Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma
Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma
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DOI：
10.1111/j.1398-9995.2009.02156.x
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发表时间：
2010-01-01
期刊：
影响因子：
12.4
通讯作者：
Getz, E. B.
中科院分区：
文献类型：
--
作者：
Tomkinson, A.;Tepper, J.;Getz, E. B.
背景：鬼臼毒素是一种来源于人白细胞介素4(IL-4)的重组蛋白，与IL-4Rα结合，是IL-4和IL-13的竞争性拮抗剂。本文报道的研究比较了皮下给药(皮下注射)对变应原诱导的气道高反应性(AHR)和气道嗜酸性粒细胞增多症(Sc)的剂量范围效应。或通过吸入猪蛔虫敏感的食蟹猴，目的是阐明Pitrakinra的抗哮喘作用的主要部位。方法：在三次过敏原暴露前后，测定吸入乙酰甲胆碱和支气管肺泡灌洗液细胞成分的气道反应性，每天两次，为期一周。南加州大学。或吸入松果菊或安慰剂治疗。在b.i.d观察到，与对照组(P<；0.05)相比，马胆碱PC100的最大作用是增加2.8到3.8倍。南加州大学。剂量为0.05-0.5 mg/kg。吸入苦参碱也显著降低了AHR，与对照组(P<；0.05)相比，名义b.i.d时，乙酰甲胆碱PC100的最大效应相似，增加了2.8到3.2倍。剂量为3-100毫克。吸入后对AHR的最大影响是通过皮下途径观察到无效的血药浓度。两种给药途径对肺嗜酸性粒细胞增多症的影响均无统计学意义，尽管所有研究中肺内嗜酸性粒细胞计数均低于对照组。结论：肺内局部给药足以抑制AHR，这是哮喘的基本特征之一，表明吸入给药对特应性哮喘的治疗潜力。
P>Background:Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4R alpha and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum-sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action.Methods:Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment.Results:Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC100 relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05-0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC100 relative to control (P < 0.05) at nominal b.i.d. doses of 3-100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control.Conclusion:Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.