Page C P, Spina D
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, Franklin Wilkins Building, London SE1 9NH, UK.
Handb Exp Pharmacol. 2011(204):391-414. doi: 10.1007/978-3-642-17969-3_17.
Phosphodiesterase 4 (PDE4) belongs to a family of enzymes which catalyzes the breakdown of 3, 5'-adenosine cyclic monophosphate (cAMP) and is ubiquitously expressed in inflammatory cells. There is little evidence that inflammatory diseases are caused by increased expression of this isoenzyme, although human inflammatory cell activity can be suppressed by selective PDE4 inhibitors. Consequently, there is intense interest in the development of selective PDE4 inhibitors for the treatment of a range of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and psoriasis. Recent clinical trials with roflumilast in COPD have confirmed the therapeutic potential of targeting PDE4 and recently roflumilast has been approved for marketing in Europe and the USA, although side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss, may limit the use of this drug class, at least when administered by the oral route. However, a number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects of PDE4 inhibitors, including delivery via the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibitors, and/or antisense biologicals targeted toward PDE4.
磷酸二酯酶4（PDE4）属于一类催化3,5'-环磷酸腺苷（cAMP）分解的酶家族，在炎症细胞中普遍表达。几乎没有证据表明炎症性疾病是由该同工酶表达增加引起的，尽管选择性PDE4抑制剂可抑制人类炎症细胞活性。因此，人们对开发选择性PDE4抑制剂以治疗一系列炎症性疾病，包括哮喘、慢性阻塞性肺疾病（COPD）、炎症性肠病和银屑病，有着浓厚的兴趣。最近在COPD患者中使用罗氟司特的临床试验证实了靶向PDE4的治疗潜力，最近罗氟司特已在欧洲和美国获批上市，尽管诸如胃肠道不适，尤其是恶心、呕吐以及头痛和体重减轻等副作用可能会限制这类药物的使用，至少口服给药时如此。然而，目前正在探索多种策略以提高PDE4抑制剂的临床疗效并减少其副作用，包括通过吸入途径给药、开发无催吐作用的PDE4抑制剂、混合PDE抑制剂和/或靶向PDE4的反义生物制剂。
