A型肉毒杆菌神经毒素在实验动物关节内应用的安全性

IF 3.6 Q2 TOXICOLOGY Toxicon: X Pub Date : 2023-06-01 DOI:10.1016/j.toxcx.2023.100155
Ana Dugonjić Okroša , Victor Ricardo Manuel Muñoz-Lora , Ivica Matak , Lidija Bach-Rojecky , Mikhail Kalinichev , Zdravko Lacković
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引用次数: 0

摘要

A型肉毒杆菌神经毒素(BoNT-A)的体内研究使其能够表征其在伤害性感觉系统中的活性,而不是其在运动和自主神经末梢中的首选作用。然而,在最近对关节炎疼痛进行的啮齿类动物研究中,使用了高关节内(i.a.)剂量(以每只动物的单位总数或U/kg表示),尚未最终排除可能的全身影响。在本文中,我们评估了注射到大鼠膝盖中的两种药物制剂,abobotulinumtoxinA(aboBoNT-A,10,20和40U/kg,对应于0.05,0.11和0.22纳克/公斤神经毒素)和onabotulinumtoxinA(onaBoNT-A、10和20U/kg,分别对应于0.09和0.18纳克/千克)对安全相关读数的影响:手指外展,运动性能和治疗后14天的体重增加。i.a.毒素对脚趾伸展反射和旋转杆性能产生剂量依赖性损伤,在10 U/kg onaBoNT-a和≤20 U/kg aboBoNT-a剂量后为中度和短暂性损伤,而在≥20 U/kg onaBoNT-a和40 U/kg aboBoNT-a剂量时为严重和持久性损伤(检查长达14天)。此外,与对照组相比,较低的毒素剂量阻止了正常的体重增加,而较高的剂量诱导了显著的体重减轻(≥20 U/kg的onaBoNT-A和40 U/kg的aboBoNT-A)。根据剂量的不同,常用的BoNT-A制剂会导致大鼠周围肌肉的局部松弛和全身不良反应。因此,为了避免毒素可能不必要的局部或系统传播,在临床前行为研究中,无论毒素应用的地点和剂量如何,都必须仔细给药和运动测试。
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The safety of botulinum neurotoxin type A's intraarticular application in experimental animals

In vivo studies of botulinum neurotoxin type A (BoNT-A) enabled characterization of its activity in the nociceptive sensory system separate from its preferred action in motor and autonomic nerve terminals. However, in the recent rodent studies of arthritic pain which employed high intra-articular (i.a.) doses (expressed as a total number of units (U) per animal or U/kg), possible systemic effects have not been conclusively excluded. Herein we assessed the effect of two pharmaceutical preparations, abobotulinumtoxinA (aboBoNT-A, 10, 20, and 40 U/kg corresponding to 0.05, 0.11, and 0.22 ng/kg neurotoxin) and onabotulinumtoxinA (onaBoNT-A, 10 and 20 U/kg corresponding to 0.09 and 0.18 ng/kg, respectively) injected into the rat knee, on safety-relevant readouts: digit abduction, motor performance and weight gain during 14 days post-treatment.

The i. a. toxin produced dose-dependent impairment of the toe spreading reflex and rotarod performance, which was moderate and transient after 10 U/kg onaBoNT-A and ≤20 U/kg aboBoNT-A doses, and severe and long-lasting (examined up to 14 days) after ≥20 U/kg of onaBoNT-A and 40 U/kg aboBoNT-A. In addition, lower toxin doses prevented the normal weight gain compared to controls, while higher doses induced marked weight loss (≥20 U/kg of onaBoNT-A and 40 U/kg aboBoNT-A).

Commonly employed BoNT-A formulations, depending on the doses, cause local relaxation of the surrounding muscles and systemic adverse effects in rats. Thus, to evade possible toxin unwanted local or systemic spread, careful dosing and motor testing should be mandatory in preclinical behavioral studies, irrespective of the sites and doses of toxin application.

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来源期刊
Toxicon: X
Toxicon: X Pharmacology, Toxicology and Pharmaceutics-Toxicology
CiteScore
6.50
自引率
0.00%
发文量
33
审稿时长
14 weeks
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