Priapism prevention program for patients with Sickle Cell Disease

复发性缺血性阴茎异常勃起是一种非故意的阴茎过度勃起的勃起障碍， 大约40%的男性患有镰状细胞病。这种紊乱并不是微不足道的， 后果包括勃起组织损伤、勃起功能障碍和心理痛苦。目前， 缺乏令人满意的医疗干预措施来解决这种疾病，这在很大程度上是因为缺乏合理的基础。 因为它的治疗方法还不清楚。我们最近阐明了一种病理生理机制， 涉及一氧化氮（NO）/环磷酸鸟苷（cGMP）信号传导的损伤（勃起 介导）途径，导致阴茎中磷酸二酯酶5型（PDE）功能下调。 PDE作为cGMP特异性降解磷酸二酯酶在NO信号传导中起调节作用， 因此在控制身体平滑肌松弛方面活性不足，导致阴茎异常勃起。我们 还表明，长期给予PDE抑制剂可导致PDEs表达上调， 阴茎组织这些临床前观察结果支持使用连续、长期PDE的建议 抑制剂疗法作为人类复发性阴茎异常勃起的干预。我们假设治疗 将阴茎中下调的PDE功能水平逆转至正常范围，从而保护 对抗疾病的发作为了验证这一假设，我们提出了一个翻译项目，其中包括 该治疗作用机制的临床前研究和其临床评估 用于治疗镰状细胞病相关的阴茎异常勃起。临床前部分将包括 用原型PDE抑制剂治疗后的分子和生理勃起实验 西地那非在镰状细胞病实验小鼠模型中的应用。临床部分将是一个电子病历， 一项随机、双盲、安慰剂对照研究，将给予西地那非 对镰状细胞病和阴茎异常勃起的患者进行治疗。通过这种翻译方法， 该项目可能为患者引入有效的二级预防计划提供关键一步 与镰状细胞病相关的阴茎异常勃起，并有合理的使用依据。该项目可能导致 在保护有性别歧视的人的性健康和心理健康方面取得了重大进展， 由阴茎异常勃起引起的镰状细胞病。

Recurrent ischemic priapism is an erection disorder of non-willful, excessive penile erection, which afflicts approximately 40% of male individuals with sickle cell disease. The disorder is not trivial, and its consequences include erectile tissue damage, erectile dysfunction, and psychological distress. Currently, satisfactory medical interventions to address the disorder are lacking, in large part because a rational basis for its treatment remains obscure. We have recently elucidated a pathophysiologic mechanism, which involves impairment in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling (erection mediatory) pathway, causing downregulation of phosphodiesterase type 5 (PDEs) function in the penis. PDEs, which serves a regulatory role in NO signaling as a cGMP-specific degradative phosphodiesterase, is therefore insufficiently active in controlling corporal smooth muscle relaxation, resulting in priapism. We have also shown that chronic PDEs inhibitor administration causes PDEs expressional upregulation in penile tissues. These preclinical observations have supported a proposal to use continuous, long-term PDEs inhibitor therapy as an intervention for recurrent priapism in humans. We hypothesize that the therapy reverses downregulated PDEs functional levels in the penis toward normative ranges, thereby protecting against episodes of the disorder. To test this hypothesis, we propose a translational project, which includes both preclinical investigation of the mechanism of action of this treatment and clinical assessment of its utility for treating sickle cell disease-associated priapism. The preclinical component will consist of molecular and physiologic erection experiments following treatment with the prototypical PDEs inhibitor sildenafil in an experimental mouse model of sickle cell disease. The clinical component will be a singlecenter, randomized, double-blind, placebo-controlled study, in which sildenafil will be administered continuously to patients with sickle cell disease and priapism. By way of this translational approach, this project may provide a critical step in introducing an effective, secondary prevention program for patients with sickle cell disease-associated priapism, supported by a rational basis for its use. The project may lead to a major advance in the preservation of the sexual health and psychological well-being of individuals with sickle cell disease afflicted by priapism.