van Helden H P, Groen B, Moor E, Westerink B H, Bruijnzeel P L
TNO Prins Maurits Laboratory, Department of Pharmacology, Rijswijk, The Netherlands.
Drug Chem Toxicol. 1998;21 Suppl 1:171-81. doi: 10.3109/01480549809007409.
Current treatment of acute organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). This treatment is not adequate since it does not prevent neuronal brain damage and incapacitation. Here, as in a recent review it is stated that other therapeutic approaches may improve protection. Former studies on the "direct effects" of oximes led to the conclusion that drug-induced inhibition of acetylcholine (ACh)-release shortly (1 min) after the acute OP-intoxication, could prevent and counteract convulsions and improve survival. In general, the accumulation of ACh in the synaptic cleft is considered to be responsible for the symptoms that ultimately lead to death. Therefore, prevention or suppression of this excessive accumulation of ACh could be a generic approach to antagonize OP-poisoning. Preliminary evidence for this concept has been put forward. Evaluation of drugs that would be able to prevent and counteract ACh accumulation, led to the conclusion that adenosine receptor agonists could be promising candidates. Pilot experiments demonstrated that intramuscular administration of the adenosine receptor agonists NECA (5'-N-ethylcarboxamido-adenosine) or CPA (N6-cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5-2LD50) in rats, resulted in (1) prevention or postponement of chewing, salivation, convulsive activity, and respiratory distress (cholinergic symptoms), (2) improvement of survival rate (24 h), (3) a low level of extracellular brain ACh, as opposed to high levels of extracellular brain ACh in untreated animals. It is concluded that (1) adenosine agonists protect acutely soman-poisoned rats without the need of additional treatment with atropine, oxime or diazepam, (2) prevention of ACh accumulation in this way may be a new generic approach in the treatment of OP-poisoning.
目前急性有机磷（OP）中毒的治疗方法包括联合使用胆碱酯酶复活剂（肟类）、毒蕈碱受体拮抗剂（阿托品）和抗惊厥药（地西泮）。但这种治疗并不充分，因为它无法预防神经元脑损伤和功能丧失。在此，正如最近一篇综述中所述，其他治疗方法可能会增强保护作用。先前关于肟类“直接作用”的研究得出结论，急性OP中毒后不久（1分钟）药物诱导的乙酰胆碱（ACh）释放抑制可预防和对抗惊厥，并提高生存率。一般来说，突触间隙中ACh的积累被认为是最终导致死亡症状的原因。因此，预防或抑制ACh的这种过度积累可能是对抗OP中毒的一种通用方法。这一概念已有初步证据。对能够预防和对抗ACh积累的药物的评估得出结论，腺苷受体激动剂可能是有前景的候选药物。初步实验表明，在大鼠皮下注射梭曼中毒（1.5 - 2倍半数致死量）1分钟后，肌肉注射腺苷受体激动剂NECA（5'-N-乙基甲酰胺基腺苷）或CPA（N6-环戊基腺苷），可导致：（1）预防或推迟咀嚼、流涎、惊厥活动和呼吸窘迫（胆碱能症状）；（2）提高生存率（24小时）；（3）脑内细胞外ACh水平较低，而未治疗动物的脑内细胞外ACh水平较高。得出的结论是：（1）腺苷激动剂可保护急性梭曼中毒的大鼠，无需额外使用阿托品、肟类或地西泮进行治疗；（2）以这种方式预防ACh积累可能是治疗OP中毒的一种新的通用方法。
