PHARMACOTHERAPY FOR XEROSTOMIA IN SJOGREN'S SYNDROME

描述(由申请人提供)：干燥综合征(SS)是一种缓慢进展的炎症性疾病，特征是淋巴细胞介导的破坏，该应用被发现具有显著的科学价值，并被推荐与外分泌腺和内脏器官受累，由于自身抗体产生或先前存在的结缔组织疾病。随着时间的推移，单个核细胞逐渐渗入泪腺和唾液腺，导致分泌物减少，由此导致的口干(口干)和干眼症(干眼)是最常见的症状。使用目前可用的治疗方法，包括泪液和唾液替代品以及中枢作用的副交感神经分泌物，如匹罗卡品和西维米林，可以提供短暂的缓解，但患者经常发现这些治疗方法昂贵、无效、不方便，并且充满了不可接受的副作用。 研究表明，颊粘膜与其他鳞状上皮细胞相似，具有通过牙髓转运钠的能力。颊粘膜可能通过主动吸收钠和被动吸收氯作为对抗离子的耦合机制来调节水的吸收。盐的吸收以渗透作用吸收水分，因此决定了颊粘膜顶面的水合状态。这一钠转运过程对上皮性钠通道阻滞剂阿米洛利抑制的敏感性表明，ENaC对钠的吸收是限速的。本申请中提供的初步数据显示，我们的先导化合物552是上皮性钠通道的有效和特异的抑制剂。我们第一次临床研究的轶事证据表明，这种ENaC阻滞剂可以增强唾液功能。这一临床发现，再加上上面提出的科学原理，支持了这样一种假设，即局部应用552将抑制钠通过上皮性钠通道的运输，同时减少口腔粘膜的吸收失水率，潜在地缓解干燥综合征患者的口干感。这些观察结果为启动我们的先导化合物作为治疗干燥综合征相关口干的治疗剂提供了理论基础。先导化合物是一种特殊的、有效的上皮性钠通道阻滞剂。 在这项第一阶段的SBIR应用中，我们建议进行一项临床研究，研究单剂量口服552制剂治疗原发性干燥综合征患者口干症的安全性和疗效(研究552-205s)。这项研究旨在实现以下研究目标： A.评估552-02口服制剂每日给药14天治疗原发性干燥综合征的安全性 评估每日服用552-02口服制剂14天对原发性干燥综合征患者口干症的疗效。 拟议的临床研究是552-02年度整体发展计划的关键组成部分。这项研究的结果将为在Sjogren患者中进行进一步的单剂量和多剂量临床研究提供基础。最终，我们的目标是全面开发552-02作为与干燥综合征相关的口干症患者的一线治疗方法。

DESCRIPTION (provided by applicant): Sjogren's syndrome (SS) is a slowly progressive inflammatory disorder characterized by lymphocyte-mediated destruction ofOverall, this application was found to have significant and substantial scientific merit, and is recommended with an exc exocrine glands and internal organ involvement due to autoantibody production or pre-existing connective tissue disorder. Over time, progressive infiltration of lacrimal and salivary glands by mononuclear cells leads to diminished secretions, with resultant xerostomia (dry mouth) and xeropthalmia (dry eye) being the most prevalent symptoms. Use of currently available treatments, including tear and saliva substitutes and centrally acting parasympathomimetic secretagogues such as pilocarpine and cevimeline, provide transient relief, but patients often find these remedies costly, ineffective, inconvenient, and fraught with unacceptable side effects. Studies indicate that the buccal mucosa resembles other squamous epithelia in its ability to transport sodium transepithelially. The buccal mucosa likely regulates the absorption of water through a coupled mechanism with the active absorption of sodium and passive absorption of chloride as the counter ion. The absorption of salt osmotically draws water absorption and therefore determines the status of hydration of the apical surface of the buccal mucosa. The sensitivity of this sodium transport process to inhibition by amiloride, an epithelial sodium channel (ENaC) blocker, suggests that sodium absorption by ENaC is rate limiting. Preliminary data presented in this application show that our lead compound, 552, is a potent and specific inhibitor of the epithelial sodium channel. Anecdotal evidence from our first clinical study suggests that this ENaC blocker can enhance salivary function. This clinical finding, coupled with the scientific rationale presented above, provides support for the hypothesis that topical administration of 552 will inhibit the transport of sodium through the epithelial sodium channel and at the same time decrease the rate of absorptive water loss from the oral mucosa, potentially providing relief from the sensation of dry mouth in Sjogren's syndrome patients. These observations provide the rationale for initiating the clinical testing of our lead compound, a specific, potent blocker of the epithelial sodium channel, as a therapeutic agent for the treatment of dry mouth associated with Sjogren's syndrome. In this Phase I SBIR application, we propose a clinical study of the safety and the effect of treatment with a single dose of a topical oral formulation of 552 on xerostomia in primary Sjogren's syndrome (Study 552-205S). This study is designed to fulfill the following study objectives: a. Evaluate the safety of a topical oral formulation of 552-02 administered daily for 14 days in patients with primary Sjogren's syndrome b. Evaluate the effect of daily administration of a topical oral formulation of 552-02 for 14 days on xerostomia in patients with primary Sjogren's syndrome. The proposed clinical study is a key component of the overall development program for 552-02. Results of this study will provide the basis for conducting further dose-ranging single-dose and multiple-dose clinical studies in Sjogren's patients. Ultimately, our goal is the full clinical development of 552-02 as a first-line therapy for patients suffering from xerostomia associated with Sjogren's syndrome.