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

脊髓损伤患者排尿功能障碍治疗方法的开发

• 批准号: 8712806
• 负责人: LESLEY MARSON
• 金额: $ 15.93万
• 依托单位: DIGNIFY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712806
• 关键词: Accounting; Acute; Adverse effects; Afferent Neurons; Agonist; Animals; Bethanechol; Bladder; Bladder Dysfunction; Blood; Catheterization; Catheters; Cessation of life; Cholinergic Agonists; Chronic; Climacteric; Clinical; Clinical Research; Clinical Trials; Community Healthcare; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Efferent Neurons; Emergency Situation; Excretory function; Experimental Designs; Female; Functional disorder; Grant; Health; Health Care Costs; Health Status; Hospitalization; In Vitro; Incidence; Individual; Intestines; Intravenous; Kidney Failure; Knowledge; Life; Maximum Tolerated Dose; Measures; Mental Depression; Mental Health; Methods; Micturition Reflex; Modeling; Multiple Sclerosis; Neurokinin A; Paraplegia; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Phase II Clinical Trials; Plasma; Production; Psychological reinforcement; Publishing; Quality of life; Rattus; Relaxation; Research Design; Rodent; Route; Sepsis; Site; Small Business Innovation Research Grant; Smooth Muscle; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Sublingual drug administration; Substance K Receptor; TAC1 gene; Technology; Testing; Therapeutic; Time; Toxic effect; Urethra; Urinary Retention; Urinary tract infection; Urination; Urine; animal data; base; drug development; drug sensitivity; human tissue; improved; in vivo; insight; intravenous injection; neuromechanism; novel; phase 1 study; phase 2 study; physical conditioning; pre-clinical; public health relevance; receptor; response; success; urinary; volunteer

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.

描述（由申请人提供）：脊髓损伤（SCI）导致的膀胱和肠功能自主控制丧失对患者的身心健康状况和生活质量产生深远影响。据估计，美国有270，000人患有SCI（https：//www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/.pdf）。SCI导致的尿潴留是不可逆的，可能危及生命。唯一可用的药物治疗包括胆碱能激动剂，其具有最小的功效和严重的副作用。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。一个“按需”，安全有效，药物替代导管将是一个改变生活的改善日常膀胱管理的SCI患者，更不用说显着减少个人和社区的医疗保健费用。Dignify Therapeutics是一家药物开发公司，专注于为SCI，多发性硬化症和导致排尿功能障碍的类似疾病患者提供新型膀胱药物治疗。通过将新型药物、平滑肌促动力剂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，并以模拟正常排尿的方式恢复这些患者自主排泄功能的尊严。在脊髓完整和SCI大鼠中进行I期研究，以确认体内概念验证（POC），提供静脉内（iv）剂量范围，并揭示SCI诱导的药物敏感性变化。确定阳性POC和iv剂量范围将作为后续II期研究的基础，II期研究将使用iv“有效剂量”数据确定治疗血浆浓度和基线PK和ADMET标准，以提供关于临床药物递送最佳模式的见解。虽然静脉给药在紧急情况下可能是可以接受的，但经皮和/或经粘膜给药将是优选的，并且是我们SBIR II期资助的主要目标。SBIR II期资助将建立用于临床研究的最终制剂（即经皮和/或经粘膜），该制剂将在平移的慢性SCI大鼠模型中进行测试，以模拟我们的II期临床试验中的给药。急性SCI与对照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大鼠中获得的PK标准，并提供关于临床1期志愿者和临床2期SCI患者之间差异的见解，以解释药物敏感性的潜在差异。