Kumar Rakesh, Khan Mohd Imran, Panwar Amit, Vashist Bhavishya, Rai Santosh Kumar, Kumar Anil
New Drug Discovery Research, Mankind Research Centre, Mankind Pharma Limited, Plot No 191-E, Sector 4-II, IMT Manesar, Gurugram, India-122051.
Open Respir Med J. 2024 Nov 13;18:e18743064340418. doi: 10.2174/0118743064340418241021095046. eCollection 2024.
Chronic Obstructive Pulmonary Disease (COPD) is associated with cough, sputum production, and a reduction in lung function, quality of life, and life expectancy. Currently, bronchodilator combinations (β2-agonists and muscarinic receptor antagonists, dual therapy) and bronchodilators combined with inhaled corticosteroids (ICS), triple therapy, are the mainstays for the management of COPD. However, the use of ICS in triple therapy has been shown to increase the risk of pneumonia in some patients. These findings have laid the foundation for developing new therapies that possess both anti-inflammatory and/or bronchodilation properties. Phosphodiesterase-4 (PDE4) inhibitors have been reported as an effective therapeutic strategy for inflammatory conditions, such as asthma and COPD, but their use is limited because of class-related side effects. Efforts have been made to mitigate these side effects by targeting the PDE4B subtype of PDE4, which plays a pivotal role in the anti-inflammatory effects. Unfortunately, no selective oral PDE4B inhibitors have progressed to clinical trials. This has led to the development of inhaled PDE4 inhibitors to minimize systemic exposure and maximize the therapeutic effect. Another approach, the bronchodilation property of PDE3 inhibitors, is combined with anti-inflammatory PDE4 inhibitors to develop dual inhaled PDE4/PDE3 inhibitors. A few of these dual inhibitors have shown positive effects and are in phase 3 studies. The current review provides an overview of various PDE4 inhibitors in the treatment of COPD. The possibility of studying different selective PDE4 inhibitors and dual PDE3/4 inhibitors in combination with currently available treatments as a way forward to increase their therapeutic effectiveness is also emphasized.
慢性阻塞性肺疾病(COPD)与咳嗽、咳痰以及肺功能、生活质量和预期寿命下降有关。目前,支气管扩张剂联合使用(β2受体激动剂和毒蕈碱受体拮抗剂,双重疗法)以及支气管扩张剂与吸入性糖皮质激素(ICS)联合使用,三重疗法,是COPD管理的主要方法。然而,在三重疗法中使用ICS已被证明会增加一些患者患肺炎的风险。这些发现为开发具有抗炎和/或支气管扩张特性的新疗法奠定了基础。磷酸二酯酶-4(PDE4)抑制剂已被报道为治疗炎症性疾病(如哮喘和COPD)的有效治疗策略,但其使用因类相关副作用而受到限制。人们已努力通过靶向在抗炎作用中起关键作用的PDE4的PDE4B亚型来减轻这些副作用。不幸的是,尚无选择性口服PDE4B抑制剂进入临床试验。这导致了吸入性PDE4抑制剂的开发,以尽量减少全身暴露并最大化治疗效果。另一种方法是将PDE3抑制剂的支气管扩张特性与抗炎PDE4抑制剂相结合,开发双重吸入性PDE4/PDE3抑制剂。其中一些双重抑制剂已显示出积极效果,正处于3期研究中。本综述概述了各种PDE4抑制剂在治疗COPD中的应用。还强调了研究不同的选择性PDE4抑制剂和双重PDE3/4抑制剂与现有治疗方法联合使用以提高其治疗效果的可能性。