Intrarectal mechanoreceptor sensitization to induce defecation after spinal injury

PROJECT SUMMARY ABSTRACT Following spinal cord injurySCImany individuals requirebowel programsconsisting of digital stimulation and manual extraction of stool from the rectumthat can take an hour or more to induce defecationand which are burdensometime consumingand undignifiedAlternativelyrectal administration of stimulant laxativessuch as bisacodyl or glycerincan induce defecationminutes after insertion of a suppositorybut can continue to promote defecation forhours or longerraising concerns about subsequent fecal incontinenceFurthermorethese surfactants act by permeabilizing the epithelial lining of the rectum and can produce inflammationwhich prevents their use on a regular basisObviouslythere is a seriousunmet medical need for a better method to initiate defecation in individuals with SCIThis Phaseapplication examines the potential of pharmacological activation of rectal afferents to trigger defecation as a proof of concept study for anintrarectalon demandrapid onsetshort durationdrug induceddefecation therapyThe primary hypothesis is that stimulation of rectal afferent terminals following insertion of a drug containing dosage forme ga suppositorywill trigger excitatory colorectaland inhibitory rectoanalreflexes to rapidly induce defecationA secondary hypothesis is that expulsion of the dosage formas it is carried along during expulsion of stoolswill result in a rapid elimination of the drug immediately upon producing its desired therapeutic effectthus reducing potential for side effects and or systemic absorptionFor individuals with complete spinal damage at or above the Tlevelthis therapy should produce no greater incidence of autonomic dysreflexia than current bowel programsBased on the clinical literatureit is reasonable to speculate that a drug induced defecation therapy might be well tolerated in otherwise healthy individuals who require on demanddrug induced defecationAimexamines the dose range and time course of an intrarectal drug for triggering colorectal activity in acute SCI ratsAimexamines the tolerability and efficacy in conscious ratsas well as the therapeutic utility of the drug with repeated dosing in acute SCI ratsFuture Phasestudies will evaluate the therapeutic potential in chronic SCI ratscharacterize the preclinical safety profileand initiate development of the final intrarectal formulation for subsequent clinical studies PROJECT NARRATIVE Individuals with spinal cord injurySCIsuffer from bowel dysfunction that results in life long fecal incontinenceas well as frequent episodes of constipation and rectal impactionand the fear of incontinence episodes often significantly restricts their professional and social livesMany SCI individuals rely on a lengthy and invasive bowel program to remove feces that often requires assistance from caregiversThis application aims to establish the dose dependence and therapeutic utility of intrarectal administration of a drug to initiate defecation