Comparison of whole body and head out plethysmography using respiratory stimulant and depressant in conscious rats
Comparison of whole body and head out plethysmography using respiratory stimulant and depressant in conscious rats
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DOI：
10.1016/j.vascn.2011.10.001
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发表时间：
2012-01-01
影响因子：
1.9
通讯作者：
Kancharla, Baburao
中科院分区：
文献类型：
--
作者：
Nirogi, Ramakrishna;Shanmuganathan, Dhanalakshmi;Kancharla, Baburao
引言：呼吸安全性评估是新化学实体最重要的要求之一（ICH指导原则S7 A）。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，以寻找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。研究方法：采用头外容积描记法和全身容积描记法监测呼吸频率（RR）、潮气量（TV）、每分钟通气量（MV）和呼气中段流量（EF 50）等呼吸功能的典型参数。在两种模型中评价了呼吸兴奋剂茶碱（100 mg/kg）和呼吸抑制剂利氮卓（100 mg/kg）的作用。普萘洛尔（60 mg/kg）也用于比较头部和全身体积描记法，因为其对气道功能的支气管收缩作用。结果：茶碱引起全身和头部体积描记法的TV、EF 50和MV明显增加。在全身体积描记法中，茶碱显著增加RR，但在头外体积描记法中未观察到这种增加。在头外容积描记法中，利血平显著降低RR、TV、EF_（50）和MV，而在全身容积描记法中，利血平仅显著降低TV。普萘洛尔在全身和头部体积描记法中均观察到TV显著降低。讨论：我们得出结论，与全身体积描记法相比，使用头外体积描记法可以准确评估排尿功能。我们的实验结果EF 50从非侵入性的方法表明，可靠的评估气道功能需要额外的侵入性方法。(C)2011 Elsevier Inc. All rights reserved.
Introduction: 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. Methods: 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 (100 mg/kg) and respiratory depressant chlordiazepoxide (100 mg/kg) were evaluated in both models. Propranolol (60 mg/kg) was also used to compare head out and whole body plethysmography because of its bronchoconstrictor effects on airway function. Results: 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. Discussion: 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. (C) 2011 Elsevier Inc. All rights reserved.