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

描述（由申请人提供）：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重大影响的疾病。口服环孢素A （CyA）治疗在这种情况下显示出一定的疗效，是美国泌尿学会指南的第五线治疗。然而，CyA是一种毒性药物，具有已知的肾毒性和潜在的高血压、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。我们建议在IC患者中进行CyA的前瞻性开放标签研究，仔细监测临床疗效，导致治疗成功的疾病特征（UPOINT表型），监测药物水平，详细监测肾功能，监测神经功能的变化，并测量血液和尿液中炎症介质的变化，这些变化表明环孢素治疗成功的结果。30名患有IC/PBS且至少2种其他药物治疗失败的成年人将参加一项为期3个月的口服CyA开放标签试验

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