Novel therapy for female sexual dysfunction

描述(由申请人提供)：女性性功能障碍日益被认为是一种严重而广泛的异常，会导致性交疼痛、性欲下降和性快感丧失。与发现纠正男性性功能障碍的方法的巨大科学投入形成对比的是，几乎没有人关注于阐明阴蒂充血、阴道润滑以及随性唤起而改变的阴道和外阴粘膜血流的基本机制。我们建议用一种新型的局部选择性硝基血管扩张剂L-PEI-NO(“DSI”)治疗女性性功能障碍，当局部给药时，有望作为生殖器循环的选择性血管扩张剂。在第一阶段的SBIR应用中，我们提出了证据表明DS-1是一种有前途的新型一氧化氮(NO)供体，具有足够的半衰期和生物利用度，可用于体内研究，我们已经证明DS-1对阴道粘膜血流量具有强大而持久的增加作用。此外，结果表明，该化合物的作用是选择性的，即局部血管扩张，没有任何全身血流动力学影响。我们在化合物的化学合成和表征方面也取得了重大进展。在目前的应用中，我们建议对DS1进行额外的临床前安全性研究，以便将其引入临床应用。我们将进行FDA授权的正式合成、配方、ADME、稳定性以及局部刺激性和毒理学研究。这些研究有望提供数据，证明重复慢性给药DS1的耐受性很好，并且在超过预计治疗剂量1-2个对数的剂量方案下是无毒的。这些数据还将建立毒性的靶器官，这将指导未来临床I期试验的毒理学监测。在第二阶段SBIR结束时，Inote k将提交一份研究药物申请(IND)，以支持DS1的临床试验。

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. We propose to treat female sexual dysfunction with a novel regionally selective nitrovasodilator, L-PEI-NO ("DSI"), expected to serve as a selective vasodilator for the genital circulation when administered topically to the in troitus. In the Phase I SBIR application, we have presented evidence that DS-1 is a promising novel nitric oxide (NO) donor, which has sufficient half-life and bio availability for in vivo studies, and we have proven that DS-1 exerts a powerful and prolonged increase in vaginal mucosal blood flow. Furthermore, the results demonstrated that the effect of the compound is selective, i.e. the local vasodilatation occurs without any systemic hemodynamic effects. We have also made major progress in the chemical synthesis and characterization of the compound. In the current application, we propose to perform additional pre-clinical safety studies with DS1 in order to introduce it into clinical use. We will conduct formal, FDA-mandated synthesis, formulation, ADME, stability, and local irritation and toxicology studies. These studies are expected to provide data demonstrating that repeated chronic administration of DS1 is well tolerated and non-toxic at a dosing regimen 1-2 logs in excess of the predicted therapeutic dose. These data will also establish the target organ for toxicity, which will guide the toxicologic surveillance of future clinical Phase I trials. At the conclusion of the Phase 2 SBIR, Inotek will submit an investigational drug application (IND) to support clinical trials of DS1.