A synthetic porphyrin as an effective dual antidote against carbon monoxide and cyanide poisoning.
A synthetic porphyrin as an effective dual antidote against carbon monoxide and cyanide poisoning.
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DOI：
10.1073/pnas.2209924120
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发表时间：
2023-02-28
影响因子：
11.1
通讯作者：
Kitagishi, Hiroaki
中科院分区：
文献类型：
--
作者：
Mao, Qiyue;Zhao, Xuansu;Kiriyama, Akiko;Negi, Shigeru;Fukuda, Yasutaka;Yoshioka, Hideki;Kawaguchi, Akira T.;Motterlini, Roberto;Foresti, Roberta;Kitagishi, Hiroaki
在火灾事故中，建筑材料燃烧过程中会同时产生一氧化碳（CO）和氰化氢（HCN）等剧毒气体。当吸入时，这两种气体强烈结合血红蛋白，细胞色素和生物体中的其他血红素，从而抑制有氧呼吸。迄今为止，没有治疗方法来克服同时中毒与CO和HCN。在这里，我们发明了一种合成血红素模型化合物（hemoCD-Twins），以提供紧急救生治疗。这种化合物通过单次注射捕获吸入动物体内的CO和氰化物，并通过尿液排泄迅速消除。具有即时解毒作用，高度安全性和储存稳定性，hemoCD-Twins具有很大的潜力，可以成为一种即用型火灾气体中毒解毒剂。一氧化碳（CO）和氰化氢同时中毒是火灾气体事故中死亡的主要原因。在这里，我们报告的发明注射解毒剂对CO和氰化物（CN-）混合中毒。该溶液含有四种化合物：铁（III）卟啉（FeIIITPPS，F），由吡啶（Py 3CD，P）和咪唑（Im 3CD，I）连接的两种甲基-β-环糊精（CD）二聚体，以及还原剂（Na 2S 2 O 4，S）。当这些化合物溶解在盐水中时，溶液含有两种合成血红素模型，包括F与P的复合物（hemoCD-P）和F与I的复合物（hemoCD-I），两者都处于铁（II）状态。hemoCD-P在其铁（II）状态下是稳定的，并且比天然血红素蛋白更强地捕获CO，而hemoCD-I一旦被注射到血液循环中就容易自动氧化成其铁（III）状态以生成HCN。混合溶液（hemoCD-Twins）对小鼠急性CO和CN-混合中毒表现出显著的保护作用（约85%的存活率，对照组为0%）。在使用大鼠的模型中，暴露于CO和CN-导致心率和血压显著降低，这通过血液中CO和CN-水平降低的hemoCD-Twins恢复。药代动力学数据显示，快速尿排泄的hemoCD双胞胎的消除半衰期为47分钟。最后，模拟火灾事故，并将我们的研究结果转化为现实生活中的场景，我们证实，燃烧气体从丙烯酸布造成严重的毒性小鼠和注射hemoCD双胞胎显着提高了生存率，导致身体失能的快速恢复。
In fire accidents, highly toxic gases such as carbon monoxide (CO) and hydrogen cyanide (HCN) are simultaneously generated during the combustion of building materials. When inhaled, these two gases strongly bind to hemoglobin, cytochromes, and other hemes in the living organisms, thus inhibiting aerobic respiration. To date, there is no therapeutic approach to overcome simultaneous poisoning with CO and HCN. Here, we invented a synthetic heme model compound (hemoCD-Twins) to provide emergency life-saving treatment. This compound captures CO and cyanide inhaled into animals with a single injection and is rapidly eliminated via urinary excretion. With an immediate antidotal effect, high degree of safety, and storage stability, hemoCD-Twins has great potential to be a ready-to-use antidote against fire gas poisoning. Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN–) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (FeIIITPPS, F), two methyl-β-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (Na2S2O4, S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN– once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN– mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN– resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN– levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.
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DOI：
10.1034/j.1600-0773.2003.930306.x
发表时间：
2003-09-01
期刊：
PHARMACOLOGY & TOXICOLOGY
影响因子：
--
作者：
Alonso, JR;Cardellach, F;Miró, O
通讯作者：
Miró, O
影响因子：
158.5
作者：
BAUD, FJ;BARRIOT, P;BISMUTH, C
通讯作者：
BISMUTH, C
影响因子：
7.3
作者：
Chan, Adriano;Jiang, Jingjing;Boss, Gerry R.
通讯作者：
Boss, Gerry R.
影响因子：
15
作者：
Kano, Koji;Itoh, Yoshiki;Hirota, Shun
通讯作者：
Hirota, Shun
影响因子：
17.1
作者：
Azarov, Ivan;Wang, Ling;Gladwin, Mark T.
通讯作者：
Gladwin, Mark T.