Swine models in the design of more effective medical countermeasures against organophosphorus poisoning
Swine models in the design of more effective medical countermeasures against organophosphorus poisoning
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DOI：
10.1016/j.tox.2006.09.013
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发表时间：
2007-04-20
期刊：
影响因子：
4.5
通讯作者：
Worek, F.
中科院分区：
文献类型：
--
作者：
Dorandeu, F.;Mikler, J. R.;Worek, F.
虽然药物安全性评估中最常用的三种大型哺乳动物仍然是狗、猕猴和狨猴，但猪，尤其是小型猪，多年来也被广泛用于许多毒理学研究。猪具有许多有趣的生物学和生理学特征。皮肤特性与人类的相似性导致了广泛的体外和体内研究。由于猪和人类生理学的共同特征，人们对心血管研究以及麻醉学和重症监护医学特别感兴趣。尽管有关猪大脑结构和功能的知识仍然不完整，但数据确实存在。药代动力学和毒代动力学研究所需的多次血液采样是可能的，也可以使用人类临床环境中使用的设备进行多参数监测和干预。实用性（操作）、科学性（减轻压力）和伦理性（侵入性监测）原因导致研究团队将麻醉纳入他们的范式中，这使得数据分析变得越来越困难。尽管没有科学数据证实，但在公众认知中，猪似乎处于非人类灵长类动物和通常称为宠物（即狗和猫）和啮齿类动物之间的中间位置。猪模型的优点证明了使用这些动物来设计针对已知化学战剂（神经毒剂、糜烂剂和肺损伤剂）的更有效的医疗对策是合理的。在发展中国家，接触有机磷 (OP) 农药是一个严重的健康问题，而致命的军用神经毒剂导致 OP 中毒不仅引起军事关注，而且构成恐怖主义威胁。当决策过程中可用的实验数据很少且人类临床数据稀疏时，根据 OP 中毒的实际情况制定治疗方案至关重要。我们将通过两个例子来阐述猪模型在 OP 对策中的一些优点和缺点。首先，我们将介绍与麻醉使用相关的问题。实验性有机磷中毒，其次我们将展示如何将猪实验的结果整合到基于动力学的动态模型中以评估肟功效。在将其作为首选非啮齿动物模型之前，对猪的 OP 中毒（比较毒代动力学、药代动力学和生物化学）有更好的了解是绝对必要的。然而，模型中存在大量关于麻醉和不同类型休克的数据，有利于其用于评估复杂情况，例如OP中毒患者的麻醉和复合损伤。 (C) 2006 Elsevier Ireland Ltd. 保留所有权利。
Although the three most commonly used large mammal species in the safety assessment of drugs remain the dog, the macaque and the marmoset, swine, especially minipigs, have also been widely used over the years in many toxicological studies. Swine present a number of interesting biological and physiological characteristics. Similarities in skin properties with humans have led to extensive in vitro and in vivo studies. There is a specific interest in cardiovascular research, as well as in anaesthesiology and critical care medicine due to common features of swine and human physiology. Although knowledge of swine brain structure and functions remains incomplete, data does exist. The multiple blood sampling that is necessary in pharmacokinetic and toxicokinetic studies are possible, as well as multiparametric monitoring and interventions with equipment used in human clinical settings. Practicality (handling), scientific (stress reduction) and ethical (invasive monitoring) reasons have led research teams to incorporate anaesthesia into their paradigms which makes the analysis of data increasingly difficult. Although not substantiated by scientific data, the swine appears to have an intermediate position in the scale of public perception between non-human primates and animals commonly referred to as pets (i.e. dogs and cats) and rodents. The benefits of the swine model justify the use of these animals in the design of more effective medical countermeasures against known chemical warfare agents (nerve agents, vesicants and lung damaging agents). Exposure to organophosphorus (OP) pesticides represents a severe health issue in developing countries, while OP intoxication with the more lethal military nerve agents is not only of military concern but also a terrorist threat. Tailoring therapeutic regimens to the reality of OP poisoning is of the utmost importance when little experimental data and sparse human clinical data are available in the decision making process. We will present some of the advantages and disadvantages of the swine model in OP countermeasures elaborating on two examples. First, we will present the issues related to the use of anaesthesia during. experimental OP poisoning and second we will show how results from experiments with swine can be integrated into a kinetic-based dynamic model to evaluate oxime efficacy. A better knowledge of OP poisoning in swine (comparative toxicokinetics, pharmacokinetics and biochemistry) is definitely necessary before accepting it as a first choice non-rodent model. However, there exists a large amount of data in themodel on anaesthesia and different types of shock favouring their use for evaluation of complex situations such as the anaesthesia of OP poisoned patients and combined injuries. (C) 2006 Elsevier Ireland Ltd. All rights reserved.