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Measurement of ART Drug Concentrations in Brain by 19F-MRS as an Indicator of Neurotoxicity

通过 19F-MRS 测量脑内 ART 药物浓度作为神经毒性指标

基本信息

批准号：
9925549
负责人：
Scott L Letendre
金额：
$ 19.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-24 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925549
关键词：
Address Adverse event Aging Animals Biological Aging Biological Assay Biomedical Research Blood Blood - brain barrier anatomy Brain CD4 Positive T Lymphocytes Cerebrospinal Fluid Cerebrum Cognition Disorders Communities Complex Data Detection Development Disease Dose Etiology Exploratory/Developmental Grant Fluorine Fluoxetine Fluvoxamine Future General Population Gifts HIV HIV antiretroviral Head Health Human In Vitro Inflammation Injury Integrase Inhibitors Investigation Investments Lead Magnetic Resonance Spectroscopy Measurement Measures Methods Mitochondria Mood Disorders Moods N-acetylaspartate National Institute of Mental Health National NeuroAids Tissue Consortium Neuraxis Neurobehavioral Manifestations Neurocognitive Neuronal Injury Neuropharmacology Participant Performance Permeability Persons Pharmaceutical Preparations Pharmacology Prevalence Protons Publications Publishing RNA Recovery Reporting Research Research Project Grants Risk Risk Factors Safety Sample Size Selective Serotonin Reuptake Inhibitor Severities Signal Transduction Sleep Symptoms Tissues United States National Institutes of Health Viral Work antiretroviral therapy brain research brain tissue cohort daily functioning efavirenz emtricitabine falls improved in vivo innovation low and middle-income countries lymph nodes neurobehavioral neuropsychiatry neurotoxicity new technology programs public health relevance radioligand side effect tool

项目摘要

ABSTRACT Antiretroviral therapy (ART) can suppress HIV RNA and improve survival but concerns about the neurotoxicity of ART drugs have arisen in recent years with the publication of reports of a) in vitro evidence of neuronal injury and b) neuropsychiatric adverse events (NP-AEs) of efavirenz, dolutegravir (DTG), and other drugs. A key gap in our understanding of the efficacy and safety of ART drugs in the CNS is the pharmacology of these drugs in the brain. Published human studies have reported that concentrations of most ART drugs are substantially lower in cerebrospinal fluid (CSF) than in blood but recent animal studies have reported that ART drug concentrations in the brain are substantially higher than expected by on CSF data. High ART drug concentrations in the brain could be a critical determinant of neurotoxicity risk. To better understand the influence of ART drug concentrations on NP-AEs, a new method is needed to measure these concentrations in the brain of living humans. This R21 application proposes highly innovative research to develop such a method, fluorine magnetic resonance spectroscopy (19F-MRS). This method can measure low concentration compounds, like fluorinated drugs, that fall within the 19F-MRS spectra in vivo. This could be highly valuable since many commonly used ART drugs, such as DTG and emtricitabine (FTC), are fluorinated. This method does not require administration of a radioligand and has successfully measured concentrations of fluorinated selective serotonin reuptake inhibitors in the past. The proposed research responds well to RFA-MH-20-115 and is organized into 3 aims: 1) Develop the 19F-MRS method to measure concentrations of DTG and FTC in the brain, 2) Measure DTG and FTC by 19F-MRS in 20 participants of the CHARTER Aging project (R01 MH107345), which will leverage NIMH’s investment in this cohort, and 3) Determine the relationships between DTG and FTC concentrations in brain tissue and assessments of neurocognitive performance, mood, sleep, and daily functioning, which are being performed by the CHARTER Aging project. While the proposed sample size is small, the findings will provide proof-of-principle and preliminary data in support of future projects. The successful project will develop a new and highly impactful tool for research on ART neuropharmacology and neurotoxicity and will lead to new, larger research projects. It may also be useful in development of new ART drugs. This method can also be used to measure ART drugs concentrations in tissues other than brain (e.g., lymph nodes) so its development could also lead to new research on HIV persistence and eradication.

文摘