Metrifonate increases neuronal excitability in CA1 pyramidal neurons from both young and aging rabbit hippocampus.
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The effects of metrifonate, a second generation cholinesterase inhibitor, were examined on CA1 pyramidal neurons from hippocampal slices of young and aging rabbits using current-clamp, intracellular recording techniques. Bath perfusion of metrifonate (10-200 microM) dose-dependently decreased both postburst afterhyperpolarization (AHP) and spike frequency adaptation (accommodation) in neurons from young and aging rabbits (AHP: p < 0.002, young; p < 0.050, aging; accommodation: p < 0.024, young; p < 0.001, aging). These reductions were mediated by muscarinic cholinergic transmission, because they were blocked by addition of atropine (1 microM) to the perfusate. The effects of chronic metrifonate treatment (12 mg/kg for 3 weeks) on CA1 neurons of aging rabbits were also examined ex vivo. Neurons from aging rabbits chronically treated with metrifonate had significantly reduced spike frequency accommodation, compared with vehicle-treated rabbits. Chronic metrifonate treatment did not result in a desensitization to metrifonate ex vivo, because bath perfusion of metrifonate (50 microM) significantly decreased the AHP and accommodation in neurons from both chronically metrifonate- and vehicle-treated aging rabbits. We propose that the facilitating effect of chronic metrifonate treatment on acquisition of hippocampus-dependent tasks such as trace eyeblink conditioning by aging subjects may be caused by this increased excitability of CA1 pyramidal neurons. (+info)
Behavioral changes and cholinesterase activity of rats acutely treated with propoxur.
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Early assessment of neurological and behavioral effects is extremely valuable for early identification of intoxications because preventive measures can be taken against more severe or chronic toxic consequences. The time course of the effects of an oral dose of the anticholinesterase agent propoxur (8.3 mg/kg) was determined on behaviors displayed in the open-field and during an active avoidance task by rats and on blood and brain cholinesterase activity. Maximum inhibition of blood cholinesterase was observed within 30 min after administration of propoxur. The half-life of enzyme-activity recovery was estimated to be 208.6 min. Peak brain cholinesterase inhibition was also detected between 5 and 30 min of the pesticide administration, but the half-life for enzyme activity recovery was much shorter, in the range of 85 min. Within this same time interval of the enzyme effects, diminished motor and exploratory activities and decreased performance of animals in the active avoidance task were observed. Likewise, behavioral normalization after propoxur followed a time frame similar to that of brain cholinesterase. These data indicate that behavioral changes that occur during intoxication with low oral doses of propoxur may be dissociated from signs characteristic of cholinergic over-stimulation but accompany brain cholinesterase activity inhibition. (+info)
Human-serum cholinesterase subunits and number of active sites of the major component.
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The major C4 component of human serum cholinesterase was highly purified by a two-step procedure involving chromatography on DEAE-cellulose and preparative disc electrophoresis. The final product was about 8 000-fold purified with a yield of 64%. The subunit structure was determined by 8M urea polyacrylamide disc electrophoresis and by the sedimentation equilibrium centrifugation method in 5M guanidine hydrochloride. It was found that the C4 enzyme has a tetrameric structure. The subunits are equal in size and charge and a molecular weight comparable to that of the C1 enzyme from native serum. The major C4 enzyme and the minor C1 enzyme were subjected to an 'active enzyme centrifugation'. It was found that the C4 enzyme was a tetramer and the C1 enzyme was a monomer in the presence of substrate. The number of diisopropylphosphofluoridate-binding sites was measured from the molar ratio of bound diisopropylphosphate to protein. A value close to two binding sites was found for the C4 enzyme. (+info)
Atypical serum cholinesterase in a family with congenital distichiasis.
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This paper describes the coexistence of genetically determined reduced cholinesterase activity and congenital distichiasis in the same family. The pedigree suggests that these two autosomal dominant diseases are segregated independently and do not show evidence of linkage. (+info)
Oral and dermal absorption of chlorpyrifos: a human volunteer study.
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OBJECTIVES: To determine the kinetics of elimination of urinary dialkylphosphate metabolites after oral and dermally applied doses of the organophosphate pesticide chlorpyrifos to human volunteers and to determine whether these doses affected plasma and erythrocyte cholinesterase activity. METHOD: Five volunteers ingested 1 mg (2852 nmol) of chlorpyrifos. Blood samples were taken over 24 hours and total void volumes of urine were collected over 100 hours. Four weeks later 28.59 mg (81567 nmol) of chlorpyrifos was administered dermally to each volunteer for 8 hours. Unabsorbed chlorpyrifos was washed from the skin and retained for subsequent measurement. The same blood and urine sampling regime was followed as for the oral administration. Plasma and erythrocyte cholinesterase concentrations were determined for each blood sample. The concentration of two urinary metabolites of chlorpyrifos--diethylphosphate and diethyl-thiophosphate--was determined for each urine sample. RESULTS: The apparent elimination half life of urinary dialkylphosphates after the oral dose was 15.5 hours and after the dermal dose it was 30 hours. Most of the oral dose (mean (range) 93% (55-115%)) and 1% of the applied dermal dose was recovered as urinary metabolites. About half (53%) of the dermal dose was recovered from the skin surface. The absorption rate through the skin, as measured by urinary metabolites was 456 ng/cm2/h. Blood plasma and erythrocyte cholinesterase activity did not fall significantly during either dosing regime. CONCLUSION: An oral dose of chlorpyrifos was readily absorbed through the skin and almost all of the dose was recovered as urinary dialkylphosphate metabolites. Excretion was delayed compared with the oral dose. Only a small proportion of the applied dose was recovered during the course of the experiment. The best time to collect urine samples for biological monitoring after dermal exposure is before the shift the next day. The amounts of chlorpyrifos used did not depress acetyl cholinesterase activity but could be readily detected as urinary dialkylphosphate metabolites indicating that the urinary assay is a more sensitive indicator of exposure. (+info)
Impaired respiratory muscle function in chemical plant workers producing chlorfenvinphos.
