PHARMACOKINETICS AND PHARMACODYNAMICS OF OBIDOXIME IN SARIN-POISONED RATS
PHARMACOKINETICS AND PHARMACODYNAMICS OF OBIDOXIME IN SARIN-POISONED RATS
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DOI：
10.1016/0041-008x(91)90097-x
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发表时间：
1991-05-01
影响因子：
3.8
通讯作者：
WASER, PG
中科院分区：
文献类型：
--
作者：
ALIOTHSTREICHENBERG, CM;BODMER, DM;WASER, PG
本文研究了双肟（Toxogonin，50 mg/kg iv）在麻醉正常大鼠和沙林中毒（50 μg/kg iv）大鼠体内的药代动力学和药效学。动力学符合二室开放模型。消除半衰期从正常大鼠的35分钟到沙林中毒大鼠的86分钟不等。在给药后的第一个小时内，正常大鼠和沙林中毒大鼠的排泄量分别为给药剂量的4.6%和0.9%。肾小球滤过率的显著降低证实了沙林中毒时双肟的排出延迟。在正常大鼠中测量的对双磷定的平均动脉血压（MAP）反应是短暂的低血压，但对沙林的反应是立即的高血压。在沙林中毒大鼠的治疗顺序的管理双异肟和阿托品（5毫克/公斤静脉注射）似乎是重要的：阿托品和双异肟沙林中毒后10分钟和20分钟后的管理对MAP产生稳定作用。双肟未发现血清白蛋白结合。在分离的烟碱受体的竞争实验证明了双肟的抗胆碱能活性。双肟的亲和力比乙酰胆碱小1000倍。它的结论是，双羟肟，由于其在沙林中毒的生物体中的停留时间延长，发挥了“箭毒样”的抑制和保护的烟碱乙酰胆碱受体，并结合阿托品，对血压正常化的协同作用。
The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 μg/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 exoretion 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.