Novel therapy for female sexual dysfunction

描述（由申请人提供）：女性性功能障碍越来越被认为是一种重要而广泛的异常，导致性交疼痛，性欲下降和性快感丧失。我们建议用一种新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，当局部施用于生殖器时，有望作为生殖器循环的选择性血管扩张剂。在I期SBIR应用中，我们已经提出证据表明DS-1是一种有前景的新型一氧化氮（NO）供体，具有足够的半衰期和生物利用度，可用于体内研究，并且我们已经证明DS-1具有强大且持久的阴道粘膜血流量增加。此外，结果表明，该化合物的作用是选择性的，即局部血管扩张发生，没有任何全身血流动力学的影响。我们在化合物的化学合成和表征方面也取得了重大进展。在目前的申请中，我们建议对DS1进行额外的临床前安全性研究，以便将其引入临床使用。我们将进行正式的、fda授权的合成、配方、ADME、稳定性、局部刺激和毒理学研究。这些研究预计将提供数据，证明在超过预期治疗剂量1-2 log的给药方案中，反复慢性给药DS1具有良好的耐受性和无毒性。这些数据还将建立毒性靶器官，这将指导未来临床I期试验的毒理学监测。在二期SBIR结束后，Inotek将提交一份研究药物申请（IND）来支持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.