Pharmacological Evaluation of Selective α2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion
Pharmacological Evaluation of Selective α2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion
复制标题
选择性α2c-肾上腺素能激动剂在鼻充血实验动物模型中的药理学评价
DOI：
10.1124/jpet.113.210666
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
R. Mcleod
中科院分区：
文献类型：
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作者：
Yanlin Jia;G. Mingo;J. Hunter;G. Lieber;J. Palamanda;H. Mei;C. Boyce;M. Koss;Yongxin Yu;M. Cicmil;J. Hey;R. Mcleod
鼻塞是许多上呼吸道疾病的最麻烦的症状之一。我们在鼻塞动物模型中描述了选择性α 2c-肾上腺素能激动剂的作用。在猪粘膜组织中，化合物A和化合物B收缩鼻静脉，对动脉仅有适度的影响。在体内实验中，我们检查了鼻减充血剂的剂量-反应特征、药代动力学/药效学关系、作用持续时间、耐受性的潜在发展以及α 2c-肾上腺素能激动剂的局部疗效。鼻内化合物48/80（1%，75 µl）给药后，使用声学散射测量法测定鼻腔尺寸。在猫实验中，化合物48/80分别使鼻腔体积和最小横截面积减少77%和40%。口服化合物A（0.1-3.0 mg/kg）、化合物B（0.3-5.0 mg/kg）和d-伪麻黄碱（0.3和1.0 mg/kg）产生剂量依赖性缓解。与d-伪麻黄碱不同，化合物A和B不改变收缩压。化合物A产生强效缓解充血的血浆暴露量（EC 80）为500 nM，这与约4.0小时的作用持续时间密切相关。对化合物A（1.0 mg/kg p.o.）观察了为了研究化合物A和B的局部功效，在化合物48/80（治疗范例）后30分钟局部给予药物，其中两种药物都逆转了鼻塞。最后，在犬中证实了鼻充血活性。我们证明，α 2c-肾上腺素能受体激动剂在上呼吸道充血的动物模型中表现为鼻减充血剂，而没有心血管作用。
Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective α2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of α2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 µl). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1–3.0 mg/kg), compound B (0.3–5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC80) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that α2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.