PDE5 inhibitor drugs for use in dementia.
PDE5 inhibitor drugs for use in dementia.
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DOI：
10.1002/trc2.12412
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Cheng, Feixiong
中科院分区：
文献类型：
--
作者：
Hainsworth, Atticus H;Arancio, Ottavio;Elahi, Fanny M;Isaacs, Jeremy D;Cheng, Feixiong
阿尔茨海默病和相关痴呆症 (ADRD) 仍然是一项重大的医疗保健挑战，获得许可的药物很少。重新利用现有药物可以预防和治疗。磷酸二酯酶-5 (PDE5) 广泛表达于血管肌细胞、神经元和神经胶质细胞中。美国食品和药物管理局批准的强效、选择性 PDE5 抑制剂（西地那非、伐地那非、他达拉非）已作为血管扩张剂用于治疗勃起功能障碍和肺动脉高压。动物数据表明 PDE5 抑制剂具有认知益处。在人类中，真实世界的患者数据表明西地那非和伐地那非与降低痴呆风险相关。虽然最近的一项急性他达拉非对脑血流量的影响是中性的，但 PDE5 抑制可能对脑血管或突触功能产生慢性作用。我们对 PDE5 抑制剂治疗 ADRD 的潜在效用提出了看法。我们的结论是，有必要对 PDE5 抑制剂进行进一步的前瞻性临床试验。药物的选择将取决于大脑渗透性、老年人的耐受性、半衰期和脱靶效应。有效的磷酸二酯酶 5 (PDE5) 抑制剂在临床上用作血管扩张剂。在动物中，PDE5 抑制剂可增强突触功能和认知能力。在人类中，PDE5 抑制剂西地那非可降低患阿尔茨海默病的风险。获得许可的 PDE5 抑制剂有可能重新用于治疗痴呆症。 PDE5 抑制剂的前瞻性临床试验是必要的。
Alzheimer's disease and related dementias (ADRD) remain a major health‐care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase‐5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration–approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real‐world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half‐life, and off‐target effects. Potent phosphodiesterase‐5 (PDE5) inhibitors are in clinical use as vasodilators. In animals PDE5 inhibitors enhance synaptic function and cognitive ability. In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease. Licensed PDE5 inhibitors have potential for repurposing in dementia. Prospective clinical trials of PDE5 inhibitors are warranted.