The pathophysiology and palliation of the paclitaxel-induced acute pain syndrome

紫杉醇诱发的急性疼痛综合征的病理生理学和缓解作用

• 批准号: 8930932
• 负责人: Alan P. Fields
• 金额: $ 17.21万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930932
• 关键词: Abdomen; Ache; Acute Pain; Affect; Antineoplastic Agents; Area; Auranofin; Autoimmune Process; Back; Biopsy; Bladder; Breast; Brief Pain Inventory; Chest; Clinical; Clinical Data; Data; Development; Disease; Dose; Drug usage; Endometrium; Esophagus; Excision; Family; Functional disorder; Future; Gold Compounds; Hand; Head and neck structure; Hip region structure; Intractable Pain; Isoenzymes; Kaposi Sarcoma; Leg; Logistic Regressions; Lung; Malignant Neoplasms; Measurement; Measures; Mediator of activation protein; Messenger RNA; Metabolic syndrome; Modeling; Muscle; Musculoskeletal Diseases; Musculoskeletal Pain; Myopathy; Neck; Opioid; Ovary; Paclitaxel; Pain; Patients; Placebos; Positioning Attribute; Protein Kinase C; Protein Kinase C Inhibitor; Publishing; Randomized; Randomized Controlled Trials; Refractory; Reporting; Role; Seminal; Severities; Shoulder; Symptoms; Syndrome; Testing; Time; arm; atypical protein kinase C; autoimmune arthritis; base; chemotherapy; foot; inhibitor/antagonist; insight; mRNA Expression; overexpression; palliation; pre-clinical; prevent; protein kinase C iota; protein kinase C zeta; public health relevance

DESCRIPTION (provided by applicant): Paclitaxel is one of the most commonly prescribed cancer drugs and serves an important role in the treatment of a variety of malignancies. The paclitaxel-induced acute pain syndrome (PIAPS) occurs after paclitaxel administration. Its seminal feature is refractory, untreatable pain. Even opioids are ineffective. Although PIAPS typically remits by day 7, patients suffer from refractory pain one-third of their time on chemotherapy. Our group was the first to prospectively characterize this syndrome from a clinical standpoint, but the pathophysiology of this syndrome remains unknown and remarkably understudied. We hypothesize that the atypical protein kinase C (PKC) isoenzymes, PKC iota and zeta, are key mediators of the PIAPS and that the gold compound auranofin, an inhibitor of of PKC iotal and zeta, prevents or palliates this syndrome. Indeed, 1) the PKC family has been implicated in a host of other musculoskeletal pain syndromes; 2) our preclinical data demonstrate that paclitaxel results in PKC iota activation; and 3) our preclinical and clinical dat also show that auranofin, a drug used to treat autoimmune arthritis, inhibits PKC iota and zeta. Hence, we propose the following specific aims: 1) To measure quantitatively the mRNA expression of PKC iota and zeta in the muscle of patients before and after paclitaxel administration and to determine whether PKC iota or zeta overexpression are associated with the development of the PIAPS (as assessed by patients' completion of the Brief Pain Inventory). 2) To conduct a pilot, randomized controlled trial to test whether auranofin prevents or palliates the PIAPS. Thirty patients (15 per arm) will be randomly assigned to either auranofin (one 6 mg dose) the day after paclitaxel versus placebo. Daily pain scores (Brief Pain Inventory) will be compared between auranofin- and placebo-exposed arms. These two independent but integrated aims -- which include two independent groups of patients for each aim -- will provide long-overdue insight into the pathophysiology of the PIAPS and will potentially position us to mount a future, definitive randomized controlled trial with auranofin to prevent or palliate the PIAPS.

说明(申请人提供)：紫杉醇是最常用的抗癌药物之一，在多种恶性肿瘤的治疗中发挥重要作用。紫杉醇诱导的急性疼痛综合征(PIAPS)发生在紫杉醇给药后。它的基本特征是难治性、不可治愈的疼痛。即使阿片类药物也是无效的。尽管PIAPS通常在第7天前缓解，但患者三分之一的化疗时间患有顽固性疼痛。我们小组是第一个从临床角度前瞻性地描述这种综合征的人，但这种综合征的病理生理学仍不清楚，而且研究还很少。我们推测，非典型的蛋白激酶C(PKC)同工酶PKC IOTA和Zeta是PIAPS的关键介质，金化合物Auranofin是PKC和Zeta的抑制剂，可以预防或缓解这种综合征。事实上，1)PKC家族与许多其他肌肉骨骼疼痛综合征有关；2)我们的临床前数据表明，紫杉醇导致PKC IOTA激活；以及3)我们的临床前和临床数据也表明，用于治疗自身免疫性关节炎的药物Auranofin可以抑制PKC IOTA和Zeta。因此，我们提出了以下具体目标：1)定量检测紫杉醇治疗前后患者肌肉中PKC iota和Zeta的mRNA表达，并确定PKC iota或Zeta的过度表达是否与PIAPS的发生有关(根据患者完成简短疼痛问卷的情况进行评估)。2)进行一项先导性随机对照试验，以测试Auranofin是否预防或缓解PIAPS。30名患者(每支手臂15名)将被随机分配给紫杉醇后第二天的金诺芬(一个6毫克剂量)和安慰剂。每日疼痛评分(简短的疼痛清单)将在金诺芬暴露的手臂和安慰剂暴露的手臂之间进行比较。这两个独立但综合的目标--每个目标包括两组独立的患者--将提供对PIAPS病理生理学的期待已久的洞察，并可能使我们有可能开展一项未来的、具有决定性的随机对照试验，使用Auranofin来预防或缓解PIAPS。