人类对硫磷中毒。毒性动力学分析。

Florian Eyer, Veronika Meischner, Daniela Kiderlen, Horst Thiermann, Franz Worek, Michael Haberkorn, Norbert Felgenhauer, Thomas Zilker, Peter Eyer
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引用次数: 100

摘要

自杀性对硫磷中毒死亡率特别高,发病时出现暴发性胆碱能症状,患者常以危及生命的症状就诊急诊。尽管有这种一致性,但患者之间的后续临床病程差异很大,主要不是由于不同的治疗延误或初级保健不足。可能,这些差异取决于吸收的毒物量和/或活性毒物的处置。我们跟踪对硫磷的毒性动力学并试图量化实际的毒性负荷。为此,我们监测了对硫磷中毒患者(需要人工通气的患者)的血浆对硫磷和对氧磷水平,以及红细胞乙酰胆碱酯酶的活性及其再激活性。血浆奥比肟浓度以及尿液对硝基酚偶联物的累积排泄作为总毒负荷的测量。所有患者均接受标准的静脉注射250mg奥比多肟方案,随后每24小时持续输注750mg,直至预期的再激活(通常为1周)。所有其他的治疗方法都是由医生判断的。建议使用低剂量阿托品以达到粘膜干燥、无支气管收缩和无心动过缓的目的。通常1-2 mg/h就足够了。七个选定的情况下,提出举例说明毒性动力学的特点。所有患者均严重中毒,对硫磷吸收量差异很大(0.12 ~ 4.4 g;致死剂量0.02-0.1 g),通常远低于亲属报告的预期。报告和调查结果之间的差异是由于夸大还是由于有效的去污染(包括自发呕吐、洗胃和活性炭),目前还没有定论。对硫磷从胃肠道的吸收有时延迟,长达5天,导致血浆谱波动。对硫磷的稳态分布体积(Vdss)约为20 L/kg。一名患者的尸检分析显示,在摄入16天后,脂肪组织中的对硫磷浓度比血浆高66倍。1例氟康唑患者在肾功能恶化时对硫磷的生物转化变化较大,严重阻滞,而苯巴比妥镇静(2例)无明显作用。血浆对硫磷与对氧磷的比例在0.3-30之间变化,也表明对氧磷的消除也不同,如一例对氧磷酶-1活性特别低的病例所示。奥比多肟在对氧磷浓度低于0.5微米时有效,前提是老化不太严重。该浓度与分离浓度或毒负荷相关性较差。根据相关文献对数据进行了讨论。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Human parathion poisoning. A toxicokinetic analysis.

The mortality rate of suicidal parathion poisoning is particularly high, the onset of fulminant cholinergic signs, and the patients frequently present to the emergency physician with life-threatening symptoms. Despite this uniformity, subsequent clinical course differs significantly among patients, mostly not as a result of different delays in treatment or insufficiency of primary care. Probably, the differences depend on the amount of poison absorbed and/or the disposition of the active poison, paraoxon. We followed the toxicokinetics of parathion and tried to quantify the actual poison load. To this end, we monitored parathion-intoxicated patients (patients requiring artificial ventilation) for plasma levels of parathion and paraoxon along with the activity of erythrocyte acetylcholinesterase and its reactivatability. Plasma obidoxime concentrations were followed as well as the cumulative urinary para-nitrophenol conjugate excretion as a measure of total poison load. All patients received a standard obidoxime scheme of a 250 mg bolus dose intravenously, followed by continuous infusion with 750 mg per 24 hours as long as reactivation could be expected (usually 1 week). All other treatment was instituted as judged by the physician. It was recommended to use atropine at low doses to achieve dry mucous membranes, no bronchoconstriction and no bradycardia. Usually 1-2 mg/h were sufficient. Seven selected cases are presented exemplifying toxicokinetic peculiarities. All patients were severely intoxicated, while the amount of parathion absorbed varied widely (between 0.12 and 4.4 g; lethal dose 0.02-0.1 g) and was generally much lower than anticipated from the reports of relatives. It remains open whether the discrepancies between reports and findings were due to exaggeration or to effective decontamination (including spontaneous vomiting, gastric lavage and activated charcoal). Absorption of parathion from the gastrointestinal tract was sometimes retarded, up to 5 days, resulting in fluctuating plasma profiles. The volume of distribution at steady-state (Vdss) of parathion was around 20 L/kg. Post-mortem analysis in one patient revealed a 66-fold higher parathion concentration in fat tissue compared with plasma, 16 days after ingestion. Biotransformation of parathion varied widely and was severely retarded in one patient receiving fluconazole during worsening of renal function, while phenobarbital (phenobarbitone) sedation (two cases) had apparently no effect. The proportion of plasma parathion to paraoxon varied from 0.3-30, pointing also to varying paraoxon elimination, as illustrated by one case with particularly low paraoxonase-1 activity. Obidoxime was effective at paraoxon concentrations below 0.5 microM, provided aging was not too advanced. This concentration correlated poorly with the paration concentration or the poison load. The data are discussed in light of the pertinent literature.

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