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

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.NARRATIVE Dignify Therapeutics is developing an “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy”, DTI-117, to initiate urination and defecation in individuals with non-obstructive urinary retention and/or anorectal dysfunction-mediated constipation. Elderly, diabetic individuals suffer from an inability to initiate efficient voiding of urine and stools due to autonomic, diabetic neuropathy, which produces conditions of non-obstructive urinary retention and/or anorectal dysfunction-mediated constipation. The proposed research will determine if DTI-117 is safe and efficacious in an elderly, diabetic animal model in consideration of including elderly, diabetic patients in subsequent clinical trials of DTI-117.