Alioth-Streichenberg C M, Bodmer D M, Waser P G
Department of Pharmacology, University of Zurich, Switzerland.
Toxicol Appl Pharmacol. 1991 May;108(3):509-19. doi: 10.1016/0041-008x(91)90097-x.
The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 micrograms/kg iv) rats. The kinetics were described by a two-compartment open model. The elimination half-life ranged from 35 min in normal rats to 86 min in sarin-poisoned rats. Obidoxime excretion occurred predominantly by the renal route, amounting to 4.6% of the administered dose in normal rats and to 0.9% in sarin-poisoned rats within the first hour of administration. The significantly diminished glomerular filtration rate confirmed the retardation of obidoxime excretion in sarin poisoning. The mean arterial blood pressure (MAP) response to obidoxime, measured in normal rats, was a transient hypotension, but to sarin an immediate hypertension. In sarin-poisoned rats the therapeutic sequence of administration of obidoxime and atropine (5 mg/kg iv) seemed to be important: the administration of atropine 10 min after and of obidoxime 20 min after sarin poisoning exerted a stabilizing effect on MAP. No serum albumin binding was found for obidoxime. Competition experiments at the isolated nicotinic receptor demonstrated the anticholinergic activity of obidoxime. The affinity of obidoxime was 1000 times smaller than that of acetylcholine. It is concluded that obidoxime, due to its prolonged residence time in the organism in sarin poisoning, exerts a "curare-like" inhibition and protection of the nicotinic acetylcholine receptor and, combined with atropine, a synergistic effect on blood pressure normalization.
在麻醉的正常大鼠和经沙林中毒（静脉注射50微克/千克）的大鼠中研究了肟类化合物氯解磷定（双复磷，静脉注射50毫克/千克）的药代动力学和药效学。其动力学用二室开放模型描述。消除半衰期在正常大鼠中为35分钟，在沙林中毒大鼠中为86分钟。氯解磷定的排泄主要通过肾脏途径，在给药后第一小时内，正常大鼠中排泄量占给药剂量的4.6%，沙林中毒大鼠中为0.9%。肾小球滤过率显著降低证实了沙林中毒时氯解磷定排泄的延迟。在正常大鼠中测量的氯解磷定对平均动脉血压（MAP）的反应是短暂性低血压，但对沙林则是立即出现高血压。在沙林中毒的大鼠中，氯解磷定和阿托品（静脉注射5毫克/千克）的给药顺序似乎很重要：沙林中毒后10分钟给予阿托品，20分钟给予氯解磷定对MAP有稳定作用。未发现氯解磷定与血清白蛋白结合。在分离的烟碱样受体上进行的竞争实验证明了氯解磷定的抗胆碱能活性。氯解磷定的亲和力比乙酰胆碱小1000倍。得出的结论是，氯解磷定由于在沙林中毒时在体内停留时间延长，对烟碱样乙酰胆碱受体发挥“箭毒样”抑制和保护作用，并与阿托品联合对血压正常化产生协同作用。
