Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions
Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions
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DOI：
10.1016/j.taap.2010.06.012
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发表时间：
2010-09-15
影响因子：
3.8
通讯作者：
Picard, Sandra
中科院分区：
文献类型：
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作者：
Goineau, Sonia;Rompion, Sonia;Picard, Sandra
自由动物全身体积描记法虽然是安全药理学中评价新药呼吸风险最常用的方法，但不适当的实验条件可能会掩盖某些物质的有害副作用。如果在标准的实验条件下，即正常的空气呼吸和昼夜节律，可以很容易地在啮齿动物身上观察到刺激性或扩张支气管的作用，那么药物引起的呼吸抑制仍然更难检测到。本研究旨在比较Wistar大鼠、Duncan Hartley豚鼠和BALB/c小鼠对茶碱(50或100 mg/kg P.O.)的呼吸特性的反应性。或吗啡(30 mg/kg ip)。在不同的条件下(100%空气和5%CO(2)富含空气、白天和黑暗阶段)，为每个物种选择最合适的实验条件，以进行安全的呼吸道调查。我们的结果表明，在常压下，吗啡的呼吸抑制作用在小鼠身上很容易观察到，在豚鼠身上很少观察到，在大鼠身上在任何一天的阶段都不能检测到。轻微的高碳酸血症增强了大鼠对吗啡的反应性，但对豚鼠没有影响，重要的是，它们不会削弱大鼠对茶碱的刺激和支气管扩张的反应性，茶碱是安全药理学研究中最广泛使用的参照剂。总之，应考虑与非侵入性全身体积描记相关的高碳酸血症条件，以优化对大鼠的吗啡类物质的呼吸抑制潜力或新药的呼吸刺激效应的评估，大鼠是啮齿动物安全性和毒理学研究中应用最广泛的物种。(C)2010 Elsevier Inc.保留所有权利。
Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100 mg/kg p.o.) or morphine (30 mg/kg i.p.) under varying conditions (100% air versus 5% CO(2)-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used reference agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations. (C) 2010 Elsevier Inc. All rights reserved.