Symptomatic treatment of botulism with a clinically approved small molecule
Symptomatic treatment of botulism with a clinically approved small molecule
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DOI：
10.1172/jci.insight.132891
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发表时间：
2020-01-30
期刊：
影响因子：
8
通讯作者：
McNutt, Patrick
中科院分区：
文献类型：
--
作者：
Vazquez-Cintron, Edwin;Machamer, James;McNutt, Patrick
肉毒杆菌神经毒素(BoNTs)是一种强效的神经麻痹毒素，可通过呼吸麻痹导致死亡。已批准的治疗BONT中毒的医学对策是输注抗毒素免疫球蛋白。然而，抗毒素对有症状的患者的治疗效果很差；因此，迫切需要减少人工呼吸机需求的治疗。我们报道，美国食品和药物管理局批准的钾通道阻滞剂3，4-二氨基吡啶(3，4-DAP)可以逆转急性和慢性肉毒杆菌中毒小鼠模型的呼吸抑制和神经肌肉无力。在体外研究中，3，4-DAP恢复了A型肉毒中毒(BoNT/A)末期小鼠分离的横隔膜的终板电位和抽动收缩。在体内，人体等量的3，4-DAP逆转了严重呼吸抑制的迹象，并在呼吸衰竭的末期恢复了BONT/A中毒小鼠的活动能力。在A型、B型和E型肉毒中毒亚致死模型中，多次给药3，4-DAP可改善呼吸，延长存活时间，LD50为5。最后，3，4-DAP减轻了腓肠肌麻痹，逆转了呼吸抑制。这些发现为改变3，4DAP的用途提供了一个令人信服的理由，以对肉毒杆菌中毒引起的肌肉麻痹症状进行有症状的治疗，而不受血清型的影响。此外，他们还表明，3，4-DAP对临床相关时间点的一系列肉毒杆菌中毒症状有效。
Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning is infusion of antitoxin immunoglobulins. However, antitoxins have poor therapeutic efficacy in symptomatic patients; thus, there is an urgent need for treatments that reduce the need for artificial ventilation. We report that the US Food and Drug Administration-approved potassium channel blacker 3,4-diaminopyridine (3,4-DAP) reverses respiratory depression and neuromuscular weakness in murine models of acute and chronic botulism. In ex vivo studies, 3,4-DAP restored end-plate potentials and twitch contractions of diaphragms isolated from mice at terminal stages of BoNT serotype A (BoNT/A) botulism. In vivo, human-equivalent doses of 3,4-DAP reversed signs of severe respiratory depression and restored mobility in BoNT/A-intoxicated mice at terminal stages of respiratory collapse. Multiple-dosing administration of 3,4 DAP improved respiration and extended survival at up to 5 LD50 BoNT/A. Finally, 3,4-DAP reduced gastrocnemius muscle paralysis and reversed respiratory depression in sublethal models of serotype A, B-, and E-induced botulism. These findings make a compelling argument for repurposing 3,4 DAP to symptomatically treat symptoms of muscle paralysis caused by botulism, independent of serotype. Furthermore, they suggest that 3,4-DAP is effective for a range of botulism symptoms at clinically relevant time points.