Vulvar vestibulitis trial: Desipramine-Lidocaine

外阴前庭炎试验：地昔帕明-利多卡因

• 批准号: 6795588
• 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/6795588
• 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）：拟对外阴前庭炎的外阴痛亚型进行研究。本申请的第一个主要目的是进行一项随机、安慰剂对照、双盲临床试验，以研究四种药物方案的临床疗效：局部利多卡因、口服地昔帕明、局部利多卡因联合口服地昔帕明和安慰剂。外阴前庭炎的标准治疗方法的有效性已被随机、安慰剂对照、盲法临床试验证实，但尚未进行评估。以地昔帕明为代表的三环类抗抑郁药已获得经验性接受，用于治疗外阴前庭炎，尽管只有少数回顾性研究或非对照临床试验报告了有利的治疗结果。尽管三环类抗抑郁药的确切作用机制尚未明确，但已提出通过背角和脑干的“中枢”作用。与口服地昔帕明相反，利多卡因的长期局部应用可能通过“局部”机制起作用。这项随机、安慰剂对照、双盲临床试验旨在确定“局部”或“中枢作用”治疗单独或联合治疗外阴前庭炎是否有效。成功的结局指标将包括总体疼痛减轻、触摸疼痛减轻、标准化机械刺激疼痛减轻、无痛性交增加、性功能改善、通过心理测量测试测量的生活质量改善以及对活性药物方案的依从性。本申请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、促炎细胞因子的组织水平和对外阴前庭炎治疗的反应之间的关系。促炎细胞因子，如白细胞介素-I β（IL-1 β）和肿瘤坏死因子α（TNF-α），从局部细胞来源分泌，并在处女膜环区域中积累超过正常水平。最近的遗传分析发现，等位基因2 IL-1受体拮抗剂（IL-1 RA*2）在外阴前庭炎病例中的纯合性为53%，而在无症状女性中的纯合性为8.5%。此外，IL-1 RA*2等位基因与体外IL-1 β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外推到外阴前庭炎的临床病例。使用我们临床试验的样本，我们将评估IL-1 RA*2的纯合性、IL-1 β和TNF-α的组织水平与治疗反应之间的关系。总之，这个项目将使我们能够回答有关外阴前庭炎的几个重要问题。药物治疗有效吗？中枢作用或局部作用治疗是否同样有效，还是一种上级优于另一种？局部和全身联合治疗是否有益？最后，遗传特征和组织细胞因子浓度是否影响治疗反应？