摘要:

AbstractThis study evaluatedlevo‐alpha‐noracetylmethadol (NorLAAM), the firstN‐demethylated metabolite oflevo‐alpha‐acetylmethadol (LAAM), a long‐acting morphine‐like (μ) agonist, approved in 1993 to treat opiate dependence. After acute and 7‐day pilot studies to define dose levels appropriate for use in longer term evaluations, Sprague‐Dawley rats (20 of each sex per group) were gavaged with doses of 4.4–25.9 mg kg−1day−1for 30 days followed by a 14‐day recovery period. Treatment‐related effects included dose‐dependent CNS depression paralleled by changes in food consumption, body weight gain and fecal output, as well as reddish urine and abdominal staining. Tolerance developed by day 7. The spectrum of activity observed differed from the parent compound primarily in its time course. Cage‐biting and gnawing behavior were observed only with NorLAAM. Mortality was dose‐dependent, with deaths occurring predominantly during the first week. At day 30, all male‐treated groups exhibited statistically significant, dose‐dependent decreases in body weight gain and increases in serum cholesterol that returned to the control range following recovery. Increases in brain/body weight and testes/body weight ratios and decreases in kidney/brain, liver/brain, spleen/brain and heart/brain ratios, as well as decreases in kidney, liver, spleen and heart absolute weights, achieved statistical significance only for males. At terminal sacrifice, histological findings in the kidneys included increased incidences of tubular mineral deposition in mid‐ and high‐dose groups of both sexes and of corticomedullary mineral deposition in females. Hepatic centrilobular hypertrophy was evident in male and female mid‐ and high‐dose groups. Histopathological changes abated following the recovery period. In summary, acute and repeated administration of NorLAAM produced a pharmacodynamic profile commensurate with its role as the primaryN‐demethylated metabolite of LAAM, which is more potent and less lipophilic than the parent compound; this was reflected in the toxicological outcomes observed. Like LAAM, NorLAAM's overall pattern of activity is consistent with its activity as a μ‐agonist, whi

ISSN:0260-437X    

DOI:10.1002/jat.2550150503

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractCarbon monoxide (CO) and hydrogen cyanide (HCN) are generated during aircraft interior fires in sufficient amounts to incapacitate cabin occupants. For typical post‐crash and in‐flight fires, minimum protection periods of 5 and 35 min, respectively, have been suggested for breathing devices to protect the occupants from smoke. Relationships of blood carboxyhemoglobin (COHb) and cyanide (CN−) levels to incapacitation have not been well defined for these gases. Therefore, time to incapacitation (ti) and blood COHb and CN−at incapacitation were examined in rats exposed to CO (5706 ppm for 5‐minti; 1902 ppm for 35‐minti), HCN (184 ppm for 5‐minti; 64 ppm for 35‐minti) and their mixtures (equipotent concentrations of each gas that produced 5‐ and 35‐minti). Blood CO and HCN uptakes were evaluated at the two concentrations of each gas. With either gas, variation intiwas higher for the 35‐mintithan the 5‐minti. The COHb level reached a plateau prior to incapacitation at both CO concentrations, and COHb levels at the 5‐ and 35‐mintiwere different from each other. Blood CN−increased as a function of both HCN concentration and exposure time, but CN−at the 5‐mintiwas half of the 35‐mintiCN−level. The HCN uptake at the high concentration was about three times that at the low concentration. In the high concentration CO–HCN mixture,tiwas shortened from 5 to 2.6 min; COHb dropped from 81 to 55% and blood CN−from 2.3 to 1.1 μg ml−1. At the low‐concentration CO–HCN mixture, wheretiwas reduced from 35 to 11.1 min, COHb decreased from 71 to 61% and blood CN−from 4.2 to 1.1 μg ml−1. Any alteration in the uptake of either gas by the presence of the other was minimal. Our findings suggest that specific levels of blood COHb and CN−cannot be correlated directly with the incapacitation onset and that post‐mortem blood COHb an

