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.

项目总结/摘要 泌乳素瘤是最常见的分泌型垂体肿瘤。它们通常会导致临床 症状包括性腺功能减退症、不孕症、骨密度低和乳腺增生症， 巨催乳素瘤可能与垂体功能减退和神经系统表现如头痛有关， 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 水平和促进肿瘤缩小，目前是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DAs缺乏 多巴胺D2-受体亚家族的特异性，并表现出交叉反应性的其他受体，包括 5 HT-2B受体在心脏瓣膜上表达，增加心脏瓣膜疾病的风险， 耐受性在帕金森病的情况下，由于最近出现的数据突出了一个 麦角林DA和心脏瓣膜病之间的关联，较新的更安全的非麦角DA，如罗匹尼罗 和普拉克索取代麦角衍生物作为优选的治疗。到目前为止，非麦角的利用 DA在泌乳素瘤治疗中的作用尚未研究。然而，D2/D3选择性越高的非麦角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氏症患者的PRL水平。 患者和健康志愿者，无严重副作用。虽然FDA只批准了 帕金森氏症和不宁腿综合征，我们的初步数据强调罗匹尼罗的潜力，作为一种新的 用于治疗泌乳素瘤的具有改善的耐受性和风险特征的疗法。利用富人 我们的神经内分泌科的病人资源，这项建议的目的是确定，第一次，如果 非麦角DA罗匹尼罗有效地和可耐受地降低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 该药物在泌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 通过进行一项为期24周的前瞻性II期研究， 剂量递增试验。我们预期罗匹尼罗将有效且可耐受地抑制PRL水平，改善PRL水平。 性腺功能，并减少肿瘤的大小在这个群体中。最终，这些目标的执行具有 有可能为泌乳素瘤的治疗带来一种实用的药理学替代方案， 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 疾病以及那些具有药物抗性或对传统药物不耐受的人， 改善目前的临床护理标准。