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

HBI-002（一种口服气体递质）在缺血性中风中的作用

基本信息

批准号：
8976791
负责人：
KYRA J BECKER
金额：
$ 47.55万
依托单位：
HILLHURST BIOPHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976791
关键词：
Acute Adult Affect Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigens Antioxidants Apoptotic Autoimmune Process Behavioral Binding Biological Availability Blood Circulation Blood flow Brain Breathing Carbon Monoxide Cause of Death Cerebral Ischemia Cerebrum Cessation of life Clinical Data Development Disease Dose Drug Formulations Drug Kinetics Event Experimental Models Goals Hemoglobin Hemoglobin concentration result Hemorrhage In Vitro Infarction Inflammation Inflammatory Inflammatory Response Injury Intravenous Ischemic Stroke Laboratories Lymphocyte Mediating Metals Methods Modeling Mus Neurological outcome Neuroprotective Agents Oral Oral Administration Outcome Pathologic Pathway interactions Patients Peripheral Pharmacodynamics Pharmacologic Substance Phase Process Property Proteins Rattus Research Research Personnel Research Support Risk Role Safety Seasons Solutions Stimulus Stroke Survivors Therapeutic Toxic effect Toxicology Transition Elements Venous Water aqueous base cytokine disability disability-adjusted life years experience healthy volunteer heme oxygenase-1 improved in vivo liquid formulation mouse model neuroinflammation neuroprotection novel pre-clinical premature prevent public health relevance response therapeutic development years lived with disability

项目摘要

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.