A neurokinin receptor agonist to treat underactive bladder in the elderly

PROJECT SUMMARY ABSTRACT Underactive bladder UAB is a condition wherein a bladder contraction of reduced strength and or duration results in prolonged bladder emptying and or a failure to achieve complete bladder emptying within a normal time span The overarching hypothesis of this application is that in the absence of physiologically induced bladder contractions pharmacologically induced contractions can serve as an alternative method of voiding in elderly patients with UAB We propose that a bladder smooth muscle inotropic drug DTI can induce and complete bladder emptying within a normal time span and provide therapeutic benefit to elderly persons DTI an NK receptor agonist is being developing as an on demand rapid onset andlt min short duration andlt min drug induced voiding therapy In vitro DTI powerfully and directly contracts bladder and GI smooth muscle of all species tested In vivo it induces voiding in control diabetic and spinal cord injury rat models In conscious dogs it induces voiding of urine within minutes of administration Adverse effects seen at higher doses are mild mostly GI related and resolve quickly In humans short term NK receptor stimulation is safe at doses that contract visceral smooth muscle with no significant cardiovascular or respiratory effects The initial clinical focus for DTI is as a therapy for voiding dysfunction associated with spinal cord injury However promising preclinical safety and efficacy studies encourage exploration of DTI andapos s therapeutic potential to treat UAB in elderly patients Because changes in bladder physiology and pharmacology are known to occur in aged humans and animals it is important to verify DTI andapos s efficacy in aged preclinical models Furthermore because elderly humans can be more sensitive to the side effects of drugs it is important to screen for potential off target effects in aged animals In Specific Aim DTI andapos s effects on bladder voiding pressure and voiding efficiency will be compared between adult adult neuropathic acute spinal cord injury aged and aged neuropathic rat models Bladder function will be assessed using voiding cystometry in anesthetized Fischer Brown Norwegian hybrid rats from the NIA colony Off target effects will be monitored as changes in cardiovascular or respiratory function These experiments will provide insight into the feasibility of pursuing on demand drug induced voiding with NK receptor agonists as a therapeutic strategy for treating UAB in the elderly PROJECT NARRATIVE Underactive bladder UAB is a condition wherein a bladder contraction of reduced strength and or duration results in prolonged bladder emptying and or a failure to achieve complete bladder emptying within a normal time span The condition is common in the elderly population This application tests the hypothesis that the voiding function of the aged underactive bladder can be restored by a drug that safely and effectively induces bladder contractions