A New Therapeutic Option for the Treatment of Prolactinomas

项目摘要/摘要 催乳素瘤是最常见的分泌性垂体瘤。它们通常会导致临床 症状包括性腺功能低下、不孕不育、低骨密度和溢乳，在 巨大的催乳素瘤可与垂体腺功能减退和神经症状有关，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能降低催乳素 水平和促进肿瘤缩小，目前是治疗催乳素瘤的标准疗法， 然而，在一小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，并表现出与其他受体的交叉反应，包括 心脏瓣膜上表达5HT-2B受体，增加心脏瓣膜疾病的风险并影响 耐受性。在帕金森氏症的情况下，由于最近出现的数据强调了 麦角林DAS与瓣膜病的相关性--新的更安全的非麦角类DAS，如罗匹尼罗 和普拉克索，已取代麦角衍生物成为首选治疗方法。到目前为止，非麦角的利用 DAS治疗催乳素瘤的研究尚未见报道。然而，D2/D3选择性非麦角DA越多 罗匹尼罗在其他受体上的活性微乎其微，已被证明可以降低帕金森氏症患者的催乳素水平 在患者和健康志愿者中没有重大副作用。尽管FDA只批准了这种治疗 关于帕金森氏症和不宁腿综合症，我们的初步数据突出了罗匹尼罗作为一种新型药物的潜力 治疗催乳素瘤具有更好的耐受性和风险。利用有钱人 我们神经内分泌科的患者资源，这项提议的目标是首次确定是否 非麦角DA罗匹尼罗有效且可耐受地降低PRL水平，恢复性腺功能，并诱导 催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 研究罗匹尼罗对催乳素浓度的影响，旨在建立罗匹尼罗的药效学和 该药在催乳素瘤患者体内的药代动力学特征。我们的目标也是确定长期疗效 罗匹尼罗进行前瞻性II期24周治疗催乳素瘤的耐受性 剂量递增试验。我们预计，罗匹尼罗将有效和可容忍地降低催乳素水平，改善 性腺功能，并缩小这一人群的肿瘤大小。归根结底，这些目标的实现具有 有可能为催乳素瘤的治疗提供一种实用的药物替代方案 扩大我们的治疗库，为已存在心脏瓣膜的患者提供新的治疗选择 对于那些具有药理抗性或对传统药物不耐受的人也是如此，因此 改善目前的临床护理标准。

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.