Lallement G, Clarençon D, Galonnier M, Baubichon D, Burckhart M F, Peoc'h M
Unité de Neuropharmacologie, CRSSA-BP, La Tronche, France. 100437,
Arch Toxicol. 1999 Mar;73(2):115-22. doi: 10.1007/s002040050595.
Organophosphorus (OP) nerve agents are still used as warfare and terrorism compounds. Classical delayed treatment of victims of organophosphate poisoning includes combined i.v. administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). The objective of this study was to evaluate, in a realistic setting, the therapeutic benefit of administration of GK-11 (gacyclidine), an antiglutamatergic compound, as a complement to the above therapy against organophosphate poisoning. Gacyclidine was injected (i.v.) in combination with atropine/diazepam/pralidoxime at man-equivalent doses after a 45- or 30-min latency period to intoxicated primates (2 LD50). The effects of gacyclidine on the animals' survival, electroencephalographic (EEG) activity, signs of toxicity, recovery after challenge and central nervous system histology were examined. The present data demonstrated that atropine/diazepam/pralidoxime alone or combined with gacyclidine did not prevent signs of soman toxicity when treatment was delayed 45 min after poisoning. Atropine/diazepam/pralidoxime also did not control seizures or prevent neuropathology in primates exhibiting severe signs of poisoning when treatment was commenced 30 min after intoxication. However, in this latter case, EEG recordings revealed that additional treatment with gacyclidine was able to stop soman-induced seizures and restore normal EEG activity. This drug also totally prevented the neuropathology observed 5 weeks after soman exposure in animals treated with atropine/diazepam/pralidoxime alone. Overall, in the case of severe OP-poisoning, gacyclidine represents a promising adjuvant therapy to the currently available polymedication to ensure optimal management of organophosphate poisoning in man. This drug is presently being evaluated in a human clinical trial for a different neuroprotective indication. However, it should always be kept in mind that, in the case of severe OP-poisoning, medical intervention must be conducted as early as possible.
有机磷（OP）神经毒剂仍被用作战争和恐怖主义化合物。对有机磷中毒受害者的传统延迟治疗包括静脉联合使用胆碱酯酶复活剂（肟类）、毒蕈碱胆碱能受体拮抗剂（阿托品）和苯二氮䓬类抗惊厥药（地西泮）。本研究的目的是在实际情况下评估给予抗谷氨酸能化合物GK-11（加环利定）作为上述有机磷中毒治疗补充的治疗益处。在中毒灵长类动物（2倍半数致死剂量）经过45或30分钟的潜伏期后，以人等效剂量静脉注射加环利定，并联合阿托品/地西泮/氯解磷定。研究了加环利定对动物存活、脑电图（EEG）活动、毒性体征、激发后恢复情况以及中枢神经系统组织学的影响。目前的数据表明，在中毒后45分钟延迟治疗时，单独使用阿托品/地西泮/氯解磷定或联合加环利定并不能预防梭曼中毒的体征。当中毒后30分钟开始治疗时，阿托品/地西泮/氯解磷定也无法控制癫痫发作或预防出现严重中毒体征的灵长类动物的神经病理学改变。然而，在后一种情况下，EEG记录显示，额外给予加环利定能够终止梭曼诱导的癫痫发作并恢复正常EEG活动。该药物还完全预防了仅接受阿托品/地西泮/氯解磷定治疗的动物在接触梭曼5周后出现的神经病理学改变。总体而言，对于严重的有机磷中毒，加环利定是目前可用的多种药物联合治疗的一种有前景的辅助治疗方法，可确保对人类有机磷中毒进行最佳管理。目前该药物正在针对另一种神经保护适应症进行人体临床试验评估。然而，应始终牢记，对于严重的有机磷中毒，必须尽早进行医学干预。
