a Pharmacology, Toxicology, and Therapeutics , University/BHF Centre for Cardiovascular Science, University of Edinburgh , Edinburgh , UK.
b Wellcome Trust Critical Care for Large Animals, Royal (Dick) School of Veterinary Studies and the Roslin Institute, University of Edinburgh , Edinburgh , UK.
Clin Toxicol (Phila). 2018 Aug;56(8):773-781. doi: 10.1080/15563650.2017.1422510. Epub 2018 Jan 15.
Colchicine poisoning is commonly lethal. Colchicine-specific Fab fragments increase rat urinary colchicine clearance and have been associated with a good outcome in one patient. We aimed to develop a porcine model of colchicine toxicity to study the pharmacokinetics and efficacy of ovine Fab.
A Göttingen minipig critical care model was established and serial blood samples taken for colchicine and Fab pharmacokinetics, clinical chemistry, and haematology. Animals were euthanised when the mean arterial pressure fell below 45 mmHg without response to vasopressor, or at study completion.
Initial studies indicated that oral dosing produced variable pharmacokinetics and time-to-euthanasia. By contrast, intravenous infusion of 0.25 mg/kg colchicine over 1 h produced reproducible pharmacokinetics (AUC 343 [SD = 21] µg/L/h), acute multi-organ injury, and cardiotoxicity requiring euthanasia a mean of 22.5 (SD = 3.2) h after dosing. A full-neutralising equimolar Fab dose given 6 h after the infusion (50% first hour, 50% next 6 h [to reduce renal-loss of unbound Fab]) produced a 7.35-fold increase in plasma colchicine (AUC 2,522 [SD = 14] µg/L/h), and removed all free plasma colchicine, but did not prevent toxicity (euthanasia at 29.1 [SD = 3.4] h). Earlier administration over 1 h of the full-neutralising dose, 1 or 3 h after the colchicine, produced a 12.9-fold (AUC 4,433 [SD = 607] µg/L/h) and 6.0-fold (AUC 2,047 [SD = 51] µg/L/h) increase in plasma colchicine, respectively, absence of free plasma colchicine until 20 h, and survival to study end without marked cardiotoxicity.
Colchicine-specific Fab given early, in equimolar dose, bound colchicine, eliciting its movement into the blood, and preventing severe toxicity. Clinical studies are now needed to determine how soon this antidote must be given to work in human poisoning.
秋水仙碱中毒通常是致命的。秋水仙碱特异性 Fab 片段可增加大鼠尿液中的秋水仙碱清除率，并在一名患者中取得良好效果。我们旨在建立猪秋水仙碱中毒模型，以研究羊 Fab 的药代动力学和疗效。
建立哥廷根小型猪重症监护模型，连续采集血样以研究秋水仙碱和 Fab 的药代动力学、临床化学和血液学参数。当平均动脉压下降至 45mmHg 以下且对血管加压药无反应，或研究结束时，对动物进行安乐死。
初步研究表明，口服给药会导致药代动力学和安乐死时间出现变化。相比之下，静脉输注 0.25mg/kg 秋水仙碱 1 小时可产生可重现的药代动力学（AUC 343 [SD=21]µg/L/h）、急性多器官损伤和需要安乐死的心脏毒性，在给药后平均 22.5（SD=3.2）小时。在输注后 6 小时给予全中和等摩尔 Fab 剂量（第 1 小时 50%，接下来 6 小时 50%[以减少未结合 Fab 的肾丢失]）可使血浆秋水仙碱增加 7.35 倍（AUC 2,522 [SD=14]µg/L/h），并清除所有游离血浆秋水仙碱，但不能预防毒性（在 29.1 [SD=3.4]小时安乐死）。在秋水仙碱后 1 小时内给予全中和剂量 1 或 3 小时，可使血浆秋水仙碱分别增加 12.9 倍（AUC 4,433 [SD=607]µg/L/h）和 6.0 倍（AUC 2,047 [SD=51]µg/L/h），直至 20 小时仍无游离血浆秋水仙碱，且无明显心脏毒性存活至研究结束。
早期给予秋水仙碱特异性 Fab 以等摩尔剂量结合秋水仙碱，诱导其进入血液，并防止严重毒性。现在需要进行临床研究以确定该解毒剂在人类中毒中需要多快时间给予才能起效。
