Vasoactive Intestinal Peptide for the treatment of Female Sexual Arousal Disorder

描述（由申请人提供）：女性性唤起障碍（FSAD），通常被描述为女性性功能障碍（FSD）的一种疾病，在老年女性中很常见，可能是老年人群生活质量下降的重要原因。FSAD被定义为持续或反复无法获得或维持足够的性兴奋，导致个人痛苦。性唤起障碍通常包括阴道润滑不足、阴蒂和阴唇感觉降低、阴蒂和阴唇充血减少和/或阴道平滑肌松弛缺乏。通常，生理原因如先前的骨盆创伤、骨盆手术、阴道或阴蒂血流减少（例如由于心血管问题）或某些药物的副作用，例如选择性5-羟色胺再摄取抑制剂，在病症的病因学中起重要作用。血管活性肠肽是女性生殖器内重要的神经递质，具有平滑肌松弛等多种功能。它已被证明可以增加女性生殖器的血流量，并诱导阴道润滑。这些特征使其成为FSAD的可能治疗方法。然而，全身给予它可能导致动脉血压的危险下降。游离肽的这些安全性问题和药代动力学特征要求其在可用作人类治疗剂之前以克服这些问题的方式配制。PharmaIN公司已经成功地在初步实验中开发了一种名为PGC-VIP的注射用聚合物VIP制剂。该制剂已被证明在炎症性疾病模型中是安全和生物活性的。此外，它表现出体内半衰期的大幅增加。本申请提出测试局部PGC-VIP制剂在FSAD大鼠模型中的功效并测试该制剂的储存稳定性。在第一阶段 将在目标1中综合说明项目目标2所述开展功效实验所需的充足材料。在目标2开始前，将该材料提交给QC，以确保其组成和性质与初步实验中使用的PGC-VIP制剂相同。目的2将测试该制剂在FSAD大鼠模型中的功效，并且在目的3中，我们将进行稳定性研究。

DESCRIPTION (provided by applicant): Female sexual arousal disorder (FSAD), one of the conditions commonly described as Female sexual dysfunction (FSD) is common among older women and can be a significant reason for decreased quality of life in the aging population. FSAD is defined as the persistent or recurring inability to attain or maintain sufficient sexual excitement, causing personal distress. Disorders of arousal often include insufficient vaginal lubrication, decreased clitoral and labial sensation, decreased clitoral and labial engorgement and/or lack of vaginal smooth muscle relaxation. Often, physiological causes like previous pelvic trauma, pelvic surgery, decreased vaginal or clitoral blood flow (e.g. due to cardiovascular problems) or the side effects of certain medications, for example selective serotonin reuptake inhibitors, play an important role in the etiology of the condition. Vasoactive intestinal peptide s an important neurotransmitter in the female genitalia with smooth muscle relaxant and other pleiotropic functions. It has been shown that it can increase blood flow in female genitalia and also induce vaginal lubrication. These features make it a possible treatment for FSAD. However, given systemically it can lead to a dangerous drop in arterial blood pressure. Theses safety concerns and the pharmacokinetics profile of the free peptide require it being formulated in a way to overcome these problems before it can be used as human therapeutic. PharmaIN Corp. has succeeded in preliminary experiments with the development of an injectable, polymer-based VIP formulation called PGC-VIP. This formulation has been shown to be safe and biologically active in a model of an inflammatory disease. Additionally, it exhibits a massive increase in in-vivo half-life. This application proposes to test a topical PGC-VIP formulation for efficacy in a rat model of FSAD and to test shelf-stability of this formulation. During the Phase I of the project sufficient material to conduct the efficacy experiment as described in aim 2 of the proposal will be synthesized in aim 1. Before the start of aim 2, this material will be submitted t QC to ensure that it is of identical composition and properties as the PGC-VIP formulation used in the preliminary experiments. Aim 2 will test the efficacy of the formulation in a rat model of FSAD and in aim 3 we will conduct a stability study.