ISSN:0260-437X    

DOI:10.1002/jat.2550150504

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractA convenientin vitrobioassay based on semiautomated quantification of live‐cell reduction of tetrazolium dyes ‐ 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MIT) and 2,3‐bis(2‐methoxy‐4‐nitro‐5‐sulphophenyl)‐2H‐tetrazolium‐5‐corboxanilide sodium salt (XTT) – to formazan was developed and used to evaluate cytotoxic effects of two commercial insecticides (BT) derived fromBacillus thuringiensissubsp.kurstaki (Btk). Comparison of two target insect cell lines MGI (Trichoplusia ni, cabbage looper midgut) andSf9(Spodoptera frugiperda, fall army worm oocyte) revealed similar cell‐dependent responses in mitochondrial‐associated electron transport activity. The 50% inhibition of formazan production (ID50) obtained by exposing these cells to 20 μM 2,4‐dinitrophenol or 5 mM sodium azide occurred in the range 10−7–10−6International Units (IU) of BT cell−124 h−1. Damage to cell adhesion and cytoarchitecture, revealed by light and electron microscopic analysis, increased with BT exposure and dose. MTT was superior to XTT as a cytotoxic indicator in kinetic studies related to spores, a major component of BT. Unless blocked by antibiotic (gentamicin), vegetative growth resulting from spore germination was the major cause of toxicity. The ID50exposure time using vegetativeBtkcells was ∼0.1–0.2 times that required for BT spores, with or without intact parasporal proteins present. This difference in exposure is an indirect measure of the time required for spores to germinate and produce vegetative cells. The assay methodology developed here, if linked with suitable target and non‐target animal cell types, should have broad application for conducting standardizable estimates of cy

ISSN:0260-437X    

DOI:10.1002/jat.2550150505

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe effect of short‐term occupational exposure to lead on erythrocyte glucose‐6‐phosphate dehydrogenase (G6PD) activity and serum cholesterol was studied in 40 male workers of a lead and zinc foundry. All parameters were measured just before employment and after 172 ± 21.3 days of work. Genetic deficiency of erythrocyte G6PD was observed in 5/40 subjects. Among G6PD normal subjects, increases in enzyme activity followed any change (increase or decrease) in blood lead. At the pre‐employment test, serum cholesterol parameters did not show any correlation with G6PD activity or blood lead, and they were not affected by exposure. Cholesterol values observed among all the G6PD‐deficient subjects were within the range of the rest of the study

ISSN:0260-437X    

DOI:10.1002/jat.2550150506

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThis study reports changes in levels of ferritin, haemoglobin and transferrin in the bone marrow, liver and spleen as an attempt to determine the causes of testicular iron depletion. A single oral dose of di‐n‐butyl phthalate (DBP) to male rats caused a sloughing of the germ cells (at 6 h) prior to testicular atrophy. Before the sloughing it was observed that DBP induced decreases both in the iron levels in the blood, bone marrow and testis and in haemoglobin (Hb) levels in the blood, bone marrow and spleen. Decrease in transferrin (Tf) levels was observed in the liver. Significant increases in ferritin and haemosiderin (Hs) levels were observed in the spleen and in the liver and spleen, respectively.In vitrostudies where mono‐n‐butyl phthalate (MBP) was incubated with liver homogenates, MBP caused both the decreases in Hb and Tf‐bound iron levels and increases in Hs and Hs–iron levels.The present study proposes that the mechanism of testicular atrophy by DBP might be associated with both the iron release from Hb and/or Tf in the liver and spleen and the subsequent depletion of iron in the blood

ISSN:0260-437X    

DOI:10.1002/jat.2550150507

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractRecently there has been growing interest in magnesium deficiency and its correlation with coronary artery disease, chronic complications of diabetes mellitus and antioxidant enzyme activity. Hypomagnesemia is a common association of diabetes mellitus, and the blood glutathione (GSH) level is significantly lower in both conditions. Metformin (Met), ‘an oral antihyperglycemic drug’ frequently used in the management of diabetes mellitus outside the USA, has been shown to have an insulin‐like action. The purpose of this study was to investigate the effect of oral administration of Met (60 mg kg−1) for 14 days on GSH and magnesium levels in blood, liver and heart of normal and streptozotocin‐induced diabetic Wistar rats. Diabetes was induced by an i.p. injection of streptozotocin (60 mg kg−1). Our results showed that Met did not affect fasting serum glucose concentration in non‐diabetic animals but reduced it significantly in diabetic animals. Serum and liver magnesium levels were significantly decreased in the untreated diabetic group compared with the normal group. Treatment with Met improved liver magnesium concentration in the diabetic group only. It has no effect on serum magnesium in diabetic or non‐diabetic rats. Heart magnesium levels showed non‐significant changes in all groups. In diabetic animals a significant decrease of GSH in both blood and liver was observed. Treatment with Met increased these levels significantly, with a similar effect on GSH levels in non‐diabetic rats. There were no significant changes in heart GSH levels in any of the groups. This study demonstrates that oral Met therapy improves the altered levels of magnesium and G

