Nitric oxide donor therapy for diabetic foot

描述(由申请人提供)： 目前的申请代表了Inote公司快速跟踪SBIR赠款的第一阶段组件，该组件提议使用一种新的、长效的、区域选择性的NO供体化合物进行概念验证有效性测试。糖尿病血管中一氧化氮的产生明显受损，这是许多糖尿病并发症的重要致病因素，包括足部溃疡。本研究的主要假设是，糖尿病患者皮肤中补充NO可替代NO的缺乏，恢复血管内环境的稳定。这种方法有望提供短期缓解(例如，防止皮肤干燥)，以及预防一些长期问题(如足部溃疡)。作为初步数据，我们提出了糖尿病患者一氧化氮产生和皮肤血管扩张受损的证据。我们还证明，氧化应激增加和氧化剂诱导的下游过程有助于糖尿病内皮功能障碍的发病机制。我们还提供了证据表明，DSI，一种新型的，长效的一氧化氮供体，在两个非真皮血管床(肺循环和阴道循环)上提供选择性的血管扩张作用。我们第一阶段成分的中心目标是在对照动物和糖尿病啮齿动物中进行体内概念验证研究，以证明我们的新的、经皮肤渗透的NO供体配方具有显著的血管扩张作用。如果这些研究证实伊诺克的NO供体配方是(在对照动物以及链脲佐菌素和NOD糖尿病模型中)有效、持久和选择性的血管扩张剂，将触发后续的II阶段成分，该阶段将专注于正式的临床前安全性测试。在目前SBIR应用的第二阶段，我们将建议使用GLP优质材料进行临床前安全性研究。将开发一种GMP质量的化合物合成方法，并将该化合物配方为外用乳膏。此外，我们建议进行正式的安全性研究，并在项目的最后一年在健康志愿者和糖尿病患者中进行临床I/II期试验。综上所述，我们请求美国国立卫生研究院提供资金，以开发一种有效的、具有区域选择性的NO捐赠者，这有望有效地减少已确立的I型和II型糖尿病的一些心血管并发症的发生率。

DESCRIPTION (provided by applicant): The current application represents the Phase I component of a Fast-Track SBIR Grant by Inotek Corporation, proposing to conduct proof-of-concept efficacy testing with a novel, long-acting, regionally selective NO donor compound. There is a marked impairment of nitric oxide production in diabetic blood vessels, which importantly contributes to the pathogenesis of many diabetic complications, including foot ulcerations. The main hypothesis of the current study is that NO supplementation to the diabetic skin substitutes for the lacking NO, and restores vascular homeostasis. This approach is expected to provide short-term relief (against skin dryness, for example), as well as prevention of some of the long-term problems (such as foot ulcerations). As preliminary data we present evidence that NO production and cutaneous vasodilatation is impaired in diabetic patients. We also demonstrate that increased oxidative stress and downstream processes induced by the oxidants contribute to the pathogenesis of diabetic endothelial dysfunction. We also present evidence that DSI, a novel, long-acting nitric oxide donor provides selective vasodilatory effects in two non-dermal vascular beds (pulmonary and vaginal circulation). The central aim of our Phase I component is to perform proof-of-concept in vivo studies in control animals and in diabetic rodents, in order to demonstrate that our novel, dermally permeable NO donor formulation exerts significant vasodilatory effects. If these studies confirm that Inotek's NO donor formulation is an effective, prolonged and selective vasodilator in (both in control animals and in streptozotocin and NOD models of diabetes), a subsequent Phase II component will be triggered, which will focus on formal preclinical safety testing. In the Phase II component of the current SBIR application, we will propose to perform pre-clinical safety studies with GLP quality material. A GMP quality synthesis of the compound will be developed and the compound formulated as a topical cream. In addition, we propose formal safety studies and, for the final year of the project a clinical Phase I/II trial in healthy volunteers and in diabetic patients. Taken together, we request funds from the NIH to develop a potent, regionally selective NO donor, which is expected to be effective in reducing the incidence of some of the cardiovascular complications of established Type I and Type II diabetes.