Intrarectal mechanoreceptor sensitization to induce defecation after spinal injury

直肠内机械感受器敏化诱导脊髓损伤后排便

• 批准号: 9906531
• 负责人: LESLEY MARSON
• 金额: $ 29.96万
• 依托单位: DIGNIFY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906531
• 关键词: Action Potentials; Acute; Agonist; Autonomic Dysreflexia; Capsaicin; Caregivers; Chronic; Circular layer of muscularis propria of anal canal; Clinical; Clinical Research; Colorectal; Conscious; Constipation; Consumption; Defecation; Dependence; Development; Dosage Forms; Dose; Electrolytes; Enterocytes; Epithelial; Exhibits; Fecal Incontinence; Feces; Formulation; Fright; Functional disorder; Future; Glycerol; Goals; Gossypium; Hour; Incidence; Incontinence; Individual; Inflammation; Intestines; Life; Liquid substance; Literature; Manuals; Mechanical Stimulation; Mechanoreceptors; Medical; Methods; Mucous body substance; Pharmaceutical Preparations; Pharmacology; Phase; Rattus; Receptor Down-Regulation; Rectal Administration; Rectum; Reflex action; Relaxation; Safety; Site; Spinal; Spinal Injuries; Spinal cord injury; Suppositories; TRPV1 gene; Tachyphylaxis; Therapeutic; Therapeutic Effect; Time; Treatment Protocols; absorption; base; desensitization; digital; instrument; laxative; phase 2 study; preclinical safety; pressure; prevent; programs; receptor; receptor expression; receptor internalization; rectal; response; side effect; social; surfactant

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.

项目概要/摘要 脊髓损伤 (SCI) 后，许多人需要“肠道计划”，包括数字刺激 以及从直肠中手动取出粪便，这可能需要一个小时或更长时间才能诱导排便，并且 或者，直肠给予刺激性泻药是繁琐、耗时且有失尊严的。 例如比沙可啶或甘油，可以在插入栓剂后 30-60 分钟诱导排便，但可以 持续促进排便2小时或更长时间，引起对随后大便失禁的担忧。 此外，这些表面活性剂通过透化直肠上皮内层发挥作用，并可以产生 炎症，这阻碍了它们的定期使用，显然，存在严重的、未得到满足的医疗需求。 寻找一种更好的方法来帮助 SCI 患者排便。此第一阶段应用程序检查了 直肠传入的药理学激活触发排便的潜力作为概念验证研究 一种“直肠内、按需、快速起效、持续时间短、药物诱导的排便疗法”。 假设是插入含药物剂型后刺激直肠传入末梢 （例如栓剂）会触发兴奋性结直肠反射和抑制性直肠肛门反射，从而迅速诱导 排便。 第二个假设是剂型的排出，因为它在粪便排出过程中被携带， 将导致药物在产生其所需的治疗效果后立即被快速消除，因此 对于脊髓完全损伤的个体来说，减少副作用和/或全身吸收的可能性。 或高于 T6 水平，该疗法不应产生比目前更高的自主神经反射异常发生率 根据临床文献，有理由推测药物引起的排便。 对于需要按需药物诱导的其他健康个体来说，治疗可能具有良好的耐受性 目标 1 检查直肠内药物触发结直肠的剂量范围和时间过程。 目的 2 检查清醒大鼠的耐受性和功效，以及 未来的 2 期研究将评估该药物在急性 SCI 大鼠中重复给药的治疗效用。 慢性 SCI 大鼠的治疗潜力，描述临床前安全性特征，并启动开发 用于后续临床研究的最终直肠内制剂。