Nirogi Ramakrishna, Shanmuganathan Dhanalakshmi, Jayarajan Pradeep, Abraham Renny, Kancharla Baburao
Department of Pharmacology, Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road No 5, Avenue-7, Banjara Hills, Hyderabad, 500034, India.
J Pharmacol Toxicol Methods. 2012 Jan;65(1):37-43. doi: 10.1016/j.vascn.2011.10.001. Epub 2011 Oct 14.
Assessment of respiratory safety is one of the most important requirements for new chemical entity (ICH Guideline S7A). The aim of the present study was to compare and validate respiratory safety pharmacology models in conscious rats, to find out the most appropriate method for detection of drug-induced adverse effects on respiratory function in preclinical safety studies.
Head out plethysmography and whole body plethysmography methods were used to monitor typical parameters of ventilatory function like respiratory rate (RR), tidal volume (TV), minute volume (MV) and mid expiratory flow (EF50). The effects of respiratory stimulant theophylline (100mg/kg) and respiratory depressant chlordiazepoxide (100mg/kg) were evaluated in both models. Propranolol (60mg/kg) was also used to compare head out and whole body plethysmography because of its bronchoconstrictor effects on airway function.
Theophylline caused a significant increase in TV, EF50 and MV in both whole body and head out plethysmography. In whole body plethysmography, theophylline significantly increased RR, but this increase was not observed in head out plethysmography. Chlordiazepoxide significantly decreased RR, TV, EF50 and MV in head out plethysmography, but it significantly reduced only TV in whole body plethysmography. A significant reduction in TV was observed with propranolol in both whole body and head out plethysmography.
We conclude that ventilatory function can be accurately assessed using head out plethysmography compared to whole body plethysmography. Our experimental results of EF50 from non-invasive methods suggest that reliable assessment of airway function demand additional invasive methods.
呼吸安全性评估是新化学实体的最重要要求之一（ICH指南S7A）。本研究的目的是比较和验证清醒大鼠的呼吸安全药理学模型，以找出在临床前安全性研究中检测药物诱导的呼吸功能不良反应的最合适方法。
采用头部外置体积描记法和全身体积描记法监测通气功能的典型参数，如呼吸频率（RR）、潮气量（TV）、分钟通气量（MV）和呼气中期流速（EF50）。在两种模型中评估呼吸兴奋剂茶碱（100mg/kg）和呼吸抑制剂氯氮卓（100mg/kg）的作用。由于普萘洛尔对气道功能有支气管收缩作用，还使用它来比较头部外置和全身体积描记法。
在全身和头部外置体积描记法中，茶碱均导致TV、EF50和MV显著增加。在全身体积描记法中，茶碱显著增加RR，但在头部外置体积描记法中未观察到这种增加。氯氮卓在头部外置体积描记法中显著降低RR、TV、EF50和MV，但在全身体积描记法中仅显著降低TV。在全身和头部外置体积描记法中，普萘洛尔均导致TV显著降低。
我们得出结论，与全身体积描记法相比，使用头部外置体积描记法可以准确评估通气功能。我们从非侵入性方法获得的EF50实验结果表明，可靠评估气道功能需要额外的侵入性方法。
