OnabotulinumtoxinA (onaVoNT-A) vs Oral Tamsulosin for PBH & LUTS (#02-10-10-05)

OnabotulinumtoxinA (onaVoNT-A) 与口服坦索罗辛治疗 PBH 的比较

• 批准号: 8333782
• 负责人: CHRISTOPHER P SMITH
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333782
• 关键词: Adrenergic Agents; Adrenergic alpha-Antagonists; Adverse effects; Affect; Aftercare; Age; American; Androgens; Animal Model; Animals; Apoptosis; Atrophic; Benign Prostatic Hypertrophy; Biological Markers; Biopsy; Categories; Cells; Chemical Models; Data; Data Coordinating Center; Denervation; Detection; Diagnosis; Effectiveness; Epithelial; Epithelium; Future; Gene Expression; Genes; Grant; Growth; Growth Factor; Human; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Inflammation; Injection of therapeutic agent; Medical; Medical center; Methodology; Molecular Profiling; Morbidity - disease rate; Nerve; Neurotransmitters; Operative Surgical Procedures; Oral; Pathologic; Patients; Persons; Physiological; Placebos; Prostate; Publishing; Quality of life; RNA; Randomized; Regulation; Relative (related person); Role; Saline; Secondary to; Spinal cord injury; Symptoms; Therapeutic; Tissues; Urinary Retention; Urinary tract; Urinary tract infection; Veterans; adrenergic; afferent nerve; angiogenesis; animal data; arm; capsule; cholinergic; clinical efficacy; design; experience; improved; laser capture microdissection; lower urinary tract symptoms; male; men; nerve supply; prevent; prostate enlargement; public health relevance; relating to nervous system; response; standard of care; tamsulosin; transmission process; urologic; volunteer

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) and its related symptoms are a common condition that affects nearly half of men over age 50 and 90% of men over 80. Lower urinary tract symptoms (LUTS) caused by BPH can be very troublesome, affect an individual's quality of life significantly, and are costly. However, the mechanisms underlying BPH and its associated LUTS remain unclear. Increasing evidence documents a significant positive trophic effect of neural input on prostate growth and function. Nerves are required for BPH growth and function. This proposal hypothesizes that onabotulinumtoxinA (onaBoNT-A)'s greater effect on the prostate neural microenvironment is responsible for its superior clinical efficacy at reducing LUTS in men with BPH as compared to the alpha-adrenergic antagonist Tamsulosin. This is the first study directly comparing the clinical efficacy of onaBoNT-A 200 U injected into the prostate versus 0.4 mg per day of oral Tamsulosin in males diagnosed with moderate to severe LUTS associated with BPH. Male volunteers at the Michael E. DeBakey Veterans Affairs Medical Center - Houston will be randomized on a 1:1 assignment by the data coordinating center to one of two treatment arms: ARM 1: onaBoNT-A 200 U and placebo oral capsule daily; ARM 2: Placebo injection (saline) and Tamsulosin 0.4 mg capsule daily. The primary endpoint will be the mean reduction in American Urological Association Symptom Score (AUASS) at 3 months following treatment. At baseline and 3 months after treatment, BPH affected transition zone biopsies will be obtained to compare gene expression profiles in epithelial and stromal BPH cells of prostates injected with onaBoNT-A and saline (tamsulosin group), respectively, using laser capture microdissection and subsequent RNA extraction. Secondary studies will also examine the effects of Tamsulosin and onaBoNT-A on human BPH prostate tissue proliferation, apoptosis, innervation, stromal response, and angiogenesis. If the proposed hypothesis proves correct, the significance of prostate denervation with onaBoNT-A will be a decrease in urinary tract symptoms that impact patient's quality of life, and the avoidance of less effective and/or intolerable alpha-adrenergic antagonist side effects. A further impact of this study will be the detection of biological markers of onaBoNT-A and Tamsulosin induced gene expression changes that will help in the search for mechanisms of action for each treatment. Data from this study will allow for the intelligent design of targeted therapies that will overcome refractoriness to the current standard of care.

描述（由申请人提供）： 良性的前列腺增生（BPH）及其相关症状是一种常见疾病，在80岁以上的男性中近一半和90％的男性影响了近一半的男性。由BPH引起的尿路症状（LUT）降低可能非常麻烦，可能会严重影响个人的生活质量，并且成本很高。但是，BPH及其相关的LUT的机制尚不清楚。越来越多的证据记录了神经输入对前列腺生长和功能的显着阳性营养作用。 BPH生长和功能需要神经。该提议假设Onabotulinumtoxina（Onabont-A）对前列腺神经微环境的影响更大，它是其在降低BPH男性中与α-肾上腺甲基甲基抗抗神经抑制素相比，其在降低BPH男性中的出色临床疗效。这是第一项直接比较注射到前列腺中的Onabont-A 200 U的临床功效，而口服TAMSULOSIN的每天0.4 mg的男性中，被诊断为与BPH相关的中度至重度LUTS的男性。迈克尔·E·Debakey退伍军人事务中心的男性志愿者 - 休斯顿将通过数据协调中心在1：1的任务中随机分配两个治疗臂之一：ARM 1：ONABONT -A 200 U和安慰剂口服胶囊；手臂2：安慰剂注射（盐水）和坦索洛丝素每天0.4 mg胶囊。主要终点将是治疗后3个月的美国泌尿外科协会症状评分（AUASS）的平均降低。在基线和治疗后3个月，将分别获得BPH影响的过渡区活检，以比较使用激光捕获的Microdosection和后续RNA提取物，分别比较注入Onabont-A和盐水（Tamsulosin群）的前列腺上皮和基质BPH细胞中的基因表达谱。二级研究还将检查tamsulosin和onabont-A对人BPH前列腺组织增殖，凋亡，神经支配，基质反应和血管生成的影响。如果提出的假设证明是正确的，那么前列腺神经支配与Onabont-A的重要性将减少影响患者生活质量的尿路症状，并避免避免效果较低和/或无法忍受的α-肾上腺素能拮抗性拮抗作用。这项研究的进一步影响将是检测Onabont-A和Tamsulosin诱导的基因表达变化的生物学标记，这将有助于寻找每种治疗的作用机制。这项研究的数据将允许智能设计有针对性的疗法，以克服磨性 达到当前的护理标准。