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

 描述(申请人提供)：拟议项目的目标是研究气体递质一氧化碳(CO)作为急性缺血性中风(AIS)神经保护剂的潜力，使用一种新的口服CO配方(HBI-002)。大量的体外和体内研究表明，CO通过抗氧化、抗炎和抗细胞凋亡等过程具有细胞保护作用。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途径在AIS动物模型中提供神经保护。在其中四项研究中，外源性给予CO，已被证明上调HO-1，在实验性中风中缩小脑梗塞范围，改善行为评分，并增加流向梗塞边缘区域的血流量。这些独立研究为CO在AIS治疗中的潜在有益作用提供了令人信服的支持。然而，一氧化碳给药策略一直局限于吸入和静脉注射方法，这些方法带有固有的安全和毒性风险。HBI-002是一种含水的羧基脂-蛋白质液体制剂，正在开发用于治疗AIS。通过口服HBI-002给予一定剂量的CO可以避免与先前研究的吸入或静脉注射载体金属CO相关的问题。HBI-002由一种含有CO的水基溶液组成。对HBI-002的概念制造进行了论证。在大鼠和两名成年健康志愿者身上的药代动力学和药效学研究已经证明了概念的可行性、耐受性和生物利用度。下一步的发展是证明通过口服HBI-002给药的CO可以改善适当的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.