Airway Disease Infection Section National Heart Lung Institute Imperial College London London United Kingdom; MRC and Asthma UK Centre for Allergic Mechanisms of Asthma London United Kingdom.
Corporate Pre-clinical R&D Chiesi Farmaceutici S.p.A. Parma Italy.
Pharmacol Res Perspect. 2016 Jan 15;4(1):e00202. doi: 10.1002/prp2.202. eCollection 2016 Feb.
Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose-response curve (1000-0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP-10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV-induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast.
呼吸道病毒感染会引发哮喘和慢性阻塞性肺疾病（COPD）恶化，其中大多数恶化是由鼻病毒感染引起的。哮喘和 COPD 恶化都不能很好地通过类固醇治疗来控制，因此人们非常有兴趣寻找改善治疗或联合治疗来控制恶化。CHF6001 是一种新型、吸入性、高选择性磷酸二酯酶 4（PDE4）抑制剂。我们使用体外人支气管上皮细胞（BEAS-2B），研究了 CHF6001 对鼻病毒（RV1B）诱导细胞因子的潜在抗炎作用。通过实时 PCR 测量细胞因子 mRNA，通过 ELISA 测量蛋白释放。CHF6001 以 7 点剂量反应曲线（1000-0.001 nmol/L）作为 1.5 小时预处理，在感染前与罗氟司特进行比较。罗氟司特和 CHF6001 均以浓度依赖性方式降低 RV1B 诱导的 IL-8、IL-29、IP-10 和 RANTES mRNA 和蛋白。一般来说，CHF6001 在降低 IL-8、IL-29、IP-10 和 RANTES mRNA 和蛋白释放方面比罗氟司特的效力高 13-16 倍（亚纳摩尔 EC50 值），但具有相似的功效。与皮质类固醇丙酸氟替卡松（1 nmol/L）联合使用时，CHF6001 具有相加作用，与单独使用皮质类固醇或 CHF6001 相比，可显著降低 RV 诱导的细胞因子。联合低剂量皮质类固醇和低剂量 CHF6001 的疗效与高剂量皮质类固醇或 CHF6001 单独使用的疗效相似，表明联合用药具有皮质类固醇和 PDE4 抑制剂节约作用。总体结果表明，PDE4 抑制剂对病毒诱导的炎症介质具有抗炎活性，CHF6001 比罗氟司特更有效。
