Development of a treatment for voiding dysfunction in spinal cord injured patient

描述（由申请人提供）：脊髓损伤（SCI）导致的对膀胱和肠道功能的自主控制丧失，对患者的身心健康状况和生活质量有着深远的影响。据估计，美国有27万人患有脊髓损伤（https://www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/.pdf）。脊髓损伤引起的尿潴留是不可逆转的，可能危及生命。唯一可用的药物治疗包括胆碱能激动剂，其疗效最小，副作用严重。因此，患者每天多次导尿以排空膀胱。导尿管的使用与健康问题的发生率增加有关，主要是反复尿路感染、败血症、隔离、抑郁和住院。一种“随需应变”、安全有效的药物替代导尿将改变SCI患者日常膀胱管理的生活，更不用说显著降低个人和社区卫生保健成本。Dignify Therapeutics是一家药物开发公司，专注于为脊髓损伤、多发性硬化症和导致排尿功能障碍的类似疾病患者推进新型膀胱药物治疗。通过将新型药物、平滑肌促动力学与新型药物递送技术相结合，Dignify Therapeutics希望重新定义排尿障碍的治疗方法，并通过模仿正常排尿的方式，为这些患者恢复自愿排泄功能的尊严。I期研究建议在脊髓完整和脊髓损伤大鼠中进行，以确认体内概念验证（POC），提供静脉注射（iv）剂量范围，并揭示任何脊髓损伤引起的药物敏感性变化。建立阳性POC和静脉注射剂量范围将作为后续II期研究的基础，II期研究将使用静脉注射“有效剂量”数据来建立治疗血浆浓度和基线PK和ADMET标准，以提供有关临床药物输送的最佳模式的见解。虽然在紧急情况下可以接受静脉给药，但透皮和/或经黏膜给药更可取，这也是我们SBIR二期资助的主要目标。SBIR二期资助将建立临床研究的最终配方（即经皮和/或经黏膜），将在转译性慢性脊髓损伤大鼠模型中进行测试，以模拟我们二期临床试验中的给药。急性脊髓损伤大鼠与对照大鼠之间的敏感性差异将设定我们在SBIR II期研究中必须在对照大鼠中获得的PK标准，并为临床1期志愿者和临床2期脊髓损伤患者之间的差异提供见解，以解释药物敏感性的潜在差异。

DESCRIPTION (provided by applicant): Loss of voluntary control over bladder and bowel function as a result of spinal cord injury (SCI) has profound impact on the mental and physical health status and quality of life of patients. It is estimated that 270,000 people in the USA have SCI ((https://www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/.pdf). Urinary retention as a result of SCI is irreversible and can be life threatening. The only available pharmacotherapy consists of cholinergic agonists, which have minimal efficacy and severe side effects. Consequently, patients catheterize multiple times daily to empty their bladder. Catheter use is associated with increased incidence of health problems, predominately repeated urinary tract infections, sepsis, isolation, depression and hospitalization. An "on demand", safe and effective, pharmaceutical alternative to catheterization would be a life-changing improvement in the daily routine of bladder management for SCI patients, not to mention a significant reduction in individual and community health care costs. Dignify Therapeutics is a drug development company focused on advancing novel bladder - drug therapies for patients with SCI, multiple sclerosis and similar diseases that result in voiding dysfunction. By combining novel pharmaceutical, smooth muscle prokinetics with novel drug delivery technology, Dignify Therapeutics hopes to redefine treatment of voiding disorders and restore the dignity of voluntary excretory function for these patients in a way that mimics normal micturition. Phase I studies are proposed in spinally intact and SCI rats to confirm in vivo proof of concept (POC), provide intravenous (iv) dose ranges, and reveal any SCI-induced changes in drug sensitivity. Establishing a positive POC and iv dose ranges will serve as the basis for subsequent Phase II studies, which will use the iv "effective doses" data to establish therapeutic plasma concentrations and baseline PK and ADMET criteria to provide insight regarding the best mode(s) of clinical drug delivery. Although iv delivery might be acceptable in emergency situations, transdermal and/or transmucosal delivery would be preferable and are a primary aim of our SBIR Phase II grant. The SBIR Phase II grant will establish the final formulation for clinical studies (i.e. transdermal and/or transmucosal) which will be tested in a translational, chronic SCI, rat model to mimic administration in our phase 2 clinical trials. Differences in sensitivity between acute SCI versus control rats will set PK criteria that must be obtained in control rats in our SBIR phase II studies, as well as provide insight regarding differences between clinical phase 1 volunteers and clinical phase 2 SCI patients to account for potential differences in drug sensitivity.