Translational Pharmacology Research Core

Buffalo, NY, United States

Translational Pharmacology Research Core

Buffalo, NY, United States
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Dube A.,University of Zimbabwe | Reynolds J.L.,State University of New York at Buffalo | Law W.-C.,State University of New York at Buffalo | Maponga C.C.,University of Zimbabwe | And 3 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2014

Infectious diseases are a worldwide health concern. For some infections, a common feature is the intracellular residence of the pathogen and evasion of the host immune response. In the case of tuberculosis (TB), Mycobacterium tuberculosis evades clearance within macrophages through suppression of intracellular reactive oxygen and nitrogen species (ROS/RNS) and pro-inflammatory cytokines. We propose new nanoparticle designs for infectious diseases, functionalized with ligands able to modulate the cellular immune response and concurrently deliver drug. We have designed 1,3-β-glucan functionalized chitosan shell, poly(lactide)co-glycolide core nanoparticles to stimulate ROS/RNS, pro-inflammatory cytokine secretion, and delivery of rifampicin inside human alveolar like macrophages (ALM). Nanoparticles significantly enhanced ALM secretion of IL-12p70 (2.9-fold), TNF-α (16-fold) and INF-γ (23-fold) compared to controls over 24. h, and doubled ROS/RNS generation over 6. h. Nanoparticles could deliver 4-fold greater rifampicin into ALM compared to rifampicin solution. These results provide proof-of-concept of multimodal nanoparticles and support their further development. From the Clinical Editor: In this paper, a new nanoparticle design is proposed to address hard to treat infectious diseases such as TB, through the use of nanoparticles functionalized with ligands that are able to concurrently modulate the cellular immune response and deliver a drug. The authors have designed 1,3-β-glucan functionalized chitosan shell - poly(lactide)co-glycolide core nanoparticles to stimulate reactive oxygen and nitrogen species production, pro-inflammatory cytokine secretion, and delivery of rifampicin inside human alveolar-like macrophages. © 2014 Elsevier Inc.


Zhang X.,Center for Biostatistics in Research | Tierney C.,Center for Biostatistics in Research | Albrecht M.,Beth Israel Deaconess Medical Center | Demeter L.M.,University of Rochester | And 5 more authors.
Therapeutic Drug Monitoring | Year: 2013

OBJECTIVE:: Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants. METHODS:: At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms. RESULTS:: Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons. CONCLUSIONS:: With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain. Copyright © 2013 by Lippincott Williams & Wilkins.

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