Phosphodiesterases as Targets for Intermittent Claudication
Phosphodiesterases as Targets for Intermittent Claudication
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DOI：
10.1007/978-3-642-17969-3_9
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发表时间：
2011-01-01
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影响因子：
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通讯作者：
Kambayashi, Junichi
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文献类型：
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作者：
Liu, Yongge;Shakur, Yasmin;Kambayashi, Junichi
间歇性跛行(IC)是下肢外周动脉疾病(PAD)最常见的形式之一，最常见的原因是动脉粥样硬化。其临床表现为运动性缺血引起四肢肌肉疲劳、不适或疼痛，从而限制了IC患者行走和运动的能力。除了改变生活方式(饮食、锻炼和戒烟)外，还需要药物治疗。病理上，动脉粥样硬化病变导致步行/锻炼时腿部肌肉的氧气供应和代谢需求不匹配。这会使肌肉遭受反复的缺血和再灌注损伤，从而改变结构和氧化代谢，导致氧气供应利用不足。尽管进行了广泛的研究工作，西洛他唑和己酮可可碱仍是仅有的用于缓解IC症状的药物，西洛他唑在这些患者的步行距离和生活质量方面显示出显著改善。西洛他唑最初是作为PDE3抑制剂开发的，后来被发现还有其他几种药理作用，它的成功归功于它对血小板、内皮、平滑肌和脂类的多因素作用。以西洛他唑为例，我们讨论了在IC中靶向PDE的原理和陷阱，以及开发新的更有效的药物治疗的潜在策略。
Intermittent claudication (IC) is one of the most frequent forms of lower extremity peripheral arterial disease (PAD) and is most commonly caused by arterial atherosclerosis. Its clinical manifestation includes fatigue, discomfort, or pain occurring in limb muscles due to exercise-induced ischemia, thus limiting the ability of IC patients to walk and exercise. In addition to lifestyle changes (diet, exercise, and smoking cessation), pharmacological treatments are needed. Pathologically, atherosclerotic lesions cause a mismatch in oxygen supply and metabolic demand in the leg muscles during walking/exercise. This subjects the muscles to repeated ischemia and reperfusion injury that can alter structure and oxidative metabolism, resulting in insufficient utilization of oxygen supply. Despite extensive research efforts, cilostazol and pentoxifylline are the only drugs indicated for relieving the symptoms of IC, with cilostazol demonstrating significant improvement in walking distance and quality of life in these patients. Originally developed as a PDE3 inhibitor, cilostazol was later found to have several other pharmacological actions, and its success has been attributed to its multifactorial actions on platelets, endothelium, smooth muscle, and lipid profiles. Using cilostazol as an example, we discuss the rationales and pitfalls of targeting PDEs in IC, and potential strategies for the development of new and more effective pharmacological treatments.