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All employees of a chemical plant division producing chlorfenvinphos were studied, i.e. 35 males aged 25-57 years (mean 42.1); their employment period ranged from 1-15 years (mean 9.0). Chronic bronchitis was diagnosed in 13 workers (37.1%). Mean air chlorfenvinphos concentrations in the work environment estimated with gas-liquid chromatography were from 0.0008-0.0018 mg/m3 (maximum allowable concentration according to Polish standards is 0. 01 mg/m3). The activity of erythrocyte acetylcholinesterase was similar to that observed in people who were not exposed to chemicals, however, a slightly lowered activity of plasma cholinesterase in the studied population was evidently the result of mild liver impairment. Spirometric investigations performed in the studied workers revealed slight alterations manifested by increased intrathoracic gas volume (ITGV) (the value of the index was 138.6% of the mean value, 24 workers with an abnormally high index), as well as by decreased specific airway conductance (sGaw); its mean value in the studied group was 58.5% of the mean standard (11 people showed an abnormal index). Substantial functional changes were found in the respiratory muscles. Maximal inspiratory pressures (MIP = 97. 2 +/- 28.3 cm H2O) as well as maximal expiratory pressures (MEP = 113.9 +/- 44.2 cm H2O) in the studied group were significantly lower (p < 0.01) as compared to those observed in the control group (MIP = 120.7 +/- 31.7; MEP = 154.4 +/- 40.2 cm H2O) of 22 males having similar cigarette smoking habit, without occupational exposure to chemicals. It was also found that the people who had worked for more than 10 years under conditions of exposure to chlorfenvinphos showed significantly lower (p < 0.05) values of maximal inspiratory pressure (87.2 +/- 28.06 cm H2O, n = 17) compared to the workers whose period of employment was shorter than 10 years (106.6 +/- 26.8 cm H2O, n = 18). The two groups were comparable with regard to age and smoking habits. The values of maximal expiratory pressures were similar in both groups. No essential disturbances in neuro-muscular transmission were observed; only in 3 workers (8.5%) the electrostimulating myasthenic test showed some disturbances in neuro-muscular transmission. It seems that respiratory muscles impairment in humans exposed to chlorfenvinphos results from changes in the metabolism and structure of muscles, and partly from lung hyperinflation. (+info)
Hepatosplenic morbidity in schistosomiasis japonica: evaluation with Doppler sonography.
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In Southeast Asia, schistosomiasis japonica is an important cause of hepatic fibrosis and gastrointestinal hemorrhage. Reliable methods to investigate portal hypertension (PHT) clinically and epidemiologically on community level are lacking. Doppler sonography is an established tool for investigating PHT in hospital settings. In Leyte, The Philippines, 137 individuals underwent color Doppler sonography, stool examination, and serology for hepatitis B and C, liver cell injury and cholestasis. A total of 85% of the study population had been infected with Schistosoma japonicum. Sonographically, periportal liver fibrosis was seen in 25% and reticular echogenicities (network pattern) in 44%. Portal blood flow was decreased or portosystemic collaterals were present in 10% (adults throughout) and correlated with periportal fibrosis, but not with network lesions. Chronic viral hepatitis was rare. Thus, hepatic lesions are frequent in adults but not in children in areas endemic for S. japonicum. Periportal liver fibrosis indicates a risk of PHT, and network pattern fibrosis apparently does not. Doppler sonography is suitable for research under tropical field conditions. (+info)
Influence of metoclopramide on plasma cholinesterase and duration of action of mivacurium.
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Mivacurium is metabolized by plasma cholinesterase (PCHE). Metoclopramide inhibits PCHE in vitro and in vivo. We have assessed the effect of metoclopramide on duration of action of mivacurium and measured PCHE at baseline and at the time of maximal block. In a randomized, double-blind study, 30 patients received metoclopramide 0.15 mg kg-1 i.v. or saline, followed by propofol anaesthesia and mivacurium 0.15 mg kg-1. Using a TOF-Guard accelerometer, times to recovery of TI to 25%, 75% and 90% were 13.4, 19.3 and 21.9 min in the saline group and 17.8, 25.3 and 28.8 min in the metoclopramide group (P < 0.01, P < 0.05, P < 0.05, respectively). There were no differences in onset time or recovery index between the groups. PCHE activity at the time of maximum block decreased within each group (P < 0.01) but there was no difference between groups. In a second biochemical study of eight patients, a small decrease in PCHE activity was detected after metoclopramide 0.15 mg kg-1, but before administration of mivacurium (P < 0.025). We conclude that metoclopramide prolongs the duration of action of mivacurium. (+info)