Department of Emergency Medicine, United Hospital, St. Paul, MN, USA.
University of Minnesota Department of Chemistry, Minneapolis, MN, USA.
J Med Toxicol. 2020 Jan;16(1):61-66. doi: 10.1007/s13181-019-00721-2. Epub 2019 Aug 5.
Toxicity related to calcium-channel blockers remains a significant cause of morbidity and mortality. Amlodipine-induced shock is unique in that its mechanism of action is thought to occur in part via the release of nitric oxide (NO) in the peripheral vasculature. Specific therapeutic interventions, including methylene blue (an NO scavenger), have been suggested, but efficacy studies are severely limited. To facilitate a larger porcine study into the effect of various interventions on amlodipine toxicity, we undertook this model development and feasibility study.
Intravenous amlodipine was prepared by dissolving commercially obtained amlodipine tablets in dimethylsulfoxide. The concentration of the drug was verified using ultraviolet spectroscopy. We administered this solution to three animals in order to determine a toxic dose, capable of facilitating a two-arm study of amlodipine toxicity.
The first pig died rapidly after the bolus infusion. The second pig developed mild toxicity, but the dissolution of the plastic tubing by the solvent and subsequent leakage limited the interpretability of the result. The third animal developed expected toxicity with an infusion rate between 2.0 and 5.5 mg/kg/h.
This study demonstrates a potentially repeatable model of amlodipine-induced toxic shock using intravenous administration of amlodipine and several methodological considerations for researchers undertaking similar work.
钙通道阻滞剂相关的毒性仍然是发病率和死亡率的重要原因。氨氯地平引起的休克是独特的，其作用机制被认为部分是通过在外周血管释放一氧化氮（NO）。已经提出了一些特殊的治疗干预措施，包括亚甲蓝（一种 NO 清除剂），但疗效研究受到严重限制。为了促进更大规模的关于各种干预措施对氨氯地平毒性影响的猪研究，我们进行了这项模型开发和可行性研究。
通过将市售的氨氯地平片剂溶解在二甲亚砜中来制备静脉内氨氯地平。使用紫外光谱法验证药物的浓度。我们给三只动物注射了这种溶液，以确定一个能促进氨氯地平毒性的两臂研究的毒性剂量。
第一只猪在推注后迅速死亡。第二只猪出现轻度毒性，但溶剂溶解塑料管并随后泄漏限制了结果的可解释性。第三只动物以 2.0 至 5.5mg/kg/h 的输注率出现预期的毒性。
本研究使用静脉内给予氨氯地平展示了一种潜在可重复的氨氯地平诱导的中毒性休克模型，并为从事类似工作的研究人员提供了一些方法学考虑因素。
