Intrarectal mechanoreceptor sensitization to induce defecation after spinal injury

项目摘要/摘要 脊髓损伤(SCI)后，许多人需要“肠道程序”，包括数字刺激。 以及人工从直肠抽出粪便，这可能需要一个小时或更长时间才能诱导排便，而且 既繁重、耗时，又有损尊严。或者，直肠注射刺激性泻药， 如双沙可定或甘油，可在插入栓剂后30-60分钟诱导排便，但可 继续促进排便2小时或更长时间，会引起人们对随后大便失禁的担忧。 此外，这些表面活性物质通过使直肠上皮衬通透性而起作用，并能产生 发炎，这阻止了他们的定期使用。显然，有一种严重的、未得到满足的医疗需求 寻找一种更好的方法来启动脊髓损伤患者的排便。此阶段1应用程序检查 药物激活直肠传入触发排便的可能性作为一项概念验证研究 一种“直肠内、按需、起效快、疗程短、药物诱导、排便疗法”。初级阶段 假设是在插入含有药物的剂型后刺激直肠传入终末 (如栓剂)会触发兴奋性结直肠和抑制性直肠肛门反射，迅速诱导 大便。 第二种假设是，在排便过程中携带的剂型的排出， 将导致药物在产生预期的治疗效果后立即迅速消除，因此 减少副作用和/或全身吸收的可能性。对于脊柱完全受损的个人，在 或在T6水平以上，这种疗法产生的自主神经反射障碍的发生率不应该比目前的 大便程序。根据临床文献，我们有理由推测药物引起的排便 在其他需要按需、药物诱导的健康个体中，治疗可能耐受性良好 大便。目的1检查一种直肠内药物引发结直肠癌的剂量范围和时间进程 急性脊髓损伤大鼠的活动性。目的2检测清醒大鼠的耐受性和疗效，以及 反复给药对急性脊髓损伤大鼠的治疗作用。未来的第二阶段研究将评估 慢性脊髓损伤大鼠的治疗潜力，临床前安全性特征，并启动 用于后续临床研究的最终直肠内配方。

PROJECT SUMMARY/ABSTRACT Following spinal cord injury (SCI), many individuals require “bowel programs,” consisting of digital stimulation and manual extraction of stool from the rectum, that can take an hour or more to induce defecation, and which are burdensome, time consuming, and undignified. Alternatively, rectal administration of stimulant laxatives, such as bisacodyl or glycerin, can induce defecation 30-60 minutes after insertion of a suppository, but can continue to promote defecation for 2 hours or longer, raising concerns about subsequent fecal incontinence. Furthermore, these surfactants act by permeabilizing the epithelial lining of the rectum and can produce inflammation, which prevents their use on a regular basis. Obviously, there is a serious, unmet medical need for a better method to initiate defecation in individuals with SCI. This Phase 1 application examines the potential of pharmacological activation of rectal afferents to trigger defecation as a proof-of-concept study for an “intrarectal, on-demand, rapid-onset, short-duration, drug-induced, defecation therapy.” The primary hypothesis is that stimulation of rectal afferent terminals following insertion of a drug-containing dosage form (e.g., a suppository) will trigger excitatory colorectal, and inhibitory rectoanal, reflexes to rapidly induce defecation. A secondary hypothesis is that expulsion of the dosage form, as it is carried along during expulsion of stools, will result in a rapid elimination of the drug immediately upon producing its desired therapeutic effect, thus reducing potential for side effects and/or systemic absorption. For individuals with complete spinal damage at or above the T6 level, this therapy should produce no greater incidence of autonomic dysreflexia than current bowel programs. Based on the clinical literature, it is reasonable to speculate that a drug-induced defecation therapy might be well-tolerated in otherwise healthy individuals who require on-demand, drug-induced defecation. Aim 1 examines the dose range and time course of an intrarectal drug for triggering colorectal activity in acute SCI rats. Aim 2 examines the tolerability and efficacy in conscious rats, as well as the therapeutic utility of the drug with repeated dosing in acute SCI rats. Future Phase 2 studies will evaluate the therapeutic potential in chronic SCI rats, characterize the preclinical safety profile, and initiate development of the final intrarectal formulation for subsequent clinical studies.