Role of HBI-002, an orally administered gasotransmitter, in ischemic stroke

 描述（由申请人提供）：拟定项目的目的是使用新型CO口服制剂（HBI-002）研究气体递质一氧化碳（CO）作为急性缺血性卒中（AIS）神经保护剂的潜力。大量体外和体内研究表明，CO通过抗氧化、抗炎和抗凋亡过程具有细胞保护特性。在三个独立实验室的五项研究中，研究人员发现血红素加氧酶（HO）-1/CO通路在AIS动物模型中提供神经保护。在这些研究中的四项研究中，外源性给予CO已被证明可上调HO-1，减少脑梗死面积，改善行为评分并增加实验性中风中梗死边缘区的血流量。这些独立研究为使用CO治疗AIS的潜在有益作用提供了令人信服的支持。然而，CO给药策略仅限于吸入和静脉途径，这些途径具有固有的安全性和毒性风险。HBI-002是一种水性羧基脂质-蛋白质液体制剂，正在开发用于治疗AIS。通过口服HBI-002递送的限定剂量的CO的施用避免了与先前研究的吸入或静脉内施用的载体-金属CO相关的问题。HBI-002包括含有CO的水基溶液。已经证明了HBI-002的概念制造的验证。在大鼠和两名成年健康志愿者中进行的药代动力学和药效学研究证明了概念可行性、耐受性和生物利用度。开发的下一步是证明通过口服HBI-002递送的CO改善适当AIS动物模型的结果，并进一步了解神经保护的潜在机制。

 DESCRIPTION (provided by applicant): The objective of the proposed project is to investigate the potential of the gasotransmitter carbon monoxide (CO) as a neuroprotective agent in acute ischemic stroke (AIS) using a novel oral formulation of CO (HBI-002). Numerous studies, both in vitro and in vivo, demonstrate that CO has cytoprotective properties through anti- oxidant, anti-inflammatory and anti-apoptotic processes. In five studies in three independent laboratories, researchers found that the heme-oxygenase (HO)-1/CO pathway provides neuroprotection in animal models of AIS. In four of these studies exogenous administration of CO, which has been shown to up-regulate HO-1, reduced cerebral infarct size, improved behavioral scores and increased blood flow to the infarct border zone in experimental stroke. These independent studies provide compelling support for a potential beneficial role for the use of CO in the treatment of AIS. However, CO administration strategies have been limited to inhalation and intravenous approaches that carry inherent risks of safety and toxicity. HBI-002, an aqueous carboxylipid-protein liquid formulation, is being developed for the treatment of AIS. The administration of a defined dose of CO delivered by oral administration of HBI-002 obviates the problems associated with previously studied inhaled or intravenously administered carrier-metal CO. HBI-002 comprises a water-based solution containing CO. Proof of concept manufacture of HBI-002 has been demonstrated. Pharmacokinetic and pharmacodynamic studies in rats and in two adult healthy volunteers have demonstrated proof of concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that CO delivered via the oral administration of HBI-002 improves outcome in appropriate AIS animal models and to further understand the potential mechanisms of neuroprotection.