NEUROTOXICOLOGY

Abstract

Obidoxime is an oxime used in several countries as an antidote in organophosphate intoxication. Its pharmacokinetics were studied in a 20 year-old female with severe and complicated methamidophos intoxication. Obidoxime elimination half life was 6.9?h, volume of distribution 0.845 L/kg, total body clearance 85.4 mL/min, and renal clearance 69 mL/min (creatinine clearance 54 mL/min). Eighty percent of the dose was excreted in the urine over 5?h. Possible reasons for the different pharmacokinetic values as compared with values previously reported in healthy volunteers are discussed. Obidoxime dose should be adjusted according to renal function. More studies are needed to establish the therapeutic window of obidoxime in patients with organophosphate intoxication.     

Molecular characterization of a gene encoding juvenile hormone esterase in the red flour beetle,Tribolium castaneum

Juvenile hormone esterases (JHEs) are required for the degradation of juvenile hormones (JHs) in insects. Here, we report the cloning and analysis of the jhe gene in the red flour beetle, Tribolium castaneum, a model insect of Coleoptera. The Tcjhe gene was strongly expressed at the final instar larva, as would be expected if it functioned to decrease the JH titer at this stage. A recombinant TcJHE protein efficiently degraded JH III, suggesting that the enzyme functions in vivo as a JH‐specific degradation enzyme. This is the first report describing the developmental expression profile of the jhe gene whose enzymatic activity was shown in Coleoptera, and the new data reported here will aid elucidation of the mechanism of JH titer regulation in insects.     

Self reported symptoms and inhibition of acetylcholinesterase activity among Kenyan agricultural workers

OBJECTIVES—This study was part of the East African pesticides project. The general objective was to assess health hazards posed by handling, storage, and use of pesticides, on agricultural estates and small farms with a view to developing strategies for prevention and control of pesticide poisoning. The aim of this paper is to describe the prevalence of symptoms in this population, to relate levels of inhibition to reported symptoms and evaluate at which levels of inhibition symptoms become increased.
METHODS—Complete data were available for 256 exposed subjects and 152 controls from four regions in Kenya. A structured questionnaire on symptoms experienced at the time of interview was given to all subjects and controls. Information was also obtained on sex, age, main occupation, and level of education. Symptoms reported during the high exposure period, were initially clustered in broader symptom categories from reference literature on health effects of pesticides that inhibit cholinesterase (organophosphate and carbamate). Prevalence ratios were estimated for symptoms with changes in cholinesterase activity in serum.
RESULTS—Symptom prevalence in exposed subjects was higher during the high exposure period than the low exposure period, although these differences were not significant. Interestingly, a clear and significant change in symptoms prevalence was found in the controls with a higher prevalence in the low exposure period. Analysis of the relation between cholinesterase inhibition and symptoms showed that prevalence ratios were significantly >1 for respiratory, eye, and central nervous system symptoms for workers with >30% inhibition. Similar results were found for analyses with the actual level of acetylcholinesterase activity.
CONCLUSION—The results suggest the presence of a relation between exposure and acetylcholinesterase inhibition, acetylcholinesterase activity, and respiratory, eye, and central nervous system symptoms. Increased symptom prevalence was found at acetylcholinesterase activities generally considered to be non-adverse.


Keywords: cholinesterase inhibition; symptoms; health effects; Kenya; agricultural workers     

The pharmacodynamics and pharmacokinetics of mivacurium in children

BACKGROUND: In children, onset time and duration of action of mivacurium are shorter than in adults. Some suggest that this is due to differences in plasma cholinesterase (pChe), whereas others indicate that there is no difference. The purpose of this study was to evaluate the pharmacodynamics and pharmacokinetics of mivacurium in phenotypically normal children aged 3-6 and 10-14 years old, respectively. METHODS: Ten children aged 3-6 years and 10 children aged 10-14 years were studied during halothane anaesthesia. Before induction of anaesthesia, a blood sample was drawn to measure the pChe activity and phenotype. The neuromuscular block was monitored at the thumb using train-of-four (TOF) nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery following mivacurium 0.2 mg/kg were recorded. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured. RESULTS: No statistically significant difference was found in pChe activity or in the pharmacodynamics of mivacurium. The onset time was 1.4 min (0.8-1.9) median (range) and 1.3 min (1.1-1.9) and the time to first response to TOF nerve stimulation was 9.6 min (6.5-12.6) and 10.5 min (7.0-14.0) in young and older children, respectively. The pharmacokinetic data were too sparse to allow analysis of the two age groups separately (8 and 8 patients), hence the data were pooled. The median clearances of the cis-cis, the cis-trans, and the trans-trans isomer were 5.5, 51.0 and 30.5 ml/kg/min, respectively. CONCLUSION: Our data indicate that there are no major differences in pharmacodynamics or pharmacokinetics of mivacurium between young (3-6 years) and older (10-14 years) children.     

Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

BACKGROUND: Mivacurium is hydrolyzed by plasma cholinesterase, and is therefore less dependent on liver metabolism and renal elimination than other neuromuscular blocking drugs. This might favor the use of mivacurium in elderly patients. The purpose of this study was to compare the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium and their metabolites in young adult and elderly patients. METHODS: Sixty-four patients were included in a dose-response study, in which 32 young adults and 32 elderly patients received one of four doses of mivacurium. An additional bolus dose of mivacurium to a total of 0.1 mg/kg was given followed by a continuous infusion adjusted to maintain a 91-99% neuromuscular block. The times to maximum block and different levels of recovery were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Thirty-two patients were randomly selected for the pharmacokinetic study. Venous samples were taken for determination of the three mivacurium isomers and the metabolites. RESULTS: The estimated ED95 were 0.053 and 0.061 mg/kg in young adults and elderly patients, respectively (NS). The median infusion rate did not differ, but duration to a TOF ratio of 0.7 was significantly longer in elderly patients than in young adult patients (21.0 vs. 16.5 min). No statistically significant difference between the age groups in clearance and elimination half-life of the isomers was seen. The half-lives of the metabolites were significantly prolonged in the elderly patients. CONCLUSION: There were no significant differences in the potency or infusion requirements between the adult and elderly patients, but the rate of recovery was significantly, though only moderately prolonged, in the elderly patients. No significant difference in clearance was seen but the elimination half-lives of the metabolites was longer in the elderly patients.     

多奈哌齐治疗轻中度阿尔茨海默病患者的临床研究

目的研究多奈哌齐治疗我国轻中度阿尔茨海默病(AD)患者的疗效和安全性.方法将48例轻中度AD患者随机均分为两组,用多奈吸哌齐和卡巴拉汀治疗16周.采用简易精神状态量表(MMSE)、Blessed-Roth量表和总体衰退量表(GDS)评定疗效.安全性检查包括生命体征,实验室及心电图检查,每4周1次.结果两组治疗前后MMSE,GDS和Blessed-Roth评分均有显著改善(P＜0.05).但两组治疗前后相关量表总分差值的t检验均无显著意义(P＞0.05).两组治疗前后Blessed-Roth各亚项分数差值比较无显著性(P＞0.05).不良反应为胃肠道反应,发生率在15.0%～29.5%之间,以卡巴拉汀组多见.结论多奈吸哌齐和卡巴拉汀可显著改善AD患者的认知功能、痴呆程度和日常生活能力,疗效相当,较为安全,耐受性较好.     

利培酮对分裂症患者血清胆碱酯酶活力的影响及疗效研究

目的：探讨利培酮对分裂症患者血清胆碱酯酶活力的影响及疗效。方法：采用自身对照的方法，分别于治疗前，治疗后1、2、3、4周测血清胆碱酯酶活力，并测BPRS和TESS。结果：治疗前与治疗后1、2,3、4周血清胆碱酯酶活力的比较差异无统计学意义（p〉0．05）。治疗前与治疗后第2、4周BPRS比较差异均有显著性，t值分别为t=2．40，P〈0．02；t=5．24，P〈0．01。结论：利培酮对分裂症患者血清胆碱酯酶活力无明显影响，有显著疗效。     

Inhibition of human plasma cholinesterase and erythrocyte acetylcholinesterase by nondepolarizing neuromuscular blocking agents

