Lallement G, Clarençon D, Masqueliez C, Baubichon D, Galonnier M, Burckhart M F, Peoc'h M, Mestries J C
Unité de Neurotoxicologie, CRSSA, La Tronche, France.
Arch Toxicol. 1998;72(2):84-92. doi: 10.1007/s002040050472.
Organophosphorus nerve agents are still in use today in warfare and as terrorism compounds. Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). However, recent experiments with primates have demonstrated that such treatment, even when administered immediately after organophosphate exposure, does not rapidly restore normal electroencephalographic (EEG) activity and fails to totally prevent neuronal brain damage. 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 available emergency therapy against organophosphate poisoning. GK-11 was injected at a dose of 0.1 mg/kg (i.v) after a 45-min latency period to heavily intoxicated (8 LD50) primates. Just after intoxication, man-equivalent doses of one autoinjector containing atropine/pralidoxime/diazepam were administered. The effects of GK-11 were examined on survival, EEG activity, signs of toxicity, recovery after challenge and central nervous system histology. The present data demonstrate that treatment with GK-11 prevents the mortality observed after early administration of classical emergency medication alone. EEG recordings and clinical observations also revealed that GK-11 prevented soman-induced seizures and motor convulsions. EEG analysis within the classical frequency bands (beta, theta, alpha, delta) demonstrated that central activity was totally restored to normal after GK-11 treatment, but remained profoundly altered in animals receiving atropine/pralidoxime/diazepam alone. GK-11 also markedly accelerated clinical recovery of soman-challenged primates. Lastly, this drug totally prevented the neuropathology observed 3 weeks after soman exposure in animals treated with classical emergency treatment alone. GK-11 represents a promising adjuvant therapy to the currently available emergency 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.
有机磷神经毒剂如今仍被用于战争以及作为恐怖主义化合物。有机磷中毒的传统紧急治疗包括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）。然而，最近对灵长类动物进行的实验表明，即使在接触有机磷后立即进行这种治疗，也不能迅速恢复正常的脑电图（EEG）活动，并且无法完全预防神经元脑损伤。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）作为现有有机磷中毒紧急治疗补充的治疗效果。在潜伏期45分钟后，以0.1mg/kg（静脉注射）的剂量给重度中毒（8倍半数致死量）的灵长类动物注射GK-11。中毒后立即给予相当于人用剂量的一支含有阿托品/氯解磷定/地西泮的自动注射器。研究了GK-11对存活、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，使用GK-11治疗可预防仅早期给予传统紧急药物治疗后出现的死亡。EEG记录和临床观察还显示，GK-11可预防梭曼引起 的癫痫发作和运动性惊厥。在经典频段（β波、θ波、α波、δ波）内的EEG分析表明，GK-11治疗后中枢活动完全恢复正常，但仅接受阿托品/氯解磷定/地西泮治疗的动物的中枢活动仍有严重改变。GK-11还显著加速了梭曼攻击的灵长类动物的临床恢复。最后，这种药物完全预防了仅接受传统紧急治疗的动物在梭曼暴露3周后出现的神经病理学改变。GK-11是目前可用的紧急多药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。这种药物目前正在针对不同的神经保护适应症进行人体临床试验评估。
