Novel therapy for female sexual dysfunction

描述（由申请人提供）：女性性功能障碍越来越多 被认为是一种重要的和广泛的异常，有助于性交 疼痛，性欲下降，性快感丧失。相对于 在发现纠正男性性行为的方法方面投入了巨大的科学投资 功能障碍，实际上没有注意到阐明 阴蒂肿胀、阴道肿胀的基本机制 润滑，阴道和外阴粘膜血流的改变 伴随着性唤起越来越多的解剖学证据表明， 一氧化氮作为女性生殖器充血的介质，类似于 男性的情况。传统一氧化氮供体的局部应用 然而，对女性生殖器产生了严重的系统性副作用， 包括头痛和低血压我们需要的是一个强有力的，但区域性的 限制性一氧化氮供体，作用于局部阴道循环 独家。为此，我们开发了一氧化氮前药（DS1） 其由于其大的 流体动力学半径一氧化氮从DS1中释放出来，并能够穿过 粘膜表面和血管舒张的基础小动脉床，而 前体药物不能穿过上皮并局限于顶端粘膜。 到达体循环的一氧化氮立即被灭活 因此不作为全身血管扩张剂循环。因此，在本发明中， DS1代表真正的“局部”血管扩张剂。我们已经获得了初步数据 在大鼠中，应用于阴道粘膜的局部DS 1产生深刻的， 立即增加阴道血流量，对全身血液无影响 压力利用麻醉大鼠模型，我们现在提出获得一个 DS 1的药效学特征。我们将同时比较区域 血流量和平均外周动脉压，以验证 区域选择性。进一步发展的理由 商业化将需要1）不降低全身血压，2） 阴道血流量增加> 100%，以及3）局部出血持续时间 充血>30分钟。 拟议商业应用：不可用

DESCRIPTION (provided by applicant): Female sexual dysfunction is increasingly recognized as a significant and widespread abnormality, contributing to coital pain, decreased libido, and a loss of sexual pleasure. In contrast to the enormous scientific investment in discovering methods to correct male sexual dysfunction, there has been virtually no attention directed at elucidating the fundamental mechanisms accounting for clitoral engorgement, vaginal lubrication, and alterations in vaginal and vulval mucosal blood flows accompanying sexual arousal. Increasing anatomic evidence points to a role for nitric oxide as a mediator of female genital hyperemia, similar to the situation in the male. Topical application of traditional nitric oxide donors to the female genitalia, however, produces profound systemic side effects, including headache and hypotension. What is needed is a potent, but regionally restricted nitric oxide donor, that acts on the local vaginal circulation exclusively. Towards this end, we have developed a nitric oxide pro-drug (DS1) that is restricted from transepithelial flux by virtue of its large hydrodynamic radius. Nitric oxide is released from DS1 and is able to traverse mucosal surfaces and vasodilate underlying arteriolar beds, whereas the pro-drug cannot traverse the epithelium and is confined to the apical mucosa. Nitric oxide that reaches the systemic circulation is immediately inactivated by hemoglobin and therefore does not circulate as a systemic vasodilator. Thus, DS1 represents a true "regional" vasodilator. We have obtained preliminary data in rats that topical DS1 applied to the vaginal mucosa produces profound and immediate increases in vaginal blood flow, with no effect on systemic blood pressure. Utilizing an anesthetized rat model, we now propose to obtain a pharmacodynamic profile of DS1. We will simultaneously compare the regional blood flow and the mean peripheral arterial pressure in order to verify regional selectivity. Justification of further development towards commercialization will require 1) no decrease in systemic blood pressure, 2) >100 percent increase in vaginal blood flow, and 3) duration of regional hyperemia >30 minutes. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE