The Protein Kinase C Inhibitor Tamoxifen in Acute Mania

蛋白激酶 C 抑制剂他莫昔芬治疗急性躁狂症

• 批准号: 6982748
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6982748
• 关键词: acute disease /disorder; biochemistry; bipolar depression manic phase; clinical trials; drug screening /evaluation; enzyme mechanism; human subject; human therapy evaluation; kinase inhibitor; lithium; mental disorder chemotherapy; patient oriented research; pharmacokinetics; protein kinase C; tamoxifen; valproate

Bipolar Disorder (BD) is a common, severe, chronic and often life-threatening illness. Suicide is the cause of death in 10-20% of individuals with BD. The discovery of lithium's efficacy as a mood-stabilizing agent has since revolutionized the treatment of patients with BD. However, approximately 50% of patients do not respond fully to lithium, and the biochemical basis for lithium's antimanic and mood-stabilizing actions remains to be fully elucidated. Elucidation of the mechanism(s) by which lithium stabilizes an underlying dysregulation of limbic and limbic-associated function also offers the potential to delineate the underlying pathophysiology of BD; however, a major problem inherent in neuropharmacologic research is the difficulty in attributing therapeutic relevance to any observed biochemical finding. One powerful approach is to identify common biochemical targets, which are modified by drugs belonging to the same therapeutic class (e.g. mood-stabilizing agents) but possessing distinct chemical structures when administered in a "therapeutically relevant" paradigm (i.e., effects which are observed upon chronic drug administration, and yet persist beyond abrupt drug discontinuation). In this context, it is noteworthy that both valproic acid (VPA) and lithium, with different chemical structures, belong to the same therapeutic class and cause considerable inhibition of protein kinase C (PKC). The PKC signaling pathway is clearly a target for the actions of two structurally highly dissimilar antimanic agents -- lithium and VPA. Do these effects of lithium and VPA on PKC signaling have any clinical relevance? There is thus a clear need to investigate the potential efficacy of a direct PKC inhibitor in the treatment of acute mania. There is currently only one relatively selective PKC inhibitor available for human use- Tamoxifen. Tamoxifen (TAM; NOLVADEX?), a synthetic nonsteroidal antiestrogen, has been widely used in the treatment of breast cancer. TAM?s potent inhibitory effects on PKC are striking. Recently, our group conducted the first open-label study with TAM in acute mania. In this study, TAM resulted in a significant decrease in manic symptoms within a short period of time (3-7 days). The overarching goal of this proposal is to test the hypothesis that PKC inhibition is part of the mechanism of the therapeutic effect of mood stabilizing drugs. The proposal derives from and builds on our published open-label study of TAM in acute mania (Bebchuk et al., 2000). However, the efficacy of TAM monotherapy in acute mania has only been reported in an open-label study and has not yet been evaluated in a randomized, double blind, placebo-controlled study. Male or female patients, ages 18 to 65, with a diagnosis of bipolar I disorder manic or mixed (with or without psychotic features), will be randomized to double-blind treatment to receive either TAM (20-140 mg/day) or placebo, for a period of 3 weeks. Following this acute period, the patients will receive either open-label TAM or treatment as clinically indicated. Approximately 50 patients with acute mania will be enrolled in the study. Biochemical measures will be obtained during the study.

双相情感障碍(BD)是一种常见、严重、慢性且常常危及生命的疾病。在10-20%的BD患者中，自杀是死因。锂作为一种情绪稳定剂的功效的发现，自那以后彻底改变了BD患者的治疗方法。然而，大约50%的患者对锂没有完全反应，锂的抗躁狂和稳定情绪作用的生化基础仍有待充分阐明。阐明锂稳定潜在的边缘和边缘相关功能失调的机制(S)也为描绘BD潜在的病理生理学提供了可能性；然而，神经药理学研究中固有的一个主要问题是很难将治疗与任何观察到的生化结果联系起来。一种有效的方法是确定共同的生化靶点，这些靶点被属于同一治疗类别的药物(例如，情绪稳定剂)改变，但在“治疗相关”范例中使用时具有不同的化学结构(即，在长期给药时观察到的效果，但在突然停药后仍然存在)。值得注意的是，丙戊酸(VPA)和锂的化学结构不同，属于同一治疗类别，对蛋白激酶C(PKC)有相当大的抑制作用。显然，PKC信号通路是两种结构高度不同的抗躁药--锂和丙戊酸--作用的靶点。锂离子和丙戊酸对PKC信号转导的影响有临床意义吗？因此，显然有必要研究一种直接的PKC抑制剂在治疗急性躁狂症中的潜在疗效。目前只有一种相对选择性的PKC抑制剂可供人类使用--他莫昔芬。他莫昔芬(；诺伐得？)是一种人工合成的非甾体类抗雌激素药物，已广泛用于乳腺癌的治疗。、S对蛋白激酶C的抑制作用显著。最近，我们课题组与进行了首次急性躁狂症的开放标签研究。在本研究中，在短时间内(3-7天)使躁狂症状显著减轻。 这项建议的首要目标是检验PKC抑制是情绪稳定药物治疗效果的部分机制的假设。该建议源于并建立在我们发表的急性躁狂症开放标签研究(Bebchuk等人，2000年)的基础上。然而，单一疗法治疗急性躁狂的疗效仅在一项开放标签研究中报道，尚未在随机、双盲、安慰剂对照研究中进行评估。 年龄18至65岁的男性或女性患者，被诊断为躁狂型或混合型双相I型障碍(有或不有精神病特征)，将被随机分成双盲治疗组，接受(20-140 mg/天)或安慰剂治疗，为期3周。在这一急性期之后，患者将接受开放标签的或临床指示的治疗。大约50名急性躁狂症患者将参加这项研究。生化指标将在研究期间获得。