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

描述(申请人提供)：脊髓损伤(SCI)导致的膀胱和肠道功能自主控制的丧失对患者的身心健康状况和生活质量有深远的影响。据估计，美国有270,000人患有SCI((https://www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/.pdf).脊髓损伤导致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方法是胆碱能激动剂，其疗效极低，副作用严重。因此，患者每天都要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。“按需”、安全有效的药物替代导尿术将改变脊髓损伤患者的日常膀胱管理，更不用说显著降低个人和社区的医疗费用了。Treatify Treateutics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的患者推进新型膀胱药物疗法。通过将新药物、平滑肌促动力与新的药物输送技术相结合，Diguify Treeutics希望重新定义排尿障碍的治疗，并以一种模拟正常排尿的方式恢复这些患者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身上进行，以确认体内概念验证(POC)，提供静脉(IV)剂量范围，并揭示脊髓损伤引起的药物敏感性的任何变化。建立积极的POC和静脉注射剂量范围将作为后续第二阶段研究的基础，该研究将使用静脉注射“有效剂量”数据来建立治疗性血药浓度以及基线PK和ADMET标准，以提供关于最佳临床给药模式(S)的见解。虽然静脉注射在紧急情况下是可以接受的，但经皮和/或经粘膜给药将是更可取的，也是我们SBIR第二阶段拨款的主要目的。SBIR第二阶段拨款将为临床研究(即经皮和/或经粘膜)建立最终配方，该配方将在翻译的慢性脊髓损伤大鼠模型中进行测试，以模拟我们第二阶段临床试验中的给药。急性脊髓损伤大鼠与对照组大鼠之间的敏感性差异将设定在我们的SBIR II期研究中必须在对照组大鼠中获得的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洞察力，以解释潜在的药物敏感性差异。

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.