ISSN:0260-437X    

DOI:10.1002/jat.2550150508

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractEffects of copper were studied in freshwater adapted rainbow trout using the perfused head preparation. In its monovalent chemical form, copper at millimolar concentrations had no significant effects on Na+and water transport. By contrast, the divalent form produced an increase in gill perfusion pressure, a significant reduction in Na+influx and water fluxes and reversed Na+net flux. Observations by light microscopy showed important cell damage (oedema, mucus production, cellular desquamation). By electron microscopy there was smoothing of apical membranes, swelling of the tubular system and destruction of mitochondria. The Na, K‐ATPase activity was totally suppressed and residual ATPase activity largely inhibited by 1 mM Cu2+. There was inhibition of the Na, K‐ATPase activity with an IC50of ± 10 μM of total copper (free and bound cupric fractions). As active sodium transport is located on the secondary lamellae, our results show that its entry mechanism is inhibited at that level by cupric ions only. Results are discussed in relation to hydromineral balance of the

ISSN:0260-437X    

DOI:10.1002/jat.2550150509

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractRenal proximal tubule cell injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. We investigated the effect of this medication on kidney function in rats. Animals received either 40 or 80 mg kg−1ifosfamide intraperitoneally daily for 3 days every 3 weeks for a total of four treatment courses. Ifosfamide‐treated rats had significantly lower body weight and hematocrit than sterile water‐treated control rats. Animals receiving 40 mg kg−1ifosfamide developed isolated phosphaturia after their fourth and final treatment course. Rats receiving 80 mg kg−1ifosfamide had low‐grade glucosuria, phosphaturia and proteinuria throughout the study. Urine flow rate, creatinine clearance, urinary sodium and potassium excretion and kidney glutathione and malondialdehyde content were not affected by ifosfamide at either dose. These findings indicate that ifosfamide produces abnormalities in rat renal function resembling subclinical Fanco

ISSN:0260-437X    

DOI:10.1002/jat.2550150510

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractWe have studied the effects of the benzene metabolites hydroquinone,p‐benzoquinone or 1,2,4‐benzenetriol on cytotoxicity, active oxygen formation, hydrogen peroxide (i.e. hydroperoxide) production and nitric oxide formation in HL‐60 cells. We also examined the effects of these compounds on antioxidant enzymes and intracellular antioxidants in these cells. The cytotoxicity of benzene metabolites to HL‐60 cells was found to be of the order ofp‐benzoquinone>hydroquinone>benzenetriol. No appreciable changes in the basal levels of either superoxide anion production or nitric oxide formation were observed following exposures to the benzene metabolites, but significant increases in superoxide were seen on stimulation with TPA for each metabolite, whereas hydroquinone andp‐benzoquinone, but not 1,2,4‐benzenetriol, increased nitric oxide production under these conditions. Following exposure to the benzene metabolites, HL‐60 cells showed significant rises in hydrogen peroxide formation compared to controls. The study of antioxidant enzymes and intracellular antioxidants suggested that the benzene metabolites inhibit or reduce the levels of different antioxidant mechanisms and, thereby, cause the accumulation of free radicals in these cells predisposing them for o

ISSN:0260-437X    

DOI:10.1002/jat.2550150511

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe effect of dosing vehicle on toxicity and metabolism of unsaturated aliphatic nitriles was investigated in male Sprague–Dawley rats. Five unsaturated aliphatic nitriles—acrylonitrile, methacrylonitrile, allylnitrile, crotononitrile and fumaronitrile—were prepared in five different dosing vehicles—saline, corn oil, safflower oil, mineral oil, olive oil and Tween‐20. Groups of six male rats were given 0.5 LD50doses of the nitriles by gavage and they were observed for 12 h for cholinomimetic and central nervous system effects. Cyanide and glutathione levels were determined in blood and various organs at 1, 3 and 6 h after nitrile administration and thiocyanate levels were determined at 6 h after nitrite administration. The results indicate that all the vehicles studied potentiated the toxicity of all the nitriles compared to nitriles administered in saline and significantly increased their metabolism to cyanide and thiocyanate and nitrile‐induced depletion of glutathione in rats. This behavior of vehicles illustrates the difficulty of identifying suitable vehicles for administration of lipophilic compounds in toxicol

ISSN:0260-437X    

DOI:10.1002/jat.2550150512

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY