Petroianu Georg A, Hasan Mohammed Y, Nurulain Syed M, Arafat Kholoud, Sheen Rajan, Saleh Ayman, Schmitt Andrea
Departments of *Pharmacology and †Biochemistry, Faculty of Medicine & Health Sciences, UAE University, Al-Ain, United Arab Emirates; and ‡Central Institute of Mental Health, Mannheim, Germany.
Anesth Analg. 2005 Feb;100(2):382-386. doi: 10.1213/01.ANE.0000143349.17443.91.
Weak and reversible inhibitors of cholinesterase(s), when coadministered in excess with a more potent inhibitor such as organophosphates, can act in a protective manner. The benzamide compound, metoclopramide, confers some protection (putatively via this mechanism) for cholinesterases against inhibition by paraoxon both in vitro and in vivo, after chronic small-dose exposure. Tiapride is a related benzamide. In this study, we compared the protection by metoclopramide and tiapride in rats acutely exposed to large doses of paraoxon with the therapeutic "gold standard," pralidoxime. Group 1 received 1 micromol paraoxon (approximately 75% lethal dose), Group 2 received 50 micromol metoclopramide, Group 3 received 50 micromol tiapride, Group 4 received 50 micromol pralidoxime, Group 5 received 1 micromol paraoxon + 50 micromol metoclopramide, Group 6 1 micromol paraoxon + 50 micromol tiapride, and Group 7 1 micromol paraoxon + 50 micromol pralidoxime. All substances were administered intraperitoneally. The animals were monitored for 48 h and mortality was recorded at 30 min, 1, 2, 3, 4, 24, and 48 h. Blood was taken for red blood cell acetylcholinesterase measurements at baseline, 30 min, 24, and 48 h. With the exception of Group 7, in which some late mortality was observed, mortality occurred mainly in the first 30 min after paraoxon administration with minimal changes occurring thereafter. Mortality at 30 min was 0% in the metoclopramide, tiapride, and pralidoxime groups and 73 +/- 20 (paraoxon), 65 +/- 15 (paraoxon + metoclopramide), 38 +/- 14 (paraoxon + tiapride), and 13 +/- 19 (paraoxon + pralidoxime). Mortality at 48 h was 75 +/- 18 (paraoxon), 67 +/- 17 (paraoxon + metoclopramide), 42 +/- 16 (paraoxon + tiapride), and 27 +/- 24 (paraoxon + pralidoxime). Metoclopramide does not significantly influence mortality after acute large-dose paraoxon exposure. Both tiapride and pralidoxime significantly decreased mortality in our model. The protection conferred by tiapride was significantly less than that conferred by pralidoxime at 30 min, but was not significantly different at 24 and 48 h.
胆碱酯酶的弱效且可逆性抑制剂与更强效的抑制剂（如有机磷酸酯类）过量共同给药时，可起到保护作用。苯甲酰胺化合物甲氧氯普胺在慢性小剂量暴露后，在体外和体内均可（推测通过此机制）为胆碱酯酶提供一定保护，使其免受对氧磷的抑制。硫必利是一种相关的苯甲酰胺。在本研究中，我们将甲氧氯普胺和硫必利对急性大剂量接触对氧磷的大鼠的保护作用与治疗“金标准”药物解磷定进行了比较。第1组接受1微摩尔对氧磷（约75%致死剂量），第2组接受50微摩尔甲氧氯普胺，第3组接受50微摩尔硫必利，第4组接受50微摩尔解磷定，第5组接受1微摩尔对氧磷 + 50微摩尔甲氧氯普胺，第6组接受1微摩尔对氧磷 + 50微摩尔硫必利，第7组接受1微摩尔对氧磷 + 50微摩尔解磷定。所有物质均腹腔注射给药。对动物进行48小时监测，并在30分钟、1、2、3、4、24和48小时记录死亡率。在基线、30分钟、24和48小时采集血液用于测量红细胞乙酰胆碱酯酶。除第7组观察到一些晚期死亡外，死亡主要发生在对氧磷给药后的前30分钟，此后变化极小。甲氧氯普胺组、硫必利组和解磷定组在30分钟时的死亡率为0%，对氧磷组为73±20，对氧磷 + 甲氧氯普胺组为65±15，对氧磷 + 硫必利组为38±14，对氧磷 + 解磷定组为13±19。48小时时的死亡率为对氧磷组75±18，对氧磷 + 甲氧氯普胺组67±17，对氧磷 + 硫必利组42±16，对氧磷 + 解磷定组27±24。急性大剂量接触对氧磷后，甲氧氯普胺对死亡率无显著影响。在我们建立的模型中，硫必利和解磷定均显著降低了死亡率。硫必利在30分钟时提供的保护显著低于解磷定，但在24和48小时时无显著差异。
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