Journal of cardiovascular electrophysiology》2014,25(2):130-137