Uhl Wolfgang, Nolting Arno, Golor Georg, Rost Karl Ludwig, Kovar Andreas
Merck KGaA, Darmstadt, Germany.
Clin Toxicol (Phila). 2006;44 Suppl 1:17-28. doi: 10.1080/15563650600811755.
This randomized, double-blind, placebo-controlled, ascending-dose study was conducted in healthy volunteers to evaluate the safety of the investigational cyanide antidote hydroxocobalamin.
Four ascending dosing groups received intravenous doses of 2.5, 5, 7.5 or 10 g hydroxocobalamin over 7.5 to 30 minutes at a constant infusion rate. Volunteers (n = 136) randomized 3:1 to receive hydroxocobalamin or placebo underwent a 4-day in-house observation after infusion on Day 1 and follow-up visits on Days 8, 15, and 28.
The most common drug-related adverse events were asymptomatic and self-limiting chromaturia and reddening of the skin, which are attributed to the red color of hydroxocobalamin. Other adverse events included pustular/papular rash, headache, erythema at the injection site, decrease in lymphocyte percentage, nausea, pruritus, chest discomfort, and dysphagia. Hydroxocobalamin was associated with an increase in blood pressure in some volunteers. Blood pressure changes peaked toward the end of hydroxocobalamin infusion and typically returned to baseline levels by 4 hours postinfusion. Maximum mean changes from baseline in systolic blood pressure ranged from 22.6 to 27.0 mmHg across hydroxocobalamin doses compared with 0.2 to 6.7 mmHg in the corresponding placebo groups. Maximum mean change from baseline in diastolic blood pressure ranged from 14.3 to 25.4 mmHg across hydroxocobalamin doses compared with -3.0 to 3.8 mmHg in the corresponding placebo groups. Two allergic reactions that occurred within minutes after start of the 5- and 10-g hydroxocobalamin infusions were successfully managed with dexamethasone and/or dimethindene maleate.
Timely intervention for acute cyanide poisoning could entail administration of an antidote in the prehospital setting based on a presumptive diagnosis. Results of this placebo-controlled study in healthy volunteers corroborate previous studies and French postmarketing experience in cyanide-exposed patients in suggesting that the safety profile of hydroxocobalamin is consistent with prehospital or hospital use.
本随机、双盲、安慰剂对照、剂量递增研究在健康志愿者中进行，以评估试验性氰化物解毒剂羟钴胺的安全性。
四个剂量递增组以恒定输注速率在7.5至30分钟内静脉注射2.5、5、7.5或10克羟钴胺。136名志愿者按3:1随机分组接受羟钴胺或安慰剂，在第1天输注后进行4天的住院观察，并在第8、15和28天进行随访。
最常见的与药物相关的不良事件是无症状且自限性的血尿和皮肤发红，这归因于羟钴胺的红色。其他不良事件包括脓疱/丘疹性皮疹、头痛、注射部位红斑、淋巴细胞百分比降低、恶心、瘙痒、胸部不适和吞咽困难。羟钴胺使一些志愿者的血压升高。血压变化在羟钴胺输注接近结束时达到峰值，通常在输注后4小时恢复到基线水平。与相应安慰剂组的0.2至6.7 mmHg相比，不同剂量羟钴胺组收缩压相对于基线的最大平均变化范围为22.6至27.0 mmHg。与相应安慰剂组的-3.0至3.8 mmHg相比，不同剂量羟钴胺组舒张压相对于基线的最大平均变化范围为14.3至25.4 mmHg。在开始输注5克和10克羟钴胺后数分钟内发生的两例过敏反应，用地塞米松和/或马来酸氯苯那敏成功处理。
急性氰化物中毒的及时干预可能需要在院前环境中基于推定诊断给予解毒剂。这项在健康志愿者中进行的安慰剂对照研究结果证实了先前的研究以及法国在氰化物暴露患者中的上市后经验，表明羟钴胺的安全性概况与院前或医院使用一致。
