Pathophysiology of Anorectal Disorders

肛门直肠疾病的病理生理学

• 批准号: 7595123
• 负责人: ADIL E. BHARUCHA
• 金额: $ 32.11万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595123
• 关键词: Acute; Adrenergic Agonists; Affect; Anus; Atropine; Bethanechol; Biofeedback; Cholinergic Agonists; Clonidine; Communities; Complex; Consensus; Controlled Study; Data; Denervation; Discipline of obstetrics; Disease; Distress; Double-Blind Method; Epidemiology; Fecal Incontinence; Functional disorder; Goals; Hypersensitivity; Hysterectomy; Injury; Institutionalization; L-Type Calcium Channels; Magnetic Resonance Imaging; Measures; Mechanics; Motor; Muscarinic Agonists; Muscarinic Antagonists; Neuropathy; Nifedipine; Patients; Perception; Postmenopause; Prevention; Property; Rectum; Research; Rest; Risk; Risk Factors; Role; Sensorimotor functions; Stress; Symptoms; Techniques; Testing; Therapeutic; United States National Institutes of Health; Vaginal delivery procedure; Woman; anorectal disorder; base; cohort; daily functioning; evidence base; improved; innovation; multidisciplinary; novel; novel strategies; placebo controlled study; pressure; programs; public health relevance; rectal; response; sphincter ani muscle structure; symposium

DESCRIPTION (provided by applicant): The goals of this research program are to enhance the prevention and improve the management of fecal incontinence (FI) in women by clarifying the risk factors and mechanisms for this disorder using multidisciplinary, innovative approaches. While current concepts emphasize the role of anal sphincter weakness, our epidemiological and mechanistic studies strongly support the hypothesis that FI is caused by complex of recto-anal sensorimotor dysfunctions rather than isolated anal dysfunction. Our specific aims are to assess the hypotheses that: (i) The rectum is stiffer in women who have had a hysterectomy and also in women with urge FI; (iia) Partially reversible rectal motor dysfunctions predominantly due to neurogenic rather than myogenic mechanisms contribute to rectal hypersensitivity in women with urge FI; (iib) denervation supersensitivity contributes to increased rectal stiffness after a hysterectomy; and (iii) clonidine will restore rectal sensorimotor functions and thereby improve symptoms in FI. Our corresponding aims are to (i) measure overall and regional rectal stress:strain relationships by simultaneous MRI during rectal balloon distention in 24 asymptomatic women and in 24 women with urge FI, also controlling for hysterectomy; (iia) compare the acute effects of atropine and nifedipine on rectal mechanical properties (i.e., compliance, capacity, and the phasic response to distention) and rectal perception of distention in 56 women with and 36 women without urge FI, also controlling for hysterectomy; (iib) assess the effects of a cholinergic agonist on rectal sensorimotor in 24 women who have or have not had a hysterectomy; and (iii) study the effects of clonidine on symptoms and rectal sensorimotor functions in a double- blind placebo-controlled study of 40 women with FI. By testing mechanistic hypotheses which are integrated with a new therapy, these studies are poised to fundamentally alter our understanding and management of FI in women. Public Health Relevance: Fecal incontinence (FI) affects 10% of all and up to 20% of postmenopausal women. FI can cause significant distress, impair daily functioning, and contribute to institutionalization. The pathophysiology of FI is poorly understood, while available therapeutic options are limited, not evidence-based, and primarily focus on improving anal sphincter function. This proposal will enhance our understanding of the mechanisms and assess novel approaches to manage FI.

描述（由申请人提供）：该研究项目的目标是通过使用多学科创新方法阐明该疾病的风险因素和机制，加强对女性大便失禁（FI）的预防和改善管理。虽然当前的概念强调肛门括约肌无力的作用，但我们的流行病学和机制研究强烈支持这样的假设：FI 是由直肠肛门感觉运动功能障碍复合体引起的，而不是孤立的肛门功能障碍。我们的具体目标是评估以下假设： (i) 接受过子宫切除术的女性以及急迫性 FI 的女性的直肠较硬； (iia) 部分可逆的直肠运动功能障碍主要是由于神经源性而非肌源性机制导致的急迫性 FI 女性的直肠过敏； (iib) 去神经超敏性导致子宫切除术后直肠僵硬增加； (iii) 可乐定将恢复直肠感觉运动功能，从而改善 FI 症状。我们相应的目标是 (i) 测量整体和区域直肠压力：在 24 名无症状女性和 24 名急需 FI 女性的直肠球囊扩张期间通过同步 MRI 测量应变关系，同时也控制子宫切除术； (iia) 比较阿托品和硝苯地平对 56 名患有急迫性 FI 的女性和 36 名未患有急迫性 FI 的女性的直肠机械特性（即顺应性、容量和对扩张的阶段性反应）和直肠扩张感知的急性影响，同时也控制了子宫切除术； (iib) 评估胆碱能激动剂对 24 名接受或未接受子宫切除术的妇女的直肠感觉运动的影响； (iii) 在一项对 40 名 FI 女性进行的双盲安慰剂对照研究中，研究可乐定对症状和直肠感觉运动功能的影响。通过测试与新疗法相结合的机制假设，这些研究有望从根本上改变我们对女性 FI 的理解和管理。 公共卫生相关性：大便失禁 (FI) 影响 10% 的绝经后妇女，甚至高达 20%。 FI 可能会造成严重的痛苦，损害日常功能，并导致住院。人们对 FI 的病理生理学知之甚少，而可用的治疗选择有限，且没有证据基础，并且主要集中于改善肛门括约肌功能。该提案将增强我们对机制的理解并评估管理金融机构的新方法。