Neurokinin-2 receptor-induced micturition and defecation in aged diabetic rats

摘要 膀胱活动不足（UAB）或肛门直肠排便功能障碍是其中 膀胱或直肠分别不完全排空，因为膀胱或结肠直肠光滑 肌肉收缩太弱或不持续，不能克服阻力， 尿道或肛门括约肌。这导致膀胱症状的尿频， 尿急、尿失禁和尿潴留（可能导致肾功能障碍） 和便秘的肠道症状（这可能导致粪便嵌塞）。UAB和肛门直肠- 相关便秘在老年人和糖尿病患者中很突出， 老年糖尿病患者Dignify Therapeutics一直在开发选择性神经激肽-2 受体（NK 2 R）激动剂作为“按需、快速起效、持续时间短、药物诱导、排泄 脊髓损伤患者的“治疗”，也在探索它们作为治疗脊髓损伤的实用性。 老年糖尿病患者UAB与肛门直肠相关性便秘我们先前已经 证明NK 2 R激动剂在老年Fischer/Brown Norway中表现出有效性和安全性 （F/BN）大鼠中的细胞毒性与年轻成年动物中的细胞毒性相当。当前应用程序扩展 这些研究包括老年糖尿病F/BN大鼠。特定目标将使用膀胱测量和 结肠直肠测压技术，以确定选择性NK 2 R激动剂DTI-117是否产生 膀胱和结肠直肠收缩的年轻和老年F/BN大鼠，已处理 链脲佐菌素（STZ）产生糖尿病膀胱和结肠直肠功能障碍。疗效和安全性 将在糖尿病与非糖尿病成年和老年大鼠中比较DTI-117的浓度。心血管 将测量DTI-117的呼吸作用，用于初步安全性评估。积极 拟议项目的结果将验证DTI-117用于治疗老年糖尿病 UAB和肛门直肠相关便秘，并为Dignify Therapeutics提供理论基础， 将老年糖尿病患者纳入DTI-117的临床开发计划。这种疗法 将大大改善UAB和肛门直肠相关疾病患者的日常生活， 通过减少UTI和相关的健康风险，降低医疗保健成本， 改善老年糖尿病患者的生活质量。

ABSTRACT Underactive bladder (UAB) or anorectal defecation dysfunction are conditions in which the bladder or rectum, respectively, do not completely empty because bladder or colorectal smooth muscle contractions are too weak or unsustained and cannot overcome the resistance of the urethral or anal sphincters, respectively. This results in bladder symptoms of urinary frequency, urgency, incontinence, and urinary retention (which can potentially lead to renal dysfunction) and bowel symptoms of constipation (which can lead to fecal impaction). UAB and anorectal- related constipation are prominent in elderly and diabetic patients and especially severe in elderly, diabetic patients. Dignify Therapeutics has been developing selective neurokinin-2 receptor (NK2R) agonists as “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy” for individuals with spinal cord injury and are also exploring their utility as treatment for UAB and anorectal-related constipation in elderly diabetic patients. We have previously demonstrated that NK2R agonists exhibit efficacy and safety in aged Fischer/Brown Norway (F/BN) rats that is comparable to that in young adult animals. The current application extends those studies to include aged, diabetic F/BN rats. The Specific Aims will use cystometric and colorectal manometric techniques to determine if a selective NK2R agonist, DTI-117, produces bladder and colorectal contractions in young and aged F/BN rats that have been treated with streptozotocin (STZ) to produce diabetic bladder and colorectal dysfunction. Efficacy and safety of DTI-117 will be compared in diabetic vs non-diabetic adult and aged rats. Cardiovascular and respiratory effects of DTI-117 will be measured for the initial assessment of safety. Positive results from the proposed project will validate the use of DTI-117 for treatment of aged, diabetic UAB and anorectal-related constipation and provide the rationale for Dignify Therapeutics to include elderly, diabetic patients in the clinical development program for DTI-117. This therapy would greatly improve the daily routine of individuals with UAB and anorectal-related constipation by reducing UTIs and associated health risks, decreasing healthcare costs, and improving quality of life for elderly, diabetic patients.