Truchetti Geoffrey, Troncy Eric, Robichaud Annette, Gold Leslie, Schuessler Thomas, Maghezzi Said, Bassett Leanne, Authier Simon
Animal Research Group in Pharmacology of Quebec (GREPAQ), Department of Veterinary Biomedical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, P.O. Box 5000, Saint-Hyacinthe, Quebec, J2S 7C6, Canada; Département de Psychiatrie et Neurosciences, Centre Hospitalier Universitaire Laval, Université Laval, 2705 Boulevard Laurier, Québec, Québec, G1V 4G2, Canada.
Animal Research Group in Pharmacology of Quebec (GREPAQ), Department of Veterinary Biomedical Sciences, Faculté de Médecine Vétérinaire, Université de Montréal, P.O. Box 5000, Saint-Hyacinthe, Quebec, J2S 7C6, Canada.
J Pharmacol Toxicol Methods. 2014 Jul-Aug;70(1):48-54. doi: 10.1016/j.vascn.2014.03.171. Epub 2014 Apr 1.
When the no observed adverse effect level (NOAEL) is determined by respiratory safety pharmacology, follow-up studies are warranted and may include airway resistance and compliance. Respiratory mechanics in commonly used large animal species (Beagle dogs, Cynomolgus monkeys, and Göttingen minipigs) were compared.
Eighteen animals were used (3/sex/species) in an anesthetized model (propofol infusion) with pancuronium as a neuromuscular blocker. Parameters of respiratory mechanics were evaluated at baseline and at peak drug effect. Resistance (Rrs) and elastance (Ers) were measured by applying a single frequency forced oscillation (0.5 Hz) to the subject's airway opening and fitting the flow, volume and pressure data to the single compartment model of the lung. Increasing doses of intravenous (IV) methacholine were administered in all three species, as well as doubling aerosolized concentrations of the same bronchoconstrictor agent before and after inhaled albuterol.
The slope of the IV methacholine dose-response curve for Rrs was similar in dogs and monkeys and both species differed from minipigs, which showed greater reactivity. At the highest IV dose tested, minipigs also reached higher levels of bronchoconstriction than the other two species. They were followed, in decreasing order, by dogs and monkeys. Albuterol induced a significant decrease in the slope of the dose-response curve only in dogs and monkeys.
Scientific literature is available on respiratory mechanics in monkeys and dogs but not in minipigs. Our results suggest that minipigs were more reactive than dogs and monkeys to IV methacholine while less sensitive to inhaled albuterol.
当通过呼吸安全药理学确定未观察到不良反应水平（NOAEL）时，有必要进行后续研究，可能包括气道阻力和顺应性。对常用大型动物物种（比格犬、食蟹猴和哥廷根小型猪）的呼吸力学进行了比较。
在以丙泊酚输注麻醉并使用泮库溴铵作为神经肌肉阻滞剂的模型中使用了18只动物（每种性别/物种3只）。在基线和药物效应峰值时评估呼吸力学参数。通过向受试者的气道开口施加单频强迫振荡（0.5Hz）并将流量、容积和压力数据拟合到肺的单室模型来测量阻力（Rrs）和弹性（Ers）。在所有三个物种中静脉注射递增剂量的乙酰甲胆碱，并且在吸入沙丁胺醇前后将相同支气管收缩剂的雾化浓度加倍。
狗和猴的Rrs静脉注射乙酰甲胆碱剂量-反应曲线斜率相似，且这两个物种与小型猪不同，小型猪表现出更高的反应性。在测试的最高静脉注射剂量下，小型猪的支气管收缩水平也高于其他两个物种。其次是狗和猴，顺序递减。沙丁胺醇仅在狗和猴中引起剂量-反应曲线斜率的显著降低。
关于猴和狗的呼吸力学有科学文献，但关于小型猪的没有。我们的结果表明，小型猪对静脉注射乙酰甲胆碱的反应性高于狗和猴，而对吸入沙丁胺醇的敏感性较低。
