Vulvar vestibulitis trial: Desipramine-Lidocaine

外阴前庭炎试验：地昔帕明-利多卡因

• 批准号: 6930330
• 负责人: DAVID Charles FOSTER
• 金额: $ 24.81万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930330
• 关键词: adult human (21+); clinical research; clinical trials; combination chemotherapy; cytokine; desipramine; female; female reproductive system disorder; genetic polymorphism; human subject; human therapy evaluation; interleukin 1; lidocaine; local anesthetics; longitudinal human study; oral administration; pain; patient oriented research; pharmacogenetics; psychometrics; quality of life; reproductive system disorder chemotherapy; reproductive system pharmacology; topical drug application; tricyclic antidepressant; tumor necrosis factor alpha; women' s health

DESCRIPTION (provided by applicant): Studies are proposed for the subtype of vulvodynia known as vulvar vestibulitis. The first major aim of this application is to conduct a randomized, placebo-controlled, double-blinded clinical trial to study the clinical efficacy of four medical regimens: topical lidocaine, oral desipramine, topical lidocaine combined with oral desipramine and placebo. The efficacy of standard treatments for vulvar vestibulitis proven by randomized, placebo-controlled, blinded clinical trials has not been assessed. The tricyclic class of antidepressants, represented by desipramine, have gained empiric acceptance for the treatment of vulvar vestibulitis, although favorable therapeutic results have been reported by only a few retrospective studies or uncontrolled clinical trials. Although the precise mechanism of action remains undefined for tricyclic antidepressants, a "central" action through the dorsal horn and brain stem has been suggested. In contrast to oral desipramine, the long-term, topical application of lidocaine may act through a "local" mechanism. This randomized, placebo-controlled, double-blinded clinical trial is designed to determine whether "local" or "centrally-acting" treatments alone, or in combination are efficacious in treating vulvar vestibulitis. Outcome measures of success will include reduced overall pain, reduced pain to touch, reduced pain to standardized mechanical stimuli, increased pain-free intercourse, improved sexual function, improved quality-of-life as measured by psychometric tests, and adherence to active drug regimens. The second major aim of this application is to study the relationship among genetic polymorphisms of the IL-1 Receptor Antagonist locus, tissue levels of pro-inflammatory cytokines, and response to treatment of vulvar vestibulitis. Pro-inflammatory cytokines, such as interleukin-I beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha), are secreted from a local cellular source and accumulate above normal levels in the region of the hymeneal ring. Recent genetic analysis finds a 53% homozygosity for allele 2 IL-1 Receptor Antagonist (IL-1 RA*2) in cases of vulvar vestibulitis, in contrast to 8.5% homozygosity in asymptomatic women. Furthermore, the IL-1 RA*2 allele has been linked to increased production of IL-1 beta in vitro. In our second aim, we will determine whether these in vitro results can be extrapolated to clinical cases of vulvar vestibulitis. Using samples from our clinical trial, we will assess the relationship between homozygosity for IL-1 RA*2, tissue levels of IL-1 beta, and TNF-alpha, and response to treatment. In summary, this project will allow us to answer several important questions about vulvar vestibulitis. Is medical treatment effective? Is centrally-acting or locally-acting treatment equally effective or is one superior to the other? Is there any benefit from combined local and systemic treatments? And finally, do genetic characteristics and tissue cytokine concentrations influence treatment response?

描述（由申请人提供）：提出了针对外阴痛的亚型的研究，称为外阴前庭炎。该应用的第一个主要目的是进行一项随机的，安慰剂对照的双盲临床试验，以研究四种医疗方案的临床功效：局部利多卡因，口服去哌啶，局部利多卡因与口腔脱发和安慰剂结合使用。尚未评估通过随机，安慰剂对照，盲目的临床试验证明的外阴前庭炎的标准治疗方法的功效。三环类抗抑郁药以去丙胺为代表的抗抑郁药已获得外阴前庭炎的经验接受，尽管仅通过一些回顾性研究或不受控制的临床试验报告了有利的治疗结果。尽管三环抗抑郁药的确切作用机理仍然不确定，但已经提出了通过背角和脑干的“中心”作用。与口服去丙胺相反，利多卡因的长期局部应用可以通过“局部”机制作用。这项随机，安慰剂对照，双盲临床试验旨在确定单独的“局部”或“中心作用”治疗方法，或者结合使用有效治疗外阴前庭炎。成功的结果度量将包括减轻整体疼痛，减轻疼痛的触摸，减轻标准化的机械刺激，无疼痛的性交，改善性功能，通过心理测试测试来改善生活质量以及对活性药物方案的遵守。该应用的第二个主要目的是研究IL-1受体拮抗剂基因座的遗传多态性，促炎性细胞因子的组织水平以及对外阴前庭炎治疗的反应。促炎性细胞因子（例如白介素-Iβ（IL-1β）和肿瘤坏死因子α（TNF-Alpha）被分泌于局部细胞来源，并在海肌环区域中积聚高于正常水平。最近的遗传分析发现，在外阴前庭炎的情况下，等位基因2 IL-1受体拮抗剂（IL-1 RA*2）的纯合性为53％，与无症状女性中的8.5％纯合性相反。此外，IL-1 RA*2等位基因与体外IL-1β的产生增加有关。在我们的第二个目标中，我们将确定这些体外结果是否可以推断到外阴前庭炎的临床病例。使用我们的临床试验中的样品，我们将评估IL-1 RA*2，IL-1β的组织水平和TNF-Alpha的纯合性之间的关系，以及对治疗的反应。总而言之，该项目将使我们能够回答有关外阴前庭炎的几个重要问题。医疗有效吗？中央作用或本地作用治疗是否同样有效，或者一种比另一种优于另一种治疗？合并的本地和全身治疗是否有任何好处？最后，遗传特征和组织细胞因子浓度是否会影响治疗反应？