Department of Biotechnology, Israel Institute for Biological Research, Ness Ziona, Israel.
Veterinary Center for Pre-clinical Research, Israel Institute for Biological Research, Ness Ziona, Israel.
Antimicrob Agents Chemother. 2018 Mar 27;62(4). doi: 10.1128/AAC.02379-17. Print 2018 Apr.
Botulinum neurotoxins (BoNTs), the most poisonous substances known in nature, pose significant concern to health authorities. The only approved therapeutic for botulism is antitoxin. While administered to patients only after symptom onset, antitoxin efficacy is evaluated in animals mostly in relation to time postintoxication regardless of symptoms. This is most likely due to the difficulty in measuring early symptoms of botulism in animals. In this study, a rabbit spirometry model was developed to quantify early respiratory symptoms of type E botulism that were further used as a trigger for treatment. Impaired respiration, in the form of a reduced minute volume, was detected as early as 18.1 ± 2.9 h after intramuscular exposure to 2 rabbit 50% lethal doses (LD) of BoNT serotype E (BoNT/E), preceding any visible symptoms. All rabbits treated with antitoxin immediately following symptom onset survived. Postsymptom antitoxin efficacy was further evaluated in relation to toxin and antitoxin dosages as well as delayed antitoxin administration. Our system enabled us to demonstrate, for the first time, full antitoxin protection of animals treated with antitoxin after the onset of objective and quantitative type E botulism symptoms. This model may be utilized to evaluate the efficacy of antitoxins for additional serotypes of BoNT as well as that of next-generation anti-BoNT drugs that enter affected cells and act when antitoxin is no longer effective.
肉毒神经毒素（BoNTs）是自然界中已知的最毒物质，对卫生当局构成重大威胁。唯一批准用于治疗肉毒中毒的方法是使用抗毒素。虽然抗毒素仅在症状出现后才给患者使用，但抗毒素的疗效主要是根据中毒后时间进行评估，而不管症状如何。这很可能是因为在动物身上很难测量肉毒中毒的早期症状。在这项研究中，建立了兔肺量测定法模型来量化 E 型肉毒中毒的早期呼吸症状，并进一步将其用作治疗的触发因素。早在肌肉内暴露于 2 个兔 50%致死剂量（LD）的 E 型肉毒梭菌神经毒素（BoNT/E）后 18.1±2.9 小时，就可以检测到呼吸受损，表现为分钟通气量减少，这早于任何可见症状。所有在出现症状后立即使用抗毒素治疗的兔子均存活。进一步根据毒素和抗毒素剂量以及延迟使用抗毒素来评估症状后使用抗毒素的疗效。我们的系统首次证明，在出现客观和定量的 E 型肉毒中毒症状后，使用抗毒素治疗的动物可以得到完全的抗毒素保护。该模型可用于评估针对其他 BoNT 血清型的抗毒素以及进入受影响细胞并在抗毒素不再有效的情况下发挥作用的下一代抗 BoNT 药物的疗效。
