Research Project
9407864
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-100, can induce and complete bladder emptying within a normal time span and provide therapeutic benefit to elderly persons. DTI-100, an NK2 receptor agonist, is being developing as an ?on-demand, rapid-onset (< 2 min), short-duration (< 5 min), drug-induced, voiding therapy?. In vitro, DTI-100 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 NK2 receptor stimulation is safe at doses that contract visceral smooth muscle with no significant cardiovascular or respiratory effects. The initial clinical focus for DTI-100 is as a therapy for voiding dysfunction associated with spinal cord injury. However, promising preclinical safety and efficacy studies encourage exploration of DTI-100'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-100'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 1, DTI-100'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 NK2 receptor agonists as a therapeutic strategy for treating UAB in the elderly.
