Cyclosporine in Interstitial Cystitis: Efficacy, Safety and Mechanism of Action

环孢素治疗间质性膀胱炎：疗效、安全性和作用机制

• 批准号: 8627734
• 负责人: Daniel Shoskes
• 金额: $ 36.54万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-27 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627734
• 关键词: Adult; Adverse effects; Aftercare; American; Anti-Inflammatory Agents; Anti-inflammatory; Antipsychotic Agents; Biological Markers; Blood; C Fiber; Calcineurin; Calcineurin inhibitor; Clinical; Cyclosporine; Data; Disease; Dose; Drug Monitoring; Enrollment; Enzyme-Linked Immunosorbent Assay; Esthesia; Fiber; Frequencies; Functional disorder; Gene Expression; Gene Proteins; Guidelines; Health; Hyperalgesia; Hypertension; Immunosuppressive Agents; Increased frequency of micturition; Infection; Inflammation Mediators; Interstitial Cystitis; Iothalamate; Kidney; Label; Measures; Medical; Monitor; Nerve; Neurons; Nociception; Nuclear; Oral; Outcome; Pain; Pain Threshold; Patients; Pelvic Pain; Perception; Peripheral; Pharmaceutical Preparations; Phenotype; Prospective Studies; Proteins; Publishing; Quality of life; RNA; Radio; Refractory; Renal clearance function; Renal function; Safety; Sampling; Symptoms; System; Testing; Therapeutic; Tissues; Urine; Wit; Work; afferent nerve; allodynia; base; clinical efficacy; effective therapy; improved; inflammatory marker; nephrotoxicity; neurotoxicity; open label; prospective; relating to nervous system; success; urologic

DESCRIPTION (provided by applicant): Interstitial cystitis (IC), also referred to as Painful Bladder Syndrome (PBS) is a condition with significant impact on quality of life. Therapy with oral Cyclosporine A (CyA) has shown some efficacy in this condition and is a fifth line therapy in the Guidelines of the American Urological Association. However CyA is a toxic drug with known nephrotoxicity and potential for hypertension, infection and neurotoxicity. While CyA is an immunosuppressive drug, it's target of action, calcineurin, is also present in neural cells suggesting that the effect of CyA on the symptoms of IC may be neurally modulated as well. We propose a prospective open label study of CyA in patients with IC with careful clinical monitoring of efficacy, features of disease (UPOINT phenotype) that leads to treatment success, monitoring of drug levels, detailed monitoring of renal function, monitoring of changes in nerve function and measuring changes in inflammatory mediators in the blood and urine that indicate successful outcomes of cyclosporine treatment. Thirty adults with IC/PBS who have failed at least 2 other classes of medical therapy will be enrolled in an open label 3 month trial of oral CyA, starting at 3 mg/kg/day in 2 divided doses. Patients will be assessed pretreatment, at 3 months and 1-2 months after stopping. We will first examine the clinical efficacy and side effects of cyclosporine treatment in patients with IC/PBS refractory to first line therapies. Patients will be assessed wit C2 blood levels for dose adjustment. Renal function will be assessed with a nuclear GFR's. Patients will be clinically phenotyped with the validated UPOINT system and clinical outcomes correlated to the phenotype. We will then measure the effects of cyclosporine treatment on current perception and pain threshold using a Neurometer before, during and after treatment. Hyperalgesia will be assessed for sensation perception and pain threshold at 3 frequencies that measure function of 3 nerve types (C, A-delta, A-beta fibers). We expect symptom improvement to correlate with reduction in hyperalgesia, especially in the C fibers. Finally, we will identify changes in inflammatory mediators in the blood and urine of IC/PBS patients that indicate successful outcomes of cyclosporine treatment. RNA and protein will be extracted from blood and urine samples before, during and after therapy. Gene expression and protein signatures will be compared between patients pretreatment and 15 normal controls to identify candidate biomarkers. ELISA will test protein levels of inflammatory mediators and proteins that have been shown to be increased in the urine of IC/PBS. These genes and proteins will be following during and after therapy and changes correlated with degree of clinical improvement. We hope to show that CyA can be an effective therapy for recalcitrant IC/PBS which can be safely administered with appropriate monitoring and identify which patients benefit most from treatment

描述（由申请方提供）：间质性膀胱炎（IC），也称为膀胱疼痛综合征（PBS），是一种对生活质量有显著影响的疾病。口服环孢素A（CyA）治疗在这种情况下显示出一定的疗效，是美国泌尿外科协会指南中的第五线治疗。然而，CyA是一种毒性药物，已知具有肾毒性，并可能导致高血压、感染和神经毒性。虽然CyA是一种免疫抑制药物，但它的作用靶点钙调神经磷酸酶也存在于神经细胞中，这表明CyA对IC症状的影响也可能是神经调节的。我们提出了一个前瞻性的开放标签研究CyA在IC患者的疗效，疾病的特点（UPOINT表型），导致治疗成功，监测药物水平，详细监测肾功能，监测神经功能的变化和测量的变化，炎症介质在血液和尿液中，表明环孢素治疗的成功结果仔细的临床监测。30名患有IC/PBS且至少2种其他类别的药物治疗失败的成人将入组口服CyA的开放标签3个月试验，从 3 mg/kg/天，分2次给药。将在治疗前、停药后3个月和1-2个月对患者进行评估。我们将首先检查环孢素的临床疗效和副作用 一线治疗难治性IC/PBS患者的治疗。将评估患者的C2血液水平以进行剂量调整。将使用核GFR评估肾功能。将使用经验证的UPOINT系统对患者进行临床表型分析，并将临床结局与表型相关。然后，我们将在治疗前、治疗期间和治疗后使用神经测量仪测量环孢素治疗对电流感知和痛阈的影响。将在测量3种神经类型（C、A-δ、A-β纤维）功能的3个频率下评估痛觉过敏的感觉和疼痛阈值。我们预期症状的改善与痛觉过敏的减少有关，特别是在C纤维中。最后，我们将确定IC/PBS患者血液和尿液中炎症介质的变化，表明环孢素治疗的成功结果。在治疗前、治疗期间和治疗后，将从血液和尿液样本中提取RNA和蛋白质。将比较治疗前患者和15名正常对照之间的基因表达和蛋白质特征，以识别候选生物标志物。ELISA将检测炎症介质的蛋白质水平和已显示在IC/PBS的尿液中增加的蛋白质。这些基因和蛋白质将在治疗期间和治疗后发生变化，并与临床改善程度相关。我们希望证明CyA可以成为顽固性IC/PBS的有效治疗方法，在适当的监测下可以安全给药，并确定哪些患者从治疗中受益最大

项目成果

Efficacy, Side Effects, and Monitoring of Oral Cyclosporine in Interstitial Cystitis-Bladder Pain Syndrome.

• DOI: 10.1016/j.urology.2017.05.016
• 发表时间: 2017-09
• 期刊: Urology
• 影响因子: 2.1
• 作者: Crescenze IM;Tucky B;Li J;Moore C;Shoskes DA
• 通讯作者: Shoskes DA