Priapism prevention program for patients with Sickle Cell Disease

镰状细胞病患者阴茎异常勃起预防计划

• 批准号: 7843556
• 负责人: Arthur Louis Burnett
• 金额: $ 24.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-23 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843556
• 关键词: Accounting; Address; Animal Model; Basic Science; Biochemical; Biological Assay; Biological Markers; Biological Preservation; Biological Process; Biology; Blood Vessels; Blood flow; Chronic; Clinical; Clinical assessments; Cyclic GMP; Disease; Disease Management; Dose; Double-Blind Method; Down-Regulation; Environmental sludge; Equipment and supply inventories; Erectile dysfunction; Erythrocytes; Experimental Animal Model; Frequencies; Health Status; Human; Impairment; In Vitro; Individual; Inflammation; Intervention; Investigation; Label; Lead; Literature; Measurement; Measures; Medical; Medicine; Metric; Modeling; Molecular; Molecular Abnormality; Monitor; Muscle relaxation phase; Necrosis; Nitric Oxide; Oxidative Stress; Pathway interactions; Patients; Penile Erection; Pharmaceutical Preparations; Physiological; Physiology; Placebos; Population; Prevalence; Prevention program; Priapism; Quality of life; Quality-of-Life Assessment; Questionnaires; Randomized; Rattus; Recurrence; Relative (related person); Research; Role; Secondary Prevention; Sexual Health; Sickle Cell; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Smooth Muscle; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Treatment Protocols; Up-Regulation; Well in self; Work; base; comparative efficacy; design; erection; improved; in vivo; inhibitor/antagonist; instrument; male; meetings; molecular site; mouse model; nitrosative stress; penis; phosphodiesterase V; phosphoric diester hydrolase; placebo controlled study; pre-clinical; psychological distress; research study; sildenafil; stem; translational approach; week trial

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.

复发性缺血性priapism是一种不愿意的，过度的阴茎勃起的勃起障碍，遭受了困扰 大约40％的男性患有镰状细胞疾病。该疾病并不小，它的疾病 后果包括勃起组织损伤，勃起功能障碍和心理困扰。现在， 缺乏解决该疾病的令人满意的医疗干预措施，这在很大程度上是因为合理的基础 因为它的治疗仍然晦涩难懂。我们最近阐明了一种病理生理机制，该机制 涉及一氧化氮（NO）/环状鸟嘌呤一磷酸（CGMP）信号的损伤（勃起） 介体途径，导致阴茎中磷酸二酯酶5（PDES）功能的下调。 PDE在NO信号中起着调节作用，作为CGMP特异性降解磷酸二酯酶，是 因此，不足以控制体平滑肌肉放松，从而导致priapism。我们 还表明，慢性PDE抑制剂给药会导致PDES表达上调 阴茎组织。这些临床前观察结果支持了使用连续的长期PDE的建议 抑制剂疗法是对人类复发性培养主的干预。我们假设治疗 逆转阴茎中下调的PDES功能水平向规范范围，从而保护 反对该疾病的发作。为了检验这一假设，我们提出了一个翻译项目，其中包括 临床前研究这种治疗的作用机理和对其临床评估的临床评估 治疗镰状细胞相关的培养基的实用程序。临床前组件将包括 用原型PDES抑制剂处理后的分子和生理勃起实验 西地那非在实验性小鼠镰状细胞疾病模型中。临床组件将是单单元， 随机，双盲，安慰剂对照研究，将对西地那非进行管理 镰状细胞疾病和priapism的患者不断。通过这种翻译方法， 项目可能在为患者引入有效的二级预防计划方面提供关键的一步 与镰状细胞疾病相关的priapism的使用，并得到其使用的合理基础的支持。该项目可能会导致 保存个人的性健康和心理健康方面的重大进步 镰状细胞疾病受priapism的困扰。