A New Therapeutic Option for the Treatment of Prolactinomas

治疗泌乳素瘤的新治疗选择

• 批准号: 9227114
• 负责人: Gabrielle PageWilson
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227114
• 关键词: Accounting; Acute; Address; Adverse effects; Adverse event; Affinity; Blindness; Bone Density; Bromocriptine; Cardiac; Chronic; Clinical; Data; Development; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Dose; Drug Kinetics; Drug resistance; Ergot Fungus; Evaluation; Exhibits; Exposure to; FDA approved; Funding; Generic Drugs; Goals; Headache; Heart Valve Diseases; Heart Valves; Hour; Hyperprolactinemia; Hypogonadism; Hypopituitarism; Incidence; Individual; Infertility; Long-Term Effects; Macroprolactinomas; Nausea; Neurologic Symptoms; Neurosecretory Systems; Operative Surgical Procedures; Orthostatic Hypotension; Outpatients; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Pituitary Neoplasms; Population; Prolactin; Prolactin Secreting Pituitary Gland Neoplasm; Prolactinoma; Radiation therapy; Randomized Clinical Trials; Resistance; Resources; Restless Legs Syndrome; Rhinitis; Risk; Safety; Serotonin; Serum; Specificity; Study models; Symptoms; Therapeutic; Time; Titrations; abstracting; alternative treatment; base; cabergoline; clinical care; clinically significant; comparative efficacy; cost; cross reactivity; drug intolerance; gonad function; healthy volunteer; improved; in vitro activity; innovation; novel therapeutics; open label; patient subsets; phase II trial; pramipexol; prospective; receptor; response; restoration; ropinirole; serotonin receptor; standard of care; trial comparing; tumor

Project Summary/Abstract Prolactinomas are the most commonly occurring secretory pituitary tumors. They routinely result in clinical symptoms including hypogonadism, infertility, low bone density and galactorrhea and in the setting of macroprolactinomas can be associated with hypopituitarism and neurologic manifestations like headaches and vision loss. The ergot dopamine agonists (DA), cabergoline and bromocriptine, have been shown to lower PRL levels and promote tumor shrinkage, and are currently standard therapy for the treatment of prolactinomas, however drug intolerance and resistance are observed in a subset of patients. Additionally, the ergot DAs lack specificity for the dopamine D2-receptor subfamily and exhibit cross-reactivity at other receptors, including the 5HT-2B receptor expressed on heart valves, increasing the risk of cardiac valve disease and impacting tolerability. In the case of Parkinson's disease, due to the recent emergence of data highlighting an association between ergoline DAs and valvular heart disease, the newer safer non-ergot DAs, like ropinirole and pramipexole, have replaced the ergot derivatives as preferred therapy. To date, the utilization of non-ergot DAs in the treatment of prolactinomas has not been studied. However, the more D2/D3 selective non-ergot DA ropinirole, which has negligible activity at other receptors, has been shown to lower PRL levels in Parkinson's patients and in healthy volunteers without major side effects. Although FDA approved solely for the treatment of Parkinson's and Restless Leg Syndrome, our preliminary data highlight ropinirole's potential as a novel therapy for the treatment of prolactinomas with an improved tolerability and risk profile. Capitalizing on the rich patient resources of our Neuroendocrine Unit, the objective of this proposal is to determine, for the first time, if the non-ergot DA ropinirole effectively and tolerably lowers PRL levels, restores gonadal function, and induces tumor shrinkage in individuals with prolactinomas. By carrying out a 24-hour forced titration dose-response study of ropinirole's effect on PRL concentrations, we aim to establish the pharmacodynamic and pharmacokinetic profile of this drug in prolactinoma patients. We also aim to determine the long-term efficacy and tolerability of ropinirole for the treatment of prolactinomas by conducting a prospective Phase II 24-week dose escalation trial. We anticipate that ropinirole will effectively and tolerably suppress PRL levels, improve gonadal function, and reduce tumor size in this population. Ultimately, the execution of these aims has the potential to bring forth a pragmatic pharmacologic alternative for the treatment of prolactinomas that will expand our therapeutic arsenal and offer a new treatment option to patients with pre-existing cardiac valve disease as well to those with pharmacologic resistance or intolerance to traditional medications, thereby improving the current clinical standard of care.

项目概要/摘要 催乳素瘤是最常见的分泌性垂体肿瘤。它们通常会导致临床 症状包括性腺机能减退、不孕、骨密度低和溢乳，以及 催乳素大瘤可能与垂体功能低下和神经系统表现（如头痛和 视力丧失。麦角多巴胺激动剂 (DA)、卡麦角林和溴隐亭已被证明可以降低 PRL 水平并促进肿瘤缩小，是目前治疗泌乳素瘤的标准疗法， 然而，在一部分患者中观察到药物不耐受和耐药性。此外，麦角 DA 缺乏 对多巴胺 D2 受体亚家族具有特异性，并与其他受体表现出交叉反应性，包括 5HT-2B 受体在心脏瓣膜上表达，增加心脏瓣膜疾病的风险并影响 耐受性。就帕金森病而言，由于最近出现的数据强调 麦角林 DA 与瓣膜性心脏病之间的关联，新型更安全的非麦角 DA，如罗匹尼罗 和普拉克索已取代麦角衍生物成为首选疗法。迄今为止，非麦角的利用 DAs 治疗催乳素瘤的作用尚未被研究。然而，D2/D3 选择性更强的非麦角 DA 罗匹尼罗对其他受体的活性可以忽略不计，已被证明可以降低帕金森病患者的 PRL 水平 患者和健康志愿者没有重大副作用。尽管FDA仅批准用于治疗 对于帕金森氏症和不宁腿综合症，我们的初步数据凸显了罗匹尼罗作为小说的潜力 用于治疗泌乳素瘤的疗法，具有改善的耐受性和风险状况。利用富人的资本 我们神经内分泌科的患者资源，该提案的目的是首次确定是否 非麦角 DA 罗匹尼罗可有效且可耐受地降低 PRL 水平，恢复性腺功能，并诱导 泌乳素瘤患者的肿瘤缩小。通过进行 24 小时强制滴定剂量反应 研究罗匹尼罗对 PRL 浓度的影响，我们的目的是建立药效学和 该药物在催乳素瘤患者中的药代动力学特征。我们还旨在确定长期疗效 通过进行为期 24 周的前瞻性 II 期研究，研究罗匹尼罗治疗泌乳素瘤的耐受性 剂量递增试验。我们预计罗匹尼罗将有效且可耐受地抑制 PRL 水平，改善 性腺功能，并减少该人群的肿瘤大小。最终，这些目标的实现 有可能为催乳素瘤的治疗带来一种实用的药物替代方案 扩大我们的治疗手段，为已有心脏瓣膜的患者提供新的治疗选择 疾病以及对传统药物有药理耐药性或不耐受的人，从而 提高当前的临床护理标准。