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.

躁郁症（BD）是一种常见，严重，慢性且常常威胁生命的疾病。自杀是10-20％的BD患者死亡的原因。此后，锂作为一种稳定剂的疗效从那以后彻底改变了BD患者的治疗。但是，大约50％的患者对锂没有完全反应，锂的抗触发和情绪稳定作用的生化基础尚待充分阐明。阐明锂可以稳定边缘和边缘相关功能的潜在失调的机制，还提供了描述BD的基本病理生理学的潜力；但是，神经药物研究固有的主要问题是将治疗相关性归因于任何观察到的生化发现的困难。一种强大的方法是识别常见的生物化学靶标，这些靶标被属于同一治疗类别的药物（例如，情绪稳定的剂）所修饰，但是当在“治疗性相关”范式中施用时具有独特的化学结构（即对长期药物管理的效果，但持续存在的效果，却持续了持续的效果）。在这种情况下，值得注意的是，丙戊酸（VPA）和锂具有不同的化学结构，属于相同的治疗类别，并引起对蛋白激酶C（PKC）的相当大抑制作用。 PKC信号通路显然是两种结构上高度相似的抗极限剂的作用的目标-LITHIUM和VPA。锂和VPA对PKC信号传导的这些影响是否具有任何临床相关性？因此，显然需要研究直接PKC抑制剂在治疗急性躁狂症中的潜在功效。目前，只有一种相对选择性的PKC抑制剂可用于人使用 - 他莫昔芬。他莫昔芬（Tam; nolvadex？）是一种合成的非甾体类抗雌激素，已被广泛用于治疗乳腺癌。 TAM对PKC的有效抑制作用正在引人注目。最近，我们的小组在急性躁狂症中对TAM进行了首次开放标签研究。在这项研究中，TAM在短时间内（3-7天）内躁狂症状显着减少。 该提案的总体目标是检验以下假设：PKC抑制是情绪稳定药物治疗作用机制的一部分。该提案源于我们在急性躁狂症中对TAM发表的开放标签研究（Bebchuk等，2000）。然而，仅在一项开放标签研究中报道了TAM单药治疗在急性躁狂症中的功效，并且尚未在一项随机的，双盲，安慰剂对照的研究中评估。 男性或女性患者，年龄在18至65岁之间，诊断为双极I疾病躁狂或混合（有或没有精神病特征），将被随机分为双盲治疗，以接受3周的TAM（20-140 mg/day）或安慰剂。在此急性期之后，患者将按照临床表明接受开放标签的TAM或治疗。该研究将招募大约50例急性躁狂症患者。在研究期间将获得生化措施。