Purpose. The kinetics of the inhibition of human plasma cholinesterase (ChE) and erythrocyte acetylcholinesterase (AChE) by alcuronium, atracurium, d-tubocurarine, pancuronium, pipecuronium, and vecuronium were studied in blood drawn from 35 surgical patients. Methods. The activities of plasma ChE and erythrocyte AChE were determined by the calorimetric method of Ellman et al., using acetylthiocholine as the substrate. Lineweaver-Burk plots and Dixon plots were used for the analysis of the kinetics of both enzymes. Results. The dissociation constants (K _m) of plasma ChE and erythrocyte AChE were 5.00 × 10⁻⁵ M and 5.28 × 10⁻⁵ M, respectively, indicating that both enzymes have similar affinity to acetylthiocholine. Both Lineweaver-Burk plots and Dixon plots indicated that the six nondepolarizing neuromuscular blocking agents (NMBAs) at different concentrations induce linear mixed-type inhibition. The apparent inhibition constants (K _i) of pancuronium (8.72 × 10⁻⁸ M) and vecuronium (3.53 × 10⁻⁷ M) for plasma ChE inhibition were lower than that of neostigmine (7.36 × 10⁻⁷ M), whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly higher than that of neostigmine. Conclusions. Both plasma ChE and erythrocyte AChE were inhibited by six nondepolarizing NMBAs, and the pattern of inhibition of both enzymes was of mixed type. The inhibitory potencies of pancuronium and vecuronium for plasma ChE were larger than that of neostigmine, whereas those of the six nondepolarizing NMBAs for erythrocyte AChE were markedly lower than that of neostigmine. The rank order of relative potency for plasma ChE was pancuronium > vecuronium > pipecuronium > alcuronium > d-tubocurarine > atracurium. Received for publication on May 10, 1999; accepted on September 22, 1999     

疲劳与睡眠剥夺对晕船和乙酰胆碱酯酶的影响

目的分析疲劳与睡眠剥夺对晕船和红细胞乙酰胆碱酯酶活性的影响,为制定抗眩晕适应性训练方案提供理论依据。方法将54名受试者随机分为3组:长时间睡眠剥夺组、运动性疲劳组和对照组。3组受试者分别在剥夺睡眠28 h后、5 km武装越野后正常安静状态下进行抗眩晕模拟实验,同时测定红细胞乙酰胆碱酯酶(RBC-AchE)活性。结果睡眠剥夺组和运动性疲劳组的重度运动病发生率分别为38.9%和33.3%,均明显高于对照组(11.1%,P<0.05)。同时,该2组模拟运动病实验后的RBC-AchE分别为(21.76±4.85)kU/L和(23.71±2.42)kU/L,明显低于对照组〔(25.29±2.70)kU/L〕(P<0.01)。结论睡眠剥夺和运动性疲劳可明显减弱机体抗渡海运动病能力,可能与2种机能状态下RBC-AchE活性降低有关。     

Low-dose cholinesterase inhibitors do not induce delayed effects on cerebral blood flow and metabolism

The acetylcholinesterase (AChE) inhibitors sarin and pyridostigmine bromide (PB) have been proposed as causes of neurobehavioral dysfunction in Persian Gulf War veterans. To test possible delayed effects of these agents, we exposed rats to low (subsymptomatic) levels of sarin (0.5 LD₅₀ s.c. 3 times weekly) and/or PB (80 mg/L in drinking water) for 3 weeks. Controls received saline s.c. and tap water. At 2, 4 and 16 weeks after exposure, regional cerebral blood flow (rCBF) and glucose utilization (rCGU) were measured in conscious animals with the Iodo-¹⁴C-antipyrine and ¹⁴C-2 deoxyglucose methods, respectively.

Two weeks after exposure, PB+sarin caused significant rCBF elevations, but no changes in rCGU, in neocortex, with lesser effects on allocortex. Four weeks after exposure, the same general pattern was found with sarin. Only a few changes were found at 16 weeks post-treatment. The predominant effects of sarin or PB+sarin on rCBF at earlier times after treatment are consistent with the well known direct cerebral vascular effect of cholinergic agonists. The lack of changes in rCBF and rCGU observed at 16 weeks after treatment does not support the hypothesis that repeat exposure to low-dose cholinesterase inhibitors can generate permanent alterations in cerebral activity.