Division of Medical Toxicology, Department of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center, New York, New York.
J Pharmacol Exp Ther. 2013 Nov;347(2):251-7. doi: 10.1124/jpet.113.206383. Epub 2013 Aug 26.
Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. Although there is no true antidote to cocaine toxicity, current management strategies address the life-threatening systemic effects, namely hyperthermia, vasospasm, and severe hypertension. Clinicians rely on rapid cooling, benzodiazepines, and α-adrenergic antagonists for management, with years of proven benefit. Experimental agents have been developed to more effectively treat acute toxicity. Pharmacodynamic approaches include antipsychotics that are thought to interfere with cocaine's actions at several neurotransmitter receptors. However, these medications may worsen the consequences of cocaine toxicity as they can interfere with heat dissipation, cause arrhythmias, and lower the seizure threshold. Pharmacokinetic approaches use cocaine-metabolizing enzymes, such as butyrylcholinesterase (BChE), cocaine hydrolase (CocH), and bacterial cocaine esterase (CocE). Experimental models with these therapies improve survival, primarily when administered before cocaine, although newer evidence demonstrates beneficial effects shortly after cocaine toxicity has manifested. CocE, a foreign protein, can induce an immune response with antibody formation. When enzyme administration was combined with vaccination against the cocaine molecule, improvement in cocaine-induced locomotor activity was observed. Finally, lipid emulsion rescue has been described in human case reports as an effective treatment in patients with hemodynamic compromise because of cocaine, which correlates well with its documented benefit in toxicity due to other local anesthetics. A pharmaceutical developed from these concepts will need to be expedient in onset and effective with minimal adverse effects while at the same time being economical.
可卡因是一种常见的滥用非法药物，会导致严重的发病率和死亡率。虽然没有真正的可卡因毒性解毒剂，但目前的管理策略针对危及生命的全身效应，即体温过高、血管痉挛和严重高血压。临床医生依靠快速降温、苯二氮䓬类药物和α-肾上腺素能拮抗剂进行治疗，多年来已证实这些方法有效。已经开发出实验性药物来更有效地治疗急性毒性。药效学方法包括抗精神病药，它们被认为可以干扰可卡因在几个神经递质受体上的作用。然而，这些药物可能会加重可卡因毒性的后果，因为它们会干扰热量散发，导致心律失常，并降低癫痫发作阈值。药代动力学方法使用可卡因代谢酶，如丁酰胆碱酯酶（BChE）、可卡因水解酶（CocH）和细菌可卡因酯酶（CocE）。使用这些治疗方法的实验模型可提高存活率，主要是在给予可卡因之前，尽管新的证据表明在可卡因毒性表现后不久就有有益的效果。CocE 是一种外来蛋白质，可以诱导抗体形成的免疫反应。当酶给药与针对可卡因分子的疫苗接种结合使用时，观察到可卡因诱导的运动活动得到改善。最后，在人类病例报告中描述了脂质乳剂抢救作为治疗因可卡因导致血流动力学受损的有效方法，这与它在其他局部麻醉剂毒性中的记录益处很好地相关。从这些概念开发的药物需要在起效时迅速，有效且副作用最小，同时具有经济性。
