Harris David, Graham Mags, Price Joanne, Munro Fiona, Templeton Alison, Young Ross, Paterson Kirsty, Anderson Lynne, Gillies Susanne, McKendrick Sue, Low Gill, Patmore Leslie, Bodine Rebeccah, Jeanne Kallman Mary, Hoffman Wherly P, Lee Cindy, Wolff Ronald K
Department of Pharmacology, Quintiles Limited, Heriot-Watt University Research Park, Riccarton, Edinburgh EH14 4AP, UK.
J Pharmacol Toxicol Methods. 2005 Jul-Aug;52(1):83-9. doi: 10.1016/j.vascn.2005.03.007.
The ICH guideline S7A recommends that the effects of drugs on the respiratory system are evaluated in laboratory mammals prior to administration in man. Previously, animals have been placed in plethysmography chambers for short durations. This study investigates the possibility of restraining animals in chambers for a longer duration to assess respiratory function over extended periods.
Respiratory function in conscious rats was assessed using plethysmography chambers where the rat body was enclosed in a sealed chamber while the head was free. Thoracic movements were measured by pressure transducers linked to a Buxco amplifier system and respiratory parameters were captured and analyzed by the Notocord HEM data acquisition system. Each animal was subjected to 5 acclimatization sessions of escalating duration (1, 2, 4, 5, and 6 hours (h)) over 5 days prior to testing, with a baseline recording session conducted the day prior to dosing. Animals (8 males/group) were dosed subcutaneously with saline or bethanecol (3, 10, or 30 mg/kg) and placed in the chambers for 6 h of continuous recording. Additionally, a recording session was conducted at 24 h post-dose.
Subcutaneous administration of 30 mg/kg bethanecol decreased respiration rate by up to 33% during the first 1.5 h post-dose and increased tidal volume by up to 46% from 0.25 to 1.25 h post-dose when compared to vehicle group data. A decrease in minute volume of up to 33% was observed 0.25 h following administration of the 10 and 30 mg/kg doses.
These data show a respiratory depression caused by the cholinergic agonist bethanecol, an effect partially compensated for by an increase in tidal volume. This also demonstrates the ability to continuously restrain and record respiratory parameters in conscious rats for up to 6 h without any negative impact on the quality of the data.
国际人用药品注册技术协调会（ICH）的S7A指南建议，在人体给药前，应在实验哺乳动物中评估药物对呼吸系统的影响。此前，动物被置于体积描记室的时间较短。本研究探讨了将动物较长时间限制在室中以评估较长时间段内呼吸功能的可能性。
使用体积描记室评估清醒大鼠的呼吸功能，大鼠身体置于密封室中，头部自由。胸部运动通过与Buxco放大器系统相连的压力传感器进行测量，呼吸参数由Notocord HEM数据采集系统捕获并分析。在测试前5天，每只动物进行5次持续时间递增（1、2、4、5和6小时（h））的适应期，给药前一天进行基线记录。动物（每组8只雄性）皮下注射生理盐水或氨甲酰甲胆碱（3、10或30mg/kg），并置于室中连续记录6小时。此外，在给药后24小时进行一次记录。
与赋形剂组数据相比，皮下注射30mg/kg氨甲酰甲胆碱在给药后前1.5小时内呼吸频率降低高达33%，给药后0.25至1.25小时潮气量增加高达46%。给予10和30mg/kg剂量后0.25小时观察到分钟通气量降低高达33%。
这些数据显示了胆碱能激动剂氨甲酰甲胆碱引起的呼吸抑制，潮气量增加可部分补偿这种作用。这也证明了在清醒大鼠中连续限制并记录呼吸参数长达6小时而对数据质量无任何负面影响的能力。
