This core will support pharmacokinetic (PK) studies for laboratory and animal nanoART investigations. In project 2, H. Gendelman mice will receive a single oral dose of individual nanoART drugs to characterize reference PK parameters. A starting single dose in mice will be scaled from the dose recommended in humans based on body-surface area (shape factor) normalization. PK, tissue distribution, blood brain barrier (BBB) penetration, and toxicity will be compared between the nanoART and free drug. Next, both nanoART and free ART will be administered to two models of infected mice as a part of a dose efficacy study. Plasma and target tissue concentrations will be determined. In project 3, multiple dose PK studies similar to that in mice will be performed in uninfected monkeys. A starting single dose in monkeys will be scaled from the dose recommended in humans based on body-surface area (shape factor) normalizations. PK parameters and linearities will be assessed by comparing PK results across dosing ranges. PK, tissue distribution, BBB penetration, and toxicity will be compared between the nanoART and free ART. Next, multiple dose efficacy studies will be performed in rhesus monkeys. The multiple dosing efficacy study will aim to achieve and maintain systemic exposure levels similar to that recommended in humans without exceeding the peak exposure levels reported in humans. The multiple dosing regimen will be designed from the single dose PK parameters. Hematology and chemistry panels will be monitored, and plasma drug concentrations measured for up to 14 weeks following multiple drug administration. Monkeys will be closely monitored for adverse events including blood pressure, pulse and cardiac rhythm, liver enzymes and renal function, and potential infusion reactions. In addition to close monitoring of safety parameters and PK analyses, the animals will undergo cerebrospinal fluid evaluations of HIV viral load and neuroinflammatory biomarkers at baseline and eight weeks on study (H. Fox, project 3). The long-term goal is to develop injectable nanoART for human use. If successful the work could lead to novel formulations that improve medication adherence, and thereby therapeutic outcomes, and novel treatment applications to include enhanced penetration into viral sanctuaries as the central nervous system. This core is already operative and has generated the preliminary data shown in project 2 (H. Gendelman) supporting the abilities to integrate each of the projects into one program.
;The goal of attaining long acting antiretroviral therapies for HIV/AIDS would have dramatic positive consequence for the course and access of HIV/AIDS and particularly pertinent for substance abusers and in resource limited settings.
| Montenegro-Burke, J Rafael; Woldstad, Christopher J; Fang, Mingliang et al. (2018) Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress. Mol Neurobiol : |
| Olson, Katherine E; Bade, Aditya N; Namminga, Krista L et al. (2018) Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice. J Neurovirol 24:398-410 |
| Schutt, Charles R; Gendelman, Howard E; Mosley, R Lee (2018) Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson's disease. Mol Neurodegener 13:26 |
| Sillman, Brady; Bade, Aditya N; Dash, Prasanta K et al. (2018) Creation of a long-acting nanoformulated dolutegravir. Nat Commun 9:443 |
| Forsberg, Erica M; Huan, Tao; Rinehart, Duane et al. (2018) Data processing, multi-omic pathway mapping, and metabolite activity analysis using XCMS Online. Nat Protoc 13:633-651 |
| Thomas, Midhun B; Gnanadhas, Divya Prakash; Dash, Prasanta K et al. (2018) Modulating cellular autophagy for controlled antiretroviral drug release. Nanomedicine (Lond) 13:2139-2154 |
| Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman et al. (2018) URMC-099 facilitates amyloid-? clearance in a murine model of Alzheimer's disease. J Neuroinflammation 15:137 |
| Guijas, Carlos; Montenegro-Burke, J Rafael; Warth, Benedikt et al. (2018) Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat Biotechnol 36:316-320 |
| Beyer, Brittney A; Fang, Mingliang; Sadrian, Benjamin et al. (2018) Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nat Chem Biol 14:22-28 |
| Herskovitz, Jonathan; Gendelman, Howard E (2018) HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication. J Neuroimmune Pharmacol : |
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