Novel Use of Ketotifen (Mast Cell Stablizier)in Fibromyalgia: A Pilot Study

酮替芬（肥大细胞稳定剂）在纤维肌痛中的新用途：初步研究

• 批准号: 8192515
• 负责人: Dennis Chua Ang
• 金额: $ 20.95万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192515
• 关键词: Accounting; Affect; Biological Markers; Biopsy; Blood; CCL2 gene; Cells; Clinical Trials; Corticotropin-Releasing Hormone; Data; Development; Disease; Drug Delivery Systems; Economics; Eotaxin; FDA approved; Fibromyalgia; Foundations; Functional disorder; Health; Human; IL8 gene; Immune; Immunologics; Inflammation Mediators; Inflammatory; Interleukin-6; Intervention; Investigation; Knowledge; Literature; Mast Cell Stabilizer; Mediator of activation protein; Medical; Minority; Monitor; Neuraxis; Norepinephrine; Outcome; Outcome Assessment; Outcome Measure; Pain; Pain Threshold; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Physical Function; Pilot Projects; Placebo Effect; Placebos; Population; Production; Productivity; Randomized; Randomized Clinical Trials; Reporting; Research; Role; Running; Serotonin; Severities; Severity of illness; Skin; Societies; Source; Stimulus; Substance P; Symptoms; Testing; Therapeutic; Translating; Treatment Efficacy; Treatment outcome; Work; afferent nerve; base; bench to bedside; central sensitization; chemokine; chronic pain; cytokine; design; effective therapy; efficacy testing; hypothalamic-pituitary-adrenal axis; improved; inflammatory pain; inhibitor/antagonist; innovation; mast cell; mortality; novel; novel therapeutic intervention; pregabalin; pressure; randomized placebo controlled trial; reuptake; tool; treatment effect; treatment trial

DESCRIPTION (provided by applicant): Despite the enormous societal and personal burden of fibromyalgia (FM), effective treatment for this condition remains suboptimal. Only one-third of patients in clinical trials derive at least some benefit from currently FDA-approved drugs for FM. Poor treatment outcomes may be accounted for by the absence of drugs that target other aspects of the pathophysiology of FM. Increased number of skin mast cell, a powerful inflammatory cell, has been noted in FM skin biopsies. Mast cells mediators (e.g., chemokines) maybe a potential source of increased peripheral stimuli reaching the central nervous system that induce and/or maintain central sensitization. Interestingly, blood levels of chemokines (i.e., IL-8, MCP-1 and eotaxin) have been reported to be elevated in patients with FM. Despite growing evidence of the immunologic basis of FM however, drug trials have largely focused on centrally-acting agents that influence the ascending (e.g., pregabalin) or the descending (e.g., serotonin-norepinephrine reuptake inhibitors) pain pathways. Perhaps adjunctive therapies directed against inflammatory mediators or towards mast cells may improve the dismal treatment outcomes in FM. Therefore, we propose to conduct a randomized clinical trial using ketotifen (mast cell stabilizer) for FM, and to obtain preliminary estimates of treatment effects for use in designing a larger trial. After a one week placebo run-in phase, 38 FM patients will be randomized to receive ketotifen or placebo for 10 weeks. Outcome assessments at baseline (week 0) and week 11 will include the following: weekly average pain severity, chemokine levels (i.e., IL-8, MCP-1 and eotaxin) and pressure pain threshold. The proposed research is innovative because it will be the first to investigate the effects of an immune-based therapy on FM-related pain, and also the first to evaluate chemokines as biomarkers of disease severity. PUBLIC HEALTH RELEVANCE: Because FM continues to pose a significantly unmet medical need, exploring a new treatment paradigm is warranted. In the proposed investigation, we seek to determine the effects of ketotifen (mast cell stabilizer) on FM-related pain, inflammatory chemokines and pain threshold. This innovative research is expected to pave the way for a large clinical trial to test the efficacy of ketotifen as an adjunctive therapy for the treatment of FM; and to provide a scientific foundation supporting the development of intervention strategies that target the immunologic aspect of FM.

描述（由申请人提供）：尽管纤维肌痛（FM）给社会和个人带来了巨大的负担，但对该病的有效治疗仍然不够理想。临床试验中只有三分之一的患者从目前 FDA 批准的 FM 药物中至少获得了一些益处。治疗结果不佳的原因可能是缺乏针对 FM 病理生理学其他方面的药物。 FM 皮肤活检中发现皮肤肥大细胞（一种强大的炎症细胞）数量增加。肥大细胞介质（例如趋化因子）可能是增加到达中枢神经系统的外周刺激的潜在来源，从而诱导和/或维持中枢敏化。有趣的是，据报道 FM 患者的血液趋化因子（即 IL-8、MCP-1 和嗜酸细胞趋化因子）水平升高。然而，尽管越来越多的证据表明 FM 的免疫学基础，但药物试验主要集中在影响上行（例如普瑞巴林）或下行（例如血清素-去甲肾上腺素再摄取抑制剂）疼痛途径的中枢作用药物。也许针对炎症介质或肥大细胞的辅助治疗可能会改善 FM 的惨淡治疗结果。因此，我们建议使用酮替芬（肥大细胞稳定剂）进行 FM 的随机临床试验，并获得治疗效果的初步估计，用于设计更大规模的试验。经过一周的安慰剂磨合期后，38 名 FM 患者将被随机分配接受酮替芬或安慰剂治疗，为期 10 周。基线（第 0 周）和第 11 周的结果评估将包括以下内容：每周平均疼痛严重程度、趋化因子水平（即 IL-8、MCP-1 和嗜酸细胞趋化因子）和压痛阈值。拟议的研究具有创新性，因为它将是第一个研究基于免疫的疗法对 FM 相关疼痛的影响的研究，也是第一个评估趋化因子作为疾病严重程度生物标志物的研究。 公共卫生相关性：由于 FM 仍然存在严重未满足的医疗需求，因此有必要探索新的治疗模式。在拟议的研究中，我们试图确定酮替芬（肥大细胞稳定剂）对 FM 相关疼痛、炎症趋化因子和疼痛阈值的影响。这项创新研究预计将为大型临床试验铺平道路，以测试酮替芬作为 FM 辅助疗法的疗效；并为支持针对 FM 免疫学方面的干预策略的制定提供科学基础。